Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe the molecular basis of a distinctive syndrome characterized by infantile stress-induced episodic weakness, ataxia, and sensorineural hearing loss, with permanent areflexia and optic nerve pallor. Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect. This variant has not been reported in context with rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood, the 2 main diseases associated with ATP1A3. The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement. While this paper was in review, a highly resembling phenotype was reported in additional patients carrying the same c.2452 G>A variant. Our findings substantiate this variant as the cause of a unique inherited autosomal dominant neurologic syndrome that constitutes a third allelic disease of the ATP1A3 gene.
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PMID:CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene. 3011 Dec 36

Patients with a mutation at Arg756 in ATP1A3 have been known to exhibit a distinct phenotype, characterized by prolonged weakness and encephalopathy, triggered by febrile illness. With only eight reports published to date, more evidence is required to correlate clinical features with a mutation at Arg756. Here we report an additional case with an Arg756Cys mutation in ATP1A3. A four-year-old boy showed mild developmental delay with recurrent paroxysmal episodes of weakness and encephalopathy from nine months of age. Motor deficits, which included bilateral hypotonia, ataxia, dysmetria, limb incoordination, dysarthria, choreoathetosis, and dystonia, were observed from one year and three months. Whole-exome sequencing detected a heterozygous de novo variant at c.2266C>T (p.Arg756Cys) in ATP1A3. The episodic course and clinical features of this case were consistent with previously reported cases with mutations at Arg756. Furthermore, his phenotype of marked ataxia was more similar to that of an Arg756Cys patient with relapsing encephalopathy and cerebellar ataxia syndrome, than to those with Arg756His and Arg756Leu mutations. This report therefore provides evidence of genotype-phenotype correlations in ATP1A3-related disorders as well as in patients with mutations at Arg756 in ATP1A3.
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PMID:A de novo p.Arg756Cys mutation in ATP1A3 causes a distinct phenotype with prolonged weakness and encephalopathy triggered by fever. 2906 18

We describe the cognitive-behavioral functioning of two adult patients with a mild form of alternating hemiplegia of childhood (AHC). AHC is a rare, chronic neurodevelopmental syndrome manifesting in infancy or early childhood, with recurrent hemiplegic or hemidystonic attacks, various nonepileptic paroxysmal events, and cognitive-behavioral impairments, including mental delay of varying degrees. We conducted neurologic and neuroimaging examinations, as well as a neuropsychological assessment, of two men (22 and 30 years old) with mutations in the ATP1A3 gene (p.Leu757Pro and p.Val332Glu) who were experiencing typical AHC transient episodes of alternating weakness or paralysis in order to investigate causes of their poor social functioning. During neurologic examinations of both patients, which were performed between attacks, we observed involuntary movements such as chorea and upper-limb tremor. One patient also had dysarthria. Magnetic resonance imaging revealed no parenchymal brain lesions or atrophy in either patient. Neuropsychological examinations demonstrated near-normal (patient 1) or normal (patient 2) global cognitive functioning, with some isolated executive functioning deficits. Both patients had emotional and social dysfunction as well as difficulties adapting to normal adult life. Although the clinical presentation of AHC is usually dramatic, some patients have mild forms of the syndrome (eg, no significant intellectual disability). However, motor and movement disorders, as well as coexisting emotional-affective abnormalities, may affect these patients' ability to adapt to independent life.
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PMID:Alternating Hemiplegia of Childhood in Two Adult Patients with a Mild Syndrome. 3056 31

Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes-CACNA1A, ATP1A2, and SCN1A-have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for CACNA1A, ATP1A2, and SCN1A mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, ATP1A3, and ATP1A4 genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified.
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PMID:Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants. 3312 86