<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 Klinefelter syndrome and can you explain it in depth? [/INST] Klinefelter syndrome (KS), also known as 47,XXY, is a syndrome where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. Usually, symptoms are subtle and subjects do not realize they are affected. Sometimes, symptoms are more evident and may include weaker muscles, greater height, poor motor coordination, less body hair, breast growth, and less interest in sex. Often, these symptoms are noticed only at puberty. Intelligence is usually normal, but reading difficulties and problems with speech are more common.Klinefelter syndrome occurs randomly. The extra X chromosome comes from the father and mother nearly equally. An older mother may have a slightly increased risk of a child with KS. The syndrome is defined  by the presence  of at least one extra X chromosome in addition to a Y chromosome yielding a total of 47 or more chromosomes rather than the usual 46. KS is diagnosed by the genetic test known as a karyotype.While no cure is known, a number of treatments may help. Physical therapy, occupational therapy, speech and language therapy, counselling, and adjustments of teaching methods may be useful. Testosterone replacement may be used in those who have significantly lower levels. Enlarged breasts may be removed by surgery. About half of affected males have a chance of fathering children with the help of assisted reproductive technology, but this is expensive and not risk free. XXY males have a ~15-fold higher risk of developing breast cancer than typical, but still lower than that of females. People with the condition have a nearly normal life expectancy.Klinefelter syndrome is one of the most common chromosomal disorders, occurring in one to two per 1,000 live male births. It is named after American endocrinologist Harry Klinefelter, who identified the condition in the 1940s. In 1956, the extra X chromosome was identified as the cause. Mice can also have the XXY syndrome, making them a useful research model.

Signs and symptoms
The primary features are infertility and small, poorly functioning testicles. Often, symptoms may be subtle and many people do not realize they are affected. Sometimes, symptoms are more prominent and may include weaker muscles, greater height, poor coordination, less body hair, breast growth, and low libido. Often, these symptoms are noticed only at puberty.

Prenatal
An estimated 60% of fetuses with Klinefelter syndrome end in miscarriage.

Physical
As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys of their age.During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may develop breast tissue and also have weaker bones, and a lower energy level than other males.By adulthood, XXY males look similar to males without the condition, although they are often taller. In adults, possible characteristics vary widely and include little to no sign of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue). Gynecomastia is present in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery.Affected males are often infertile, or have reduced fertility. Advanced reproductive assistance is sometimes possible. An estimated 50% of males with Klinefelter syndrome can produce sperm.The term "hypogonadism" in XXY symptoms is often misinterpreted to mean "small testicles", when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism. Despite this misunderstanding of the term, however, XXY men may also have microorchidism (i.e., small testicles).The testicles of affected males are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4 ml in volume.XXY males are more likely than other men to have certain health problems, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. In contrast to these potentially increased risks, rare X-linked recessive conditions are thought to occur less frequently in XXY males than in XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.

Cognitive and developmental
Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be overcome through early intervention. Also, delays in motor development may occur, which can be addressed through occupational and physical therapies. XXY males may sit up, crawl, and walk later than other infants; they may also struggle in school, both academically and with sports. It is estimated that 10% of those with Klinefelter syndrome are autistic.Additional abnormalities may include impaired attention, reduced organizational and planning abilities, deficiencies in judgment (often presented as a tendency to interpret non-threatening stimuli as threatening), and dysfunctional decision processing.Compared to individuals with a normal number of chromosomes,  males affected by Klinefelters syndrome may display behavioral abnormalities. These are phenotypically displayed as higher level of anxiety and depression, and mood dysregulation. These neurocognitive abnormalities are most likely due to the presence of the extra X chromosome, as indicated by studies carried out on animal models carrying an extra X chromosome.

Cause
Klinefelter syndrome is not an inherited condition. Maternal age is the only known risk factor. Women at 40 years have a four times higher risk for a child with Klinefelter syndrome than women aged 24 years.The extra chromosome is retained because of a nondisjunction event during paternal meiosis I, maternal meiosis I, or maternal meiosis II (gametogenesis). The relevant nondisjunction in meiosis I occurs when homologous chromosomes, in this case the X and Y or two X sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome or an egg with two X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY offspring (Klinefelter). Fertilizing a double X egg with a normal sperm also produces an XXY offspring (Klinefelter).Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction occurs when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced, which when fertilized with a Y sperm, yields an XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about one in 500 live male births. See also Triple X syndrome.
In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males, as well as normal XX females. However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes have corresponding genes on their Y chromosome and are capable of being expressed.

Variations
The condition 48,XXYY or 48,XXXY occurs in one in 18,000–50,000 male births. The incidence of 49,XXXXY is one in 85,000 to 100,000 male births. These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, and other anomalies.About 15–20% of males with KS may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often, symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges. Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only about 10 cases of 47,XXY/46,XX have been described in literature.Analogous XXY syndromes are known to occur in cats—specifically, the presence of calico or tortoiseshell markings in male cats is an indicator of the relevant abnormal karyotype. As such, male cats with calico or tortoiseshell markings are a model organism for KS, because a color gene involved in cat tabby coloration is on the X chromosome.

Random X-inactivation
Women typically have two X chromosomes, with half of their X chromosomes switching off early in embryonic development. The same happens with people with Klinefelters, including in both cases a small proportion of individuals with a skewed ratio between the two Xs.

Diagnosis
The standard diagnostic method is the analysis of the chromosomes karyotype on lymphocytes. A small blood sample is sufficient as test material. In the past, the observation of the Barr body was common practice, as well. To investigate the presence of a possible mosaicism, analysis of the karyotype using cells from the oral mucosa is performed. Physical characteristics of a Klinefelter syndrome can be tall stature, low body hair, and occasionally an enlargement of the breast. Usually, a small testicle volume of 1–5 ml per testicle (standard values: 12–30 ml) occurs. During puberty and adulthood, low testosterone levels with increased levels of the pituitary hormones FSH and LH in the blood can indicate the presence of Klinefelter syndrome. A spermiogram can also be part of the further investigation. Often. an azoospermia is present, or rarely an oligospermia. Furthermore, Klinefelter syndrome can be diagnosed as a coincidental prenatal finding in the context of invasive prenatal diagnosis (amniocentesis, chorionic villus sampling). About 10% of KS cases are found by prenatal diagnosis.The symptoms of KS are often variable, so a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long arms/legs, developmental delay, speech/language deficits, learning disabilities/academic issues, and/or behavioral issues are present in an individual.

Treatment
As the genetic variation is irreversible, no causal therapy is available. From the onset of puberty, the existing testosterone deficiency can be compensated by appropriate hormone-replacement therapy. Testosterone preparations are available in the form of syringes, patches, or gel. If gynecomastia is present, the surgical removal of the breast may be considered for both the psychological reasons and to reduce the risk of breast cancer.The use of behavioral therapy can mitigate any language disorders, difficulties at school, and socialization. An approach by occupational therapy is useful in children, especially those who have dyspraxia.

Infertility treatment
Methods of reproductive medicine, such as intracytoplasmic sperm injection (ICSI) with previously conducted testicular sperm extraction (TESE), have led to men with Klinefelter syndrome producing biological offspring. By 2010, over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with KS.

Prognosis
The lifespan of individuals with Klinefelter syndrome appears to be reduced by around 2.1 years compared to the general male population. These results are still questioned data, are not absolute, and need further testing.

Epidemiology
This syndrome, evenly distributed in all ethnic groups, has a prevalence of approximately four subjects per every 10,000 (0.04%) males in the general population. However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives. The rate of Klinefelter syndrome among infertile males is 3.1%. The syndrome is also the main cause of male hypogonadism.

History
The syndrome was named after American endocrinologist Harry Klinefelter, who in 1942 worked with Fuller Albright and E. C. Reifenstein at Massachusetts General Hospital in Boston, Massachusetts, and first described it in the same year. The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used </s>


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<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 Hypodysfibrinogenemia and can you explain it in depth? [/INST] Hypodysfibrinogenemia, also termed congenital hypodysfibrinogenemia, is a rare hereditary fibrinogen disorder cause by mutations in one or more of the genes that encode a factor critical for blood clotting, fibrinogen. These mutations result in the production and circulation at reduced levels of fibrinogen at least some of which is dysfunctional.  Hypodysfibrinogenemia exhibits reduced penetrance, i.e. only some family members with the mutated gene develop symptoms.The disorder is similar to a form of dysfibrinogenemia termed congenital dysfibrinogenemia. However, congenital dysfibrinogenemia differs form hypodysfibrinogenemia in four ways. Congenital dysfibrinogenemia involves: the circulation at normal levels of fibrinogen at least some of which is dysfunctional; a different set of causative gene mutations; a somewhat different mix of clinical symptoms; and a much lower rate of penetrance.Hypodysfibrinogenemia causes episodes of pathological bleeding and thrombosis due not only to low levels of circulating fibrinogen but also to the dysfunction of a portion of the circulating fibrinogen. The disorder can lead to very significant bleeding during even minor surgical procedures and women afflicted with the disorderoften suffer significant bleeding during and after giving child birth, higher rates of miscarriages, and menorrhagia, i.e. abnormally heavy bleeding during the menstrual period.

Presentation
In a study of 32 individuals diagnosed with hypodysfibrinogenemia, 41% presented with episodic bleeding, 43% presented with episodic thrombosis, and 16% were asymptomatic, being detected by abnormal blood tests. Bleeding and thrombosis generally begin in adulthood with the average age at the time of presentation and diagnosis being 32 years. Bleeding is more frequent and severe in women of child-bearing age; these women may suffer miscarriages, menometrorrhagia, and excessive bleeding during child birth and/or the postpartum period. Excessive bleeding following major or minor surgery, including dental extractions, occurs in both females and males with the disorder. Thrombotic complications of the disorder are often (~50%) recurrent and can involve central and peripheral arteries, deep and superficial veins. Thrombotic events may be serious and involve occlusion of a cerebral artery leading to stroke, splanchnic venous thrombosis, and pulmonary thrombosis presumptively secondary to deep vein thrombosis.

Fibrinogen
Circulating fibrinogen is a glycoprotein made of two trimers each of which is composed of three polypeptide chains, Aα (also termed α) encoded by the FGA gene, Bβ (also termed β) encoded by the FGB gene, and γ encoded by the FGG gene. All three genes are located on the long or "q" arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively) and are the sites where mutations occur that code for a dysfunctional fibrinogen and/or reduced fibrinogen levels which are the cause of congenital hypodysfibrinogenemia.

Pathophysiology
Congenital hypodysfibrinogenemia is inherited as an autosomal dominant disorder caused by at least 32 different types of single mutations. Ten of these mutations are in the fibrinogen alpha chain gene (also termed the FGA gene), 5 in the fibrinogen beta chain gene (also termed the FGB gene), and 17 in the fibrinogen gamma chain gene (also termed the FGG gen). The mutations are mainly missense mutations with nonsense and Frameshift mutations each occurring in 12.5% of cases. The causes of two fibrinogen abnormalities that characterize hypodysfibrinogenemia, i.e. circulation at reduced levels of fibrinogen at least some of which is dysfunctional, reflect different molecular mechanisms:
A heterozygous mutation in one of the two copies of either the FGA, FGB, or FGG gene leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Vlissingen, fibrinogen Philadelphia, and fibrinogen Freiburg.
A homozygous mutation in both copies of one of the cited genes leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Otago,  fibrinogen Marburg, and fibrinogen Sfax.
Two different mutations (see Compound heterozygosity) occur in each of the two copies of one of the cited genes, with one mutation coding for reduced formation of a functionally normal circulating fibrinogen and the second mutation coding for the circulation of a dysfunctional fibrinogen, e.g. fibrinogen Leipzig.
Two different mutations occur in one copy of the cited genes, with one mutation causing hypofibrinogenemia and the other mutation coding for a dysfunctional fibrinogen, e.g. fibrinogen Keokuk.The following Table adds further information on the just cited examples of hypodysfibrinogenemias. The Table gives: a) each mutated proteins trivial name; b) the gene mutated (i.e. FGA, FGB, or FGG), its mutation site (i.e. numbered nucleotide in the cloned gene), and name of the nucleotides (i.e. C, T, A, G) at these sites before>after the mutation; c) the name of the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using standard abbreviations) occurring before-after the mutation at the numbered amino acid(s) sites in the circulating mutated fibrinogen; d) the pathophysiology for the mutated fibrinogens misfunction(s); and e) the clinical consequence(s) of the mutation. Unless noted as a deletion (del) or frame shift (fs), all mutations are missense or nonsense mutations. A nonsense mutation causing a premature stop codon and thereby a shorten polypeptide chain is notated by an X (PSC) after the altered amino acid codon.

Diagnosis
Hypodysfibrinogenemia is usually diagnosed in individuals who: have a history of abnormal bleeding or thrombosis or are a close blood relative of such an individual. Initial laboratory findings include a decrease in serum fibrinogen mass levels as measured by immunoassay plus a reduction in inducible blood clot formation so that the ratio of functionally-detected fibrinogen mass (i.e. detected in induced clots) to immunoassay-detected fibrinogen mass is abnormally low, i.e </s>


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<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 Osteodystrophy 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 Pituicytoma and can you explain it in depth? [/INST]  </s>


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<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 Macrognathism 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 Physical urticaria and can you explain it in depth? [/INST] Physical urticaria is a distinct subgroup of the urticaria that are induced by an exogenous physical stimulus rather than occurring spontaneously. There are seven subcategories that are recognized as independent diseases </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 Lafora disease and can you explain it in depth? [/INST] Lafora disease is a rare, adult-onset and autosomal recessive genetic disorder which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of inclusion bodies, known as Lafora bodies, within the cytoplasm of the cells in the heart, liver, muscle, and skin.: 545  Lafora disease is also a neurodegenerative disease that causes impairment in the development of cerebral cortical neurons and is a glycogen metabolism disorder.
Lafora disease (LD) was described by the Spanish Neuropathologist Gonzalo Rodríguez Lafora (1886-1971) in 1911, while directing the Neuropathology Section at the Government Hospital for Mental Insane (current NIH, USA)
Gonzalo Rodríguez Lafora was a disciple of Santiago Ramón y Cajal (Nobel laureate in Physiology or Medicine 1906) and one of the most brilliant exponents of the Cajal School or the Spanish Neurological School.
Typically Lafora is very rare in children, adolescents and adults worldwide. However, Lafora disease has a higher incidence among children and adolescents with ancestry from regions where incestuous relationships are common, namely the Mediterranean (North Africa, Southern Europe), the Middle East, India, and Pakistan.  Dogs can also have the condition. In canines, Lafora disease can spontaneously occur in any breed, but the Miniature Wire Haired Dachshund, Bassett Hound, and the Beagle are predisposed to LD.Most human patients with this disease do not live past the age of twenty-five, and death within ten years of symptoms is usually inevitable. Late onset symptoms of this disease can begin at any age depending on the genes affected. At present, there is no cure for this disease but there are ways to deal with symptoms through treatments and medications.

Signs and symptoms
Symptoms of Lafora disease begin to develop during the early adolescent years, and symptoms progress as time passes. In the years before then, there is generally no indication of the presence of the disease, though in a few cases, the disease presents as a learning disorder around 5 years of age. In extremely rare cases, symptoms may not show at all until as late as the 3rd decade of life, though these cases have slower progression than typical LD. The most common feature of Lafora disease is seizures that have been reported mainly as occipital seizures and myoclonic seizures with some cases of generalized tonic-clonic seizures, atypical absence seizures, and atonic and complex partial seizures. Other symptoms common with the seizures are drop attacks, ataxia, temporary blindness, visual hallucinations, and a quickly-developing and dramatic dementia.Other common signs and symptoms associated with Lafora disease are behavioral changes due to the frequency of seizures. Over time those affected with Lafora disease have brain changes that cause confusion, speech difficulties, depression, decline in intellectual function, impaired judgement and impaired memory. If areas of the cerebellum are affected by seizures, it is common to see problems with speech, coordination, and balance in Lafora patients.For dogs that are affected with Lafora disease, common symptoms are rapid shuddering, shaking, or jerking of the canines head backwards, high pitched vocalizations that could indicate the dog is panicking, seizures, and as the disease progresses dementia, blindness, and loss of balance.Within ten years of developing symptoms, life expectancy has known to go down. People who advance to adulthood tend to lose their ability to do daily tasks by themselves, which can lead them to having to have comprehensive care. If their symptoms have become onset extremely fast or at an early age, comprehensive care allows one to get treatment in ways that are not only regarding receiving their medication, but it also includes both physical and mental health towards the daily activities that one would normally perform by themselves.

Genetics
Lafora disease is an autosomal recessive disorder, caused by loss of function mutations in either laforin glycogen phosphatase gene (EPM2A) or malin E3 ubiquitin ligase gene (NHLRC1). These mutations in either of these two genes lead to polyglucosan formation or lafora body formation in the cytoplasm of heart, liver, muscle, and skin.Graph 1 shows the data for 250 families that have been affected by Lafora Disease and the distribution of cases around the world. The graph shows that there is a very large number of cases in Italy because of the EPM2A gene mutation compared to any other country in the world.

Graph 2 shows the percentage distribution of the cases from either an EPM2A gene mutation or an EPM2B (NHLRC1) gene mutation. 42% of the cases are caused by EPM2A and 58% are caused by EPM2B (NHLRC1). The most common mutation on the EPM2A gene is the R241X mutation. This genetic mutation is the cause for 17% of the EPM2A caused Lafora Disease cases.EPM2A codes for the protein laforin, a dual-specificity phosphatase that acts on carbohydrates by taking phosphates off.NHLRC1 encodes the protein malin, an E3 ubiquitin ligase, that regulates the amount of laforin.Laforin is essential for making the normal structure of a glycogen molecule. When the mutation occurs on the EPM2A gene, laforin protein is down-regulated and less amount of this protein is present or none is made at all. If there is also a mutation in the NHLRC1 gene that makes the protein malin, then laforin cannot be regulated and thus less of it is made.

Less Laforin means more phosphorylation of glycogen, causing conformational changes, rendering it insoluble, leading to an accumulation of misformed glycogen, which has neurotoxic effects.
In a laforin mutation, glycogen would be hyperphosphorylated; this has been confirmed in laforin knock-out mice.Research literature also suggests that over-activity of glycogen synthase, the key enzyme in synthesizing glycogen, can lead to the formation of polyglucosans and it can be inactivated by phosphorylation at various amino acid residues by many molecules, including GSK-3beta, Protein phosphatase 1, and malin.As defective enzyme molecules participate in the production of these molecules (GSK-3beta, PP1, and malin), excessive glycogen synthase activity occurs in combination with mutations in laforin that phosphorylates the excess glycogen being made, rendering it insoluble. The key player missing is ubiquitin. It is not able to degrade the excess amount of the insoluble lafora bodies. Since mutations arise in malin, an e3 ubiquitin ligase, this directly interferes with the degradation of laforin, causing the laforin not to be degraded; it can then hyperphosphorylate.

Lafora bodies
Lafora disease is distinguished by the presence of inclusions called Lafora bodies within the cytoplasm of cells. Lafora bodies are aggregates of polyglucosans or abnormally shaped glycogen molecules. Glycogen in Lafora disease patients has abnormal chain lengths, which causes them to be insoluble, accumulate, and have a neurotoxic effect.For glycogen to be soluble, there must be short chains and a high frequency of branching points, but this is not found in the glycogen in Lafora patients. LD patients have longer chains that have clustered arrangement of branch points that form crystalline areas of double helices making it harder for them to clear the blood-brain barrier. The glycogen in LD patients also has higher phosphate levels and is present in greater quantities.

Diagnosis
Lafora Disease is diagnosed by conducting a series of tests by a neurologist, epileptologist (person who specializes in epilepsy), or geneticist. To confirm the diagnosis, an EEG, MRI, and genetic testing are needed. A biopsy may be necessary as well to detect and confirm the presence of Lafora bodies in the skin. Typically, if a patient comes to a doctor and has been having seizures, as patients with LD characteristically have, these are the standard screening tests.

Epidemiology
All the reports that have been published on Lafora Disease have shown that the overall prevalence of the disease is about 4 cases per million individuals around the world. Due to Laforas disease (LD) being so rare, there have been very few case series documented. The prevalence of Lafora Disease varies throughout the world because of the differing customs of each country that it is present in. It is much more prevalent in countries that have higher cases of inbreeding. Usually, these locations are generally more isolated from the world at large. In the western countries the prevalence of Lafora Disease is much lower because of the greater city size and less isolated communities that would participate in inbreeding.

Treatment
Unfortunately there is no cure for Lafora Disease with treatment being limited to controlling seizures through anti-epileptic and anti-convulsant medications. The treatment is usually based on the individuals specific symptoms and the severity of those symptoms. Some examples of medications include valproate, levetiracetam, topiramate, benzodiazepines, or perampanel. Although the symptoms and seizures can be controlled for a long period by using anti-epileptic drugs, the symptoms will progress and patients lose their ability to perform daily activities leading to the survival rate of approximately 10 years after symptoms begin. Quality of life worsens as the years go on, with some patients requiring a feeding tube so that they can get the nutrition and medication they need in order to keep living, but not necessarily functioning. Recently Metformin is approved for the treatment.
Due to the severity of Laforas disease being exceedingly rare, it is recommended to contact a specialist, such as one specialized in genetics, as well as looking into universities and other medical centers around because they will have the most up to date technology.

Research
The disease is named after Gonzalo Rodríguez Lafora (1886–1971), a Spanish neuropathologist who first recognized small inclusion bodies in Lafora patients. Since the discovery of Lafora Disease in early to mid 1900s there has not been too much research into it, until more recent years.
An approach to studying this rare disease would be performing a case-control study </s>


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<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 Leber congenital amaurosis and can you explain it in depth? [/INST] Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.It affects about 1 in 40,000 newborns. LCA was first described by Theodor Leber in the 19th century. It should not be confused with Lebers hereditary optic neuropathy, which is a different disease also described by Theodor Leber.
One form of LCA was successfully treated with gene therapy in 2008.

Signs and symptoms
The term congenital refers to a condition present from birth (not acquired) and amaurosis refers to a loss of vision not associated with a lesion. However, beyond these general descriptions, the presentation of LCA can vary, because it is associated with multiple genes.LCA is typically characterized by nystagmus, sluggish or absent pupillary responses, and severe vision loss or blindness.

Genetics
It is usually autosomal recessive; however, importantly for family planning, it is sometimes autosomal dominant. It is a disorder thought to be caused by abnormal development of photoreceptor cells.OMIM currently recognizes 18 types of LCA.
The gene CEP290 has been associated with Joubert syndrome, as well as type 10 LCA.

Diagnosis
Genetic tests and related research are currently being performed at Centogene AG in Rostock, Germany; John and Marcia Carver Nonprofit Genetic Testing Laboratory in Iowa City, IA; GENESIS Center for Medical Genetics in Poznan, Poland; Miraca Genetics Laboratories in Houston, TX; Asper Biogene in Tartu, Estonia; CGC Genetics in Porto, Portugal; CEN4GEN Institute for Genomics and Molecular Diagnostics in Edmonton, Canada; and Reference Laboratory Genetics - Barcelona, Spain.

Treatment
One form of LCA, in patients with LCA2 bearing a mutation in the RPE65 gene, has been successfully treated in clinical trials using gene therapy. The results of three early clinical trials were published in 2008 demonstrating the safety and efficacy of using adeno-associated virus to deliver gene therapy to restore vision in LCA patients. In all three clinical trials, patients recovered functional vision without apparent side effects. These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.The results of a phase 1 trial conducted by the University of Pennsylvania and Children’s Hospital of Philadelphia and published in 2009 showed sustained improvement in 12 subjects (ages 8 to 44) with RPE65-associated LCA after treatment with AAV2-hRPE65v2, a gene replacement therapy. Early intervention was associated with better results. In that study, patients were excluded based on the presence of particular antibodies to the vector AAV2 and treatment was only administered to one eye as a precaution. A 2010 study testing the effect of administration of AAV2-hRPE65v2 in both eyes in animals with antibodies present suggested that immune responses may not complicate use of the treatment in both eyes. On 19 December 2017, the U.S. Food and Drug Administration approved voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy for children and adults with biallelic RPE65 gene mutations responsible for retinal dystrophy, including Leber congenital amaurosis. Patients must have viable retinal cells as a prerequisite for the intraocular administration of Luxturna.Retina surgeon Dr. Albert Maguire and gene therapy expert Dr. Jean Bennett developed the technique used by the Childrens Hospital.Dr. Sue Semple-Rowland at the University of Florida has recently restored sight in an avian model using gene therapy.In March 2020, doctors at the Casey Eye Institute of the Oregon Health & Science University injected a CRISPR-modified virus into a patients eye in an attempt to treat LCA10.

Popular culture
In the episode "The Blackout in the Blizzard" (season 6, episode 16) of the television drama Bones, Dr. Jack Hodgins and his pregnant wife Angela Montenegro, who is an LCA carrier, have to wait during a citywide blackout for Hodginss genetic test results, to see if he is also an LCA carrier. He does indeed turn out to be a carrier, giving their unborn child a 25% chance of having LCA.
In the television series ER (season 14, episode 12 "Believe the Unseen") Dr. Abby Lockhart diagnoses a young foster girl with Leber congenital amaurosis. The girl to this point hid her condition from her foster families. The episode contains some information about symptoms, clinical diagnosis and mentions gene replacement therapy and clinical trials as hope for help in managing the condition.
In the Korean drama The King of Dramas (episode 16, "In Search of Lost Time") Anthony Kim, played by Kim Myung-min, is diagnosed with Leber congenital amaurosis, the same disease that made his mother blind.
Four-year-old Gavin who suffers from a form of LCA was made famous in 2013 by a YouTube video showing him using his white cane for the first time to navigate down a curb. He later appeared on the TV show Little Big Shots.

See also
Visual cycle

References
Further reading
Gambino, Megan (December 17, 2008). "Jocelyn Kaiser on Gene Therapy in a New Light" </s>


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Signs and symptoms
This benign patch appears on the skin at birth or in early childhood. In most people these are under 10 centimeters (3.9 in) in size. If there is doubt about the diagnosis, rubbing the area causes the skin around the lesion to become red while the lesion itself does not change in color </s>


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<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 Pelvic girdle pain and can you explain it in depth? [/INST] Pelvic girdle pain (abbreviated PGP) can be described as a pregnancy discomfort for some women and a severe disability for others. PGP can cause pain, instability and limitation of mobility and functioning in any of the three pelvic joints. PGP has a long history of recognition, mentioned by Hippocrates and later described in medical literature by Snelling.
The affection appears to consist of relaxation of the pelvic articulations, becoming apparent suddenly after parturition or gradually during pregnancy and permitting a degree of mobility of the pelvic bones which effectively hinders locomotion and gives rise to the most peculiar and alarming sensations.

Classification
Prior to the 20th century, specialists of pregnancy-related PGP used varying terminologies. It is now referred to as Pregnancy Related Pelvic Girdle Pain that may incorporate the following conditions:

Diastasis of the symphysis pubis (DSP)
Symphysis pubis dysfunction (SPD)
Pelvic Joint Syndrome
Physiological Pelvic Girdle Relaxation
Symptom Giving Pelvic Girdle Relaxation
Posterior Pelvic Pain
Pelvic Arthropathy
Inferior Pubic Shear/ Superior Pubic Shear /Symphyseal Shear
Symphysiolysis
Osteitis pubis (usually postpartum)
Sacroiliitis
One-sided Sacroiliac Syndrome /Double Sided Sacroiliac Syndrome
Hypermobility"The classification between hormonal and mechanical pelvic girdle instability is no longer used. For treatment and/or prognosis it makes no difference whether the complaints started during pregnancy or after childbirth." Mens (2005)

Signs and symptoms
A combination of postural changes, baby, unstable pelvic joints under the influence of pregnancy hormones, and changes in the centre of gravity can all add to the varying degrees of pain or discomfort. In some cases it can come on suddenly or following a fall, sudden abduction of the thighs (opening too wide too quickly) or an action that has strained the joint.
PGP can begin as early as the first trimester of pregnancy. Pain is usually felt low down over the symphyseal joint, and this area may be extremely tender to the touch. Pain may also be felt in the hips, groin and lower abdomen and can radiate down the inner thighs. Women with PGP may begin to waddle or shuffle, and may be aware of an audible clicking sound coming from the pelvis. PGP can develop slowly during pregnancy, gradually gaining in severity as the pregnancy progresses.
During pregnancy and postpartum, the symphyseal gap can be felt moving or straining when walking, climbing stairs or turning over in bed; these activities can be difficult or even impossible. The pain may remain static, e.g., in one place such as the front of the pelvis, producing the feeling of having been kicked; in other cases it may start in one area and move to other areas. It is also possible that a woman may experience a combination of symptoms.
Any weight bearing activity has the potential of aggravating an already unstable pelvis, producing symptoms that may limit the ability of the woman to carry out many daily activities. She may experience pain involving movements such as dressing, getting in and out of the bath, rolling in bed, climbing the stairs or sexual activity. Pain may also be present when lifting, carrying, pushing or pulling.
The symptoms (and their severity) experienced by women with PGP vary, but include:

Present swelling and/or inflammation over joint.
Difficulty lifting leg.
Pain pulling legs apart.
Inability to stand on one leg.
Inability to transfer weight through pelvis and legs.
Pain in hips and/or restriction of hip movement.
Transferred nerve pain down leg.
Can be associated with bladder and/or bowel dysfunction.
A feeling of the symphysis pubis giving way.
Stooped back when standing.
Malalignment of pelvic and/or back joints.
Struggle to sit or stand.
Pain may also radiate down the inner thighs.
Waddling or shuffling gait.
Audible clicking sound coming from the pelvis.

Severity
The severity and instability of the pelvis can be measured on a three level scale.
Pelvic type 1:The pelvic ligaments support the pelvis sufficiently. Even when the
muscles are used incorrectly, no complaints will occur when performing everyday activities. This is the most common situation in persons who have never been pregnant, who have never been in an accident, and who are not hypermobile.
Pelvic type 2:The ligaments alone do not support the joint sufficiently. A
coordinated use of muscles around the joint will compensate for ligament weakness. In case the muscles around the joint do not function, the patient will experience pain and weakness when performing everyday activities. This type often occurs after giving birth to a child weighing 3000 grams or more, in cases of hypermobility, and sometimes after an accident involving the pelvis. Type 2 is the most common form of pelvic instability. Treatment is based on learning how to use the muscles around the pelvis more efficiently.
Pelvic type 3:The ligaments do not support the joint sufficiently. This is a serious
situation whereby the muscles around the joint are unable to compensate for ligament weakness. This type of pelvic instability usually only occurs after an accident, or occasionally after a (small) accident in combination with giving birth. Sometimes a small accident occurring long before giving birth is forgotten so that the pelvic instability is attributed only to the childbirth. Although the difference between Type 2 and 3 is often difficult to establish, in case of doubt an exercise program may help the patient. However, if Pelvic Type 3 has been diagnosed then invasive treatment is the only option: in this case parts of the pelvis are screwed together. (Mens 2005)

Psychosocial impact
PGP in pregnancy seriously interferes with participation in society and activities of daily life; the average sick leave due to posterior pelvic pain during pregnancy is 7 to 12 weeks.In some cases women with PGP may also experience emotional problems such as anxiety over the cause of pain, resentment, anger, lack of self-esteem, frustration and depression; she is three times more likely to develop postpartum depressive symptoms. Other psychosocial risk factors associated with woman experiencing PGP include higher level of stress, low job satisfaction and poorer relationship with spouse.

Causes
Sometimes there is no obvious explanation for the cause of PGP but usually there is a combination of factors such as:

The pelvic joints moving unevenly.
A change in the activity of the muscles in the pelvis, hip, abdomen, back and pelvic floor.
A history of pelvic trauma.
The position of the baby altering the loading stresses on the pelvic ligaments and joints.
Strenuous work.
Previous lower back pain.
Previous pelvic girdle pain during pregnancy.
Hypermobility, genetical ability to stretch joints beyond normal range.
An event during the pregnancy or birth that caused injury or strain to the pelvic joints or rupture of the fibrocartilage.
The occurrence of PGP is associated with twin pregnancy, first pregnancy and a higher age at first pregnancy.

Mechanism
Pregnancy related Pelvic Girdle Pain (PGP) can be either specific (trauma or injury to pelvic joints or genetical i.e. connective tissue disease) and non-specific. PGP disorder is complex and multi-factorial and likely to be also represented by a series of sub-groups driven by pain varying from peripheral or central nervous system,
altered laxity/stiffness of muscles, laxity to injury of tendinous/ligamentous structures to mal-adaptive body mechanics.Pregnancy begins the physiological changes through a pattern of hormonal secretion and signal transduction thus initiating the remodelling of soft tissues, cartilage and ligaments. Over time, the ligaments could be stretched either by injury or excess strain and in turn may cause PGP.

Anatomy
The pelvis is the largest bony part of the skeleton and contains three joints: the pubic symphysis, and two sacroiliac joints. A highly durable network of ligaments surrounds these joints giving them tremendous strength.
The pubic symphysis has a  fibrocartilage joint which may contain a fluid filled cavity and is avascular; it is supported by the superior and arcuate ligaments. The sacroiliac joints are synovial, but their movement is restricted throughout life and they are progressively obliterated by adhesions. The nature of the bony pelvic ring with its three joints determines that no one joint can move independently of the other two.

Relaxin hormone
Relaxin is a hormone produced mainly by the corpus luteum of the ovary and breast, in both pregnant and non-pregnant females. During pregnancy it is also produced by the placenta, chorion, and decidua. The body produces relaxin during menstruation that rises to a peak within approximately 14 days of ovulation and then declines. In pregnant cycles, rather than subsiding, relaxin secretion continues to rise during the first trimester and then again in the final weeks. During pregnancy relaxin has a diverse range of effects, including the production and remodelling of collagen thus increasing the elasticity of muscles, tendons, ligaments and tissues of the birth canal in view of delivery.
Although relaxins main cellular action in pregnancy is to remodel collagen by biosynthesis (thus facilitating the changes of connective tissue) it does not seem to generate musculoskeletal problems. European Research has determined that relaxin levels are not a predictor of PGP during pregnancy.

Gait changes
The pregnant woman has a different pattern of "gait". The step lengthens as the pregnancy progresses due to weight gain and changes in posture. Both the length and height of the footstep shortens with PGP. Sometimes the foot can turn inwards due to the rotation of the hips when the pelvic joints are unstable. On average, a womans foot can grow by a half size or more during pregnancy. Pregnancy hormones that are released to adapt the bodily changes also remodel the ligaments in the foot. In addition, the increased body weight of pregnancy, fluid retention and weight gain lowers the arches, further adding to the foots length and width. There is an increase of load on the lateral side of the foot and the hind foot. These changes may also be responsible for the musculoskeletal complaints of lower limb pain in pregnant women.
During the motion of walking, an upward movement of the pelvis, one side then the other, is required to let the leg follow through. The faster or longer each step the pelvis adjusts accordingly. The flexibility within the knees, ankles and hips are stabilized by the pelvis. Normal gait tends to minimize displacement of centre of gravity whereas abnormal gait through pelvic instability tends to amplify displacement. During pregnancy there may be an increased demand placed on hip abductor, hip extensor, and ankle plantar flexor muscles during walking. To avoid pain on weight bearing structures a very short stance phase and limp occurs on the injured side(s), this is called Antalgic Gait.

Treatment
A number of treatments have some evidence for benefits include an exercise program. Paracetamol (acetaminophen) has not been found effective but is safe. NSAIDs are sometimes effective but should not be used after 30 weeks of pregnancy </s>


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