Identification of a Novel Intronic Mutation in VMA21 Associated with a Classical Form of X-Linked Myopathy with Autophagy.

Introduction VMA21 -related myopathy is one of the rare forms of slowly progressive myopathy observed in males. Till now, there have been only a handful of reports, mainly from Europe and America, and two reports from India. Method Here, we describe a case of genetically confirmed VMA21 -associated myopathy with clinical, histopathological, and imaging features with a list of known VMA21 mutations. Results A 29-year-old man had the onset of symptoms at 18 years of age with features of proximal lower limb weakness. Muscle magnetic resonance imaging showed the preferential involvement of vasti and adductor magnus. A biopsy of the left quadriceps femoris showed features of autophagic vacuolar myopathy with vacuoles containing granular eosinophilic materials. In targeted next-generation sequencing, hemizygous mutation in the 3' splice site of intron 2 of the VMA21 gene (c.164-7 T > A) was identified and confirmed the diagnosis of X-linked myopathy with excessive autophagy. Conclusion This report expands the phenotypic and genotypic profile of VMA21 -related myopathy, with a yet unreported mutation in India.

Partial loss of desmin expression due to a leaky splice site variant in the human DES gene is associated with neuromuscular transmission defects.

Recessive desminopathies are rare and often present as severe early-onset myopathy. Here we report a milder phenotype in three unrelated patients from southern India (2 M, 1F) aged 16, 21, and 22 years, who presented with childhood-onset, gradually progressive, fatigable limb-girdle weakness, ptosis, speech and swallowing difficulties, without cardiac involvement. Serum creatine kinase was elevated, and repetitive nerve stimulation showed decrement in all. Clinical improvement was noted with pyridostigmine and salbutamol in two patients. All three patients had a homozygous substitution in intron 5: DES(NM_001927.4):c.1023+5G>A, predicted to cause a donor splice site defect. Muscle biopsy with ultrastructural analysis suggested myopathy with myofibrillar disarray, and immunohistochemistry showed partial loss of desmin with some residual staining, while western blot analysis showed reduced desmin. RT-PCR of patient muscle RNA revealed two transcripts: a reduced normal desmin transcript and a larger abnormal transcript suggesting leaky splicing at the intron 5 donor site. Sequencing of the PCR products confirmed the inclusion of intron 5 in the longer transcript, predicted to cause a premature stop codon. Thus, we provide evidence for a leaky splice site causing partial loss of desmin associated with a unique phenotypic presentation of a milder form of desmin-related recessive myopathy overlapping with congenital myasthenic syndrome.

Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant.

Background and Objectives: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy. Methods: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records. Results: All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene. Discussion: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.

A novel DHTKD1 gene mutation with ALS like presentation: a case report.

DHTKD1 is a nuclear gene that encodes "dehydrogenase E1 and transketolase domain-containing 1", essential in mitochondrial metabolism. First identified in the patients of 2-amino-apidic and 2 oxoapidic aciduria, mutation in this gene has recently been implicated in CMT2Q and ALS. Here we report the case of a septuagenarian who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical exome sequencing revealed a heterozygous nonsense variant in exon 8 of the DHTKD1 gene, which was previously described in CMT2Q. This report highlights the pleotropic phenotypic presentation of DHTKD1 mutation and the need for genetic testing even in sporadic cases of ALS presenting at a later age.

Clinical spectrum, biochemical profile and disease progression of Kennedy disease in an Indian cohort.

BACKGROUND: Kennedy disease (KD) is a slowly progressive lower motor neuron degenerative disease. The prevalence of KD is unknown in India. AIM: To describe the phenotypic and laboratory features of an Indian cohort of KD patients. METHODS: A retrospective study was done on seven genetically confirmed KD patients based on demographic, clinical and laboratory details. RESULTS: Mean age at onset and presentation was 37 ± 11.9 and 44.6 ± 13.5 years respectively. Progressive asymmetric proximal and distal limb weakness was the commonest symptom (57.1%). All patients had motor symptoms along with non-specific symptoms such as cramps from the onset. Easy fatigability, decremental response along with ptosis were noted in two patients, which was a novel finding. Gynaecomastia and tongue wasting with fasciculations were universal findings. All five patients with nerve conduction studies showed sensorimotor neuropathy. Magnetic resonance imaging muscle done in two patients showed a prominent moth-eaten appearance in the thigh and posterior leg compartment in one patient. The mean cytosine-adenine-guanine repeats were 44 ± 3.7, and there was no association between age of onset or severity with repeat length. Only one patient required an assistive device for ambulation after 15 years of symptom onset. CONCLUSIONS: This study showed phenotypic heterogeneity in the Indian cohort. The age of onset was earlier with a slowly progressive indolent course as compared with other ethnic cohorts. This highlights the importance of considering the KD diagnosis in patients with the indolent course and suspected ALS diagnosis even with ptosis and fatigability in an appropriate clinical context.

Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort.

Congenital myasthenic syndromes (CMS) are a rare group of inherited disorders caused by gene defects associated with the neuromuscular junction and potentially treatable with commonly available medications such as acetylcholinesterase inhibitors and ß2 adrenergic receptor agonists. In this study, we identified and genetically characterized the largest cohort of CMS patients from India to date. Genetic testing of clinically suspected patients evaluated in a South Indian hospital during the period 2014-19 was carried out by standard diagnostic gene panel testing or using a two-step method that included hotspot screening followed by whole-exome sequencing. In total, 156 genetically diagnosed patients (141 families) were characterized and the mutational spectrum and genotype-phenotype correlation described. Overall, 87 males and 69 females were evaluated, with the age of onset ranging from congenital to fourth decade (mean 6.6 ± 9.8 years). The mean age at diagnosis was 19 ± 12.8 (1-56 years), with a mean diagnostic delay of 12.5 ± 9.9 (0-49 years). Disease-causing variants in 17 CMS-associated genes were identified in 132 families (93.6%), while in nine families (6.4%), variants in genes not associated with CMS were found. Overall, postsynaptic defects were most common (62.4%), followed by glycosylation defects (21.3%), synaptic basal lamina genes (4.3%) and presynaptic defects (2.8%). Other genes found to cause neuromuscular junction defects (DES, TEFM) in our cohort accounted for 2.8%. Among the individual CMS genes, the most commonly affected gene was CHRNE (39.4%), followed by DOK7 (14.4%), DPAGT1 (9.8%), GFPT1 (7.6%), MUSK (6.1%), GMPPB (5.3%) and COLQ (4.5%). We identified 22 recurrent variants in this study, out of which eight were found to be geographically specific to the Indian subcontinent. Apart from the known common CHRNE variants p.E443Kfs*64 (11.4%) and DOK7 p.A378Sfs*30 (9.3%), we identified seven novel recurrent variants specific to this cohort, including DPAGT1 p.T380I and DES c.1023+5G>A, for which founder haplotypes are suspected. This study highlights the geographic differences in the frequencies of various causative CMS genes and underlines the increasing significance of glycosylation genes (DPAGT1, GFPT1 and GMPPB) as a cause of neuromuscular junction defects. Myopathy and muscular dystrophy genes such as GMPPB and DES, presenting as gradually progressive limb girdle CMS, expand the phenotypic spectrum. The novel genes MACF1 and TEFM identified in this cohort add to the expanding list of genes with new mechanisms causing neuromuscular junction defects.

Monomelic Amyotrophy/Hirayama Disease: Surgical Outcome in a Large Cohort of Indian Patients.

BACKGROUND: Hirayama disease (HD) is a cervical compressive myelopathy. Anterior cervical discectomy and fusion (ACDF) is identified as the best surgical approach. We evaluated surgical outcomes and factors influencing ACDF in HD. METHODS: Between 2015 and 2019, 126 patients with HD underwent ACDF. Contrast magnetic resonance imaging of the cervical spine in full flexion was performed. Clinical examination and preoperative/postoperative assessment of hand function using Fugl-Meyer assessment, Jebsen-Taylor hand function test, and handheld dynamometry were performed at 3-monthly intervals for 1 year. Surgical outcomes were assessed as per the Odom criteria and Hirayama outcome questionnaire. RESULTS: Age at onset and duration of illness were 12-31 years (mean, 18 ± 2.7) and 1-96 months (32.7 ± 24.4), respectively. All patients had progressive weakness and wasting of the affected limb. Cord atrophy was seen in 97.1%, with epidural detachment and engorgement of the posterior epidural venous plexus in all. All patients underwent ACDF. Of these patients, 54% had an excellent/good outcome and 39% had a satisfactory outcome as per the Odom scale at last follow-up (mean, 44.9 ± 16.5 months) after surgery. Handheld dynamometry showed improvement from preoperative values to 1 year follow-up. Duration of illness and age at onset had a negative correlation and the preoperative Fugl-Meyer score had a positive correlation with improvement. CONCLUSIONS: ACDF resulted in remarkable improvement or stabilization in neurologic deficits in many patients with HD. Because motor disability ensues over time, early surgical intervention during the progressive phase is advocated.

Adult Onset Episodic Encephalopathy Due to Citrin Deficiency-A Case Report.

Hyperammonemia is a rare cause of adult episodic encephalopathy. Citrin deficiency resulting in citrullinemia type 2 (CTLN2) can lead to recurrent delirium in adults. Here we report a case of adult onset episodic encephalopathy due to citrin deficiency. A 40 years old male presented with one-year history of episodic encephalopathy triggered by high protein and fat diet. He also had chronic pancreatitis and subacute intestinal obstruction which is a novel manifestation of CTLN2. Evaluation showed elevated blood liver enzymes, ammonia, and citrulline. MRI brain showed frontal hyperintensities and bulky basal ganglia which have not been reported. Diagnosis was confirmed by next-generation sequencing which showed a novel variant c. 1591G > A in exon15 of SLC25A13. Hyperammonemic syndromes should be considered in differential diagnosis of episodic encephalopathy in adults. This report shows novel features of subacute intestinal obstruction and MRI findings in CTLN2 expanding spectrum of manifestation.

Atypical Presentation of Tangier Disease-Expanding the Clinical Spectrum.

ABSTRACT: Tangier disease is an autosomal recessive multisystem metabolic disorder with neuromuscular manifestations including peripheral neuropathy such as multifocal mononeuropathy or pseudosyringomyelia patterns. We report a novel phenotype of Tangier disease with predominant anterior horn cell involvement. A 16-year-old adolescent girl born to consanguineous parents had a 1-year history of hip girdle weakness with waddling gait and progressive atrophy of the right leg. She had orange tonsils, prominent lingual tonsils, soft skin, distal joint laxity, diffuse hypotonia with asymmetric wasting of legs, proximodistal moderate weakness in lower limbs, and tendon reflexes were hypoactive. The creatine kinase level was 70 U/L. Serum showed an abnormally low level of high- and low-density lipoprotein. Whole-exome sequencing showed a novel likely pathogenic splice site homozygous mutation c.2542+1G > A in the ABCA1 gene at intron 17. Hence, a high degree of suspicion and search for peripheral clinical markers is needed in patients with unusual anterior horn cell syndromes.

MYH2-related Myopathy: Expanding the Clinical Spectrum of Chronic Progressive External Ophthalmoplegia (CPEO).

Chronic progressive external ophthalmoplegia (CPEO) is symptom complex with progressive ptosis and restricted ocular motility without diplopia. MYH2 myopathy is rare disorder presenting with CPEO and muscle weakness. We report two Indian patients of MYH2 myopathy with unique features. Patient-1 presented with early adult-onset esophageal reflux followed by, proximal lower limb weakness, proptosis, CPEO without ptosis. He had elevated creatine kinase along with characteristic muscle MRI findings of prominent semitendinosus and medial gastrocnemius involvement. Patient -2 presented with early adult onset CPEO without limb weakness. His creatine kinase was normal. Both the patients had novel MYH2 mutations: a homozygous 5'splice variation in intron 4 (c.348 + 2dup) in patient 1 and homozygous single base pair deletion in exon 32 (p. Ala1480ProfsTer11) in patient 2. Unique features noted include adult onset, isolated CPEO, proptosis, esophageal reflux disease and absence of skeletal abnormalities. MYH2 myopathy has to be considered in adult patients with CPEO.

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.

A Rare Case of Neurosyphilis Presenting As Normal Pressure Hydrocephalus Syndrome.

Neurosyphilis, a chronic infection of the nervous system by Treponema pallidum can present in all stages of syphilis. Recently, it is found that neurosyphilis presents with novel manifestations. Here, we report a young patient who had neurosyphilis presenting as Normal Pressure Hydrocephalus (NPH) with bilateral optic atrophy. The patient showed improvement with treatment for neurosyphilis. Hence, it is evident that in young patients presenting with NPH and associated features, secondary etiologies should be investigated.

A Rare Case of Eosinophilic Myelitis Due to Gnathostomiasis.

Eosinophilic myelitis is an important cause of transverse myelopathy and has to be considered in an appropriate clinical setting. Eosinophilic myelitis due to parasitic infection should be suspected in cases with cerebrospinal fluid (CSF) eosinophilia along with migratory serpiginous skin lesions and recent travel to endemic areas. We report a case with a 1-month history of fever followed by truncal paresthesias, erythematous creeping skin eruptions, and paraparesis with blood and CSF eosinophilia on a background history of consuming undercooked fish. Magnetic resonance imaging (MRI) spine showed long segment T2 hyperintensities with contrast enhancement. He was tested positive for 24kDa antigenic component of Gnathostoma spinigerum in CSF and serum by immunoblot testing. The patient showed significant improvement with parenteral steroids.

Antibodies to Zika virus, Campylobacter jejuni and gangliosides in Guillain-Barre syndrome: A prospective single-center study from southern India.

BACKGROUND: The objective of this article was to study the presence of antibodies against Zika virus (ZIKV), Campylobacter jejuni, and gangliosides in patients with Guillain-Barre syndrome (GBS). MATERIALS AND METHODS: Ninety consecutive patients (age more than 12 years) with GBS admitted to a tertiary care center in southern India were included in this study. Data on clinical manifestations, nerve conduction studies, and response to therapy were collected. The following tests were done in stored serum samples - anti-ZIKV (IgM) antibodies, anti-C. jejuni (IgG) antibodies, and anti-ganglioside antibodies (IgG). Those samples which were positive to anti-Zika antibodies were tested for conventional polymerase chain reaction for ZIKV and IgM antibodies against dengue, and Japanese encephalitis virus. RESULTS: Of the 90 patients, 3 died and 8 had persistent weakness. Acute inflammatory demyelinating polyradiculoneuropathy was the most common type of GBS (56.7%). Anti-ganglioside antibodies were present in 62.2% patients with GT1b being the most common. Anti-C. jejuni antibodies were present in 46.6%. Anti-Zika antibodies (IgM) were present in 14 patients (15.5%). Four of these patients also had anti-dengue antibody (IgM) positivity. CONCLUSION: This is one of the largest studies on GBS from India and the first one to report on the presence of Zika virus antibodies from this geographical area. Our study had a high prevalence of anti-C. jejuni and anti-ganglioside antibodies. Evidence of recent ZIKV infection, as evidenced by anti-IgM antibodies, was present in 14 patients, with 4 of them being tested positive for anti-dengue IgM antibody. Whether this represents cross-reaction with dengue or prior/co-infection with dengue virus could not be addressed in this study.

Uncommon cause of cirrhosis-A case of Werner syndrome with a novel WRN mutation.

Werner syndrome is a rare progeroid syndrome caused by the WRN gene mutation. It is characterized by a general appearance of premature aging, diabetes mellitus, and atherosclerosis, and an increased risk of malignancies. We report a patient who presented with hematemesis due to cirrhosis of liver and was subsequently diagnosed with Werner syndrome. Further genetic analysis showed a novel mutation in the WRN gene which has not previously been reported. Werner syndrome should be considered for the cases of liver cirrhosis when accompanied by the features of accelerated aging.