<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Leech and can you explain it in depth? [/INST] Leeches are segmented parasitic or predatory worms that comprise the subclass Hirudinea within the phylum Annelida. They are closely related to the oligochaetes, which include the earthworm, and like them have soft, muscular segmented bodies that can lengthen and contract. Both groups are hermaphrodites and have a clitellum, but leeches typically differ from the oligochaetes in having suckers at both ends and in having ring markings that do not correspond with their internal segmentation. The body is muscular and relatively solid, and the coelom, the spacious body cavity found in other annelids, is reduced to small channels.
The majority of leeches live in freshwater habitats, while some species can be found in terrestrial or marine environments. The best-known species, such as the medicinal leech, Hirudo medicinalis, are hematophagous, attaching themselves to a host with a sucker and feeding on blood, having first secreted the peptide hirudin to prevent the blood from clotting. The jaws used to pierce the skin are replaced in other species by a proboscis which is pushed into the skin. A minority of leech species are predatory, mostly preying on small invertebrates.
The eggs are enclosed in a cocoon, which in aquatic species is usually attached to an underwater surface; members of one family, Glossiphoniidae, exhibit parental care, the eggs being brooded by the parent. In terrestrial species, the cocoon is often concealed under a log, in a crevice or buried in damp soil. Almost seven hundred species of leech are currently recognised, of which some hundred are marine, ninety terrestrial and the remainder freshwater.
Leeches have been used in medicine from ancient times until the 19th century to draw blood from patients. In modern times, leeches find medical use in treatment of joint diseases such as epicondylitis and osteoarthritis, extremity vein diseases, and in microsurgery, while hirudin is used as an anticoagulant drug to treat blood-clotting disorders.

Diversity and phylogeny
Some 680 species of leech have been described, of which around 100 are marine, 480 freshwater and the remainder terrestrial. Among Euhirudinea, the true leeches, the smallest is about 1 cm (1⁄2 in) long, and the largest is the giant Amazonian leech, Haementeria ghilianii, which can reach 30 cm (12 in). Except for Antarctica, leeches are found throughout the world but are at their most abundant in temperate lakes and ponds in the northern hemisphere. The majority of freshwater leeches are found in the shallow, vegetated areas on the edges of ponds, lakes and slow-moving streams; very few species tolerate fast-flowing water. In their preferred habitats, they may occur in very high densities; in a favourable environment with water high in organic pollutants, over 10,000 individuals were recorded per square metre (over 930 per square foot) under rocks in Illinois. Some species aestivate during droughts, burying themselves in the sediment, and can lose up to 90% of their bodyweight and still survive. Among the freshwater leeches are the Glossiphoniidae, dorso-ventrally flattened animals mostly parasitic on vertebrates such as turtles, and unique among annelids in both brooding their eggs and carrying their young on the underside of their bodies.The terrestrial Haemadipsidae are mostly native to the tropics and subtropics, while the aquatic Hirudinidae have a wider global range; both of these feed largely on mammals, including humans. A distinctive family is the Piscicolidae, marine or freshwater ectoparasites chiefly of fish, with cylindrical bodies and usually well-marked, bell-shaped, anterior suckers. Not all leeches feed on blood; the Erpobdelliformes, freshwater or amphibious, are carnivorous and equipped with a relatively large, toothless mouth to ingest insect larvae, molluscs, and other annelid worms, which are swallowed whole. In turn, leeches are prey to fish, birds, and invertebrates.The name for the subclass, Hirudinea, comes from the Latin hirudo (genitive hirudinis), a leech; the element -bdella found in many leech group names is from the Greek βδέλλα bdella, also meaning leech. The name Les hirudinées was given by Jean-Baptiste Lamarck in 1818. Leeches were traditionally divided into two infraclasses, the Acanthobdellidea (primitive leeches) and the Euhirudinea (true leeches). The Euhirudinea are divided into the proboscis-bearing Rhynchobdellida and the rest, including some jawed species, the "Arhynchobdellida", without a proboscis.The phylogenetic tree of the leeches and their annelid relatives is based on molecular analysis (2019) of DNA sequences. Both the former classes "Polychaeta" (bristly marine worms) and "Oligochaeta" (including the earthworms) are paraphyletic: in each case the complete groups (clades) would include all the other groups shown below them in the tree. The Branchiobdellida are sister to the leech clade Hirudinida, which approximately corresponds to the traditional subclass Hirudinea. The main subdivision of leeches is into the Rhynchobdellida and the Arhynchobdellida, though the Acanthobdella are sister to the clade that contains these two groups.

Evolution
The most ancient annelid group consists of the free-living polychaetes that evolved in the Cambrian period, being plentiful in the Burgess Shale about 500 million years ago. Oligochaetes evolved from polychaetes and the leeches branched off from the oligochaetes. The oldest leech fossils are from the Jurassic period around 150 million years ago, but a fossil with external ring markings found in Wisconsin in the 1980s, with what appears to be a large sucker, seems to extend the groups evolutionary history back to the Silurian, some 437 million years ago.

Anatomy and physiology
Leeches show a remarkable similarity to each other in morphology, very different from typical annelids which are cylindrical with a fluid-filled space, the coelom (body cavity). In leeches, the coelom is reduced to four slender longitudinal channels, and the interior of the body is filled with a solid dermis in between the various organs. Typically, the body is dorso-ventrally flattened and tapers at both ends. Longitudinal and circular muscles in the body wall are supplemented by diagonal muscles, giving the leech the ability to adopt a large range of body shapes and show great flexibility. Most leeches have a sucker at both the anterior (front) and posterior (back) ends, but some primitive leeches have a single sucker at the back.

Like other annelids, the leech is a segmented animal, but unlike other annelids, the segmentation is masked by external ring markings (annulations). The number of annulations varies, both between different regions of the body and between species. In one species, the body surface is divided into 102 annuli, but the body consists of 33 segments, a number constant across all leech species. Of these segments, the first five are designated as the head and include the anterior brain, several ocelli (eyespots) dorsally and the sucker ventrally. The following 21 mid-body segments each contain a nerve ganglion, and between them contain two reproductive organs, a single female gonopore and nine pairs of testes. The last seven segments contain the posterior brain and are fused to form the animals tail sucker.The body wall consists of a cuticle, an epidermis and a thick layer of fibrous connective tissue in which are embedded the circular muscles, the diagonal muscles and the powerful longitudinal muscles. There are also dorso-ventral muscles. The coelomic channels run the full length of the body, the two main ones being on either side; these have taken over the function of the hemal system (blood vessels) in other annelids. Part of the lining epithelium consists of chloragogen cells which are used for the storage of nutrients and in excretion. There are 10 to 17 pairs of metanephridia (excretory organs) in the mid-region of the leech. From these, ducts typically lead to a urinary bladder, which empties to the outside at a nephridiopore.

Reproduction and development
Leeches are hermaphrodites, with the male reproductive organs, the testes, maturing first and the ovaries later. In hirudinids, a pair will line up with the clitellar regions in contact, with the anterior end of one leech pointing towards the posterior end of the other; this results in the male gonopore of one leech being in contact with the female gonopore of the other. The penis passes a spermatophore into the female gonopore and sperm is transferred to, and probably stored in, the vagina.Some jawless leeches (Rhynchobdellida) and proboscisless leeches (Arhynchobdellida) lack a penis, and in these, sperm is passed from one individual to another by hypodermic injection. The leeches intertwine and grasp each other with their suckers. A spermatophore is pushed by one through the integument of the other, usually into the clitellar region. The sperm is liberated and passes to the ovisacs, either through the coelomic channels or interstitially through specialist "target tissue" pathways.Some time after copulation, the small, relatively yolkless eggs are laid. In most species, an albumin-filled cocoon is secreted by the clitellum and receives one or more eggs as it passes over the female gonopore. In the case of the North American Erpobdella punctata, the clutch size is about five eggs, and some ten cocoons are produced. Each cocoon is fixed to a submerged object, or in the case of terrestrial leeches, deposited under a stone or buried in damp soil. The cocoon of Hemibdella soleae is attached to a suitable fish host. The glossiphoniids brood their eggs, either by attaching the cocoon to the substrate and covering it with their ventral surface, or by securing the cocoon to their ventral surface, and even carrying the newly hatched young to their first meal.When breeding, most marine leeches leave their hosts and become free-living in estuaries. Here they produce their cocoons, after which the adults of most species die. When the eggs hatch, the juveniles seek out potential hosts when these approach the shore. Leeches mostly have an annual or biannual life cycle.

Feeding and digestion
About three quarters of leech species are parasites that feed on the blood of a host, while the remainder are predators. Leeches either have a pharynx that they can protrude, commonly called a proboscis, or a pharynx that they cannot protrude, which in some groups is armed with jaws.In the proboscisless leeches, the jaws (if any) of Arhynchobdellids are at the front of the mouth, and have three blades set at an angle to each other. In feeding, these slice their way through the skin of the host, leaving a Y-shaped incision. Behind the blades is the mouth, located ventrally at the anterior end of the body. It leads successively into the pharynx, a short oesophagus, a crop (in some species), a stomach and a hindgut, which ends at an anus located just above the posterior sucker. The stomach may be a simple tube, but the crop, when present, is an enlarged part of the midgut with a number of pairs of ceca that store ingested blood. The leech secretes an anticoagulant, hirudin, in its saliva which prevents the blood from clotting before ingestion. A mature medicinal leech may feed only twice a year, taking months to digest a blood meal.

The bodies of predatory leeches are similar, though instead of a jaw many have a protrusible proboscis, which for most of the time they keep retracted into the mouth. Such leeches are often ambush predators that lie in wait until they can strike prey with the proboscises in a spear-like fashion. Predatory leeches feed on small invertebrates such as snails, earthworms and insect larvae. The prey is usually sucked in and swallowed whole. Some Rhynchobdellida however suck the soft tissues from their prey, making them intermediate between predators and blood-suckers.

Blood-sucking leeches use their anterior suckers to connect to hosts for feeding. Once attached, they use a combination of mucus and suction to stay in place while they inject hirudin into the hosts blood. In general, blood-feeding leeches are non host-specific, and do little harm to their host, dropping off after consuming a blood meal. Some marine species however remain attached until it is time to reproduce. If present in great numbers on a host, these can be debilitating, and in extreme cases, cause death.Leeches are unusual in that they do not produce certain digestive enzymes such as amylases, lipases or endopeptidases. A deficiency of these enzymes and of B complex vitamins is compensated for by enzymes and vitamins produced by endosymbiotic microflora. In Hirudo medicinalis, these supplementary factors are produced by an obligatory mutualistic relationship with the bacterial species, Aeromonas veronii. Non-bloodsucking leeches, such as Erpobdella octoculata, are host to morew bacterial symbionts. In addition, leeches produce intestinal exopeptidases which remove amino acids from the long protein molecules one by one, possibly aided by proteases from endosymbiotic bacteria in the hindgut. This evolutionary choice of exopeptic digestion in Hirudinea distinguishes these carnivorous clitellates from oligochaetes, and may explain why digestion in leeches is so slow.

Nervous system
A leechs nervous system is formed of a few large nerve cells; their large size makes leeches convenient as model organisms for the study of invertebrate nervous systems. The main nerve centre consists of the cerebral ganglion above the gut and another ganglion beneath it, with connecting nerves forming a ring around the pharynx a little way behind the mouth. A nerve cord runs backwards from this in the ventral coelomic channel, with 21 pairs of ganglia in segments six to 26. In segments 27 to 33, other paired ganglia fuse to form the caudal ganglion. Several sensory nerves connect directly to the cerebral ganglion; there are sensory and motor nerve cells connected to the ventral nerve cord ganglia in each segment.Leeches have between two and ten pigment spot ocelli, arranged in pairs towards the front of the body. There are also sensory papillae arranged in a lateral row in one annulation of each segment. Each papilla contains many sensory cells. Some rhynchobdellids have the ability to change colour dramatically by moving pigment in chromatophore cells; this process is under the control of the nervous system but its function is unclear as the change in hue seems unrelated to the colour of the surroundings.Leeches can detect touch, vibration, movement of nearby objects, and chemicals secreted by their hosts; freshwater leeches crawl or swim towards a potential host standing in their pond within a few seconds. Species that feed on warm-blooded hosts move towards warmer objects. Many leeches avoid light, though some blood feeders move towards light when they are ready to feed, presumably increasing the chances of finding a host.

Gas exchange
Leeches live in damp surroundings and in general respire through their body wall. The exception to this is in the Piscicolidae, where branching or leaf-like lateral outgrowths from the body wall form gills. Some rhynchobdellid leeches have an extracellular haemoglobin pigment, but this only provides for about half of the leechs oxygen transportation needs, the rest occurring by diffusion.

Movement
Leeches move using their longitudinal and circular muscles in a modification of the locomotion by peristalsis, self-propulsion by alternately contracting and lengthening parts of the body, seen in other annelids such as earthworms. They use their posterior and anterior suckers (one on each end of the body) to enable them to progress by looping or inching along, in the manner of geometer moth caterpillars. The posterior end is attached to the substrate, and the anterior end is projected forward peristaltically by the circular muscles until it touches down, as far as it can reach, and the anterior end is attached. Then the posterior end is released, pulled forward by the longitudinal muscles, and reattached; then the anterior end is released, and the cycle repeats. Leeches explore their environment with head movements and body waving. The Hirudinidae and Erpobdellidae can swim rapidly with up-and-down or sideways undulations of the body; the Glossiphoniidae in contrast are poor swimmers and curl up and fall to the sediment below when disturbed.

Interactions with humans
Bites
Leech bites are generally alarming rather than dangerous, though a small percentage of people have severe allergic or anaphylactic reactions and require urgent medical care. Symptoms of these reactions include red blotches or an itchy rash over the body, swelling around the lips or eyes, a feeling of faintness or dizziness, and difficulty in breathing. An externally attached leech will detach and fall off on its own accord when it is satiated on blood, which may take from twenty minutes to a few hours; bleeding from the wound may continue for some time. Internal attachments, such as inside the nose, are more likely to require medical intervention.Bacteria, viruses, and protozoan parasites from previous blood sources can survive within a leech for months, so leeches could potentially act as vectors of pathogens. Nevertheless, only a few cases of leeches transmitting pathogens to humans have been reported.Leech saliva is commonly believed to contain anaesthetic compounds to numb the bite area, but this has never been proven. Although morphine-like substances have been found in leeches, they have been found in the neural tissues, not the salivary tissues. They are used by the leeches in modulating their own immunocytes and not for anaesthetising bite areas on their hosts. Depending on the species and size, leech bites can be barely noticeable or they can be fairly painful.

In human culture
The leech appears in Proverbs 30:15 as an archetype of insatiable greed. More generally, a leech is a persistent social parasite or sycophant.The medicinal leech Hirudo medicinalis, and some other species, have been used for clinical bloodletting for at least 2,500 years: Ayurvedic texts describe their use for bloodletting in ancient India. In ancient Greece, bloodletting was practised according to the theory of humours found in the Hippocratic Corpus of the fifth century BC, which maintained that health depended on a balance of the four humours: blood, phlegm, black bile and yellow bile. Bloodletting using leeches enabled physicians to restore balance if they considered blood was present in excess.Pliny the Elder reported in his Natural History that the horse leech could drive elephants mad by climbing up inside their trunks to drink blood. Pliny also noted the medicinal use of leeches in ancient Rome, stating that they were often used for gout, and that patients became addicted to the treatment. In Old English, lǣce was the name for a physician as well as for the animal, though the words had different origins, and lǣcecraft, leechcraft, was the art of healing.

William Wordsworths 1802 poem "Resolution and Independence" describes one of the last of the leech-gatherers, people who travelled Britain catching leeches from the wild, and causing a sharp decline in their abundance, though they remain numerous in Romney Marsh. By 1863, British hospitals had switched to imported leeches, some seven million being imported to hospitals in London that year.
In the nineteenth century, demand for leeches was sufficient for hirudiculture, the farming of leeches, to become commercially viable. Leech usage declined with the demise of humoral theory, but made a small-scale comeback in the 1980s after years of decline, with the advent of microsurgery, where venous congestion can arise due to inefficient venous drainage. Leeches can reduce swelling in the tissues and promote healing, helping in particular to restore circulation after microsurgery to reattach body parts </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Subacute combined degeneration of spinal cord and can you explain it in depth? [/INST] Subacute combined degeneration of spinal cord, also known as myelosis funiculus, or funicular myelosis, also Lichtheims disease, and Putnam-Dana syndrome, refers to degeneration of the posterior and lateral columns of the spinal cord as a result of vitamin B12 deficiency (most common), vitamin E deficiency, and copper deficiency. It is usually associated with pernicious anemia.

Signs and symptoms
The onset is gradual and uniform.  The pathological findings of subacute combined degeneration consist of patchy losses of myelin in the dorsal and lateral columns </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Prognathism and can you explain it in depth? [/INST] Prognathism, also called Habsburg jaw or Habsburgs jaw primarily in the context of its prevalence amongst members of the House of Habsburg, is a positional relationship of the mandible or maxilla to the skeletal base where either of the jaws protrudes beyond a predetermined imaginary line in the coronal plane of the skull. In general dentistry, oral and maxillofacial surgery, and orthodontics, this is assessed clinically or radiographically (cephalometrics). The word prognathism derives from Greek πρό (pro, meaning forward) and γνάθος (gnáthos, jaw). One or more types of prognathism can result in the common condition of malocclusion, in which an individuals top teeth and lower teeth do not align properly.

Presentation
Prognathism in humans can occur due to normal variation among phenotypes. In human populations where prognathism is not the norm, it may be a malformation, the result of injury, a disease state or a hereditary condition.Prognathism is considered a disorder only if it affects chewing, speech or social function as a byproduct of severely affected aesthetics of the face.Clinical determinants include soft tissue analysis where the clinician assesses nasolabial angle, the relationship of the soft tissue portion of the chin to the nose, and the relationship between the upper and lower lips; also used is dental arch relationship assessment such as Angles classification.Cephalometric analysis is the most accurate way of determining all types of prognathism, as it includes assessments of skeletal base, occlusal plane angulation, facial height, soft tissue assessment and anterior dental angulation. Various calculations and assessments of the information in a cephalometric radiograph allow the clinician to objectively determine dental and skeletal relationships and determine a treatment plan.Prognathism should not be confused with micrognathism, although combinations of both are found. It affects the middle third of the face, causing it to jut out, thereby increasing the facial area, similar to the phenotype of archaic hominids and other apes. Mandibular prognathism is a protrusion of the mandible, affecting the lower third of the face. Alveolar prognathism is a protrusion of that portion of the maxilla where the teeth are located, in the dental lining of the upper jaw.Prognathism can also be used to describe ways that the maxillary and mandibular dental arches relate to one another, including malocclusion (where the upper and lower teeth do not align). When there is maxillary or alveolar prognathism which causes an alignment of the maxillary incisors significantly anterior to the lower teeth, the condition is called an overjet. When the reverse is the case, and the lower jaw extends forward beyond the upper, the condition is referred to as retrognathia (reverse overjet).

Classification
Alveolar prognathism
Not all alveolar prognathism is anomalous, and significant differences can be observed among different ethnicities.Harmful habits such as thumb sucking or tongue thrusting can result in or exaggerate an alveolar prognathism, causing teeth to misalign. Functional appliances can be used in growing children to help modify bad habits and neuro-muscular function, with the aim of correcting this condition.Alveolar prognathism can also easily be corrected with fixed orthodontic therapy. However, relapse is quite common, unless the cause is removed or a long-term retention is used.

Maxillary prognathism
In disease states, maxillary prognathism is associated with Cornelia de Lange syndrome; however, so-called false maxillary prognathism, or more accurately, retrognathism, where there is a lack of growth of the mandible, is by far a more common condition.Prognathism, if not extremely severe, can be treated in growing patients with orthodontic functional or orthopaedic appliances. In adult patients this condition can be corrected by means of a combined surgical/orthodontic treatment, where most of the time a mandibular advancement is performed. The same can be said for mandibular prognathism.

Mandibular prognathism (progenism)
Pathologic mandibular prognathism is a potentially disfiguring genetic disorder where the lower jaw outgrows the upper, resulting in an extended chin and a crossbite. In both humans and animals, it can be the result of inbreeding. In brachycephalic or flat-faced dogs, like shih tzus and boxers, it can lead to problems such as underbite.In humans, it results in a condition sometimes called lantern jaw, reportedly derived from 15th century horn lanterns, which had convex sides. Traits such as these were often exaggerated by inbreeding, and can be traced within specific families.Although more common than appreciated, the best known historical example is Habsburg jaw, or Habsburg or Austrian lip, due to its prevalence in members of the House of Habsburg, which can be traced in their portraits. The process of portrait-mapping has provided tools for geneticists and pedigree analysis; most instances are considered polygenic, but a number of researchers believe that this trait is transmitted through an autosomal recessive type of inheritance.

Allegedly introduced into the family by a member of the Piast dynasty, it is clearly visible on family tomb sculptures in St. Johns Cathedral, Warsaw. A high propensity for politically motivated intermarriage among Habsburgs meant the dynasty was virtually unparalleled in the degree of its inbreeding. Charles II of Spain, who lived 1661 to 1700, is said to have had the most pronounced case of the Habsburg jaw on record, due to the high number of consanguineous marriages in the dynasty preceding his birth.

Treatment
Prior to the development of modern dentistry, there was no treatment for this condition; those who had it simply endured it. Today, the most common treatment for mandibular prognathism is a combination of orthodontics and orthognathic surgery. The orthodontics can involve braces, removal of teeth, or a mouthguard.

In insects
In entomology, prognathous means that the mouthparts face forwards, being at the front of the head, rather than facing downwards as in some insects.

See also
Dental pathology

Notes
References
Sources
Beuchat, Carol (12 March 2015). "Why all the fuss about inbreeding?". Institute of Canine Biology. Retrieved 16 April 2020.
Mitchell, Sylvia Z (2013). Mariana of Austria and Imperial Spain: Court, Dynastic, and International Politics in Seventeenth-Century Europe (Thesis).
Vilas, Román; Ceballos, Francisco C.; Al-Soufi, Laila; González-García, Raúl; Moreno, Carlos; Moreno, Manuel; Villanueva, Laura; Ruiz, Luis; Mateos, Jesús; González, David; Ruiz, Jennifer; Cinza, Aitor; Monje, Florencio; Álvarez, Gonzalo (17 November 2019). "Is the Habsburg jaw related to inbreeding?". Annals of Human Biology. 46 (7–8): 553–561. doi:10.1080/03014460.2019.1687752. PMID 31786955. S2CID 208536371.
Vioarsdóttir, US; OHiggins, O; Stringer, C (2002). "A geometric morphometric study of regional differences in the ontogeny of the modern human facial skeleton". J. Anat </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Kearns–Sayre syndrome and can you explain it in depth? [/INST] Kearns–Sayre syndrome (KSS), oculocraniosomatic disorder or oculocranionsomatic neuromuscular disorder with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia (abbreviated CPEO), a syndrome that is characterized by isolated involvement of the muscles controlling movement of the eyelid (levator palpebrae, orbicularis oculi) and eye (extra-ocular muscles). This results in ptosis and ophthalmoplegia respectively. KSS involves a combination of the already described CPEO as well as pigmentary retinopathy in both eyes and cardiac conduction abnormalities. Other symptoms may include cerebellar ataxia, proximal muscle weakness, deafness, diabetes mellitus, growth hormone deficiency, hypoparathyroidism, and other endocrinopathies. In both of these diseases, muscle involvement may begin unilaterally but always develops into a bilateral deficit, and the course is progressive. This discussion is limited specifically to the more severe and systemically involved variant.

Signs and symptoms
Individuals with KSS present initially in a similar way to those with typical CPEO. Onset is in the first and second decades of life.The first symptom of this disease is a unilateral ptosis, or difficulty opening the eyelids, that gradually progresses to a bilateral ptosis. As the ptosis worsens, the individual commonly extends their neck, elevating their chin in an attempt to prevent the eyelids from occluding the visual axis. Along with the insidious development of ptosis, eye movements eventually become limited causing a person to rely more on turning the head side to side or up and down to view objects in the peripheral visual field.

Mitochondrial retinopathy
Kearns and Sayre described patients with “pigmentary degeneration” on funduscopy, night vision abnormalities, and some histologic similarities, but also clinical differences, to retinitis pigmentosa Subsequently, the retinal phenotype of KSS was described as retinitis pigmentosa, atypical retinitis pigmentosa, tapetoretinal degeneration, salt-and-pepper retinopathy, and pigmentary retinopathy. As the clinical characterization, however, was not always comprehensive the term "mitochondrial retinopathy" appears most accurate and the diagnosis of RP may have been imprecise. Patients with KSS show widespread granular pigmented alterations in the posterior fundus which correspond to granular patterns on fundus autofluorescence imaging. Associated changes on optical coherence tomography (OCT) include reflectivity changes predominantly at the level of the ellipsoid and interdigitation zone and an increased distance between the ellipsoid band and the retinal pigment epithelium. Night blindness may be seen in patients with KSS. Visual acuity loss is usually mild and only occurs in 40–50% of patients.

Cardiac conduction abnormalities
These most often occur years after the development of ptosis and ophthalmoplegia.  Atrioventricular (abbreviated "AV") block is the most common cardiac conduction deficit.  This often progresses to a Third-degree atrioventricular block, which is a complete blockage of the electrical conduction from the atrium to the ventricle.  Symptoms of heart block include syncope, exercise intolerance, and bradycardia.

Cerebral folate deficiency
Kearns-Sayre patients are consistently found to have cerebral folate deficiency, a syndrome in which 5-MTHF levels are decreased in the cerebrospinal fluid despite being normal in serum. Treatment with folinic acid can in some cases alleviate the associated symptoms and partially correct associated brain abnormalities, especially if started early in the course of illness. The proposed cause of cerebral folate deficiency in the Kearns–Sayre syndrome is the failure of the mechanisms in the choroid plexus that are responsible for passage of folates from the serum to the cerebrospinal fluid.

Cause and prevalence
As characterized in Kearns original publication in 1965 and in later publications, inconsistent features of KSS that may occur are weakness of facial, pharyngeal, trunk, and extremity muscles, hearing loss, small stature, electroencephalographic changes, cerebellar ataxia and elevated levels of cerebrospinal fluid protein.Kearns–Sayre syndrome occurs spontaneously in the majority of cases. In some cases it has been shown to be inherited through mitochondrial, autosomal dominant, or autosomal recessive inheritance. There is no predilection for race or sex, and there are no known risk factors. As of 1992 there were only 226 cases reported in published literature. Although NIH and other studies estimate occurrence in the population to be 1–3 and some as high as 9 in 100,000 individuals but a failure to be referred to specialist centres and recognise the disease symptoms is common

Genetics
KSS is the result of deletions in mitochondrial DNA (mtDNA) that cause a particular constellation of medical signs and symptoms. mtDNA is transmitted exclusively from the mothers ovum.  Mitochondrial DNA is composed of 37 genes found in the single circular chromosome measuring 16,569 base pairs in length.  Among these, 13 genes encode proteins of the electron transport chain (abbreviated "ETC"), 22 encode transfer RNA (tRNA), and two encode the large and small subunits that form ribosomal RNA (rRNA).  The 13 proteins involved in the ETC of the mitochondrion are necessary for oxidative phosphorylation.  Mutations in these proteins results in impaired energy production by mitochondria.  This cellular energy deficit manifests most readily in tissues that rely heavily upon aerobic metabolism such as the brain, skeletal and cardiac muscles, sensory organs, and kidneys.  This is one factor involved in the presentation of mitochondrial diseases.There are other factors involved in the manifestation of a mitochondrial disease besides the size and location of a mutation.  Mitochondria replicate during each cell division during gestation and throughout life.  Because the mutation in mitochondrial disease most often occurs early in gestation in these diseases, only those mitochondria in the mutated lineage are defective.  This results in an uneven distribution of dysfunctional mitochondria within each cell, and among different tissues of the body.  This describes the term heteroplasmic which is characteristic of mitochondrial diseases including KSS.  The distribution of mutated mtDNA in each cell, tissue, and organ, is dependent on when and where the mutation occurs.  This may explain why two patients with an identical mutation in mtDNA can present with entirely different phenotypes and in turn different syndromes.  A publication in 1992 by Fischel-Ghodsian et al. identified the same 4,977-bp deletion in mtDNA in two patients presenting with two entirely different diseases.  One of the patients had characteristic KSS, while the other patient had a very different disease known as Pearson marrow pancreas syndrome.  Complicating the matter, in some cases Pearsons syndrome has been shown to progress into KSS later in life.More recent studies have concluded that mtDNA duplications may also play a significant role in determining what phenotype is present.  Duplications of mtDNA seem to be characteristic of all cases of KSS and Pearsons syndrome, while they are absent in CPEO.Deletions of mtDNA in KSS vary in size (1.3–8kb), as well as position in the mitochondrial genome.  The most common deletion is 4.9kb and spans from position 8469 to position 13147 on the genome.  This deletion is present in approximately ⅓ of people with KSS

Diagnosis
A neuro-ophthalmologist is usually involved in the diagnosis and management of KSS.  An individual should be suspected of having KSS based upon clinical exam findings.  Suspicion for myopathies should be increased in patients whose ophthalmoplegia does not match a particular set of cranial nerve palsies (oculomotor nerve palsy, fourth nerve palsy, sixth nerve palsy).  Initially, imaging studies are often performed to rule out more common pathologies.  Diagnosis may be confirmed with muscle biopsy, and may be supplemented with PCR determination of mtDNA mutations.

Biopsy findings
It is not necessary to biopsy an ocular muscle to demonstrate histopathologic abnormalities. Cross-section of muscle fibers stained with Gömöri trichrome stain is viewed using light microscopy.  In muscle fibers containing high ratios of the mutated mitochondria, there is a higher concentration of mitochondria.  This gives these fibers a darker red color, causing the overall appearance of the biopsy to be described as "ragged red fibers. Abnormalities may also be demonstrated in muscle biopsy samples using other histochemical studies such as mitochondrial enzyme stains, by electron microscopy, biochemical analyses of the muscle tissue (ie electron transport chain enzyme activities), and by analysis of muscle mitochondrial DNA."

Laboratory studies
Blood lactate and pyruvate levels usually are elevated as a result of increased anaerobic metabolism and a decreased ratio of ATP:ADP.  CSF analysis shows an elevated protein level, usually >100 mg/dl, as well as an elevated lactate level.

Management
Currently there is no curative treatment for KSS. Because it is a rare condition, there are only case reports of treatments with very little data to support their effectiveness. Several promising discoveries have been reported which may support the discovery of new treatments with further research.  Satellite cells are responsible for muscle fiber regeneration. It has been noted that mutant mtDNA is rare or undetectable in satellite cells cultured from patients with KSS. Shoubridge et al. (1997) asked the question whether wildtype mtDNA could be restored to muscle tissue by encouraging muscle regeneration. In the forementioned study, regenerating muscle fibers were sampled at the original biopsy site, and it was found that they were essentially homoplasmic for wildtype mtDNA </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Smith–Lemli–Opitz syndrome and can you explain it in depth? [/INST] Smith–Lemli–Opitz syndrome is an inborn error of cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a broad spectrum of effects, ranging from mild intellectual disability and behavioural problems to lethal malformations.

Signs and symptoms
SLOS can present itself differently in different cases, depending on the severity of the mutation and other factors. Originally, SLOS patients were classified into two categories (classic and severe) based on physical and mental characteristics, alongside other clinical features. Since the discovery of the specific biochemical defect responsible for SLOS, patients are given a severity score based on their levels of cerebral, ocular, oral, and genital defects. It is then used to classify patients as having mild, classical, or severe SLOS.

Physical characteristics
The most common facial features of SLOS include microcephaly, bitemporal narrowing (reduced distance between temples), ptosis, a short and upturned nose, micrognathia, epicanthal folds, and capillary hemangioma of the nose. Other physical characteristics include:
low-set and posteriorly rotated ears
high-arched, narrow, hard palate
cleft lip/palate
agenesis or hypoplasia of the corpus callosum
cerebellar hypoplasia
increased ventricular size
decreased frontal lobe size
polydactyly of hands or feet
short, proximally placed thumb
other finger malformations
syndactyly of second and third toes
ambiguous or female-like male genitalia
congenital heart defects
renal, pulmonary, liver and eye abnormalities

Behavioural characteristics
Certain behaviours and attributes are commonly seen among patients with SLOS. They may have low normal intelligence, and react negatively or with hypersensitivity to different sensory stimuli. This is particularly true for certain auditory and visual stimuli. Many patients show aggressiveness and self-injurious behaviours, and sleep disturbances are common. Specific behaviours resembling those of people with autism are often present as well as hyperactivity, which provides genetic and biological insights into autism spectrum disorders. The autistic behaviours most characteristic of SLOS patients are opisthokinesis (an upper body movement), stretching of the upper body, and hand flicking. Autism is typically diagnosed separately from SLOS using the DSM-V, and approximately 50–75% of SLOS patients meet the criteria for autism.Other behaviours associated with SLOS can be linked directly to physical abnormalities. For example, infants often show feeding problems or feeding intolerance, and patients may require increased caloric intake due to accelerated metabolism. Recurrent infections, including ear infections and pneumonia, are also common.

Biochemical phenotype
Given that SLOS is caused by a mutation in an enzyme involved in cholesterol synthesis, the resulting biochemical characteristics may be predictable. Most patients have lowered plasma cholesterol levels (hypocholesterolemia). However, approximately 10% may show normal cholesterol levels,  and decreased concentrations of cholesterol are not solely indicative of SLOS. Increased levels of cholesterol precursors are also common in SLOS. In particular, elevated levels of 7-dehydrocholesterol are fairly specific to SLOS.

Genetics
DHCR7
The gene encoding DHCR7 (labeled as DHCR7) was cloned in 1998, and has been mapped to chromosome 11q12-13. It is 14100 base pairs of DNA in length, and contains nine exons, the corresponding mRNA is 2786 base pairs in length (the remaining DNA sequence is intronic). The structure of the DHCR7 rat gene is very similar to the structure of the human gene.The highest levels of DHCR7 expression have been detected in the adrenal gland, the testis, the liver and in brain tissue. Its expression is induced by decreased sterol concentrations via sterol regulatory binding proteins (SREBP). There is also evidence that its activity may be regulated by tissue specific transcription, and alternative splicing.As outlined above, the enzyme DHCR7 catalyzes the reduction of 7DHC to cholesterol, as well as the reduction of 7-dehydrodesmosterol to desmosterol. It requires NADPH as a cofactor for this reduction, and may involve the activity of cytochrome-P450 oxidoreductase. It is also thought to contain iron. DHCR7 is an integral membrane protein of the endoplasmic reticulum, and computer models have predicted up to nine transmembrane domains. DHCR7 is most efficient at reducing 7DHC, but it is known to reduce the carbon 7 double bond of other sterols, indicating a range of substrate specificity. The human version of this enzyme is predicted to have a molecular weight of 54,489 kDa, and an isoelectric point of 9.05.The amino acid sequence that encodes DHCR7 is predicted to contain 475 amino acids, as well as several protein motifs. It contains multiple sterol reductase motifs, as would be expected given its function. It contains a potential sterol-sensing domain (SSD), whose function is unknown but thought to be necessary for binding sterol substrates. It also includes multiple sites of phosphorylation, including potential protein kinase C and tyrosine kinase sites (regulatory enzymes responsible for phosphorylation). The exact function of phosphorylating DHCR7 is yet unknown, but it is thought to be involved in the regulation of its activity.

Mutations and incidence
SLOS is an autosomal recessive disorder. More than 130 different types of mutations have been identified.  Missense mutations (single nucleotide change resulting in a code for a different amino acid) are the most common, accounting for 87.6% of the SLOS spectrum. These typically reduce the function of the enzyme but may not inhibit it completely. Much depends on the nature of the mutation (i.e. which amino acid is replaced and where). Null mutations are much less common, these mutations produce either a completely dysfunctional enzyme, or no enzyme at all. Thus, missense mutations may be more common overall because they are less lethal than nonsense mutations; nonsense mutations may simply result in spontaneous abortion.The IVS8-1G>C is the most frequently reported mutation in DHCR7. This disrupts the joining of exons eight and nine, and results in the insertion of 134 nucleotides into the DHCR7 transcript. This is a nonsense mutation, thus patients that are homozygous for this allele are severely affected. It is thought that this mutation first occurred in the British Isles, and it has a carrier (those that are heterozygous for the allele but not affected) frequency of 1.09% for Caucasians of European heritage. The frequency of mutations differs for various ethnicities, depending on the origin of the mutation. In all Caucasian populations, this particular mutation has an estimated carrier frequency of 3%.The next most common mutation is 278C>T, and results in a threonine at the amino acid position 93. It is a missense mutation and tends to be associated with less severe symptoms. This mutation is the most common one seen in patients of Italian, Cuban, and Mediterranean descent.The third most common mutation is  452G>A. This nonsense mutation causes protein termination, such that the enzyme DHCR7 would not be formed. It is thought to have arisen in Southern Poland and is most common in Northern Europe.Other mutations are less common, although appear to target certain protein domains more so than others. For example, the sterol reductase motifs are common sites of mutation. Overall, there is an estimated carrier frequency (for any DHCR7 mutation causing SLOS) of 3-4% in Caucasian populations (it is less frequent among Asian and African populations). This number indicates a hypothetical birth incidence between 1/2500 and 1/4500. However, the measured incidence is between 1/10,000 to 1/60,000 (it differs depending on heritage and descent). This is much lower than expected. This indicates that many cases of SLOS are undetected, and is likely due to either spontaneous abortion caused by severe mutations (miscarriage), or mild cases that are undiagnosed. Females lack the characteristic genital malformations that affected males have, and thus are less likely to be correctly diagnosed.

Cholesterol metabolism and function
Metabolism
Cholesterol can be obtained through the diet, but it can also be formed by metabolism in the body. Cholesterol metabolism primarily takes place in the liver, with significant amounts in the intestine as well. It should also be noted that cholesterol cannot pass the blood–brain barrier, thus within the brain, biosynthesis is the only source of cholesterol.

In humans, cholesterol synthesis begins with the mevalonate pathway (see diagram), leading to the synthesis of farnesyl pyrophosphate (FPP). This pathway uses two acetyl-CoA and two NADPH to make mevalonate, which is metabolized to isopentenyl pyrophosphate (IPP) using three ATP. From there, three IPP are needed to make one FPP. The combination of two FPP leads to the formation of squalene; this represents the first committed step towards cholesterol biosynthesis. Squalene leads to the creation of lanosterol, from which there are multiple pathways that lead to cholesterol biosynthesis. The rate limiting step of cholesterol synthesis is the conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate, this is an early step in the mevalonate pathway catalyzed by HMG-CoA reductase.

Through a complicated series of reactions, lanosterol leads to the formation of zymosterol. As shown in a diagram to the right, it is at this point that the pathway diverges. In humans, the main pathway leading to cholesterol is known as the Kandutsch–Russell pathway. Zymosterol is metabolized to 5α-cholesta-7,24-dien-3β-ol, then to lathosterol, and then to 7-dehydrocholesterol, or 7-DHC. 7-DHC is the immediate precursor to cholesterol, and the enzyme DHCR7 is responsible for converting 7-DHC to cholesterol. DHCR7 reduces the double bond on carbon 7 of 7-DHC, leading to the unesterified product. Mutations in this enzyme are responsible for the wide range of defects present in SLOS. In another pathway leading to cholesterol synthesis, DHCR7 is required for the reduction of 7-Dehydrodesmosterol to desmosterol.

Regulation
Regulation of cholesterol synthesis is complex and occurs primarily through the enzyme HMG-CoA reductase (catalyst of the rate-limiting step). It involves a feedback loop that is sensitive to cellular levels of cholesterol. The four main steps of regulation are:
The synthesis of the enzyme HMG-CoA reductase is controlled by sterol regulatory element binding protein (SREBP). This is a transcription factor that is inactive when cholesterol levels are high, and active when cholesterol levels are low. When cholesterol levels fall, SREBP is released from the nuclear membrane or endoplasmic reticulum, it then migrates to the nucleus and causes the transcription of the HMG-CoA reductase gene.
The translation (creating the enzyme from the mRNA transcript) of HMG-CoA reductase is inhibited by derivatives of mevalonate and by dietary cholesterol.
The degradation of HMG-CoA reductase is tightly controlled. The part of the enzyme that is bound to the endoplasmic reticulum senses signals, such as increased cholesterol levels, that lead to its degradation or proteolysis.
When HMG-CoA reductase is phosphorylated, its activity decreases. This means cholesterol synthesis is reduced when cell energy (ATP) levels are low.

Function
Cholesterol is an important lipid involved in metabolism, cell function, and structure. It is a structural component of the cell membrane, such that it provides structure and regulates the fluidity of the phospholipid bilayer. Furthermore, cholesterol is a constituent in lipid rafts. These are congregations of proteins and lipids (including sphingolipids and cholesterol) that float within the cell membrane, and play a role in the regulation of membrane function. Lipid rafts are more ordered or rigid than the membrane bilayer surrounding them. Their involvement in regulation stems mostly from their association with proteins; upon binding substrates, some proteins have a higher affinity for attaching to lipid rafts. This brings them in close proximity with other proteins, allowing them to affect signaling pathways. Cholesterol specifically acts as a spacer and a glue for lipid rafts; absence of cholesterol leads to the dissociation of proteins.Given its prevalence in cell membranes, cholesterol is highly involved in certain transport processes. It may influence the function of ion channels and other membrane transporters. For example, cholesterol is necessary for the ligand binding activity of the serotonin receptor. In addition, it appears to be very important in exocytosis. Cholesterol modulates the properties of the membrane (such as membrane curvature), and may regulate the fusion of vesicles with the cell membrane. It may also facilitate the recruitment of complexes necessary for exocytosis. Given that neurons rely heavily on exocytosis for the transmission of impulses, cholesterol is a very important part of the nervous system.

One particularly relevant pathway in which cholesterol takes place is the Hedgehog signaling pathway. This pathway is very important during embryonic development, and involved in deciding the fate of cells (i.e., which tissue they need to migrate to). Hedgehog proteins are also involved in the transcription of genes that regulate cell proliferation and differentiation. Cholesterol is important to this pathway because it undergoes covalent bonding to Hedgehog proteins, resulting in their activation. Without cholesterol, the signaling activity is disrupted and cell differentiation may be impaired.Cholesterol is a precursor for many important molecules. These include bile acids (important in processing dietary fats), oxysterols, neurosteroids (involved in neurotransmission and excitation), glucocorticoids (involved in immune and inflammatory processes), mineralocorticoids (osmotic balance), and sex steroids (i.e. estrogen and testosterone; wide range of function but involved in genital development prenatally). Finally, cholesterol is a major component of myelin, a protective layer around neurons. Myelination occurs most rapidly during prenatal development, meaning that the demand for cholesterol biosynthesis is very high.

Pathogenesis
Given that the function of cholesterol encompasses a very wide range, it is unlikely that the symptoms of SLOS are due to a single molecular mechanism. Some of the molecular effects are yet unknown, but could be extrapolated based on the role of cholesterol. In general, the negative effects are due to decreased levels of cholesterol and increased levels of cholesterol precursors-most notably, 7DHC. Although 7DHC is structurally similar to cholesterol, and could potentially act as a substitute, the effects of this are still being studied.Most patients with SLOS present decreased cholesterol levels, particularly in the brain (where cholesterol levels rely primarily on new synthesis). This also means that any sterol derivatives of cholesterol would also have reduced concentrations. For example, reduced levels of neurosteroids may be seen in SLOS. These are lipids which take part in signaling within the brain, and must be produced within the brain itself. They are responsible for interacting with nuclear steroid receptors, and bind to neurotransmitter-gated ion channels. Specifically, they modulate the effects of GABA and NMDA receptors, resulting in calming effects, improved memory, and more. Thus, given that some characteristics of SLOS are the opposite of these effects (hyperactivity, anxiety), a reduction in neurosteroids could influence both neurological development and behaviour.

Furthermore, as outlined above, cholesterol is an important aspect in Hedgehog signaling. With lower levels of cholesterol, hedgehog proteins would not undergo the necessary covalent modification and subsequent activation. This would result in impaired embryonic development, and may contribute to the observed physical birth defects in SLOS. One particular hedgehog signaling protein, sonic hedgehog (SHH), is important in the pattern of the central nervous system, facial features, and limbs. Other hedgehog proteins may be involved in the development of the genital tract and the skeleton.The altered sterol levels in SLOS are particularly relevant to cell membranes, which are made primarily of lipids. SLOS patients may show cell membranes with abnormal properties or composition, and reduced cholesterol levels greatly affect the stability and proteins of lipid rafts. Despite their structural similarity, 7DHC is unable to replace cholesterol in lipid rafts. In addition, a lack of cholesterol contributes to the increased fluidity of the cell membrane, and may cause abnormal granule secretions. All of these changes in the membrane likely contribute to changes in transport functions that are observed in SLOS. They may cause defects in IgE receptor-mediated mast cell degranulation and cytokine production, which are cells involved in allergic and immune responses. The NMDA receptor is affected, as well as the binding capability of the hippocampal serotonin receptor. Cell to cell interaction, which is very important in development, may be impaired. Exocytosis in synaptic vesicles has been shown to be reduced, likely due to impaired vesicle fusion to the cell membrane, or poor vesicle recycling. Finally, cholesterol is highly prevalent in myelin, therefore SLOS patients show reduced myelination of the cerebral hemispheres, peripheral nerves, and cranial nerves.In addition to lowered levels of cholesterol, many of the symptoms shown in SLOS stem from the toxic effects of 7DHC. 7DHC is known to impair intracellular cholesterol transport. It also increases the degradation of HMG-CoA reductase (the enzyme that catalyzes the rate-limiting step in cholesterol synthesis). 7DHC leads to novel oxysterol and steroid derivatives, and many of their functions or effects are yet unknown. A very important finding with respect to 7DHC is that it is the most reactive lipid for lipid peroxidation, and results in systemic oxidative stress. Lipid peroxidation is known to destroy membranes of both cells and membrane-bound organelles. The derivative of 7DHC that is used to indicate oxidative stress is 3β,5α-dihydroxy-cholest-7-en-6-one (DHCEO); it is formed from a primary product of 7DHC peroxidation, 7-DHC-5α,6α-epoxide. DHCEO is toxic to cortical neuronal and glial cells, and accelerates their differentiation and arborization. Through oxidative stress, 7DHC is thought to be responsible for the increased photosensitivity shown in SLOS patients. Normal UVA exposure may lead to oxidative stress in skin cells. Given that 7DHC is more readily oxidized, it enhances the effects of UVA, leading to increased membrane lipid oxidation and increased production of reactive oxygen species (ROS).Typically, more altered the levels of 7DHC and cholesterol lead to more severe symptoms of SLOS. The levels of these metabolites also correspond to the severity of the mutation (nonsense versus missense); some mutations of DHCR7 may still show residual cholesterol synthesis, and others may not. However, even individuals with the same mutations or genotype may still show variability in their symptoms. This may be due to maternal factors, such as the transfer of cholesterol to the fetus during pregnancy, as well as the amount of cholesterol present in the brain before the blood–brain barrier forms prenatally. The rate of accumulation and excretion of toxic metabolites may vary from person to person. Maternal apolipoprotein E has also been implicated in individual variability in SLOS, although the exact nature of this relationship is unknown. There are likely more factors contributing to the wide spectrum of effects in SLOS which have not yet been discovered.

Screening and diagnosis
Prenatally
The most characteristic biochemical indicator of SLOS is an increased concentration of 7DHC (reduced cholesterol levels are also typical, but appear in other disorders as well). Thus, prenatally, SLOS is diagnosed upon finding an elevated 7DHC:total sterol ratio in fetal tissues, or increased levels of 7DHC in amniotic fluid. The 7DHC:total sterol ratio can be measured at 11–12 weeks of gestation by chorionic villus sampling, and elevated 7DHC in amniotic fluid can be measured by 13 weeks. Furthermore, if parental mutations are known, DNA testing of amniotic fluid or chorionic villus samples may be performed.

Amniocentesis (process of sampling amniotic fluid) and chorionic villus sampling cannot be performed until approximately 3 months into the pregnancy. Given that SLOS is a very severe syndrome, parents may want to choose to terminate their pregnancy if their fetus is affected. Amniocentesis and chorionic villus sampling leave very little time to make this decision (abortions become more difficult as the pregnancy advances), and can also pose severe risks to the mother and baby. Thus, there is a very large desire for noninvasive midgestation diagnostic tests. Examining the concentrations of sterols in maternal urine is one potential way to identify SLOS prenatally. During pregnancy, the fetus is solely responsible for synthesizing the cholesterol needed to produce estriol. A fetus with SLOS cannot produce cholesterol, and may use 7DHC or 8DHC as precursors for estriol instead. This creates 7- or 8-dehydrosteroids (such as 7-dehydroestriol), which may show up in the maternal urine. These are novel metabolites due to the presence of a normally reduced double bond at carbon 7 (caused by the inactivity of DHCR7), and may be used as indicators of SLOS. Other cholesterol derivatives which possess a double bond at the 7th or 8th position and are present in maternal urine may also be indicators of SLOS. 7- and 8-dehydropregnanetriols have been shown to be present in the urine of mothers with an affected fetus but not with an unaffected fetus, and thus are used in diagnosis. These pregnadienes originated in the fetus and traveled through the placenta before reaching the mother. Their excretion indicates that neither the placenta nor the maternal organs have necessary enzymes needed to reduce the double bond of these novel metabolites.

Postnatally
If SLOS goes undetected until after birth, diagnosis may be based on the characteristic physical features as well as finding increased plasma levels of 7DHC.There are many different ways of detecting 7DHC levels in blood plasma, one way is using the Liebermann–Burchard (LB) reagent. This is a simple colorimetric assay developed with the intention of use for large scale screening. When treated with the LB reagent, SLOS samples turn pink immediately and gradually become blue; normal blood samples are initially colorless and develop a faint blue color. Although this method has limitations and is not used to give a definitive diagnosis, it has appeal in that it is a much faster method than using cell cultures.Another way of detecting 7DHC is through gas chromatography, a technique used to separate and analyze compounds. Selected ion
monitoring gas chromatography/mass-spectrometry (SIM-GC/MS) is a very sensitive version of gas chromatography, and permits detection of even mild cases of SLOS. Other methods include time-of-flight mass spectrometry, particle-beam LC/MS, electrospray tandem MS, and ultraviolet absorbance, all of which may be used on either blood samples, amniotic fluid, or chorionic villus. Measuring levels of bile acids in patients urine, or studying DCHR7 activity in tissue culture are also common postnatal diagnostic techniques.

Treatment
Management of individuals with SLOS is complex and often requires a team of specialists. Some of the congenital malformations (cleft palate) can be corrected with surgery. Other treatments have yet to be proven successful in randomized studies, however anecdotally they appear to cause improvements.

Cholesterol supplementation
Currently, the most common form of treatment for SLOS involves dietary cholesterol supplementation. Anecdotal reports indicate that this has some benefits; it may result in increased growth, lower irritability, improved sociability, less self-injurious behaviour, less tactile defensiveness, fewer infections, more muscle tone, less photosensitivity and fewer autistic behaviours. Cholesterol supplementation begins at a dose of 40–50 mg/kg/day, increasing as needed. It is administered either through consuming foods high in cholesterol (eggs, cream, liver), or as purified food grade cholesterol. Younger children and infants may require tube feeding. However, dietary cholesterol does not reduce the levels of 7DHC, cannot cross the blood–brain barrier, and does not appear to improve developmental outcomes. One empirical study found that cholesterol supplementation did not improve developmental delay, regardless of the age at which it began. This is likely because most developmental delays stem from malformations of the brain, which dietary cholesterol cannot ameliorate due to its inability to cross the blood–brain barrier.

Simvastatin therapy
HMG-CoA reductase inhibitors have been examined as treatment for SLOS. Given that this catalyzes the rate-limiting step in cholesterol synthesis, inhibiting it would reduce the buildup of toxic metabolites such as 7DHC. Simvastatin is a known inhibitor of HMG-CoA reductase, and most importantly is able to cross the blood–brain barrier. It has been reported to decrease the levels of 7DHC, as well as increase the levels of cholesterol. The increased cholesterol levels are due to simvastatins effect on the expression of different genes. Simvastatin increases the expression of DHCR7, likely leading to increased activity of DHCR7. It has also been shown to increase the expression of other genes involved in cholesterol synthesis and uptake. However, these benefits are dependent on the amount of residual cholesterol synthesis. Because some individuals possess less severe mutations and demonstrate some amount of DCHR7 activity, these people benefit the most from simvastatin therapy as they still have a partially functioning enzyme. For individuals that show no residual DCHR7 activity, such as those homozygous for null alleles or mutations, simvastatin therapy may actually be toxic. This highlights the importance of identifying the specific genotype of the SLOS patient before administering treatment. It is still unknown if simvastatin will improve the behavioural or learning deficits in SLOS.

Antioxidant supplementation
Antioxidants are those which inhibit the oxidation of molecules or reduce metabolites that were previously oxidized. Given that some symptoms of SLOS are thought to result from the peroxidation of 7DHC and its derivatives, inhibiting this peroxidation would likely have beneficial effects. Antioxidants have been shown to increase the level of lipid transcripts in SLOS cells, these transcripts play a role in lipid (cholesterol) biosynthesis and are known to be down-regulated in SLOS. Furthermore, vitamin E specifically is known to decrease DHCEO levels, which is an indicator of oxidative stress in SLOS, as well as present beneficial changes in gene expression. Vitamin E appears to be the most powerful antioxidant for treating SLOS, and in mouse models has reduced the levels of oxysterols in the brain. However, antioxidants have only been studied in animal models of SLOS or isolated SLOS cells. Thus, their clinical significance and negative side effects are still unknown, and their use has yet to be studied in humans.

Further considerations
When treating SLOS, a recurring issue is whether or not the intellectual and behavioural deficits are due to fixed developmental problems (i.e. fixed brain malformations), or due to ongoing abnormal sterol levels that interrupt the normal function of the brain and other tissues. If the latter is true, then treatments which change the sterol levels and ratios, particularly in the brain, will likely improve the developmental outcome of the patient. However, if the former is true, then treatment is likely to help only with symptoms and not with specific developmental deficits.

Research
The most common animal used to study SLOS is the mouse. According to BioCyc, cholesterol biosynthesis in mice is very similar to that of humans. Most importantly, mice possess both DHCR7 (the enzyme responsible for SLOS), and HMG-CoA reductase (the rate limiting step of cholesterol synthesis. Rats are similar to mice and have also been used. There are two popular ways in which animal models of SLOS are created. The first is using teratogens, the second is using genetic manipulations to create mutations in the DHCR7 gene.

Teratogenic models
Teratogenic models are induced by feeding pregnant rats or mice inhibitors of DCHR7. Two common inhibitors are BM15766 (4-(2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl)-benzoic acid) and AY9944 (trans-l,4-bis(2-chlorobenzylaminomethy1)cyclohexane dihydrochloride). These compounds have different chemical and physical properties, but induce similar effects. AY9944 has been shown to induce holoprosencephaly and sexual malformations similar to those seen in humans with SLOS. It is also known to cause impairments in the serotonin receptor, another defect commonly seen in SLOS patients. BM15766 has produced the lack of cholesterol and bile acid synthesis that is seen in SLOS patients with homozygous mutations. All teratogenic models can be effectively used to study SLOS; however, they present lower levels of 7-DHC and 8-DHC than are seen in humans. This can be explained by the fact that humans experience a permanent block in their DHCR7 activity, where mice and rats treated with inhibitors experience only transient blocks. Furthermore, different species of mice and rats are more resistant to teratogens, and may be less effective as models of SLOS. Teratogenic models are most commonly used to study more long-term effects of SLOS, because they survive longer than genetic models. For example, one study examined the retinal degeneration of SLOS, which in rats does not occur until at least one month after birth.

Genetic models
Genetic models of SLOS are created by knocking out the DHCR7 gene. One study used homologous recombination to disrupt DCHR7 in mouse embryonic stem cells. Similar to what is found in humans, heterozygous mice (having only one mutated allele) were phentoypically normal, and were crossed to produce pups (young mice) homozygous for the mutated allele. Although these pups died within the first day of life due to their inability to feed, they showed characteristics similar to humans with SLOS. They had decreased levels of cholesterol, increased levels of 7- and 8DHC, showed less growth and smaller birth weights, had craniofacial malformations, and less movement. Many also had a cleft palate, and decreased neuronal responses to glutamate. Overall however, the pups had fewer dysmorphic features than human patients with SLOS; they did not present limb, renal, adrenal or central nervous system malformations </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Nasal septum deviation and can you explain it in depth? [/INST] Nasal septum deviation is a physical disorder of the nose, involving a displacement of the nasal septum. Some displacement is common, affecting 80% of people, mostly without their knowledge.

Signs and symptoms
The nasal septum is the bone and cartilage in the nose that separates the nasal cavity into the two nostrils. The cartilage is called the quadrangular cartilage and the bones comprising the septum include the maxillary crest, vomer and the perpendicular plate of the ethmoid. Normally, the septum lies centrally, and thus the nasal passages are symmetrical. A deviated septum is an abnormal condition in which the top of the cartilaginous ridge leans to the left or the right, causing obstruction of the affected nasal passage.
It is common for nasal septa to depart from the exact centerline; the septum is only considered deviated if the shift is substantial or causes problems. By itself, a deviated septum can go undetected for years and thus be without any need for correction.Symptoms of a deviated septum include infections of the sinus and sleep apnea, snoring, repetitive sneezing, facial pain, nosebleeds, mouth breathing, difficulty with breathing and mild to severe loss of the ability to smell. Only more severe cases of a deviated septum will cause symptoms of difficulty breathing and require treatment.

Causes
It is most frequently caused by impact trauma, such as by a blow to the face. It can also be a congenital disorder, caused by compression of the nose during childbirth. Deviated septum is associated with genetic connective tissue disorders such as Marfan syndrome, Homocystinuria and Ehlers–Danlos syndrome.

Diagnosis
Nasal septum deviation is the most common cause of nasal obstruction. A history of trauma to the nose is often present including trauma from the process of birth or microfractures </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Postpericardiotomy syndrome and can you explain it in depth? [/INST] Postpericardiotomy syndrome (PPS) is a medical syndrome referring to an immune phenomenon that occurs days to months (usually 1–6 weeks) after surgical incision of the pericardium (membranes encapsulating the human heart). PPS can also be caused after a trauma, a puncture of the cardiac or pleural structures (such as a bullet or stab wound), after percutaneous coronary intervention (such as stent placement after a myocardial infarction or heart attack), or due to pacemaker or pacemaker wire placement.

Signs and symptoms
The typical signs of post-pericardiotomy syndrome include fever, pleuritis (with possible pleural effusion),  pericarditis (with possible pericardial effusion), occasional but rare pulmonary infiltrates, and fatigue. Cough, pleuritic or retrosternal chest pain, joint pain and decreased oxygen saturation can also be seen in some cases.Other signs include arthritis, together with petechiae on the skin and palate.: 827

Complications
Complications include pericarditis, pericardial effusion, pleuritis, pulmonary infiltration, and very rarely pericardial tamponade. Of these cardiac tamponade is the most life-threatening complication. The pericardial fluid increases intra-pericardial pressure therefore preventing complete expansion of the atria and the ventricles upon the diastole. This causes equilibration of the pressure in all four heart chambers, and results in the common findings of the tamponade which are pulsus paradoxus, Becks triad of hypotension, muffled heart sounds, and raised jugular venous pressure, as well as EKG or Holter monitor findings such as electrical alternans. Physically the patients who progress to severe pericardial tamponade obtundate, become mentally altered, and lethargic. If left untreated, severe decrease in cardiac output, vascular collapse, and hypoperfusion of body including the brain results in death.

Pathogenesis
The cause is believed to be an autoimmune response against damaged cardiac tissue.  This is supported by excellent response to immunosuppressive (steroid) therapy.This condition is a febrile illness caused by immune attack of the pleura and the pericardium. Possible cell mediated immunity led by Helper T-cells and Cytotoxic T-cells is postulated to be important in the pathogenesis of this condition. There is also possibility of anti-cardiac antibodies created idiopathically, or due to concurrent cross-reactivity of the antibodies produced against viral antigens, however the latter assumption is not fool-proof or completely reliable due to conflicting studies.

Diagnosis
A chest X-ray might depict pleural effusion, pulmonary infiltration, or pericardial effusion.During medical doctor examination, a pericardial friction rub can be auscultated indicating pericarditis. Auscultation of the lungs can show crackles indicating pulmonary infiltration, and there can be retrosternal/pleuritic chest pain worse on inspiration (breathing in). Patient can also depict sweating (diaphoresis) and agitation or anxiety.

Treatment
Colchicine
Colchicine has been used effectively to prevent pericarditis, and inflammation that follows surgery of the pericardium. Although no current drug on the market prevents post-pericardiotomy syndrome, colchicine seems to provide an effective and safe way to treat pericarditis by reducing inflammation. Colchicine is a natural product extracted from plants, and is a secondary metabolite (an organic compound not directly related to growth and development in an organism).Colchicine interferes with the inflammatory process by altering several important steps in the pathway.  Microtubules are structural components of the cytoskeleton that lengthen and shrink for important cell functions.  Colchicine binds to β- tubulin and forms tubulin-colchicine complexes., These complexes interfere with microtubule formation microtubules. Low doses of colchicine can inhibit the formation of microtubules, while high doses depolymerize or break down a polymer to a monomer. Therefore, any process involving cytoskeleton change, including mitosis and motility of white blood cells, are highly impacted.Microtubule disruption decrease neutrophil adhesion, an important step for inflammation.  Neutrophils are recruited to the target location of inflammation via signals from the endothelium where they adhere and play a role in the inflammatory response </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Nasal vestibulitis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Breast disease and can you explain it in depth? [/INST] Breast diseases make up a number of conditions. The most common symptoms are a breast mass, breast pain, and nipple discharge.A majority of breast diseases are noncancerous.

Tumor
A breast tumor is an abnormal mass of tissue in the breast as a result of neoplasia. A breast neoplasm may be benign, as in fibroadenoma, or it may be malignant, in which case it is termed breast cancer. Either case commonly presents as a breast lump. Approximately 7% of breast lumps are fibroadenomas and 10% are breast cancer, the rest being other benign conditions or no disease.Phyllodes tumor is a fibroepithelial tumor which can either benign, borderline or malignant.

Breast cancer
Breast cancer is cancer of the breast tissues, most commonly arising from the milk ducts.  Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases.  It is most common in women over age 50.
Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin.  Diagnosis may also be made when the cancer is asymptomatic, through breast cancer screening programs, such as mammograms.  Outcomes for breast cancer vary depending on the cancer type, extent of disease, and persons age </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Neonatal acne and can you explain it in depth? [/INST] Neonatal acne, also known as acne neonatorum, is an acneiform eruption that occurs in newborns or infants within the first 4-6 weeks of life, and presents with open and closed comedones on the cheeks, chin and forehead.The main cause is not known for certain but it may be caused by maternal androgens transferred from the mother to the newborn from the placenta and androgens produced by the fetal adrenal gland and neonatal testicles that stimulate sebaceous glands to increase production of sebum. As a self-limiting condition, neonatal acne tends to resolve on its own but treatment options can include topical benzoyl peroxide, topical retinoids, topical antibiotics and topical antifungals.

Signs and Symptoms
Neonatal acne presents from birth to within the first 4-6 weeks of life. Common symptoms are open and closed comedones such as papules and pustules that occur most commonly on the face on the areas of the cheeks, chin and forehead. Less commonly, lesions can be present on the chest and back.

Causes
It is believed that maternal androgens passed to the infant through the placenta has a role in stimulating sebaceous glands leading to increased sebum production that causes comedone formation. Dehydroepiandrosterone (DHEA) produced from the fetal adrenal gland and androgen production from neonatal testicles may also stimulate sebum production from sebaceous glands.The role of genetics is unclear but a positive family history supports association with neonatal acne.Some researchers suggest the role of Malassezia colonization causing hypersensitivity reactions in skin but this tends to be linked to neonatal cephalic pustulosis more so than neonatal acne.

Diagnosis
A work up is suggested in cases of severe acneiform eruptions or with signs of growth abnormalities to rule out potential endocrine diseases, tumor formation, or gonadal development abnormalities. A referral to a pediatric endocrinologist may be warranted.

Differential Diagnosis
Other causes of acneiform eruptions such as those induced by the use of topical products like creams, ointments and shampoos on the skin are often ruled out before diagnosis. Maternal medications like lithium and high dose corticosteroids may also induce formulation of pustules in newborns and can be assessed with a thorough family history. Likewise, newborns can be assessed for infection whether bacterial, fungal or viral in nature.  Erythema toxicum neonatorum, neonatal cephalic pustulosis, transient neonatal pustular melanosis, folliculitis, miliaria and milia are often ruled out before diagnosis.Some experts consider neonatal cephalic pustulosis (NCP) a form of neonatal acne while others do not. NCP presents with facial papules and pustules but no comedones. NCP has been linked to Malassezia colonization, a normal yeast found on skin, but inconsistent patterns of positive colonization and NCP suggests that Malassezia hypersensitivity reactions in susceptible newborns are the cause of the acneiform eruptions rather than colonization itself.

Treatment
Neonatal acne will typically resolve by itself in 2-6 months. In mild cases, cleansing the face daily with gentle soap and water while avoiding use of potential comedogenic soaps, lotions and oils is often enough. Further treatment is not necessary but in severe or persistent cases topical therapy can be initiated.

Benzoyl Peroxide
Topical benzoyl peroxide (BPO) may be indicated in persistent or inflammatory cases. BPO is a lipophilic agent that penetrates into sebaceous glands and generates reactive oxygen species that kill P. acnes. It also has comedolytic and anti-inflammatory properties and can prevent development of antimicrobial resistance.

Topical Retinoids
Topical retinoids can be used alone or in combination with BPO. Retinoids are derived from vitamin A. They bind to retinoic receptors to normalize the rate of keratinocyte growth and prevent inflammation. Overactive keratinocyte production can lead to comedone formation.

Topical Antibiotics
In cases where scarring is a concern, topical antibiotics may be recommended. Topical clindamycin and erythromycin are the most commonly prescribed options for acne. Antibiotics kill P. acnes on skin that could be causing inflammation. With the emergence of resistant P. acnes, experts recommend topical antibiotics to be used in combination with BPO to reduce the risk of development of antimicrobial resistance. The most common side effects of topical antibiotics are stinging, burning and redness at the site of application.

Topical antifungals
Some experts suggest the use of topical ketoconazole in newborns with more pustular neonatal acne as there is evidence it shortens duration of lesions. This may be in cases more suggestive of neonatal cephalic pustulosis than neonatal acne.

Epidemiology
20% of newborns will develop neonatal acne however there has been debate if this is an accurate representation of actual diagnosed cases of acne as this could include other acneiform eruptions that do not present with comedones like neonatal cephalic pustulosis. Neonatal acne occurs more often in boys than in girls.

See also
Acne aestivalis
Infantile acne
List of cutaneous conditions

References
Further reading
Katsambas AD, Katoulis AC, Stavropoulos P (February 1999). "Acne neonatorum: a study of 22 cases". Int </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Rothmund–Thomson syndrome and can you explain it in depth? [/INST] Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive skin condition.
There have been several reported cases associated with osteosarcoma. A hereditary basis, mutations in the DNA helicase RECQL4 gene, causing problems during initiation of DNA replication has been implicated in the syndrome.

Signs and symptoms
Sun-sensitive rash with prominent poikiloderma and telangiectasias
Juvenile cataracts
Saddle nose
Congenital bone defects, including short stature and radial ray anomalies such as absent thumbs
Hair growth problems (absent eyelashes, eyebrows and/or hair)
Hypogonadism has not been well documented
Hypodontia
Calcium problems (not documented in journals)
Ear problems (not documented in journals but identified by patients in support groups)
Produces osteosarcomaThe skin is normal at birth. Between 3 and 6 months of age, the affected carrier develops poikiloderma on the cheeks. This characteristic "rash" that all RTS carriers have can develop on the arms, legs and buttocks </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Spondyloarthropathy and can you explain it in depth? [/INST] Spondyloarthropathy or spondyloarthrosis refers to any joint disease of the vertebral column. As such, it is a class or category of diseases rather than a single, specific entity. It differs from spondylopathy, which is a disease of the vertebra itself, but many conditions involve both spondylopathy and spondyloarthropathy.
Spondyloarthropathy with inflammation is called axial spondyloarthritis </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cerebellar degeneration and can you explain it in depth? [/INST] Cerebellar degeneration is a condition in which cerebellar cells, otherwise known as neurons, become damaged and progressively weaken in the cerebellum. There are two types of cerebellar degeneration; paraneoplastic cerebellar degeneration, and alcoholic or nutritional cerebellar degeneration. As the cerebellum contributes to the coordination and regulation of motor activities, as well as controlling equilibrium of the human body, any degeneration to this part of the organ can be life-threatening. Cerebellar degeneration can result in disorders in fine movement, posture, and motor learning in humans, due to a disturbance of the vestibular system. This condition may not only cause cerebellar damage on a temporary or permanent basis, but can also affect other tissues of the central nervous system, those including the cerebral cortex, spinal cord and the brainstem (made up of the medulla oblongata, midbrain, and pons).Cerebellar degeneration can be attributed to a plethora of hereditary and non-hereditary conditions. More commonly, cerebellar degeneration can also be classified according to conditions that an individual may acquire during their lifetime, including infectious, metabolic, autoimmune, paraneoplastic, nutritional or toxic triggers.

Signs and symptoms
Patients with cerebellar degeneration experience a progressive loss of nerve cells (Purkinje cells) throughout the cerebellum. As well as this, it is common to incur an elevated blood protein level and a high volume of lymph cells within the cerebrospinal fluid, resulting in swelling and enlargement of the brain. The most characteristic signs and symptoms experienced by patients with cerebellar degeneration include:
muscle weakness
an uncoordinated, staggering walk
quivering of the torso
jerky arm and leg movements
tendency to falling over
dysarthria (difficulty in articulating speech)
dysphagia (difficulty in deglutition/swallowing of solids and liquids)
vertigo (dizziness)
nystagmus (rapid, involuntary eye movements), causing sleep disturbances
ophthalmoplegia (paralysis of extraocular muscles)
diplopia (double vision)Scientific studies have revealed that psychiatric symptoms are also common in patients with cerebellar degeneration, where dementia is a typical psychiatric disorder resulting from cerebellar damage. Approximately 50% of all patients experience dementia as a result of paraneoplastic cerebellar degeneration.

Causes
The root cause of incurring a cerebellar degenerative condition can be due to a range of different inherited or acquired (non-genetic and non-inherited) conditions, including neurological diseases, paraneoplastic disorders, nutritional deficiency, and chronic heavy alcohol use.

Neurological diseases
A neurological disease refers to any ailment of the central nervous system, including abnormalities of the brain, spinal cord and other connecting nerve fibres. Where millions of people are affected by neurological diseases on a worldwide scale, it has been identified that the number of different types of neurological diseases exceeds six hundred, any of which an individual can incur. Some of the most prevalent types include Alzheimers disease, cerebral palsy, epilepsy, Parkinsons disease and stroke. More specifically, the neurological diseases that can cause cerebellar degeneration include:

Inherited
Spinocerebellar ataxia (SCA), which refers to a group of conditions caused by mutations in the genes of a human, and are characterised by degenerative changes to many parts of the central nervous system, inclusive of the cerebellum, brain stem, and spinal cord. If a parent is affected by SCA, each of their children will have a 50% risk of inheriting the mutated gene.

Non-inherited
Multiple sclerosis (MS), a progressive and incurable condition caused by the combination of an individuals genetic influences and environmental circumstances. It occurs when the myelin sheath of the nerve cells becomes damaged. As the myelin sheath is responsible for protecting the nerves and conducting rapid impulses between them, any damage to this lipid-rich layer will result in delayed and interrupted nerve impulses to and from the brain.
Transmissible spongiform encephalopathies (TSEs), which refers to a combination of diseases caused by the subsistence of foreign proteins in the blood, called prions. Prions originate in the bloodstream via ingestion of contaminated foods or through contact with contaminated medical instruments, body fluids, or infected tissue. This causes severe inflammation of the brain, impairing ones memory, personality and muscular coordination.
Acute & haemorrhagic stroke, resulting in the death of neurons in the cerebellum due to a disrupted flow of oxygen to the brain. This disrupted flow may be due to one of two causes; either a narrowing or blocked artery which derives from a build-up of plaque in the inner walls of the coronary arteries, or a ruptured blood vessel, commonly deriving from high blood pressure or head trauma.

Paraneoplastic disorders
Paraneoplastic disorders are a combination of non-inherited conditions that are activated by an individuals autoimmune response to a malignant tumour. These disorders prevail when T-cells (also known as white blood cells) begin to harm familiar cells in the central nervous system rather than the cancerous cells, resulting in degeneration of neurons in the cerebellum. Other signs and symptoms that commonly result from the incursion of a paraneoplastic disorder include an impaired ability to talk, walk, sleep, maintain balance and coordinate muscle activity, as well as experiencing seizures and hallucinations. Paraneoplastic disorders are prevalent among middle-aged individuals, typically those with lung, lymphatic, ovarian or breast cancer.

Nutritional deficiency
Nutritional deficiency relates to an insufficient amount of macronutrients and micronutrients being provided to the body. Nutrient deficiencies are most prevalent among infants, the elderly, the poverty-stricken, and individuals with eating disorders. Alcohol use disorder is the diagnosis of which an individual frequently consumes excessive amounts of alcohol, and thus becomes dependent on the intoxicating substance. Studies show that men of every age group consume more alcohol than women, where the prevalence is higher in some regions of the world than others, such as across Western Europe and Australia. Nutritional deficiency is a non-inherited conditions that lead to impaired absorption or utilisation of the vitamin thiamine (B-1) by the body, thus causing temporary or permanent damage to cerebellar cells. Alcoholic degeneration of cerebellar cells is the most common trigger of spinocerebellar ataxia.

Diagnosis
To select an appropriate and accurate diagnostic test for cerebellar degeneration, it is crucial that a range of factors specific to each patient are taken into consideration. These include; the patients age, acuity of their signs and symptoms, associated neurological conditions, and family history of hereditary forms of cerebellar degeneration. A diagnosis for cerebellar degeneration is regarded after any of the aforementioned signs and symptoms surface. For genetically classified forms of cerebellar degeneration, genetic testing can be carried out in order to confirm or deny the diagnosis, where this form of testing is only possible if the gene responsible for the cause of the condition is recognised. In saying this, for most conditions the genetic cause of cerebellar degeneration is unidentified, hence these patients cannot proceed with genetic testing. In cases where cerebellar degeneration is acquired, a diagnosis can be established using imaging methods such as computerised tomography (CT scans) and magnetic resonance imaging (MRI), necessary to detect brain abnormalities in patients with cerebellar degeneration.

Treatment
Like any other disease, treatment for cerebellar degeneration is contingent on the underlying cause, unique to each patient. As of present time, hereditary forms of cerebellar degeneration are incurable, though they can be managed. Management is centred around coping with symptoms and improving a patients quality of life. In these cases, immediate management of inherited cerebellum damage should involve consultation with a neurologist, followed by specific management approaches based on the signs and symptoms experienced by each unique patient </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Atypical lichen myxedematosus and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Excoriated acne and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Central pain syndrome and can you explain it in depth? [/INST] Central pain syndrome is a neurological condition consisting of constant, moderate to severe pain due to damage to the central nervous system (CNS) which causes a sensitization of the pain system. The extent of pain and the areas affected are related to the cause of the injury.

Signs and symptoms
Pain can either be relegated to a specific part of the body or spread to the entire body. It is typically constant, and may be moderate to severe in intensity.  Those who are afflicted describe it as being stuck in a loop of pain. It is often made worse by touch, movement, emotions, barometric pressure and temperature changes, usually cold temperatures along with many other similar triggers. Cold temperatures regularly make the burning pain worse in certain body parts. Burning pain is the most common sensation, but patients also report pins and needles, pressing, lacerating, aching, and extreme bursts or constant sharp or unremitting excruciating pain. Individuals may have reduced sensitivity to touch in the areas affected by the pain, as if the part is falling asleep. The burning and loss of sense of touch are usually, but not always, most severe on the distant parts of the body, such as the feet or hands, spreading until it is in some cases felt from head to toe. Usually the burning pain in body parts is a result of old injuries that seem like they should have healed long ago, yet the pain lingers on and even years afterwards </s>