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.
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.
Objectives: Frontotemporal dementia (FTD) syndromes are a complex group of disorders characterised by profound changes in behaviour and cognition. Many of the observed behavioural abnormalities are ...now recognised to be due to impaired social cognition. While deficits in emotion recognition and empathy are well-recognised in behavioural-variant (Bv)FTD, limited information exists about the nature of social cognitive impairment in the language variant primary progressive aphasia (PPA) that includes progressive non-fluent aphasia (PNFA) and semantic dementia (SD), and in the motor variants FTD amyotrophic lateral sclerosis (FTD-ALS) and FTD progressive supranuclear palsy (FTD-PSP). This prospective study sought to explore the nature and profile of social cognition deficits across the spectrum of FTD. Methods: Sixty patients on the FTD spectrum, i.e., classical (16 with BvFTD and 20 with PPA) and overlap FTD syndromes (13 with FTD-ALS and 11 with FTD-PSP) were evaluated by means of the social cognition tasks, the Interpersonal Reactivity Index (IRI) for empathy, and pictures of facial affect (POFA) for emotion recognition. General cognition and behaviour were also assessed. Results: A significant impairment in emotion recognition and empathy was detected in both the classical and overlap FTD syndromes. The recognition of positive emotions was relatively preserved compared to that of negative emotions. Among the FTD subtypes, maximal impairment of empathy was demonstrated in FTD-PSP. Conclusion: Social cognition impairment is pervasive across the spectrum of FTD disorders, and tests of emotion recognition and empathy are clinically useful to identify the nature of behavioural problems in both classical and overlap FTD. Our findings also have implications for understanding the neural basis of social cognition in FTD.
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.
To identify the distinct patterns of muscle involvement in GMPPB gene mutations.
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.
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.
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.
BACKGROUND AND PURPOSEPathogenic 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. ...METHODSA 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. RESULTSTwo 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). CONCLUSIONSThis 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.
Abstract
Calpainopathy is caused by mutations in the
CAPN3
. There is only one clinical and genetic study of
CAPN3
from India and none from South India. A total of 72 (maleM:female F = 34:38) ...genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique
CAPN3
variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.
Introduction. Histidine Triad Nucleotide binding protein 1 (HINT1) also known as Protein kinase C inhibitor 1 (PRKCNH-1); Protein kinase C interacting protein 1 (PKCI-1), mapped to chromosome 5q31, ...is a purine phosphoramidase homodimer and is ubiquitously expressed. HINT1 is a tumour suprresor gene and is involved in several apoptotic pathways. Biallelic variants in the HINT1 gene are known to cause Neuromyotonia with Axonal Neuropathy (NMAN). Zimon et al. have identified 8 HINT1 variants in 33 families of NMAN.
Results. A 13-year-old male child, born of consanguineous parentage; presented for the first time in 2018 with of bilateral foot drop of 2 years duration. This was followed one and half year later by bilateral forearm and hand muscle weakness in the form of finger and wrist drop with ulner deviation of the wrist. Hyperpigmentation of the knuckles was noted on the examination. Investigations were negative for screening of inborn errors of metabolism by Tandem mass spectrometry. His serum vitamin B12 level was 692 pg/ml (180-914 pg/ml). ENMG demonstrated neurogenic myotonia. NGS of the proband reported a pathogenic start-loss variation c.3G>C_NM005340.7 (p.Met1Ile) in the HINT1 gene aligned to human reference genome (GRCh37/hg19). The variant is not reported in the ClinVar and the Human gemone mutation (HGMD) databases. A variant at c.2T>C has been reported as likely pathogenic for NMAN in the ClinVar database. The variant is reported as damaging by SIFT, possibly damaging by PolyPhen2, and disease causing by MutationTaster2. CADD score is 24. The variant is not reported in gnomAD, 1000 genome and ExAC population frequency databases.
Conclusion. Rare genetic causes of CMT are important contributions to the full allelic spectrum of the disease. Here we report an ultra-rare NMAN case of Indian origin; mediated by a novel, pathogenic, biallelic start-loss variant in the HINT1 gene.
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