Phenotype-genotype spectrum of a cohort of congenital muscular dystrophies: a single-centre experience from India.

Congenital Muscular Dystrophies (CMD) are phenotypically and genotypically heterogenous disorders with a prevalence of 0.68 to 2.5/100,000, contributing to significant morbidity and mortality. We aimed to study the phenotype-genotype spectrum of genetically confirmed cases of CMD. This was retrospective & descriptive study done at a quaternary care referral centre in south India. Genetically confirmed cases of CMDs seen between 2010 to 2020 were recruited. Detailed clinical history, including pedigree, MRI brain/muscle, next generation sequencing results of 61 CMD cases were collected. Collagen VI-related dystrophy (COL6-RD) (36%) was the most common subtype with variants frequently seen in COL6A1 gene. Other CMDs identified were LAMA2-RD (26%), alpha-dystroglycan-RD (19%), LMNA-RD (8%), CHKB-RD (7%) and SEPN1-RD (3%). Similar to previous cohorts, overall, missense variants were common in COL-6 RD. Variants in triple helical domain (THD) of COL6-RD were seen in 11/22 patients, 5 of whom were ambulatory contrary to previous literature citing severe disease with these variants. However, our follow-up period was shorter. In the LAMA2-RD, 2/16 patients were ambulatory & all 16 carried truncating variants. Among dystroglycanopathies, FKRP-RD was the commonest. Milder phenotype of FKRP- RD was observed with variant c.1343C > T, which was also a recurrent variant in our cohort. p.Arg249Trp variant in LMNA-CMD associated with early loss of ambulation was also identified in 1/5 of our patients who expired at age 2.8 years. The current retrospective series provides detailed clinical features and mutation patterns of genetically confirmed cases of CMD from a single center in India.

Genotype-phenotype correlation and natural history study of dysferlinopathy: a single-centre experience from India.

Dysferlinopathies are a group of limb-girdle muscular dystrophies causing significant disability in the young population. There is a need for studies on large cohorts to describe the clinical, genotypic and natural history in our subcontinent. To describe and correlate the clinical, genetic profile and natural history of genetically confirmed dysferlinopathies. We analysed a retrospective cohort of patients with dysferlinopathy from a single quaternary care centre in India. A total of 124 patients with dysferlinopathy were included (40 females). Median age at onset and duration of illness were 21 years (range, 13-50) and 48 months (range, 8-288), respectively. The average follow-up period was 60 months (range, 12-288). Fifty-one percent had LGMD pattern of weakness at onset; 23.4% each had Miyoshi and proximo-distal type while isolated hyperCKemia was noted in 1.6%. About 60% were born to consanguineous parents and 26.6% had family history of similar illness. Twenty-three patients (18.6%) lost ambulation at follow-up; the median time to loss of independent ambulation was 120 months (range, 72-264). Single-nucleotide variants (SNVs) constituted 78.2% of patients; INDELs 14.5% and 7.3% had both SNVs and INDELs. Earlier age at onset was noted with SNVs. There was no correlation between the other clinical parameters and ambulatory status with the genotype. Thirty-seven (45.7%) novel pathogenic/likely pathogenic (P/LP) variants were identified out of a total of 81 variations. The c.3191G > A variant was the most recurrent mutation. Our cohort constitutes a clinically and genetically heterogeneous group of dysferlinopathies. There is no significant correlation between the clinico-genetic profile and the ambulatory status.

Muscle ultrasonography in detecting fasciculations: A noninvasive diagnostic tool for amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVES: Muscle ultrasound (MUS) is an emerging noninvasive tool to identify fasciculations in amyotrophic lateral sclerosis (ALS). We assessed the utility of MUS in detecting fasciculations in suspected ALS patients. METHODS: Thirty-three patients (25 men) with possible (n = 7), probable (n = 12), or definite ALS according to Awaji criteria were studied. Electromyography was done in biceps brachii, quadriceps, and thoracic paraspinal muscles and MUS in biceps, triceps, deltoid, abductor-digiti-minimi, quadriceps, hamstrings, tibialis anterior, thoracic paraspinal, and tongue muscles. RESULTS: The age at onset and illness duration was 49.73 ± 12.7 years and 13.57 ± 9.7 months, respectively. Limb-onset = 24 patients (72.7%) and bulbar-onset = 9 (27.3%). Totally 561 muscles were examined by MUS. Fasciculations were detected in 84.3% of muscles, 98.4% with and 73% without clinical fasciculations (p < 0.001). Fasciculation detection rate (FDR) by MUS was significantly higher in muscles with wasting (95.6%) than without wasting (77.6%, p < 0.001). Compared with EMG, FDR was significantly higher with MUS in quadriceps (81.8% vs. 51.5%, p = 0.002) and thoracic paraspinal muscles (75.8% vs. 42.4%, p = 0.013). The proportion of patients with definite ALS increased from 42% by clinical examination to 70% after combining EMG and MUS findings. CONCLUSIONS: MUS is more sensitive in detecting fasciculations than electromyography (EMG) and provides a safer, faster, painless, and noninvasive alternative to EMG in detecting fasciculations in ALS.

Diaphragmatic ultrasound: Prospects as a tool to assess respiratory muscle involvement in amyotrophic lateral sclerosis.

BACKGROUND: Ultrasonography (USG) of the diaphragm is a promising alternative to pulmonary function tests (PFT) for assessing respiratory function in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). METHODS: We studied 33 patients fulfilling Awaji criteria (definite = 14; probable = 12; possible = 7) and 33 age and gender-matched controls. Diaphragm thickness was measured using USG at the end of expiration (DTex) and end of inspiration (DTin). The thickness ratio (TR) was calculated as DTin/DTex. The mean age at onset and duration were 49.73 ± 12.7 years and 13.57 ± 9.7 months, respectively. Men = 25 (75.8%); Limb onset ALS/MND = 24 patients (72.7%); bulbar onset = 9 (27.3%). RESULTS: Compared to controls, ALS/MND patients had reduced mean DTex (2.22 ± 0.29 mm vs. 2.02 ± 0.32 mm, p = .012) and DTin (4.0 ± 0.71 mm vs. 3.41 ± 0.38 mm, p < .001). PFTs done in 31 patients showed restrictive abnormality in 80.6%. Significant positive correlation was seen between percentage of predicted forced vital capacity (FVC%) and DTin (p = .009) and TR (p = .037) but not with DTex (p = .852). No significant correlation was seen between diaphragmatic thickness and other PFT parameters or ALSFRS scores. CONCLUSION: The diaphragmatic thickness showed a significant decrease in ALS/MND as compared to controls. End-inspiratory diaphragmatic thickness and TR correlated well with %FVC. Thus, diaphragmatic USG could be a potential alternative to PFTs in assessing respiratory function in ALS/MND patients having the advantage of less patient participation and ease of performing in late stages of ALS/MND.

A founder mutation in the GMPPB gene [c.1000G > A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients.

Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing-based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.

Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

Myotonic Dystrophy Type 1 (DM1): Clinical Characteristics and Disease Progression in a Large Cohort.

BACKGROUND: DM1 is a multisystem disorder caused by expansion of a CTG triplet repeat in the 3' non-coding region of DMPK. Neuropsychological consequences and sleep abnormalities are important associations in DM1. OBJECTIVE: To describe the clinical phenotype, disease progression and characterize the sleep alterations and cognitive abnormalities in a sub-set of patients. MATERIALS AND METHODS: A retrospective study on 120 genetically confirmed DM1 cases. Findings in neuropsychological assessment and multiple sleep questionnaires were compared with 14 age and sex matched healthy individuals. All 120 patients were contacted through letters/telephonic consultation/hospital visits to record their latest physical and functional disabilities. RESULTS: The mean age at symptom onset was 23.1 ± 11.4 years, M: F = 3.8:1, mean duration of illness = 14.3 ± 9.5 years. Clinically 54.2% had adult onset form, juvenile = 27.5%, infantile = 10.8%, late adult onset = 7.5%. Paternal transmission occurred more frequently. The predominant initial symptoms were myotonia (37.5%), hand weakness (21.7%), lower limb weakness (23.3%) and bulbar (10%). Twenty patients completed sleep questionnaires (SQ). Abnormal scores were noted in Epworth sleepiness scale (55%); Pittsburgh sleep quality index (45%); Berlin SQ (30%); Rapid eye movement sleep Behaviour Disorder SQ (15%); Restless leg syndrome rating scale (10%). Neuropsychological assessment of 20 patients revealed frontal executive dysfunction, attention impairment and visuospatial dysfunction. Frontal lobe was most affected (72%) followed by parietal (16%) and temporal lobe (12%). CONCLUSIONS: The current study provides a comprehensive account of the clinical characteristics in Indian patients with DM1. Hypersomnolence was most commonly seen. Excessive daytime sleepiness and Sleep disordered breathing were the most common sleep related abnormality. Cognitive impairment comprised predominantly of frontal lobe dysfunction.

Tofersen: Silver Lining or Hyperbole??

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not have a cure for this disorder. Edaravone, Riluzole, and combination of phenylbutyrate and taurursodiol are a handful of FDA-approved drugs that only delay the progression of the disease by a few months. Tofersen, an antisense oligonucleotide, in SOD1 related ALS, has joined the bandwagon of FDA-approved drugs for ALS recently. It is a gene therapy that has been found to lower SOD1 concentrations and neurofilament light chain concentrations in blood and CSF, a known biomarker of ALS, leading to the accelerated approval of the drug. Although it did not show any statistically significant clinical improvement. In this article, we discuss the development and approval process of the first gene-based therapy, Tofersen, for ALS.

Uncommon Bilateral Carotid Artery Dissection in a Farmer: The Perils of Heavy Weight Lifting.

Bilateral internal carotid artery (ICA) dissection on heavy weight lifting is a very rare cause of stroke in young patients. Arterial dissection is due to a tear in the intima and internal elastic lamina which leads to extravasation of blood into the media and subintimal plane. Clinical diagnosis of carotid artery dissection is difficult with common clinical presentations like headache and neck pain. Here we present a case of a 40-year-old young man who presented to us (tertiary referral center) with headache and quadriparesis. MRI brain showed multiple acute infarcts in bilateral centrum semiovale extending up to frontal periventricular white matter with few tiny foci in bilateral medial temporal and left gangliocapsular regions and CT cerebral angiography showed bilateral ICA dissection. He was treated with low molecular weight heparin and was discharged for follow-up with regular physiotherapy.

Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes.

BACKGROUND: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. MATERIALS AND METHODS: We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. RESULTS: The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). CONCLUSION: We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).

Mutation Spectrum of Primary Lipid Storage Myopathies.

Background: Lipid storage myopathies (LSM) constitute an important group of treatable myopathies. Genetic testing is essential for confirming the diagnosis and also helps in explaining phenotypic heterogeneity. The objective of this study was to describe the clinical features and genetic spectrum of LSM seen in a quaternary referral center in India. Methods: Eleven cases of suspected LSM underwent clinical, biochemical, histopathological and genetic evaluation. Tandem Mass Spectrometry and clinical exome sequencing with Sanger validation were performed. Results: All patients had exertion induced myalgia and either progressive or episodic limb girdle muscle weakness (LGMW). The age of onset ranged 10 to 31 years (mean- 21 ± 6.7y), age at presentation- 14 to 49 years (mean- 26.5 ± 9.5y). Mutations identified: ETFDH = 5, CPT2 = 3, FLAD1 = 1, ACADVL = 1, FLAD1 = 1. Dropped head syndrome was seen in two patients with ETFDH mutations. Bulbar symptoms and Beevor's sign were noted in a patient with FLAD1 variant. Novel variants were identified in seven patients. Conclusions: This is the first report on the genetic spectrum of LSM from India. LSM should be considered in patients with exertion induced myalgias, LGMW, cranial nerve involvement or dropped head syndrome. Genetic testing is essential for identification of these treatable disorders.

PET-MRI in idiopathic inflammatory myositis: a comparative study of clinical and immunological markers with imaging findings.

BACKGROUND: We sought to determine the utility of PET-MRI in diagnosing Idiopathic Inflammatory Myositis (IIM), and look for association between FDG uptake and clinical, pathological and laboratory parameters. METHODS: A retrospective, observational study was conducted on IIM patients having positive serum autoantibodies and who underwent PET-MRI (3-Tesla SIEMENS Biograph MR scanner) between 2017 and 2021. Thirty patients who underwent PET-MRI to detect systemic metastasis without muscle involvement formed the control group. RESULTS: In the IIM cohort, female: male sex ratio was 1.73, mean age at diagnosis was 40.33 years, and the mean duration of illness was 7 months. 33.33% of patients had severe limb weakness. Mi2B (43.33%), Mi2A (43.33%), PL-7(10%), PL-12(6.67%), SRP (16.67%), Tif1gamma (3.33%), NxP2 (3.33%), Ro-52(40%), PM-Scl, U1-RNP, ANA (26.67%) were the serum autoantibodies identified. Using SUV max Ratio to quantify FDG uptake, PET-MRI showed a sensitivity of 100% with 93.3% specificity in diagnosing IIM.FDG uptake was maximum in proximal lower limb region followed by proximal upper limb. Multivariate regression analysis showed that the severity of muscle weakness, serum Mi2B antibody positivity and serum creatinine kinase levels had a significant positive correlation with FDG uptake (value of 0.005, 0.043, 0.042, respectively for whole-body FDG uptake). FDG uptake also showed good correlation with histopathological features and muscle MRI, but there was no significant association with treatment response. Three female patients in our cohort had primary malignancy involving the breast, uterus, and cervix. CONCLUSIONS: PET-MRI is a promising diagnostic modality for IIM. PET-MRI reflects the severity of muscle inflammation, showing good association with various clinical/laboratory parameters, histopathology, and muscle MRI. Parameters associated with severe muscle inflammation in PET-MRI-clinical severity of muscle weakness, Mi2B positivity, and serum creatine kinase levels-may be used as clinical/laboratory markers of disease severity in IIM. PET-MRI has the added advantage of detection of systemic malignancy.

Distinct and Recognisable Muscle MRI Pattern in a Series of Adults Harbouring an Identical GMPPB Gene Mutation.

BACKGROUND AND PURPOSE: Mutations in the GMPPB gene affect glycosylation of α-dystroglycan, leading to varied clinical phenotypes. We attempted to delineate the muscle MR imaging spectrum of GMPPB-related Congenital Myasthenic syndrome (CMS) in a single-center cohort study. OBJECTIVE: To identify the distinct patterns of muscle involvement in GMPPB gene mutations. METHODS: We analyzed the muscle MR images of 7 genetically proven cases of GMPPB dystroglycanopathy belonging to three families and studied the potential qualitative imaging pattern to aid in clinico -radiological diagnosis in neuromuscular practice. All individuals underwent muscle MRI (T1, T2, STIR/PD Fat sat. sequences in 1.5 T machine) of the lower limbs. Qualitative assessment and scoring were done for muscle changes using Mercuri staging for fibro-fatty replacement on T1 sequence and Borsato score for myoedema on STIR sequence. RESULTS: All patients were of South Indian origin and presented as slowly progressive childhood to adult-onset fatigable limb-girdle muscle weakness, elevated creatine kinase level, and positive decrement response in proximal muscles. Muscle biopsy revealed features of dystrophy. All patients demonstrated identical homozygous mutation c.1000G > A in the GMPPB gene. MRI demonstrated early and severe involvement of paraspinal muscles, gluteus minimus, and relatively less severe involvement of the short head of the biceps femoris. A distinct proximo-distal gradient of affliction was identified in the glutei, vasti, tibialis anterior and peronei. Also, a postero-anterior gradient was observed in the gracilis muscle. CONCLUSION: Hitherto unreported, the distinctive MR imaging pattern described here, coupled with relatively slowly progressive symptoms of fatigable limb-girdle weakness, would facilitate an early diagnosis of the milder form of GMPPB- dystroglycanopathy associated with homozygous GMPPB gene mutation.

Cognitive Dysfunction in Juvenile Myoclonic Epilepsy (JME) - A Tertiary Care Center Study.

BACKGROUND AND AIM: Epilepsy often leads to cognitive impairment. Idiopathic generalized epilepsy as a group is considered to be benign in terms of its effects on cognition. Though, neuropsychological testing reveals subtle frontal impairment in patients with juvenile myoclonic epilepsy (JME). The aim of this study is to evaluate cognitive dysfunction in patients with JME. METHOD: We compared 50 JME patients and 50 age and sex matched healthy controls above 12 years of age on various cognitive tests which included Mini Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Executive Interview (EXIT), PGI Memory Scale (PGIMS), Clock Drawing Test (CDT), Cube copying test (CCT), and Nahor Benson Test (NBT). We correlated the cognitive dysfunction with education level, age of onset, duration of epilepsy, electroencephalogram (EEG) abnormalities, treatment, and seizure control status. RESULTS: JME patients performed significantly worse on MMSE (P = 0.001), PGI MS (P value = 0.001), FAB (P =.001), EXIT (P =.001), CDT (P =.02), and CCT (P =.001) when compared to the controls. JME patients had impaired attention, verbal fluency, design fluency, verbal memory, visual memory, conceptualization, set shifting, mental flexibility, response inhibition, and visuospatial functions. Cognitive dysfunction correlated with education level, duration of epilepsy and EEG abnormality. No correlation was seen with seizure frequency or type of antiepileptic therapy. CONCLUSIONS: JME patients demonstrate both frontal and parietooccipital lobe dysfunction. Hence detailed higher mental function tests supplemented by functional neuroimaging studies should be done in JME patients for their comprehensive management. This would also enhance our knowledge about the pathogenesis of JME.

Case Report: Post-Chikungunya-Associated Myeloneuropathy.

Chikungunya virus (CHIKV) is an arbovirus endemic to South Asia with frequent outbreaks. A wide spectrum of neurological complications has been described in Chikungunya infections. Myeloneuropathy is a rare complication seen in Chikungunya and is proposed to have an underlying immune mediated pathogenesis. We report a case of a 45-year-old man presenting to the emergency services with acute onset of quadriparesis, breathlessness, urinary retention, profound pain, and sensory disturbances 6 weeks after the onset of high-grade fever and arthralgia. On examination, the patient had Medical Research Council grade 1 flaccid quadriparesis with prominent wasting and areflexia with distinct sensory level at T4. Immunoglobulin M CHIKV antibodies were positive, tested twice at a 1-week interval. He had notable magnetic resonance imaging (MRI) findings in the form of patchy T2 hyperintensities involving the entire length of the cervical and thoracic cord with normal brain imaging and extensive short tau inversion recovery hyperintense signal changes on muscle MRI. He was treated with five cycles of plasmapheresis and intravenous methylprednisolone followed by oral steroids for 8 weeks. At 20-week follow-up, the patient had improvement in upper limb weakness, but paraparesis persisted. The case highlights the presence of unusual MRI findings and also the importance of early recognition of after infective neurological complications, and prompt treatment with immunomodulation may be beneficial.

Lead Encephalopathy with Distinctive Brain Magnetic Resonance Imaging Findings.

Lead poisoning is a multisystem disorder, more commonly affecting children. Occupational exposure, traditional medicines, and contaminated alcohol have been associated with lead encephalopathy in adults. Herein, we report a patient of lead toxicity presenting to the emergency services as acute encephalopathy with symptomatic hyponatremia and chronic recurrent abdominal colic and vomiting. This 50-year-old battery mechanic had multisystem involvement with anemia, basophilic stippling, lead line on the gums, and chronic hypertension. The blood lead level was more than 65 mcg/dL. Computed tomography of the brain showed intracranial calcifications and the MRI brain showed bilateral symmetric involvement of the thalamus, basal ganglia, brainstem, and external capsule. His sensorium improved rapidly after the correction of hyponatremia, however, apathy and psychomotor slowing persisted. This case highlights the importance of recognizing clinical markers and characteristic imaging findings, which can provide clues to an early diagnosis of this otherwise rare clinical condition, and prompt chelation therapy and avoid further lead exposure.

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 splice-site 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.

Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes - A recognizable clinical phenotype.

Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes.

Comparison of The Carrier Frequency of Pathogenic Variants of DMD Gene in an Indian Cohort.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder caused due to large deletions, duplications,and small pathogenic variants. This article compares the carrier frequency of different pathogenic variants in the DMD gene for the first time in an Indian cohort. METHODS: Ninety-one mothers of genetically confirmed DMD probands are included in this study. Pathogenic variants in the DMD gene in probands were detected by multiplex ligation-dependent probe amplification (MLPA) or next-generation sequencing (NGS). Maternal blood samples were evaluated either by MLPA or Sanger sequencing. The demographic and clinical details for screening of muscle weakness and cardiomyopathy were collected from the confirmed carriers. RESULTS: Out of 91 probands, large deletions and duplications were identified in 46 and 6 respectively, while 39 had small variants. Among the small variants, substitutions predicted to cause nonsense mutations were the most common (61.5%), followed by frameshift causing small insertion/deletions (25.6%) and splice affecting intronic variants (12.8%). Notably, 19 novel small variants predicted to be disease-causing were identified. Of the 91 mothers, 53 (58.7%) were confirmed to be carriers. Exonic deletions had a significantly lower carrier frequency of 47.8% as compared to small variants (64.1%). The mean age of the carriers at evaluation was 30 years. Among the carriers, two were symptomatic with onset in the 4th decade, manifesting with progressive proximal muscle weakness and dilated cardiomyopathy. CONCLUSION: Carrier frequency of small pathogenic variants differs significantly from large deletions. Small pathogenic variants are more commonly inherited, whereas large deletions arise de novo.