Nemaline Rod/Cap Myopathy Due to Novel Homozygous MYPN Mutations: The First Report from South Asia and Comprehensive Literature Review

Background@#and Purpose Pathogenic variants in the myopalladin gene (MYPN) are known to cause mildly progressive nemaline/cap myopathy. Only nine cases have been reported in the English literature. @*Methods@#A detailed evaluation was conducted of the clinical, muscle magnetic resonance imaging (MRI), and genetic findings of two unrelated adults with MYPN-related cap myopathy. Genetic analysis was performed using whole-exome sequencing. MRI was performed on a 1.5-T device in patient 1. @*Results@#Two unrelated adults born to consanguineous parents, a 28-year-old male and a 23-year-old female, were diagnosed with pathogenic variants in MYPN that cause cap myopathy. Both patients presented with early-onset, insidiously progressive, and minimally disabling proximodistal weakness with mild ptosis, facial weakness, and bulbar symptoms. Patient 1 had a prominent foot drop from the onset. Both patients were followed up at age 30 years, at which point serum creatine kinase concentrations were minimally elevated. There were no cardiac symptoms; electrocardiograms and two-dimensional echocardiograms were normal in both patients. Muscle MRI revealed preferential involvement of the glutei, posterior thigh muscles, and anterior leg muscles. Whole-exome sequencing revealed significant homozygous splicesite variants in both of the probands, affecting intron 10 of MYPN: c.1973+1G>C (patient 1) and c.1974-2A>C (patient 2). @*Conclusions@#This study elaborates on two patients with homozygous MYPN pathogenic variants, presenting as slowly progressive congenital myopathy. These patients are only the tenth and eleventh cases reported in the English literature, and the first from South Asia. The clinical phenotype reiterates the mild form of nemaline rod/cap myopathy. A comprehensive literature review is presented.

Nemaline Rod/Cap Myopathy Due to Novel Homozygous MYPN Mutations: The First Report from South Asia and Comprehensive Literature Review

Background@#and Purpose Pathogenic variants in the myopalladin gene (MYPN) are known to cause mildly progressive nemaline/cap myopathy. Only nine cases have been reported in the English literature. @*Methods@#A detailed evaluation was conducted of the clinical, muscle magnetic resonance imaging (MRI), and genetic findings of two unrelated adults with MYPN-related cap myopathy. Genetic analysis was performed using whole-exome sequencing. MRI was performed on a 1.5-T device in patient 1. @*Results@#Two unrelated adults born to consanguineous parents, a 28-year-old male and a 23-year-old female, were diagnosed with pathogenic variants in MYPN that cause cap myopathy. Both patients presented with early-onset, insidiously progressive, and minimally disabling proximodistal weakness with mild ptosis, facial weakness, and bulbar symptoms. Patient 1 had a prominent foot drop from the onset. Both patients were followed up at age 30 years, at which point serum creatine kinase concentrations were minimally elevated. There were no cardiac symptoms; electrocardiograms and two-dimensional echocardiograms were normal in both patients. Muscle MRI revealed preferential involvement of the glutei, posterior thigh muscles, and anterior leg muscles. Whole-exome sequencing revealed significant homozygous splicesite variants in both of the probands, affecting intron 10 of MYPN: c.1973+1G>C (patient 1) and c.1974-2A>C (patient 2). @*Conclusions@#This study elaborates on two patients with homozygous MYPN pathogenic variants, presenting as slowly progressive congenital myopathy. These patients are only the tenth and eleventh cases reported in the English literature, and the first from South Asia. The clinical phenotype reiterates the mild form of nemaline rod/cap myopathy. A comprehensive literature review is presented.

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort

BACKGROUND AND PURPOSE: Studies of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) confirmed by multiplex ligation-dependent probe amplification (MLPA) have determined the clinical characteristics, genotype, and relations between the reading frame and phenotype for different countries. This is the first such study from India. METHODS: A retrospective genotype-phenotype analysis of 317 MLPA-confirmed patients with DMD or BMD who visited the neuromuscular clinic of a quaternary referral center in southern India. RESULTS: The 317 patients comprised 279 cases of DMD (88%), 32 of BMD (10.1%), and 6 of intermediate phenotype (1.9%). Deletions accounted for 91.8% of cases, with duplications causing the remaining 8.2%. There were 254 cases of DMD (91%) with deletions and 25 (9%) due to duplications, and 31 cases (96.8%) of BMD with deletions and 1 (3.2%) due to duplication. All six cases of intermediate type were due to deletions. The most-common mutation was a single-exon deletion. Deletions of six or fewer exons constituted 68.8% of cases. The deletion of exon 50 was the most common. The reading-frame rule held in 90% of DMD and 94% of BMD cases. A tendency toward a lower IQ and earlier wheelchair dependence was observed with distal exon deletions, though a significant correlation was not found. CONCLUSIONS: The reading-frame rule held in 90% to 94% of children, which is consistent with reports from other parts of the world. However, testing by MLPA is a limitation, and advanced sequencing methods including analysis of the structure of mutant dystrophin is needed for more-accurate assessments of the genotype-phenotype correlation.

Identification of Ganglion cyst causing suprascapular nerve neuropathy by high resolution neurosonography

Suprascapular neuropathy is a rare cause of non-specific shoulder pain affecting all age groups. Magnetic resonance imaging is the most common modality utilized to investigate the cause of suprascapular neuropathy. We report here a case of 22 year old man who presented with diffuse right shoulder region pain and severe wasting of the right infraspinatus muscle of 2 months duration. He was engaged in regular overhead activities at a gymnasium for about 2 years. A possible diagnosis of suprascapular nerve entrapment was considered. The patient was investigated with high resolution neurosonography, which showed a ganglion (paralabral) cyst at the spinoglenoid notch compressing the suprascapular nerve. We propose the use of neurosonography as an economical and effective tool for initial screening of non-specific shoulder pain with or without wasting/weakness of scapular muscles. An early identification of the cause of the neuropathy prior to the onset of muscle weakness/ wasting, and therapeutic intervention is able to avoid permanent disability

Central motor conduction in brachial monomelic amyotrophy.

BACKGROUND: Prevalence of subclinical involvement of motor pathways in clinically diagnosed Brachial Monomelic Amyotrophy (BMMA) is unknown. AIMS: To determine the prevalence of subclinical involvement of central motor pathways in BMMA using transcranial magnetic stimulation. SETTING AND DESIGN: Prospective case-control study. MATERIALS AND METHODS: Central motor conduction time (CMCT) was determined by 'F' wave method using figure-of-eight coil attached to Magstim 200 stimulator, in 17 patients with BMMA. Motor evoked potentials were recorded from first dorsal interosseous of the affected (AFF) and unaffected upper limbs (UNAFF) at rest and during partial contraction. Comparison was made with data from 10 healthy controls (CTRL). STATISTICAL ANALYSIS: Descriptive analysis and Analysis of Variance (ANOVA). RESULTS: Compared to controls, the mean CMCT of AFF was significantly prolonged, both at rest and contraction: (a) Rest: AFF-6.68+/-1.78 ms, UNAFF-6.36+/-1.16 ms, CTRL-5.71+/-1.02 ms; Fisher's PLSD for AFF vs. CTRL: P =0.037, (b) Contraction: AFF-5.78+/-1.62 ms, UAFF - 4.86+/-1.38 ms, CTRL-4.06+/-0.80 ms; Fisher's PLSD for AFF vs. CTRL; P =0.0002, AFF vs. UNAFF- P =0.044). Prolonged CMCT (>mean+2SD of controls) was observed in 29.4% of AFF and 6.25% of UNAFF at rest, and in 47.1% and 23.5% respectively during contraction. CONCLUSIONS: Dysfunction of central motor pathways was observed in both affected and unaffected upper limbs of some patients with BMMA of upper limbs. The dysfunction was more pronounced during voluntary contraction. A larger study is needed to validate the significance of these findings.