Adult-Onset Myoclonus-Dystonia Syndrome Preceding Characteristic Facial Myoclonus in Indian ADCY5-related Dyskinesia.
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ABSTRACT:
SUBMITTER: Agarwal PA
PROVIDER: S-EPMC6417756 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Adult-Onset Myoclonus-Dystonia Syndrome Preceding Characteristic Facial Myoclonus in Indian <i>ADCY5</i>-related Dyskinesia.
Agarwal Pankaj Ashok PA Ramprasad Vedam L VL
Movement disorders clinical practice 20190220 3
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Project description:We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated with a novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse whole-exome sequencing data from an affected grandmother-granddaughter pair. Whole-exome sequencing identified 18,000 shared variants, of which 46 were non-synonymous changes not present in a local cohort of control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele frequency in the 1000 Genomes Project and on phylogenetic conservation yielded 13 candidate variants, of which the heterozygous missense mutation c.3086T>G, p. M1029R in ADCY5 most closely matched the observed phenotype. This report illustrates the utility of whole-exome sequencing in cases of undiagnosed movement disorders with clear autosomal dominant inheritance. Moreover, ADCY5 mutations should be considered in cases with apparent myoclonus-dystonia, particularly where SCGE mutations have been excluded. ADCY5-related dyskinesia may manifest variable expressivity within a single family, and affected individuals may be initially diagnosed with differing neurological phenotypes.
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| S-EPMC5612768 | biostudies-literature
Project description:To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).Whole exome sequencing was performed on 2 parent-child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions.The same de novo mutation (c.1252C>T, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176G>A, p.A726T) in ADCY5 was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane-spanning domain, respectively. Functional studies revealed a statistically significant increase in ?-receptor agonist-stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild-type protein, indicative of a gain-of-function effect.FDFM is likely caused by gain-of-function mutations in different domains of ADCY5-the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis-free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history.
| S-EPMC4457323 | biostudies-literature
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| S-EPMC6325365 | biostudies-literature
Project description:KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal dominant neurological disorder characterized by varying combinations of generalized dystonia, psychomotor developmental delay, mild-to-moderate intellectual disability and short stature. Disease onset occurs typically before 10 years of age. We report the clinical and genetic findings of a series of subjects affected by adult-onset dystonia, hearing loss or intellectual disability carrying rare heterozygous KMT2B variants. Twelve cases from five unrelated families carrying four rare KMT2B missense variants predicted to impact protein function are described. Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature. Genome-wide DNA methylation profiling allowed to discriminate these adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients. These findings document the relevance of KMT2B variants as a potential genetic determinant of adult-onset dystonia and prompt to further characterize KMT2B carriers investigating non-dystonic features.
| S-EPMC9724767 | biostudies-literature
Project description: Not available
| S-EPMC8513963 | biostudies-literature
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| S-EPMC5566795 | biostudies-literature
Project description:BackgroundAdult-onset dystonia can also spread to other parts of the body, although it is not as common as childhood-onset dystonia.ObjectiveOur study aimed to examine the clinical factors determining spreading patterns in all adult-onset dystonia types.MethodsWe retrospectively analyzed the medical records of patients with a diagnosis of isolated dystonia followed longitudinally at our center. We included patients reporting symptom onset after 18 years. We then compared the clinical factors between groups with and without spreading.ResultsAmong 434 patients (396 focal, 29 segmental, and nine generalized onset dystonia. mean follow-up of 8.6 ± 7.8 years), 48 (11.1%) experienced spread of dystonia, with 37 progressing from focal to segmental, two from focal to generalized, two from segmental to generalized, and seven from focal to segmental to generalized dystonia. Blepharospasm was the most common focal dystonia noted to spread, followed by oromandibular dystonia, cervical dystonia, laryngeal dystonia, and upper extremity dystonia, in decreasing order. A spreading pattern was observed in approximately one in 10 dystonia patients, and the spreading was more frequent in the segmental dystonia group. While there was no difference between the spreading groups regarding sensory tricks, tremor, and gender, family history was more common in the non-spreading group (p = 0.023). Older age at onset was independently associated with increased odds of spreading (hazards ratio: 1.054, p < 0.001, B = 0.053).ConclusionAlthough risk factors for spread are variable, the underlying mechanisms are not fully known. Genetic factors may be possibly related to the spread, and future studies are needed on this subject.
| S-EPMC11623075 | biostudies-literature
Project description: Not available
| S-EPMC8680907 | biostudies-literature
Project description:ObjectiveTo investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship.MethodsWe analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases.ResultsWe identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation.ConclusionsADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis.
| S-EPMC4676753 | biostudies-literature