Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Scores of monogenic Mendelian ion channel diseases serve to anchor the pathophysiology of the channelopathies, but there are also now clear examples of environmental, pharmacogenetic, and acquired channelopathy mechanisms. The cardinal feature of heritable ion channel disease is a periodic disturbance of rhythmic function in constitutionally hyperexcitable tissue. While the complexity of neuroanatomy obscures functional analysis of mutations causing monogenic seizure, ataxia, or migraine syndromes, extrapolation from the cardiac (Long QT [LQT]) and muscle (Periodic Paralysis) channelopathy syndromes provides a simplified predictive framework of molecular pathology: electrically stabilizing potassium ion (K(+)) and chloride ion (Cl(-)) channels, likely having lesions that diminish their current, and excitatory Na(+) channels, likely having gain-of-function lesions. The voltage-gated calcium channel gene family that contains CACNA1C, the newest LQT locus, causing Timothy Syndrome with a phenotype including autism, has proven to be particularly informative for its members' ability to tie the various central nervous system (CNS) phenotypes together in an interpretable fashion, now including direct extension to the classically multigenic neuropsychiatric phenotypes. Features of a promising ion channel candidate gene arise from its broad locus, gene family, nature of alleles, physiology and pharmacology, tissue expression profile, and phenotype in model organisms. KCNN3 is explored as a paradigm to consider.
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PMID:Ion channel functional candidate genes in multigenic neuropsychiatric disease. 1649 76

Timothy syndrome (TS) is a rare genetic condition that associates long QT syndrome, structural heart defects, dysmorphic facial features, syndactyly, seizures, developmental delay, and autism. Timothy syndrome type 1 is caused by a recurrent de novo mutation (p.Gly406Arg) in exon 8A of the L-type calcium channel gene CACNA1C. Timothy syndrome type 2 was originally reported to be associated with a more severe cardiac phenotype but without syndactyly. Timothy syndrome type 2 is caused by mutation in an alternatively spliced exon 8 of the CACNA1C gene. Other mutations in CACNA1C are also reported with long QT syndrome with and without syndromic features overlapping that described in Timothy syndrome. The purpose of this report is to describe the presentation, physical features and natural history of a 4-year-old girl with Timothy syndrome type 2 due to the recurrent p.Gly406Arg mutation in exon 8 of CACNA1C. She has similar facial features to Timothy syndrome type 1 without syndactyly. She is developmentally delayed without autism. She recently had her first episode of torsade de pointes associated with febrile illness and hypoglycemia. The findings in this case provide further information about the phenotype and natural history of CACNA1C exon 8 mutation and together with previously reported cases of Timothy syndrome question whether the clinical and molecular distinction between Timothy syndromes types 1 and 2 remains clinically useful.
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PMID:Long QT syndrome with craniofacial, digital, and neurologic features: Is it useful to distinguish between Timothy syndrome types 1 and 2? 2622 24

Timothy syndrome (TS) is a congenital long QT syndrome that is associated with syndactyly and mutations in CACNA1C, encoding an L-type voltage-dependent calcium channel, Cav1.2. Recently, TS has been associated with autism and other psychological disorders. This case indicated bradycardia by prenatal screening and was diagnosed as TS by the occurrence of syndactyly and QT prolongation at birth. Despite therapy with anti-arrhythmia reagents and a pacemaker, the patient died 2 months after birth and was autopsied. The heart showed mild dilation and mild hypertrophy with a focal disarray pattern, which may be inconsistent with typical cardiomyopathy. Unexpectedly, bilateral adrenal glands showed marked shrinkage and severe fibrosis of the medulla with a small number of single-strand DNA positive medullary cells and accumulation of hemosiderin-containing macrophages. This finding suggests that CACNA1C mutation may induce drop-out of medulla cells via apoptosis. This may be due to increased concentration of calcium ions consistent with Cav1.2 expression in adrenal glands as well as in the brain and the heart. This is the first report describing a systemic autopsy of TS with adrenal medullary dystrophy.
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PMID:A case of Timothy syndrome with adrenal medullary dystrophy. 2759 53