<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 Sydenhams chorea and can you explain it in depth? [/INST] Sydenhams chorea, also known as chorea minor and historically and occasionally referred to as St Vitus dance, is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. Sydenhams chorea is an autoimmune disease that results from childhood infection with Group A beta-haemolytic Streptococcus.  It is reported to occur in 20–30% of people with acute rheumatic fever and is one of the major criteria for it, although it sometimes occurs in isolation. The disease occurs typically a few weeks, but up to 6 months, after the acute infection, which may have been a simple sore throat (pharyngitis).
Sydenhams chorea is more common in females than males and most cases affect children between the ages of 5 and 15 years of age. Adult onset of Sydenhams chorea is comparatively rare, and the majority of the adult cases are recurrences following childhood Sydenhams chorea.

Signs and symptoms
Sydenhams chorea is characterized by the abrupt onset (sometimes within a few hours) of neurologic symptoms, classically chorea, which are non-rhythmic, writhing or explosive involuntary movements.  Usually all four limbs are affected, but there are cases reported where just one side of the body is affected (hemichorea). Typical chorea includes repeated wrist hyperextension, grimacing, lip pouting. The fingers can move as if playing the piano. There may be tongue fasciculations ("bag of worms") and motor impersistence for example the "milk maid sign" (grip strength fluctuates, as if hand milking), or inability to sustain tongue protrusion or eye closure.  There is usually loss of fine motor control, particularly obvious in handwriting if the child is of school age.  Speech is often affected (dysarthria), as is walking; legs will suddenly give way or flick out to one side, giving an irregular gait and the appearance of skipping or dancing. Underlying the abnormal movements is often low tone (hypotonia) which may not become obvious until treatment is started to suppress the chorea.  In severe cases, the loss of tone and weakness predominate (chorea paralyticum).
The severity of the condition can vary from just some instability on walking and difficulty with hand writing, to the extreme of being wholly unable to walk, talk, or eat.
Movements cease during sleep. The eye muscles are not affected, curiously.It is a neuropsychiatric disorder, so besides the motor problems there is classically emotional lability (mood swings, or inappropriate mood), anxiety, attention deficit.  These can precede the motor symptoms.Non-neurologic manifestations of acute rheumatic fever may be present, namely carditis (up to 70% of cases, often subclinical, so echocardiography required), arthritis, erythema marginatum, and subcutaneous nodules.

Differentiating these signs from other involuntary movements such as tics and stereotypies can be difficult, and since these things are not uncommon they can potentially co-exist.  Diagnosis is often delayed and attributed to another condition such as tic disorder or conversion disorder.  The controversial PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) hypothesis has overlapping clinical features but Sydenhams chorea is one of the exclusion criteria.  PANDAS can present with chorea but more typically there are tics, stereotypies with a psychological component (e.g., OCD).

Differential diagnosis
Other disorders that may be accompanied by chorea include benign hereditary chorea, bilateral striatal necrosis, abetalipoproteinemia, ataxia–telangiectasia, biotin-thiamine-responsive basal ganglia disease, Fahr disease, familial dyskinesia–facial myokymia (Bird–Raskind syndrome) due to an ADCY5 gene mutation, glutaric aciduria, Lesch–Nyhan syndrome, mitochondrial disorders, Huntingtons disease, Wilson disease, hyperthyroidism, lupus erythematosus, pregnancy (chorea gravidarum), drug intoxication and side effects of certain anticonvulsants (e.g. phenytoin) or psychotropic agents. Although some of these can similarly present in an acute way, there will typically be other neurological signs (such as ataxia or cognitive impairment), or other disease manifestations, or positive family history, which will help distinguish between them.

Pathology
One of the important manifestations of acute rheumatic fever, Sydenhams chorea is similarly caused by an autoimmune response following infection by group A β-hemolytic streptococci.Two cross reactive streptococcal antigens have been identified, the M protein and N-acetyl-beta-D-glucosamine, whereby infection leads to autoantibodies being produced against host tissues (molecular mimicry) causing a variety of streptococcal related diseases including Sydenhams chorea but also rheumatic heart disease and nephritic syndrome. Autoantibodies against basal ganglia proteins have been found in Sydenhams chorea but these are non-specific. Dopamine receptor autoantibodies have been reported to correlate with clinical symptoms. Whether these antibodies represent an epi-phenomenon or are pathogenic, remains to be proven.

Epidemiology
As with rheumatic fever, Sydenhams chorea is seen more often in less affluent communities, whether in the developing world or in aboriginal communities in the global North.  High rates of impetigo are a marker for widespread streptococcal transmission.

Diagnosis
Chorea is distinctive, if the health care provider is familiar with it.  The diagnosis is then made by the typical acute onset in the weeks following a sore throat or other minor infection, plus evidence of inflammation (raised CRP and/or ESR) and evidence of recent streptococcal infection.
To confirm recent streptococcal infection:

Throat culture
Anti-DNAse B titre (peaks at 8–12 weeks after infection)
Anti-streptolysin O titre (peaks at 3–5 weeks)None of these tests are 100% reliable, particularly when the infection was some months previously.
Further testing is directed more towards alternative diagnoses and other manifestations of rheumatic fever:

Echocardiography
EEG
Lumbar puncture
Magnetic resonance imaging or computed tomography scan of the brain (alterations in caudate nucleus and putaminal enlargement have been described in some patients)

Management
Management of Sydenhams chorea is based on the following principles:

Eliminate the streptococcus – it may not be of any use for the index patient but further spread of that specific clone will be prevented.
Treat the movement disorder
Immunosuppression
Prevention of relapses and further cardiac damage
Manage the disabilityThere is a UFMG rating scale for Sydenhams chorea, from Brazilian Universidade Federal de Minas Gerais (UFMG), for research purposes, but it only looks at motor function not psychiatric/behavioural symptoms.
Occupational therapy and physiotherapy is useful for maintaining function and muscle tone.
Treatment with sodium valproate is effective for controlling symptoms, but it doesn’t speed up recovery. Haloperidol was used previously, but caused serious side effects e.g. tardive dyskinesia. Case reports exist to support carbamazepine and levetiracetam; other drugs tried include pimozide, clonidine, and phenobarbitone.

Immunosuppression
Immunosuppression is used inconsistently in Sydenhams chorea.  The model of an autoimmune disorder would support its use.  One randomized controlled trial of steroids from Paz, Brazil in 2006 (22 cases) showed remission reduced to 54 days from 119 days. Various other reports of use of oral or IV steroids from Israel, Italy and Brazil .  Immunoglobulin has been used in Holland and South Africa. Some improvement can be seen within a few days of IV steroids. In Italy, prednisolone reduced average duration of symptoms from 9 weeks to 4 weeks, and these were severe cases. South African group found less neuropsychiatric complications at 6 months with IVIG treatment (IVIG preferred due to fear of TB reactivation).A course of penicillin is usually given at diagnosis to definitively clear any remaining streptococci, but there is no evidence that this is an effective treatment. Active infection is usually cleared by diagnosis. Penicillin prophylaxis, on the other hand, is essential to treat cardiac features of rheumatic fever, even if subclinical (American Heart Association guideline). If the case is of isolated chorea, it is arguable whether cardiac risk justifies prophylaxis or not, however it is likely to reduce recurrence.
There are several historical case series reporting successful treatment of Sydenhams chorea by inducing fever.

Prognosis
Motor problems including chorea settle within an average of 2–3 months.
Recurrence seen in 16–40% of cases. Recurrence is more likely with poor compliance with penicillin prophylaxis. Intramuscular penicillin is given every 2–3 weeks superior to 4 weekly regime, and oral penicillin is also prescribed.  Recurrences are sometimes associated with rise in ASO titre or other evidence of new streptococcal infection. There is no obvious clinical parameter that might predict those at risk of recurrence. More likely if failure to remit in initial 6 months, can recur with pregnancy (chorea gravidorum).
Higher recurrence rates seen in longest follow up – can recur up to 10 years after the initial episode, so might be underestimated by series with shorter follow up.
Recurrence is usually only chorea, even if the original case was associated with rheumatic fever. There are two total reports of heart disease worsening after recurrence of chorea. The Thailand study also had 2 cases where carditis, which had improved after initial diagnosis, came back again. Some suggest that recurrent chorea is a different disease altogether.10% reported long term tremor in one study (10 years follow up). Long term neuropsychiatric difficulties are increasingly recognized (49 studies so far, especially obsessive-compulsive disorder but also attention-deficit hyperactivity disorder, affective disorders, tic disorders, executive function disturbances, psychotic features, and language impairment).Heart involvement improves in about a third of cases (whether silent or not).[PMID 22734303]

Family support
Sydenhams Chorea Association

History
The incidence of acute rheumatic fever and rheumatic heart disease is not declining. Recent figures quote the incidence of Acute Rheumatic Fever as 0.6–0.7/1,000 population in the United States and Japan compared with 15–21/1,000 population in Asia and Africa </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 Alacrima 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 Dyskinetic cerebral palsy and can you explain it in depth? [/INST] Dyskinetic cerebral palsy (DCP) is a subtype of cerebral palsy (CP) and is characterized by impaired muscle tone regulation, coordination and movement control. Dystonia and choreoathetosis are the two most dominant movement disorders in patients with DCP.

Presentation
In dyskinetic cerebral palsy, both motor and non-motor impairments are present. Motor impairments, such as impaired muscle tone regulations, lack of muscle control and bone deformations are often more severe compared to the other subtypes of CP. Non-motor impairments increase with motor severity. Half of the DCP group shows severe learning disabilities, 51% has epilepsy. Hearing and visual impairments occur frequently, respectively 11% and 45%. Dysarthria or anarthria are also common, so alternative and augmentative communication tools are needed.

Dystonia and choreoathetosis
Dystonia and choreoathetosis mostly occur concurrently in DCP, but they are two independent motor disorders with their own characteristics. Dystonia predominates in most patients.
Dystonia (DYS) is defined by twisting and repetitive movements, abnormal postures due to sustained muscle contractions, and hypertonia. Dystonia is aggravated by voluntary movements and postures, or with stress, emotion or pain. A video of dystonia in a patient with dyskinetic cerebral palsy can be seen here: Dyskinetic cerebral palsy: dystonia on YouTubeChoreoathetosis (CA) is characterized by hyperkinesia (chorea i.e. rapid involuntary, jerky, often fragmented movements) and hypokinesia (athetosis i.e. slower, constantly changing, writhing or contorting movements). A video of choreoathetosis in a patient with dyskinetic cerebral palsy can be seen here: Dyskinetic cerebral palsy: choreoathetosis on YouTube

Clinical patterns
Patients with DCP are more likely to obtain a high level of functional disability. Respectively 12,7% and 49% of the patients were assigned in level IV and V of the Gross Motor Function Classification System (GMFCS). The same trend appeared in manual ability with 21,8% in level IV and 43,6% in level V of the Manual Ability Classification System (MACS). A good correlation between the functional classification scales and the total dystonia level was found, meaning that a higher level of functional disability correlates with a higher dystonia level. The same study showed no associations with choreoathetosis. These results suggest that dystonia typically has a bigger impact on functionality and a larger effect on activity, participation and quality of life than choreoathetosis.As previously mentioned, dystonia predominates in most patients, partly because dystonia is often more noticeable and severe than choreoathetosis. Both increase with activity and are generalized over all body regions with a higher severity in the upper limbs than in the lower limbs. Dystonia has a significantly higher level of severity in the distal parts of the extremities, whereas choreoathetosis is more equally distributed.

Causes
Dyskinetic cerebral palsy could have multiple causes. The majority of the children are born at term and experience perinatal adverse events which can be supported by neuroimaging. Possible causes are perinatal hypoxic-ischaemia and neonatal shock in children born at term or near term. Hyperbilirubinaemia used to be a common contributing factor, but is now rare in high-income countries due to preventive actions. Other aetiological factors are growth retardation, brain maldevelopment, intracranial haemorrhage, stroke or cerebral infections.

Diagnosis
Multiple classification systems using Magnetic Resonance Imaging (MRI) have been developed, linking brain lesions to time of birth, cerebral palsy subtype and functional ability. The overall goal of these studies is to elucidate etiology, timing of injury and pathogenesis of cerebral palsy.Around 70% of patients with DCP show lesions in the cortical and deep grey matter of the brain, more specifically in the basal ganglia and thalamus. However, other brain lesions and even normal-appearing MRI findings can occur, for example white matter lesions and brain maldevelopments. Patients with pure basal ganglia and thalamus lesions are more likely to show more severe choreoathetosis whereas dystonia may be associated with other brain lesions, such as the cerebellum. These lesions occur mostly during the peri- and postnatal period since these regions have a high vulnerability during the late third trimester of the pregnancy. Unfortunately, contemporary imaging is not sophisticated enough to detect all subtle brain deformities and network disorders in dystonia. Research with more refined imaging techniques including diffusion tensor imaging and functional MRI is required.

Prevention
Prevention strategies have been developed for the different risk factors of the specific cerebral palsy subtypes. Primary prevention consists of reducing the possible risk factors. However, when multiple risk factors cluster together, prevention is much more difficult. Secondary preventions may be more appropriate at that time, e.g. prevention of prematurity. Studies showed a reduced risk of cerebral palsy when administering magnesium sulfate to women at risk of preterm delivery.Cooling or therapeutic hypothermia for 72 hours immediately after birth has a significant clinical effect on reducing mortality and severity of neurodevelopmental disabilities in neonates with birth asphyxia. This has been documented for newborns with hypoxic-ischemic encephalopathy.

Management
Measurement
Measuring dystonia and choreoathetosis can be very challenging. It is however crucial to have reliable measurements for the evaluation and effects of targeted management. So far, measurements involved the usage of clinical qualitative assessment scales judged by video observation. The Barry-Albright Dystonia Rating Scale (BADS), the Burke-Fahn-Marsden Dystonia Rating Scale (BFMS) and the Dyskinesia Impairment Scale (DIS) are most commonly used.The BADS was developed and validated to assess secondary dystonia in patients with CP. The BFMS has been validated for use in primary dystonia and is clinically the most used scale in both primary and secondary dystonia. Both the BADS and BFMS do not include scoring for choreoathetosis. The DIS is currently stated as the most sensitive, valid and reliable scale. It has been validated for use in secondary dystonia, as it occurs in patients with DCP. The value lays in its detailed full-body consideration and the differentiation action-rest, proximal-distal limb and duration-amplitude. Moreover, the DIS includes both the evaluation of dystonia and choreoathetosis. Although this scale is currently seen as the gold standard to evaluate patients with DCP in research, substantial time and experience with the current CA and DYS definitions is needed from the rater in scoring dystonia and choreoathetosis.Both the DIS and BFMS can be used as outcome measure in intervention studies such as deep brain stimulation (DBS) or intrathecal baclofen.

Aim of treatment interventions
Dyskinetic cerebral palsy is a non-progressive, non-reversible disease. The current management is symptomatic, since there is no cure. The main goal is to improve daily activity, quality of life and autonomy of the children by creating a timed and targeted management.
The many management options for patients with DCP are not appropriate as standalone treatment but must be seen within an individualized multidisciplinary rehabilitation program.

Medical and rehabilitation interventions
Management options can be subdivided into medical treatment and rehabilitation interventions.
Medical treatment consists of oral medication and surgery. Before using oral drugs, it is important to differentiate between spasticity, dystonia and choreoathetosis since each motor disorder has a specific approach. In general, many oral drugs have low efficacy, unwanted side-effects and variable effects. Oral baclofen and trihexyphenidyl are commonly used to decrease dystonia, although its efficacy is relatively low in most patients. Adverse effects of the latter can include worsening of choreoathetosis. Since dystonia predominates over choreoathetosis in most patients, reducing dystonia allows the possibility of a full expression of choreoathetosis. This suggests that the discrimination of dystonia and choreoathetosis is crucial, since misinterpretations in diagnosing can contribute to the administration of inappropriate medication, causing unwanted effects. Intrathecal baclofen pump (ITB) is often used as an alternative to reduce side-effects of the oral dystonic medication over the whole body and botulinum toxin injections are applied to decrease dystonia in specific muscles or muscle groups </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 Mitochondrial myopathy 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 Cornelia de Lange syndrome and can you explain it in depth? [/INST] Cornelia de Lange syndrome (CdLS) is a genetic disorder. People with this syndrome experience a range of physical, cognitive, and medical challenges ranging from mild to severe. The syndrome has a widely varied phenotype, meaning people with the syndrome have varied features and challenges. The typical features of CdLS include thick or long eyebrows, a small nose, small stature, developmental delay, long or smooth philtrum, thin upper lip and downturned mouth.The syndrome is named after Dutch pediatrician Cornelia Catharina de Lange, who described it in 1933.
It is often termed Brachmann de Lange syndrome or Bushy syndrome and is also known as Amsterdam dwarfism. Its exact incidence is unknown, but it is estimated at 1 in 10,000 to 30,000.

Signs and symptoms
The phenotype of CdLS is highly varied and is described as a spectrum; from Classic CdLS (with a greater number of key features) to mild variations with only a few features. Some people will have a small number of features but dont have CdLS.Key features:

Long and/or thick eyebrows
Short nose
Concave nasal ridge  and/or upturned nasal tip
Long and/or smooth philtrum
Thin upper lip vermilion and/or downturned corners of mouth
Missing fingers or toes
Congenital diaphragmatic herniaOther suggestive features:

Developmental delay and/or intellectual disability
Small prenatal and birth size / weight
Small stature
Microcephaly (prenatally and/or postnatally)
Small hands and/or feet
Short fifth finger
HirsutismThe following health conditions are more common in people with CdLS than in the general population.

Respiratory illness
Heart defects (e.g., pulmonary stenosis, VSD, ASD, coarctation of the aorta)
Hearing impairment
Vision abnormalities (e.g., ptosis, nystagmus, high myopia, hypertropia)
Partial joining of the second and third toes
Incurved 5th fingers (clinodactyly)
Gastroesophageal reflux
Gastrointestinal abnormalities
Musculoskeletal problems
Scoliosis
Social anxiety
Seizures
Cleft palate
Feeding problemsChildren with this syndrome are often found to have long eyelashes, bushy eyebrows and synophrys (joined eyebrows). Body hair can be excessive and affected individuals are often shorter than their immediate family members. They present a characteristic facial phenotype.Children with CdLS often have gastrointestinal tract difficulties, particularly gastroesophageal reflux. Vomiting, intermittent poor appetite, constipation, diarrhea or gaseous distention are known to be a regularity in cases where the GI tract problems are acute. Symptoms may range from mild to severe.
People with CdLS may exhibit behaviours that have been described as "autistic-like," including self-stimulation, aggression, self-injury or strong preference to a structured routine. Behavior problems in CdLS are not inevitable. Many behaviour issues associated with CdLS are reactive (i.e., something happens within the persons body or environment to bring on the behavior) and cyclical (comes and goes). Often, an underlying medical issue, pain, social anxiety, environmental or caregiver stress can be associated with a change behaviour. If pain or a medical issue is the cause, once treated, the behaviour diminishes.
There is evidence for some features of premature aging including the early development of Barrett’s esophagus, osteoporosis present in the teenage years, premature greying of hair and some changes to the skin of the face causing a more aged appearance compared to chronological age.

Causes
The vast majority of cases are thought to be due to spontaneous genetic mutations. It can be associated with mutations affecting the cohesin complex.As of 2018, it was confirmed that 500 genetic mutations have been associated with the condition; occurring on 7 different genes.  In around 30% of cases of CdLS the genetic cause remains undiscovered. The wide variation in phenotype is attributed to a high degree of somatic mosaicism in CdLS as well as the different genes and type of mutations. For this reason people with CdLS can have very different appearance,  abilities,  and associated health issues.
The latter two genes seem to correlate with a milder form of the syndrome.In 2004, researchers at the Childrens Hospital of Philadelphia (United States) and the University of Newcastle upon Tyne (England) identified a gene (NIPBL) on chromosome 5 that causes CdLS when it is mutated. Since then, additional genes have been found (SMC1A, SMC3 and HDAC8, RAD21) that cause CdLS when changed. In July 2012, the fourth "CdLS gene"—HDAC8—was announced.  HDAC8 is an X-linked gene, meaning it is located on the X chromosome. Individuals with CdLS who have the gene change in HDAC8 make up just a small portion of all people with CdLS. Evidence of a linkage at chromosome 3q26.3 is mixed.Genetic alterations associated with CdLS have been identified in genes NIPBL, SMC1A and SMC3 as well as the more recently identified genes RAD21 and HDAC8.  All of these genetic alterations occurring in CdLS patients affect proteins that function in the cohesin pathway.  SMC1A, SMC3 and RAD21 proteins are structural components of the cohesin ring complex. NIPBL is involved in the loading of the cohesin ring onto chromosomes, and HDAC8 deacylates SMC3 to facilitate its function.  The cohesin pathway is involved in cohesion of sister chromatids during mitosis, DNA repair, chromosome segregation and the regulation of developmental gene expression </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 Hereditary gingival fibromatosis and can you explain it in depth? [/INST] Hereditary gingival fibromatosis (HGF), also known as idiopathic gingival hyperplasia, is a rare condition of gingival overgrowth. HGF is characterized as a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of keratinized gingiva. It can cover teeth in various degrees, and can lead to aesthetic disfigurement. Fibrous enlargement is most common in areas of maxillary and mandibular tissues of both arches in the mouth. Phenotype and genotype frequency of HGF is 1:175,000 where males and females are equally affected but the cause is not entirely known. It mainly exists as an isolated abnormality but can also be associated with a multi-system syndrome.

Signs and symptoms
There may or may not be any evidence of history of HGF in the family nor any usage of taking long-term medicines for any particular disease when it comes to diagnosing HGF. There also may or may not be any signs of medical and/or family history of mental retardation, hypertrichosis, nor clinical symptoms that can be associated with gingival enlargement. Although, enlargement of gingiva, interdental papilla, hindered speech, and secondary inflammatory changes taking place in the mouth commonly at the marginal gingiva are all very indicative of this condition. Commonly the patient will have mandibular and maxilliary inflammation and overgrowth as opposed to the traditional pink, firm, and fleshy consistency of healthy gingiva. The patients jaw may also appear distorted because of the gingiva enlargements. Overgrowth of the gingiva can range from slightly covering the surface of teeth or it can even completely cover the surrounding teeth. The patient can also experience damage or loss of teeth.

Obvious signs
Most obvious sign is gingival overgrowth (overgrowth of the gums)
Hindered chewing efficiency and difficulties eating
Increasing mobility of teeth
Abnormally shaped teeth and abnormal movement of teeth
Inflammation and/or swelling of the gums/gingiva
Not necessarily any signs of pain but experiencing pain is possible
Difficulties in speaking, oftentimes can lead to speech disorders
Other dental and oral problems
In some cases, Hereditary Gingival Fibromatosis may cause bleeding from the gums, or gum ulcerations.

Cause
Though much more research needs to be done, researchers have mostly agreed that a mutation in SOS1, son-of-sevenless gene, is responsible for this disease. SOS1 is a guanine nucleotide-exchange factor that functions in the transduction of signals that control cell growth and differentiation. A mutation in the SOS1 gene results in a single nucleotide insertion. Specific linkage studies have localized the mutation for isolated, nonsyndromic autosomal dominant forms of gingival fibromatosis to chromosomes 2 and 5, more specifically 2p21-p22 and 5q13-q22.

Genetic
HGF1 - Caused by a mutation in the SOS1 gene localized on chromosome 2p21-p22HGF2 - Caused by a mutation in the SOS1 gene localized on chromosome 5q13-q22Mutations in the RE1-silencing transcription factor (REST) gene can also cause this syndrome.

Non genetic
HGF may also be caused by unwanted side effects of pharmacological agents like phenytoin, ciclosporin, and some calcium-channel blockers, meaning HGF is a disease that can be drug-induced. However, there is little next to no research done in this area to support the claim.

Inflammation
Hormonal Imbalance
Neoplasia
More commonly associated with an autosomal dominant gene inheritance
Multi-system syndromes: Zimmerman-Laband syndrome, Jones syndrome, Ramon syndrome, Rutherford syndrome, juvenile hyaline fibromatosis, systemic infantile hyalinosis, and mannosidosis
Some unknown causes

Mechanism
Genetic linkage studies are among the most popular methods of study to look at the mechanism of this HGF. Genetic linkage studies have found to localize genetic loci for autosomal dominant forms of HGF to chromosome 2p21-p22 (indicative of HGF1) and chromosome 5q13-q22 (indicative of HGF2). Chromosome 2p21-p22 has been refined to an interval of ~2.3 Mb to construct an integrated physical and genetic map of the 16 genes interval. Here, a mutation is found in sequencing these 16 genes.There is an insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the SOS1 gene, meaning there is a mutation in SOS1. This causes a problem because SOS1 introduces a frameshift mutation and creates a premature stop codon. Also, it can segregate over generations, most commonly four. Once it causes a premature stop codon, the chromosome loses four important proline-rich SH-3 binding domains in the carboxyl-terminal region of the SOS1 protein. As a result, the N-terminal amino acids for SOS1 is fused into a 22–amino acid carboxyl terminus. Researchers claim that this mutation in the SOS1 gene is a probable primary cause of this disease but limited information supports the mechanism of this claim.

Diagnosis
There are very few ways to test a patient for HGF. Currently, the most common way to diagnose a patient is by means of a physical evaluation. The physician can make a physical evaluation of the patient and send them to a dentist or better yet a specialist like a periodontist to evaluate signs of gingival overgrowth, quality of gingiva, inflammation, mechanical difficulties of the mouth, tooth conditions, and any sort of discomfort.Aside from obvious physical symptoms seen in a physical evaluation, molecular tests can be run to check if there is a mutation in the SOS1 gene to confirm the diagnosis. If there is indeed a mutation in this gene coupled with the typical physical symptoms, then it is quite probable that a patient suffers from this disease. Also, looking at family history is also becoming more prominent in aiding to diagnose the patient. Otherwise, researchers are working to find new and better ways to test for the presence of HGF.

Prevention
Since this condition is generally agreed upon to be hereditary, nothing can be done to prevent HGF. However, in some cases where it can develop as a result of rare multi-system syndromes, such as: Zimmerman-Laband, Jones, Ramon Syndrome, Rutherford Syndrome, Juvenile Hyaline Fibromatosis, Systemic Infantile Hyalinosis, and Mannosidosis, it is best for one to simply monitors the possible progression for HGF with regular dental check-ups.If the patients disease is treated by means of surgery, it is recommended that the patient undergoes post-surgical therapies for maintenance and periodic monitoring of gums for the sake of the possibility of re-occurrence of HGF.

Treatment
This disease has not been shown to be life-threatening or the cause of death in patients </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 Zinc and can you explain it in depth? [/INST] Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic table. In some respects, zinc is chemically similar to magnesium: both elements exhibit only one normal oxidation state (+2), and the Zn2+ and Mg2+ ions are of similar size. Zinc is the 24th most abundant element in Earths crust and has five stable isotopes. The most common zinc ore is sphalerite (zinc blende), a zinc sulfide mineral. The largest workable lodes are in Australia, Asia, and the United States. Zinc is refined by froth flotation of the ore, roasting, and final extraction using electricity (electrowinning).
Zinc is an essential trace element for humans and other animals, for plants and for microorganisms and is necessary for prenatal and postnatal development. It is the second most abundant trace metal in humans after iron and it is the only metal which appears in all enzyme classes. Zinc deficiency affects about two billion people in the developing world and is associated with many diseases. In children, deficiency causes growth retardation, delayed sexual maturation, infection susceptibility, and diarrhea. Enzymes with a zinc atom in the reactive center are widespread in biochemistry, such as alcohol dehydrogenase in humans. Consumption of excess zinc may cause ataxia, lethargy, and copper deficiency.
Brass, an alloy of copper and zinc in various proportions, was used as early as the third millennium BC in the Aegean area and the region which currently includes Iraq, the United Arab Emirates, Kalmykia, Turkmenistan and Georgia. In the second millennium BC it was used in the regions currently including West India, Uzbekistan, Iran, Syria, Iraq, and Israel. Zinc metal was not produced on a large scale until the 12th century in India, though it was known to the ancient Romans and Greeks. The mines of Rajasthan have given definite evidence of zinc production going back to the 6th century BC. To date, the oldest evidence of pure zinc comes from Zawar, in Rajasthan, as early as the 9th century AD when a distillation process was employed to make pure zinc. Alchemists burned zinc in air to form what they called "philosophers wool" or "white snow".
The element was probably named by the alchemist Paracelsus after the German word Zinke (prong, tooth). German chemist Andreas Sigismund Marggraf is credited with discovering pure metallic zinc in 1746. Work by Luigi Galvani and Alessandro Volta uncovered the electrochemical properties of zinc by 1800. Corrosion-resistant zinc plating of iron (hot-dip galvanizing) is the major application for zinc. Other applications are in electrical batteries, small non-structural castings, and alloys such as brass. A variety of zinc compounds are commonly used, such as zinc carbonate and zinc gluconate (as dietary supplements), zinc chloride (in deodorants), zinc pyrithione (anti-dandruff shampoos), zinc sulfide (in luminescent paints), and dimethylzinc or diethylzinc in the organic laboratory.

Characteristics
Physical properties
Zinc is a bluish-white, lustrous, diamagnetic metal, though most common commercial grades of the metal have a dull finish. It is somewhat less dense than iron and has a hexagonal crystal structure, with a distorted form of hexagonal close packing, in which each atom has six nearest neighbors (at 265.9 pm) in its own plane and six others at a greater distance of 290.6 pm. The metal is hard and brittle at most temperatures but becomes malleable between 100 and 150 °C. Above 210 °C, the metal becomes brittle again and can be pulverized by beating. Zinc is a fair conductor of electricity. For a metal, zinc has relatively low melting (419.5 °C) and boiling points (907 °C). The melting point is the lowest of all the d-block metals aside from mercury and cadmium; for this reason among others, zinc, cadmium, and mercury are often not considered to be transition metals like the rest of the d-block metals.Many alloys contain zinc, including brass. Other metals long known to form binary alloys with zinc are aluminium, antimony, bismuth, gold, iron, lead, mercury, silver, tin, magnesium, cobalt, nickel, tellurium, and sodium. Although neither zinc nor zirconium is ferromagnetic, their alloy ZrZn2 exhibits ferromagnetism below 35 K.

Occurrence
Zinc makes up about 75 ppm (0.0075%) of Earths crust, making it the 24th most abundant element. Typical background concentrations of zinc do not exceed 1 μg/m3 in the atmosphere; 300 mg/kg in soil; 100 mg/kg in vegetation; 20 μg/L in freshwater and 5 μg/L in seawater. The element is normally found in association with other base metals such as copper and lead in ores. Zinc is a chalcophile, meaning the element is more likely to be found in minerals together with sulfur and other heavy chalcogens, rather than with the light chalcogen oxygen or with non-chalcogen electronegative elements such as the halogens. Sulfides formed as the crust solidified under the reducing conditions of the early Earths atmosphere. Sphalerite, which is a form of zinc sulfide, is the most heavily mined zinc-containing ore because its concentrate contains 60–62% zinc.Other source minerals for zinc include smithsonite (zinc carbonate), hemimorphite (zinc silicate), wurtzite (another zinc sulfide), and sometimes hydrozincite (basic zinc carbonate). With the exception of wurtzite, all these other minerals were formed by weathering of the primordial zinc sulfides.Identified world zinc resources total about 1.9–2.8 billion tonnes. Large deposits are in Australia, Canada and the United States, with the largest reserves in Iran. The most recent estimate of reserve base for zinc (meets specified minimum physical criteria related to current mining and production practices) was made in 2009 and calculated to be roughly 480 Mt. Zinc reserves, on the other hand, are geologically identified ore bodies whose suitability for recovery is economically based (location, grade, quality, and quantity) at the time of determination. Since exploration and mine development is an ongoing process, the amount of zinc reserves is not a fixed number and sustainability of zinc ore supplies cannot be judged by simply extrapolating the combined mine life of todays zinc mines. This concept is well supported by data from the United States Geological Survey (USGS), which illustrates that although refined zinc production increased 80% between 1990 and 2010, the reserve lifetime for zinc has remained unchanged. About 346 million tonnes have been extracted throughout history to 2002, and scholars have estimated that about 109–305 million tonnes are in use.

Isotopes
Five stable isotopes of zinc occur in nature, with 64Zn being the most abundant isotope (49.17% natural abundance). The other isotopes found in nature are 66Zn (27.73%), 67Zn (4.04%), 68Zn (18.45%), and 70Zn (0.61%).Several dozen radioisotopes have been characterized. 65Zn, which has a half-life of 243.66 days, is the least active radioisotope, followed by 72Zn with a half-life of 46.5 hours. Zinc has 10 nuclear isomers, of which 69mZn has the longest half-life, 13.76 h. The superscript m indicates a metastable isotope. The nucleus of a metastable isotope is in an excited state and will return to the ground state by emitting a photon in the form of a gamma ray. 61Zn has three excited metastable states and 73Zn has two. The isotopes 65Zn, 71Zn, 77Zn and 78Zn each have only one excited metastable state.The most common decay mode of a radioisotope of zinc with a mass number lower than 66 is electron capture. The decay product resulting from electron capture is an isotope of copper.
n30Zn + e− → n29CuThe most common decay mode of a radioisotope of zinc with mass number higher than 66 is beta decay (β−), which produces an isotope of gallium.
n30Zn → n31Ga + e− + νe

Compounds and chemistry
Reactivity
Zinc has an electron configuration of [Ar]3d104s2 and is a member of the group 12 of the periodic table. It is a moderately reactive metal and strong reducing agent. The surface of the pure metal tarnishes quickly, eventually forming a protective passivating layer of the basic zinc carbonate, Zn5(OH)6(CO3)2, by reaction with atmospheric carbon dioxide.Zinc burns in air with a bright bluish-green flame, giving off fumes of zinc oxide. Zinc reacts readily with acids, alkalis and other non-metals. Extremely pure zinc reacts only slowly at room temperature with acids. Strong acids, such as hydrochloric or sulfuric acid, can remove the passivating layer and the subsequent reaction with the acid releases hydrogen gas.The chemistry of zinc is dominated by the +2 oxidation state. When compounds in this oxidation state are formed, the outer shell s electrons are lost, yielding a bare zinc ion with the electronic configuration [Ar]3d10. In aqueous solution an octahedral complex, [Zn(H2O)6]2+ is the predominant species. The volatilization of zinc in combination with zinc chloride at temperatures above 285 °C indicates the formation of Zn2Cl2, a zinc compound with a +1 oxidation state. No compounds of zinc in positive oxidation states other than +1 or +2 are known. Calculations indicate that a zinc compound with the oxidation state of +4 is unlikely to exist. Zn(III) is predicted to exist in the presence of strongly electronegative trianions; however, there exists some doubt around this possibility. But in 2021 another compound was reported with more evidence that had the oxidation state of +3 with the formula ZnBeB11(CN)12.Zinc chemistry is similar to the chemistry of the late first-row transition metals, nickel and copper, though it has a filled d-shell and compounds are diamagnetic and mostly colorless. The ionic radii of zinc and magnesium happen to be nearly identical. Because of this some of the equivalent salts have the same crystal structure, and in other circumstances where ionic radius is a determining factor, the chemistry of zinc has much in common with that of magnesium. In other respects, there is little similarity with the late first-row transition metals. Zinc tends to form bonds with a greater degree of covalency and much more stable complexes with N- and S- donors. Complexes of zinc are mostly 4- or 6- coordinate, although 5-coordinate complexes are known.

Zinc(I) compounds
Zinc(I) compounds are very rare. The [Zn2]2+ ion is implicated by the formation of a yellow diamagnetic glass by dissolving metallic zinc in molten ZnCl2.  The [Zn2]2+ core would be analogous to the [Hg2]2+ cation present in mercury(I) compounds. The diamagnetic nature of the ion confirms its dimeric structure. The first zinc(I) compound containing the Zn–Zn bond, (η5-C5Me5)2Zn2.

Zinc(II) compounds
Binary compounds of zinc are known for most of the metalloids and all the nonmetals except the noble gases. The oxide ZnO is a white powder that is nearly insoluble in neutral aqueous solutions, but is amphoteric, dissolving in both strong basic and acidic solutions. The other chalcogenides (ZnS, ZnSe, and ZnTe) have varied applications in electronics and optics. Pnictogenides (Zn3N2, Zn3P2, Zn3As2 and Zn3Sb2), the peroxide (ZnO2), the hydride (ZnH2), and the carbide (ZnC2) are also known. Of the four halides, ZnF2 has the most ionic character, while the others (ZnCl2, ZnBr2, and ZnI2) have relatively low melting points and are considered to have more covalent character.In weak basic solutions containing Zn2+ ions, the hydroxide Zn(OH)2 forms as a white precipitate. In stronger alkaline solutions, this hydroxide is dissolved to form zincates ([Zn(OH)4]2−). The nitrate Zn(NO3)2, chlorate Zn(ClO3)2, sulfate ZnSO4, phosphate Zn3(PO4)2, molybdate ZnMoO4, cyanide Zn(CN)2, arsenite Zn(AsO2)2, arsenate Zn(AsO4)2·8H2O and the chromate ZnCrO4 (one of the few colored zinc compounds) are a few examples of other common inorganic compounds of zinc.Organozinc compounds are those that contain zinc–carbon covalent bonds. Diethylzinc ((C2H5)2Zn) is a reagent in synthetic chemistry. It was first reported in 1848 from the reaction of zinc and ethyl iodide, and was the first compound known to contain a metal–carbon sigma bond.

Test for zinc
Cobalticyanide paper (Rinnmanns test for Zn) can be used as a chemical indicator for zinc. 4 g of K3Co(CN)6 and 1 g of KClO3 is dissolved on 100 ml of water. Paper is dipped in the solution and dried at 100 °C. One drop of the sample is dropped onto the dry paper and heated. A green disc indicates the presence of zinc.

History
Ancient use
The Charaka Samhita, thought to have been written between 300 and 500 AD, mentions a metal which, when oxidized, produces pushpanjan, thought to be zinc oxide. Zinc mines at Zawar, near Udaipur in India, have been active since the Mauryan period (c.  322 and 187 BCE). The smelting of metallic zinc here, however, appears to have begun around the 12th century AD. One estimate is that this location produced an estimated million tonnes of metallic zinc and zinc oxide from the 12th to 16th centuries. Another estimate gives a total production of 60,000 tonnes of metallic zinc over this period. The Rasaratna Samuccaya, written in approximately the 13th century AD, mentions two types of zinc-containing ores: one used for metal extraction and another used for medicinal purposes.

Various isolated examples of the use of impure zinc in ancient times have been discovered. Zinc ores were used to make the zinc–copper alloy brass thousands of years prior to the discovery of zinc as a separate element. Judean brass from the 14th to 10th centuries BC contains 23% zinc.Knowledge of how to produce brass spread to Ancient Greece by the 7th century BC, but few varieties were made. Ornaments made of alloys containing 80–90% zinc, with lead, iron, antimony, and other metals making up the remainder, have been found that are 2,500 years old. A possibly prehistoric statuette containing 87.5% zinc was found in a Dacian archaeological site.The oldest known pills were made of the zinc carbonates hydrozincite and smithsonite. The pills were used for sore eyes and were found aboard the Roman ship Relitto del Pozzino, wrecked in 140 BC.The manufacture of brass was known to the Romans by about 30 BC. They made brass by heating powdered calamine (zinc silicate or carbonate), charcoal and copper together in a crucible. The resulting calamine brass was then either cast or hammered into shape for use in weaponry. Some coins struck by Romans in the Christian era are made of what is probably calamine brass.Strabo writing in the 1st century BC (but quoting a now lost work of the 4th century BC historian Theopompus) mentions "drops of false silver" which when mixed with copper make brass. This may refer to small quantities of zinc that is a by-product of smelting sulfide ores. Zinc in such remnants in smelting ovens was usually discarded as it was thought to be worthless.The Berne zinc tablet is a votive plaque dating to Roman Gaul made of an alloy that is mostly zinc.

Early studies and naming
Zinc was distinctly recognized as a metal under the designation of Yasada or Jasada in the medical Lexicon ascribed to the Hindu king Madanapala (of Taka dynasty) and written about the year 1374. Smelting and extraction of impure zinc by reducing calamine with wool and other organic substances was accomplished in the 13th century in India. The Chinese did not learn of the technique until the 17th century.

Alchemists burned zinc metal in air and collected the resulting zinc oxide on a condenser. Some alchemists called this zinc oxide lana philosophica, Latin for "philosophers wool", because it collected in wooly tufts, whereas others thought it looked like white snow and named it nix album.The name of the metal was probably first documented by Paracelsus, a Swiss-born German alchemist, who referred to the metal as "zincum" or "zinken" in his book Liber Mineralium II, in the 16th century. The word is probably derived from the German zinke, and supposedly meant "tooth-like, pointed or jagged" (metallic zinc crystals have a needle-like appearance). Zink could also imply "tin-like" because of its relation to German zinn meaning tin. Yet another possibility is that the word is derived from the Persian word سنگ seng meaning stone. The metal was also called Indian tin, tutanego, calamine, and spinter.German metallurgist Andreas Libavius received a quantity of what he called "calay" of Malabar from a cargo ship captured from the Portuguese in the year 1596. Libavius described the properties of the sample, which may have been zinc. Zinc was regularly imported to Europe from the Orient in the 17th and early 18th centuries, but was at times very expensive.

Isolation
Metallic zinc was isolated in India by 1300 AD, much earlier than in the West. Before it was isolated in Europe, it was imported from India in about 1600 CE. Postlewayts Universal Dictionary, a contemporary source giving technological information in Europe, did not mention zinc before 1751 but the element was studied before then.Flemish metallurgist and alchemist P. M. de Respour reported that he had extracted metallic zinc from zinc oxide in 1668. By the start of the 18th century, Étienne François Geoffroy described how zinc oxide condenses as yellow crystals on bars of iron placed above zinc ore that is being smelted. In Britain, John Lane is said to have carried out experiments to smelt zinc, probably at Landore, prior to his bankruptcy in 1726.In 1738 in Great Britain, William Champion patented a process to extract zinc from calamine in a vertical retort-style smelter. His technique resembled that used at Zawar zinc mines in Rajasthan, but no evidence suggests he visited the Orient. Champions process was used through 1851.German chemist Andreas Marggraf normally gets credit for discovering pure metallic zinc, even though Swedish chemist Anton von Swab had distilled zinc from calamine four years previously. In his 1746 experiment, Marggraf heated a mixture of calamine and charcoal in a closed vessel without copper to obtain a metal. This procedure became commercially practical by 1752.

Later work
William Champions brother, John, patented a process in 1758 for calcining zinc sulfide into an oxide usable in the retort process. Prior to this, only calamine could be used to produce zinc. In 1798, Johann Christian Ruberg improved on the smelting process by building the first horizontal retort smelter. Jean-Jacques Daniel Dony built a different kind of horizontal zinc smelter in Belgium that processed even more zinc.
Italian doctor Luigi Galvani discovered in 1780 that connecting the spinal cord of a freshly dissected frog to an iron rail attached by a brass hook caused the frogs leg to twitch. He incorrectly thought he had discovered an ability of nerves and muscles to create electricity and called the effect "animal electricity". The galvanic cell and the process of galvanization were both named for Luigi Galvani, and his discoveries paved the way for electrical batteries, galvanization, and cathodic protection.Galvanis friend, Alessandro Volta, continued researching the effect and invented the Voltaic pile in 1800. Voltas pile consisted of a stack of simplified galvanic cells, each being one plate of copper and one of zinc connected by an electrolyte. By stacking these units in series, the Voltaic pile (or "battery") as a whole had a higher voltage, which could be used more easily than single cells. Electricity is produced because the Volta potential between the two metal plates makes electrons flow from the zinc to the copper and corrode the zinc.The non-magnetic character of zinc and its lack of color in solution delayed discovery of its importance to biochemistry and nutrition. This changed in 1940 when carbonic anhydrase, an enzyme that scrubs carbon dioxide from blood, was shown to have zinc in its active site. The digestive enzyme carboxypeptidase became the second known zinc-containing enzyme in 1955.

Production
Mining and processing
Zinc is the fourth most common metal in use, trailing only iron, aluminium, and copper with an annual production of about 13 million tonnes. The worlds largest zinc producer is Nyrstar, a merger of the Australian OZ Minerals and the Belgian Umicore. About 70% of the worlds zinc originates from mining, while the remaining 30% comes from recycling secondary zinc. Commercially pure zinc is known as Special High Grade, often abbreviated SHG, and is 99.995% pure.Worldwide, 95% of new zinc is mined from sulfidic ore deposits, in which sphalerite (ZnS) is nearly always mixed with the sulfides of copper, lead and iron.: 6  Zinc mines are scattered throughout the world, with the main areas being China, Australia, and Peru. China produced 38% of the global zinc output in 2014.Zinc metal is produced using extractive metallurgy.: 7  The ore is finely ground, then put through froth flotation to separate minerals from gangue (on the property of hydrophobicity), to get a zinc sulfide ore concentrate: 16  consisting of about 50% zinc, 32% sulfur, 13% iron, and 5% SiO2.: 16 Roasting converts the zinc sulfide concentrate to zinc oxide:

          2

          ZnS
          +
          3

            O

              2

              →

                  t
                  o

          2

          ZnO
          +
          2

            SO

              2

    {\displaystyle {\ce {2ZnS + 3O2 ->[t^o] 2ZnO + 2SO2}}}
  The sulfur dioxide is used for the production of sulfuric acid, which is necessary for the leaching process. If deposits of zinc carbonate, zinc silicate, or zinc-spinel (like the Skorpion Deposit in Namibia) are used for zinc production, the roasting can be omitted.For further processing two basic methods are used: pyrometallurgy or electrowinning. Pyrometallurgy reduces zinc oxide with carbon or carbon monoxide at 950 °C (1,740 °F) into the metal, which is distilled as zinc vapor to separate it from other metals, which are not volatile at those temperatures. The zinc vapor is collected in a condenser. The equations below describe this process:

          ZnO
          +
          C

              →

                  950
                  o

                C

          Zn
          +
          CO

    {\displaystyle {\ce {ZnO + C ->[950^oC] Zn + CO}}}

          ZnO
          +
          CO

              →

                  950
                  o

                C

          Zn
          +

            CO

              2

    {\displaystyle {\ce {ZnO + CO ->[950^oC] Zn + CO2}}}
  In electrowinning, zinc is leached from the ore concentrate by sulfuric acid and impurities are precipitated:

          ZnO
          +

            H

              2

            SO

              4

          ⟶

            ZnSO

              4

          +

            H

              2

          O

    {\displaystyle {\ce {ZnO + H2SO4 -> ZnSO4 + H2O}}}
  Finally, the zinc is reduced by electrolysis.

          2

            ZnSO

              4

          +
          2

            H

              2

          O
          ⟶
          2

          Zn
          +

            O

              2

          +
          2

            H

              2

            SO

              4

    {\displaystyle {\ce {2ZnSO4 + 2H2O -> 2Zn + O2 + 2H2SO4}}}
  The sulfuric acid is regenerated and recycled to the leaching step.
When galvanised feedstock is fed to an electric arc furnace, the zinc is recovered from the dust by a number of processes, predominantly the Waelz process (90% as of 2014).

Environmental impact
Refinement of sulfidic zinc ores produces large volumes of sulfur dioxide and cadmium vapor. Smelter slag and other residues contain significant quantities of metals. About 1.1 million tonnes of metallic zinc and 130 thousand tonnes of lead were mined and smelted in the Belgian towns of La Calamine and Plombières between 1806 and 1882. The dumps of the past mining operations leach zinc and cadmium, and the sediments of the Geul River contain non-trivial amounts of metals. About two thousand years ago, emissions of zinc from mining and smelting totaled 10 thousand tonnes a year. After increasing 10-fold from 1850, zinc emissions peaked at 3.4 million tonnes per year in the 1980s and declined to 2.7 million tonnes in the 1990s, although a 2005 study of the Arctic troposphere found that the concentrations there did not reflect the decline. Man-made and natural emissions occur at a ratio of 20 to 1.Zinc in rivers flowing through industrial and mining areas can be as high as 20 ppm. Effective sewage treatment greatly reduces this; treatment along the Rhine, for example, has decreased zinc levels to 50 ppb. Concentrations of zinc as low as 2 ppm adversely affects the amount of oxygen that fish can carry in their blood.

Soils contaminated with zinc from mining, refining, or fertilizing with zinc-bearing sludge can contain several grams of zinc per kilogram of dry soil. Levels of zinc in excess of 500 ppm in soil interfere with the ability of plants to absorb other essential metals, such as iron and manganese. Zinc levels of 2000 ppm to 180,000 ppm (18%) have been recorded in some soil samples.

Applications
Major applications of zinc include (numbers are given for the US)
Galvanizing (55%)
Brass and bronze (16%)
Other alloys (21%)
Miscellaneous (8%)

Anti-corrosion and batteries
Zinc is most commonly used as an anti-corrosion agent, and galvanization (coating of iron or steel) is the most familiar form. In 2009 in the United States, 55% or 893,000 tons of the zinc metal was used for galvanization.Zinc is more reactive than iron or steel and thus will attract almost all local oxidation until it completely corrodes away. A protective surface layer of oxide and carbonate (Zn5(OH)6(CO3)2) forms as the zinc corrodes. This protection lasts even after the zinc layer is scratched but degrades through time as the zinc corrodes away. The zinc is applied electrochemically or as molten zinc by hot-dip galvanizing or spraying. Galvanization is used on chain-link fencing, guard rails, suspension bridges, lightposts, metal roofs, heat exchangers, and car bodies.The relative reactivity of zinc and its ability to attract oxidation to itself makes it an efficient sacrificial anode in cathodic protection (CP). For example, cathodic protection of a buried pipeline can be achieved by connecting anodes made from zinc to the pipe. Zinc acts as the anode (negative terminus) by slowly corroding away as it passes electric current to the steel pipeline. Zinc is also used to cathodically protect metals that are exposed to sea water. A zinc disc attached to a ships iron rudder will slowly corrode while the rudder stays intact. Similarly, a zinc plug attached to a propeller or the metal protective guard for the keel of the ship provides temporary protection.
With a standard electrode potential (SEP) of −0.76 volts, zinc is used as an anode material for batteries. (More reactive lithium (SEP −3.04 V) is used for anodes in lithium batteries ). Powdered zinc is used in this way in alkaline batteries and the case (which also serves as the anode) of zinc–carbon batteries is formed from sheet zinc. Zinc is used as the anode or fuel of the zinc–air battery/fuel cell. The zinc-cerium redox flow battery also relies on a zinc-based negative half-cell.

Alloys
A widely used zinc alloy is brass, in which copper is alloyed with anywhere from 3% to 45% zinc, depending upon the type of brass. Brass is generally more ductile and stronger than copper, and has superior corrosion resistance. These properties make it useful in communication equipment, hardware, musical instruments, and water valves.

Other widely used zinc alloys include nickel silver, typewriter metal, soft and aluminium solder, and commercial bronze. Zinc is also used in contemporary pipe organs as a substitute for the traditional lead/tin alloy in pipes. Alloys of 85–88% zinc, 4–10% copper, and 2–8% aluminium find limited use in certain types of machine bearings. Zinc has been the primary metal in American one cent coins (pennies) since 1982. The zinc core is coated with a thin layer of copper to give the appearance of a copper coin. In 1994, 33,200 tonnes (36,600 short tons) of zinc were used to produce 13.6 billion pennies in the United States.Alloys of zinc with small amounts of copper, aluminium, and magnesium are useful in die casting as well as spin casting, especially in the automotive, electrical, and hardware industries. These alloys are marketed under the name Zamak. An example of this is zinc aluminium. The low melting point together with the low viscosity of the alloy makes possible the production of small and intricate shapes. The low working temperature leads to rapid cooling of the cast products and fast production for assembly. Another alloy, marketed under the brand name Prestal, contains 78% zinc and 22% aluminium, and is reported to be nearly as strong as steel but as malleable as plastic. This superplasticity of the alloy allows it to be molded using die casts made of ceramics and cement.Similar alloys with the addition of a small amount of lead can be cold-rolled into sheets. An alloy of 96% zinc and 4% aluminium is used to make stamping dies for low production run applications for which ferrous metal dies would be too expensive. For building facades, roofing, and other applications for sheet metal formed by deep drawing, roll forming, or bending, zinc alloys with titanium and copper are used. Unalloyed zinc is too brittle for these manufacturing processes.As a dense, inexpensive, easily worked material, zinc is used as a lead replacement. In the wake of lead concerns, zinc appears in weights for various applications ranging from fishing to tire balances and flywheels.Cadmium zinc telluride (CZT) is a semiconductive alloy that can be divided into an array of small sensing devices. These devices are similar to an integrated circuit and can detect the energy of incoming gamma ray photons. When behind an absorbing mask, the CZT sensor array can determine the direction of the rays.

Other industrial uses
Roughly one quarter of all zinc output in the United States in 2009 was consumed in zinc compounds; a variety of which are used industrially. Zinc oxide is widely used as a white pigment in paints and as a catalyst in the manufacture of rubber to disperse heat. Zinc oxide is used to protect rubber polymers and plastics from ultraviolet radiation (UV). The semiconductor properties of zinc oxide make it useful in varistors and photocopying products. The zinc zinc-oxide cycle is a two step thermochemical process based on zinc and zinc oxide for hydrogen production.Zinc chloride is often added to lumber as a fire retardant and sometimes as a wood preservative. It is used in the manufacture of other chemicals. Zinc methyl (Zn(CH3)2) is used in a number of organic syntheses. Zinc sulfide (ZnS) is used in luminescent pigments such as on the hands of clocks, X-ray and television screens, and luminous paints. Crystals of ZnS are used in lasers that operate in the mid-infrared part of the spectrum. Zinc sulfate is a chemical in dyes and pigments. Zinc pyrithione is used in antifouling paints.Zinc powder is sometimes used as a propellant in model rockets. When a compressed mixture of 70% zinc and 30% sulfur powder is ignited there is a violent chemical reaction. This produces zinc sulfide, together with large amounts of hot gas, heat, and light.Zinc sheet metal is used to make zinc bars.64Zn, the most abundant isotope of zinc, is very susceptible to neutron activation, being transmuted into the highly radioactive 65Zn, which has a half-life of 244 days and produces intense gamma radiation. Because of this, zinc oxide used in nuclear reactors as an anti-corrosion agent is depleted of 64Zn before use, this is called depleted zinc oxide. For the same reason, zinc has been proposed as a salting material for nuclear weapons (cobalt is another, better-known salting material). A jacket of isotopically enriched 64Zn would be irradiated by the intense high-energy neutron flux from an exploding thermonuclear weapon, forming a large amount of 65Zn significantly increasing the radioactivity of the weapons fallout. Such a weapon is not known to have ever been built, tested, or used.65Zn is used as a tracer to study how alloys that contain zinc wear out, or the path and the role of zinc in organisms.Zinc dithiocarbamate complexes are used as agricultural fungicides; these include Zineb, Metiram, Propineb and Ziram. Zinc naphthenate is used as wood preservative. Zinc in the form of ZDDP, is used as an anti-wear additive for metal parts in engine oil.

Organic chemistry
Organozinc chemistry is the science of compounds that contain carbon-zinc bonds, describing the physical properties, synthesis, and chemical reactions. Many organozinc compounds are important. Among important applications are

The Frankland-Duppa Reaction in which an oxalate ester (ROCOCOOR) reacts with an alkyl halide RX, zinc and hydrochloric acid to form the α-hydroxycarboxylic esters RRCOHCOOR
On the downside, organozincs are much less nucleophilic than Grignards, and they are expensive and difficult to handle. Commercially available diorganozinc compounds are dimethylzinc, diethylzinc and diphenylzinc. In one study, the active organozinc compound is obtained from much cheaper organobromine precursors.Zinc has found many uses as a catalyst in organic synthesis including asymmetric synthesis, being cheap and easily available alternative to precious metal complexes. The results (yield and enantiomeric excess) obtained with chiral zinc catalysts are comparable to those achieved with palladium, ruthenium, iridium and others, and zinc becomes a metal catalyst of choice.

Dietary supplement
In most single-tablet, over-the-counter, daily vitamin and mineral supplements, zinc is included in such forms as zinc oxide, zinc acetate,  zinc gluconate, or zinc amino acid chelate.Generally, zinc supplement is recommended where there is high risk of zinc deficiency (such as low and middle income countries) as a preventive measure. Although zinc sulfate is a commonly used zinc form, zinc citrate, gluconate and picolinate may be valid options as well. These forms are better absorbed than zinc oxide.

Gastroenteritis
Zinc is an inexpensive and effective part of treatment of diarrhea among children in the developing world. Zinc becomes depleted in the body during diarrhea and replenishing zinc with a 10- to 14-day course of treatment can reduce the duration and severity of diarrheal episodes and may also prevent future episodes for as long as three months. Gastroenteritis is strongly attenuated by ingestion of zinc, possibly by direct antimicrobial action of the ions in the gastrointestinal tract, or by the absorption of the zinc and re-release from immune cells (all granulocytes secrete zinc), or both.

Common cold
Weight gain
Zinc deficiency may lead to loss of appetite. The use of zinc in the treatment of anorexia has been advocated since 1979. At least 15 clinical trials have shown that zinc improved weight gain in anorexia. A 1994 trial showed that zinc doubled the rate of body mass increase in the treatment of anorexia nervosa. Deficiency of other nutrients such as tyrosine, tryptophan and thiamine could contribute to this phenomenon of "malnutrition-induced malnutrition".
A meta-analysis of 33 prospective intervention trials regarding zinc supplementation and its effects on the growth of children in many countries showed that zinc supplementation alone had a statistically significant effect on linear growth and body weight gain, indicating that other deficiencies that may have been present were not responsible for growth retardation.

Other
A Cochrane review stated that people taking zinc supplement may be less likely to progress to age-related macular degeneration. Zinc supplement is an effective treatment for acrodermatitis enteropathica, a genetic disorder affecting zinc absorption that was previously fatal to affected infants. Zinc deficiency has been associated with major depressive disorder (MDD), and zinc supplements may be an effective treatment.

Topical use
Topical preparations of zinc include those used on the skin, often in the form of zinc oxide. Zinc oxide can be formulated into a sunscreen to mitigate sunburn. Applied thinly to a babys diaper area (perineum) with each diaper change, it can protect against diaper rash.Chelated zinc is used in toothpastes and mouthwashes to prevent bad breath; zinc citrate helps reduce the build-up of calculus (tartar).Zinc pyrithione is widely included in shampoos to prevent dandruff.Topical zinc has also been shown to effectively treat, as well as prolong remission in genital herpes.

Biological role
Zinc is an essential trace element for humans and other animals, for plants and for microorganisms. Zinc is required for the function of over 300 enzymes and 1000 transcription factors, and is stored and transferred in metallothioneins. It is the second most abundant trace metal in humans after iron and it is the only metal which appears in all enzyme classes.In proteins, zinc ions are often coordinated to the amino acid side chains of aspartic acid, glutamic acid, cysteine and histidine. The theoretical and computational description of this zinc binding in proteins (as well as that of other transition metals) is difficult.Roughly 2–4 grams of zinc are distributed throughout the human body. Most zinc is in the brain, muscle, bones, kidney, and liver, with the highest concentrations in the prostate and parts of the eye. Semen is particularly rich in zinc, a key factor in prostate gland function and reproductive organ growth.Zinc homeostasis of the body is mainly controlled by the intestine. Here, ZIP4 and especially TRPM7 were linked to intestinal zinc uptake essential for postnatal survival.In humans, the biological roles of zinc are ubiquitous. It interacts with "a wide range of organic ligands", and has roles in the metabolism of RNA and DNA, signal transduction, and gene expression. It also regulates apoptosis. A review from 2015 indicated that about 10% of human proteins (~3000) bind zinc, in addition to hundreds more that transport and traffic zinc; a similar in silico study in the plant Arabidopsis thaliana found 2367 zinc-related proteins.In the brain, zinc is stored in specific synaptic vesicles by glutamatergic neurons and can modulate neuronal excitability. It plays a key role in synaptic plasticity and so in learning. Zinc homeostasis also plays a critical role in the functional regulation of the central nervous system. Dysregulation of zinc homeostasis in the central nervous system that results in excessive synaptic zinc concentrations is believed to induce neurotoxicity through mitochondrial oxidative stress (e.g., by disrupting certain enzymes involved in the electron transport chain, including complex I, complex III, and α-ketoglutarate dehydrogenase), the dysregulation of calcium homeostasis, glutamatergic neuronal excitotoxicity, and interference with intraneuronal signal transduction. L- and D-histidine facilitate brain zinc uptake. SLC30A3 is the primary zinc transporter involved in cerebral zinc homeostasis.

Enzymes
Zinc is an efficient Lewis acid, making it a useful catalytic agent in hydroxylation and other enzymatic reactions. The metal also has a flexible coordination geometry, which allows proteins using it to rapidly shift conformations to perform biological reactions. Two examples of zinc-containing enzymes are carbonic anhydrase and carboxypeptidase, which are vital to the processes of carbon dioxide (CO2) regulation and digestion of proteins, respectively.In vertebrate blood, carbonic anhydrase converts CO2 into bicarbonate and the same enzyme transforms the bicarbonate back into CO2 for exhalation through the lungs. Without this enzyme, this conversion would occur about one million times slower at the normal blood pH of 7 or would require a pH of 10 or more. The non-related β-carbonic anhydrase is required in plants for leaf formation, the synthesis of indole acetic acid (auxin) and alcoholic fermentation.Carboxypeptidase cleaves peptide linkages during digestion of proteins. A coordinate covalent bond is formed between the terminal peptide and a C=O group attached to zinc, which gives the carbon a positive charge. This helps to create a hydrophobic pocket on the enzyme near the zinc, which attracts the non-polar part of the protein being digested.

Signalling
Zinc has been recognized as a messenger, able to activate signalling pathways. Many of these pathways provide the driving force in aberrant cancer growth. They can be targeted through ZIP transporters.

Other proteins
Zinc serves a purely structural role in zinc fingers, twists and clusters. Zinc fingers form parts of some transcription factors, which are proteins that recognize DNA base sequences during the replication and transcription of DNA. Each of the nine or ten Zn2+ ions in a zinc finger helps maintain the fingers structure by coordinately binding to four amino acids in the transcription factor.In blood plasma, zinc is bound to and transported by albumin (60%, low-affinity) and transferrin (10%). Because transferrin also transports iron, excessive iron reduces zinc absorption, and vice versa. A similar antagonism exists with copper. The concentration of zinc in blood plasma stays relatively constant regardless of zinc intake. Cells in the salivary gland, prostate, immune system, and intestine use zinc signaling to communicate with other cells.Zinc may be held in metallothionein reserves within microorganisms or in the intestines or liver of animals. Metallothionein in intestinal cells is capable of adjusting absorption of zinc by 15–40%. However, inadequate or excessive zinc intake can be harmful; excess zinc particularly impairs copper absorption because metallothionein absorbs both metals.The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro. The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites. Some EF-hand calcium binding proteins such as S100 or NCS-1 are also able to bind zinc ions.

Nutrition
Dietary recommendations
The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for zinc in 2001. The current EARs for zinc for women and men ages 14 and up is 6.8 and 9.4 mg/day, respectively. The RDAs are 8 and 11 mg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy is 11 mg/day. RDA for lactation is 12 mg/day. For infants up to 12 months the RDA is 3 mg/day. For children ages 1–13 years the RDA increases with age from 3 to 8 mg/day. As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of zinc the adult UL is 40 mg/day (lower for children). Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For people ages 18 and older the PRI calculations are complex, as the EFSA has set higher and higher values as the phytate content of the diet increases. For women, PRIs increase from 7.5 to 12.7 mg/day as phytate intake increases from 300 to 1200 mg/day; for men the range is 9.4 to 16.3 mg/day. These PRIs are higher than the U.S. RDAs. The EFSA reviewed the same safety question and set its UL at 25 mg/day, which is much lower than the U.S. value.For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For zinc labeling purposes 100% of the Daily Value was 15 mg, but on May 27, 2016, it was revised to 11 mg. A table of the old and new adult daily values is provided at Reference Daily Intake.

Dietary intake
Animal products such as meat, fish, shellfish, fowl, eggs, and dairy contain zinc. The concentration of zinc in plants varies with the level in the soil. With adequate zinc in the soil, the food plants that contain the most zinc are wheat (germ and bran) and various seeds, including sesame, poppy, alfalfa, celery, and mustard. Zinc is also found in beans, nuts, almonds, whole grains, pumpkin seeds, sunflower seeds, and blackcurrant.Other sources include fortified food and dietary supplements in various forms. A 1998 review concluded that zinc oxide, one of the most common supplements in the United States, and zinc carbonate are nearly insoluble and poorly absorbed in the body. This review cited studies that found lower plasma zinc concentrations in the subjects who consumed zinc oxide and zinc carbonate than in those who took zinc acetate and sulfate salts. For fortification, however, a 2003 review recommended cereals (containing zinc oxide) as a cheap, stable source that is as easily absorbed as the more expensive forms. A 2005 study found that various compounds of zinc, including oxide and sulfate, did not show statistically significant differences in absorption when added as fortificants to maize tortillas.

Deficiency
Nearly two billion people in the developing world are deficient in zinc. Groups at risk include children in developing countries and elderly with chronic illnesses. In children, it causes an increase in infection and diarrhea and contributes to the death of about 800,000 children worldwide per year. The World Health Organization advocates zinc supplementation for severe malnutrition and diarrhea. Zinc supplements help prevent disease and reduce mortality, especially among children with low birth weight or stunted growth. However, zinc supplements should not be administered alone, because many in the developing world have several deficiencies, and zinc interacts with other micronutrients. While zinc deficiency is usually due to insufficient dietary intake, it can be associated with malabsorption, acrodermatitis enteropathica, chronic liver disease, chronic renal disease, sickle cell disease, diabetes, malignancy, and other chronic illnesses.In the United States, a federal survey of food consumption determined that for women and men over the age of 19, average consumption was 9.7 and 14.2 mg/day, respectively. For women, 17% consumed less than the EAR, for men 11%. The percentages below EAR increased with age. The most recent published update of the survey (NHANES 2013–2014) reported lower averages – 9.3 and 13.2 mg/day – again with intake decreasing with age.Symptoms of mild zinc deficiency are diverse. Clinical outcomes include depressed growth, diarrhea, impotence and delayed sexual maturation, alopecia, eye and skin lesions, impaired appetite, altered cognition, impaired immune functions, defects in carbohydrate utilization, and reproductive teratogenesis. Zinc deficiency depresses immunity, but excessive zinc does also.Despite some concerns, western vegetarians and vegans do not suffer any more from overt zinc deficiency than meat-eaters. Major plant sources of zinc include cooked dried beans, sea vegetables, fortified cereals, soy foods, nuts, peas, and seeds. However, phytates in many whole-grains and fibers may interfere with zinc absorption and marginal zinc intake has poorly understood effects. The zinc chelator phytate, found in seeds and cereal bran, can contribute to zinc malabsorption. Some evidence suggests that more than the US RDA (8 mg/day for adult women; 11 mg/day for adult men) may be needed in those whose diet is high in phytates, such as some vegetarians. The European Food Safety Authority (EFSA) guidelines attempt to compensate for this by recommending higher zinc intake when dietary phytate intake is greater. These considerations must be balanced against the paucity of adequate zinc biomarkers, and the most widely used indicator, plasma zinc, has poor sensitivity and specificity.

Soil remediation
Species of Calluna, Erica and Vaccinium can grow in zinc-metalliferous soils, because translocation of toxic ions is prevented by the action of ericoid mycorrhizal fungi.

Agriculture
Zinc deficiency appears to be the most common micronutrient deficiency in crop plants; it is particularly common in high-pH soils. Zinc-deficient soil is cultivated in the cropland of about half of Turkey and India, a third of China, and most of Western Australia. Substantial responses to zinc fertilization have been reported in these areas. Plants that grow in soils that are zinc-deficient are more susceptible to disease. Zinc is added to the soil primarily through the weathering of rocks, but humans have added zinc through fossil fuel combustion, mine waste, phosphate fertilizers, pesticide (zinc phosphide), limestone, manure, sewage sludge, and particles from galvanized surfaces. Excess zinc is toxic to plants, although zinc toxicity is far less widespread.

Precautions
Toxicity
Although zinc is an essential requirement for good health, excess zinc can be harmful. Excessive absorption of zinc suppresses copper and iron absorption. The free zinc ion in solution is highly toxic to plants, invertebrates, and even vertebrate fish. The Free Ion Activity Model is well-established in the literature, and shows that just micromolar amounts of the free ion kills some organisms. A recent example showed 6 micromolar killing 93% of all Daphnia in water.The free zinc ion is a powerful Lewis acid up to the point of being corrosive. Stomach acid contains hydrochloric acid, in which metallic zinc dissolves readily to give corrosive zinc chloride. Swallowing a post-1982 American one cent piece (97.5% zinc) can cause damage to the stomach lining through the high solubility of the zinc ion in the acidic stomach.Evidence shows that people taking 100–300 mg of zinc daily may suffer induced copper deficiency. A 2007 trial observed that elderly men taking 80 mg daily were hospitalized for urinary complications more often than those taking a placebo. Levels of 100–300 mg may interfere with the utilization of copper and iron or adversely affect cholesterol. Zinc in excess of 500 ppm in soil interferes with the plant absorption of other essential metals, such as iron and manganese. A condition called the zinc shakes or "zinc chills" can be induced by inhalation of zinc fumes while brazing or welding galvanized materials. Zinc is a common ingredient of denture cream which may contain between 17 and 38 mg of zinc per gram. Disability and even deaths from excessive use of these products have been claimed.The U.S. Food and Drug Administration (FDA) states that zinc damages nerve receptors in the nose, causing anosmia. Reports of anosmia were also observed in the 1930s when zinc preparations were used in a failed attempt to prevent polio infections. On June 16, 2009, the FDA ordered removal of zinc-based intranasal cold products from store shelves. The FDA said the loss of smell can be life-threatening because people with impaired smell cannot detect leaking gas or smoke, and cannot tell if food has spoiled before they eat it.Recent research suggests that the topical antimicrobial zinc pyrithione is a potent heat shock response inducer that may impair genomic integrity with induction of PARP-dependent energy crisis in cultured human keratinocytes and melanocytes.

Poisoning
In 1982, the US Mint began minting pennies coated in copper but containing primarily zinc </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 Pleomorphic lipoma 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 Gitelman syndrome and can you explain it in depth? [/INST] Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is caused by genetic mutations resulting in improper function of the thiazide-sensitive sodium-chloride symporter (SLC12A3, also known as NCC, NCCT, or TSC) located in the distal convoluted tubule of the kidney. The distal convoluted tubule of the kidney plays an important homoestatic role in sodium and chloride absorption as well as of the reabsorption of magnesium and calcium.Genetic mutations of NCC, lead to loss of function and subsequently, reduced transport of sodium and chloride via NCC. Secondary derangement of calcium, magnesium, and potassium concentrations are caused by secondary effects in the distal tubule and collecting duct. The effect is an electrolyte imbalance similar to that seen with thiazide diuretic therapy (which causes pharmacological inhibition of NCC activity).Gitelman syndrome was formerly considered a subset of Bartter syndrome until the distinct genetic and molecular bases of these disorders were identified. Bartter syndrome is also an autosomal recessive cause of hypokalemic metabolic alkalosis, but it derives from a mutations of a number of genes that reduce NKCC2 activity. NKCC2 is found in the thick ascending limb of the loop of Henle.

Signs and symptoms
Affected individuals may not have symptoms in some cases. Symptomatic individuals present with symptoms identical to those of patients who are on thiazide diuretics, given that the affected transporter is the exact target of thiazides, (unlike in Bartter syndrome, in which patients present as though on loop diuretics).
Clinical signs of Gitelman syndrome include a high blood pH in combination with low levels of chloride, potassium, and magnesium in the blood and decreased calcium excretion in the urine. In contrast to people with Gordons syndrome, those affected by Gitelman syndrome generally have low or normal blood pressure. Individuals affected by Gitelman syndrome often complain of severe muscle cramps or weakness, numbness, thirst, waking up at night to urinate, salt cravings, abnormal sensations, chondrocalcinosis, or weakness expressed as extreme fatigue or irritability. Though cravings for salt are most common and severe, cravings for sour foods (e.g. vinegar, lemons, and sour figs) have been noted in some persons affected. More severe symptoms such as seizures, tetany, and paralysis have been reported. Abnormal heart rhythms and a prolonged QT interval can be detected on electrocardiogram and cases of sudden cardiac death have been reported due to low potassium levels.  Quality of life is decreased in Gitelman syndromePhenotypic variations observed among patients probably result from differences in their genetic background and may depend on which particular amino acid in the NCCT protein has been mutated. A study by Riviera-Munoz et al. identified a subset of individuals with Gitelman syndrome with a severe phenotypic expression. The clinical manifestations observed in this group were neuromuscular manifestations, growth retardation, and ventricular arrhythmias. The patients were mostly male and were found to have at least one allele of a splice defect on the SLC12A3 gene.

Cause
The sodium chloride symporter is a protein made up of 1021 amino acids and 12 transmembrane domains. Mutations that occur on the SLC12A3 gene range from missense, nonsense, frame-shift and splice-site mutations which occur throughout the gene.Most cases of Gitelman syndrome are linked to inactivating mutations in the SLC12A3 gene, resulting in a loss of function of the thiazide-sensitive sodium-chloride co-transporter (NCCT). This genetic mutation in SLC12A3 is present in 80% of adults with Gitelman syndrome. More than 180 mutations of this transporter protein have been described. This cell membrane protein participates in the control of ion homeostasis at the distal convoluted tubule portion of the nephron. Loss of this transporter also has the indirect effect of increasing calcium reabsorption in a transcellular fashion. This has been suggested to be the result of a putative basolateral Na+/Ca2+ exchanger and apical calcium channel.When the sodium-chloride cotransporter (NCCT) is inactivated, continued action of the basolateral Na+/K+-ATPase creates a favourable sodium gradient across the basolateral membrane. This increases the reabsorption of divalent cations by secondary active transport. It is currently unknown why calcium reabsorption is increased while magnesium absorption is decreased, often leading to a low level of magnesium in the blood .A secondary effect of the inactivated sodium-chloride cotransporter is the subsequent activation of the renin-angiotensin aldosterone system (RAAS). RAAS activation is a byproduct of the failure of the distal convoluted tubule in reuptaking electrolytes specifically sodium and chloride leading to cellular dehydration. RAAS attempts to compensate for this dehydration resulting in low serum blood potassium.A small percentage of Gitelman syndrome cases can be attributed to mutations in the CLCNKB gene. This gene is related to the function of the renal chloride channel CLC-Kb located at the basolateral membrane of cells in the thick ascending limb of the Henles loop. Genetic variations or mutations in the CLCNKB was initially linked to classic Bartter Syndrome. When mutations are not found within the SLC12A3 gene, screening can be done to rule out involvement of CLCNKB gene.Gitelman syndrome is inherited in an autosomal-recessive manner: one defective allele has to be inherited from each parent.In 2021, mutations in the tRNAs encoding Isoleucine (MT-TI) and Phenylalanine (MT-TF) in the mitochondrial DNA were described to cause Gitelman syndrome. These homomplasmic mtDNA mutations are maternally inherited.

Diagnosis
Diagnosis of Gitelman syndrome can be confirmed after eliminating other common pathological sources of hypokalemia and metabolic alkalosis. A complete metabolic panel (CMP) or basic metabolic panel (BMP) can be used to evaluate serum electrolyte levels. Renin and aldosterone can be tested in the blood. Electrolyte measurement and aldosterone levels can be done via urine. The pathognomonic clinical markers include low serum levels of potassium, sodium, chloride, and magnesium in the blood as a result of urinary excretion. Urinary fractional excretion potassium is high or inappropriately normal in the context of hypokalaemia, and high levels of urinary sodium and chloride are observed.  Other clinical indicators include elevated serum renin and aldosterone in the bloodstream, and metabolic alkalosis. The symptomatic features of this syndrome are highly variable ranging from asymptomatic to mild manifestations (weakness, cramps) to severe symptoms (tetany, paralysis, rhabdomyolysis). Symptom severity is multi-factorial, with phenotypic expression varying amongst individuals within the same family. Genetic testing is another measure of identifying the underlying mutations which cause the pathologic symptoms of the disease. This mode of testing is available at select laboratories.Work-up to exclude the differential diagnosis of the electrolyte abnormalities is key.
In Gitelman syndrome hypocalciuria is present, and a urine calcium:creatinine ratio may help distinguish it from Bartter syndrome as the two disorders can be clinically indistinguishable.  Additionally in Bartter syndrome maximal urine concentrating ability is lost.
Laxative abuse can mimic the serum electrolyte abnormalities, but fractional excretion of potassium will be low
Diuretic abuse could be suspected if urinary chloride excretion varies by time of day but may require a diuretic assay to detect
Surreptitious vomiting can cause metabolic alkalosis and hypokalaemia, but urinary chloride levels will be low
Medication history; Proton-pump inhibitors can cause an isolated hypomagnesaemia phenotype, and aminoglycosides such as gentamicin can cause a transient metabolic alkalosis with hypokalaemia and hypomagnesaemia that resolves 2–6 weeks after drug termination.
Primary aldosteronism will cause metabolic alkalosis and hypokalaemia, but hypertension will be present and serum renin will be low
EAST syndrome, though neurological features will predominate
Renal cysts and diabetes syndrome can cause hypomagnesaemia and hypocalcuria, but is distinguished by early onset chronic kidney disease and an autosomal dominant inheritance pattern of renal cysts and/or diabetes

Treatment
Most asymptomatic individuals with Gitelman syndrome can be monitored without medical treatment. Dietary modification of a high salt diet incorporated with, potassium and magnesium supplementation to normalize blood levels is the mainstay of treatment. Large doses of potassium and magnesium are often necessary to adequately replace the electrolytes lost in the urine. Diarrhea is a common side effect of oral magnesium which can make replacement by mouth difficult but dividing the dose to 3-4 times a day is better tolerated. Severe deficits of potassium and magnesium require intravenous replacement. If low blood potassium levels are not sufficiently replaced with replacement by mouth, aldosterone antagonists (such as spironolactone or eplerenone) or epithelial sodium channel blockers such as amiloride can be used to decrease urinary wasting of potassium.In patients with early onset of the disease such as infants and children, indomethacin is the drug of choice utilized to treat growth disturbances. Indomethacin in a study by Blanchard et al. 2015 was shown to increase serum potassium levels, and decrease renin concentration. Adverse effects of indomethacin include a decrease in the glomerular filtration rate, and gastrointestinal disturbances.Cardiac evaluation is promoted in the prevention of dysrhythmias and monitoring of QT interval activity </s>