Mutation in the caveolin‐3 gene causes asymmetrical distal myopathy

Mutations in the gene encoding caveolin‐3 (CAV3) can cause a broad spectrum of clinical phenotypes, including limb girdle muscular dystrophy, rippling muscle disease, distal myopathy (MD), idiopathic persistent elevation of serum creatine kinase and cardiomyopathy. MD is a relatively rare subtype of caveolinopathy. Here, we report a sporadic case of a middle‐aged female Chinese patient with MD in which a CAV3 mutation was identical to that previously reported in cases of rippling muscle disease. T1‐weighted enhanced skeletal muscle MRI of the lower limbs showed an abnormal signal in the distal and proximal muscles. A muscle biopsy revealed moderate dystrophic changes, and immunohistochemical staining showed reduced CAV‐3 expression in the plasmalemma. Genetic analysis revealed a heterozygous c.136G > A (p.Ala46Thr) CAV3 mutation that appeared to be de novo because it was absent from the patient's parents. This study suggested that the CAV3 c.136G > A (p.Ala46Thr) mutation can cause MD as well as different phenotypes in different individuals, suggesting that additional unknown loci must affect the disease phenotypes.     

Paramyotonia congenita due to a de novo mutation: a case report

A Japanese man with a negative family history of paramyotonia congenita (PMC) was evaluated for symptoms of cold-induced weakness and stiffness. Exercise testing revealed findings characteristic of PMC, and a genetic analysis was therefore performed. A well-known sodium channel mutation for PMC (T1313M) was identified in the patient, but was absent in his biological parents. These data demonstrate the occurrence of a de novo mutation, suggesting that evaluation for PMC should be performed in patients with typical symptoms even if the family history is negative.     

Whole genome/exome sequencing in mood and psychotic disorders

Recent developments in DNA sequencing technologies have allowed for genetic studies using whole genome or exome analysis, and these have been applied in the study of mood and psychotic disorders, including bipolar disorder, depression, schizophrenia, and schizoaffective disorder. In this review, the current situation, recent findings, methodological problems, and future directions of whole genome/exome analysis studies of these disorders are summarized. Whole genome/exome studies of bipolar disorder have included pedigree analysis and case–control studies, demonstrating the role of previously implicated pathways, such as calcium signaling, cyclic adenosine monophosphate response element binding protein (CREB) signaling, and potassium channels. Extensive analysis of trio families and case–control studies showed that de novo mutations play a role in the genetic architecture of schizophrenia and indicated that mutations in several molecular pathways, including chromatin regulation, activity‐regulated cytoskeleton, post‐synaptic density, N‐methyl‐D‐aspartate receptor, and targets of fragile X mental retardation protein, are associated with this disorder. Depression is a heterogeneous group of diseases and studies using exome analysis have been conducted to identify rare mutations causing Mendelian diseases that accompany depression. In the near future, clarification of the genetic architecture of bipolar disorder and schizophrenia is expected. Identification of causative mutations using these new technologies will facilitate neurobiological studies of these disorders.     

A de novo dominant mutation in KIF1A associated with axonal neuropathy,spasticity and autism spectrum disorder

Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A.     

Dopaminergic modulation of resting‐state functional connectivity in de novo patients with Parkinson's disease

Parkinson's disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine‐dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP‐CIT positron emission tomography imaging and resting‐state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine‐dependent functional networks. The major finding is that the patterns of dopamine‐dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine‐dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine‐dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine‐dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine‐dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian‐related motor and cognitive performance. Hum Brain Mapp 35:5431–5441, 2014. © 2014 Wiley Periodicals, Inc .     

Re‐sequencing of ankyrin 3 exon 48 and case‐control association analysis of rare variants in bipolar disorder type I

Doyle GA, Lai AT, Chou AD, Wang M‐J, Gai X, Rappaport EF, Berrettini WH. Re‐sequencing of ankyrin 3 exon 48 and case‐control association analysis of rare variants in bipolar disorder type I. Bipolar Disord 2012: 14: 809–821. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Genome‐wide association studies (GWAS) recently identified ankyrin 3 (ANK3) as a candidate gene for bipolar disorder type I (BPD‐I). Because the GWAS suggested multiple common haplotypes associated with BPD‐I (with odds ratio ～1.3), we hypothesized that rare variants within these common haplotypes might increase risk for BPD‐I. Methods: We undertook a project in which the serine‐rich domain–tail domain (SRD‐TD)‐encoding exon of ANK3 was amplified from genomic DNA (gDNA) of 384 BPD‐I patients and re‐sequenced by next generation sequencing (NGS; SOLiD?). Results: We confirmed 18 novel mis‐sense rare variants and one novel insertion/deletion variant within the SRD‐TD exon, many of which change amino acid residues with extremely high evolutionary conservation. We genotyped most of these mis‐sense variants in ≥ 1000 BPD‐I and ≥ 1000 control individuals. We found no statistically significant association of any of the rare variants detected with BPD‐I. Conclusions: Thus, we conclude that rare variants within the re‐sequenced structural domains of ANK3 exon 48 do not contribute to BPD‐I.     

Identification of a de novo Lys304Gln mutation in the glycine receptor α‐1 subunit gene in a Korean infant with hyperekplexia

Startle disease or hyperekplexia (STHE; MIM 149400) is a rare disorder that is characterized by marked muscular hypertonia in infancy and an exaggerated startle response to unexpected acoustic or tactile stimuli. Mutations in the gene encoding the α‐1 subunit of the inhibitory glycine receptor (GLRA1) were reported as causes of STHE. Recently, we encountered a Korean male infant with generalized stiffness that was observed from the first 3 days of life. The abnormal startle response was evident from the fourth week of life, and he showed marked improvement in the startle response and muscle hypertonia after being administered phenobarbital and clonazepam. Direct sequencing analysis of the infant and his parents revealed a de novo variation (c.910A>C) in the GLRA1 gene, resulting in a novel Lys304Gln missense mutation. © 2007 Movement Disorder Society     

Mitochondrial myopathy with dystrophic features due to a novel mutation in the MTTM gene

Introduction: A 61‐year‐old woman with a 5‐year history of progressive muscle weakness and atrophy had a muscle biopsy characterized by a combination of dystrophic features (necrotic fibers and endomysial fibrosis) and mitochondrial alterations [ragged‐red, cytochrome c oxidase (COX)‐negative fibers]. Methods: Sequencing of the whole mtDNA, assessment of the mutation load in muscle and accessible nonmuscle tissues, and single fiber polymerase chain reaction. Results: Muscle mitochondrial DNA (mtDNA) sequencing revealed a novel heteroplasmic mutation (m.4403G>A) in the gene (MTTM) that encodes tRNA^Met. The mutation was not present in accessible nonmuscle tissues from the patient or 2 asymptomatic sisters. Conclusions: The clinical features and muscle morphology in this patient are very similar to those described in a previous patient with a different mutation, also in MTTM, which suggests that mutations in this gene confer a distinctive “dystrophic” quality. This may be a diagnostic clue in patients with isolated mitochondrial myopathy. Muscle Nerve 50:292–295, 2014