Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy.

Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN.

Characterisation of Patients with SH3TC2 Associated Neuropathy in an Indian Cohort.

Background: SH3TC2 variations lead to demyelinating recessive Charcot-Marie-Tooth (CMT) disease, which is commonly associated with early-onset scoliosis and cranial neuropathy. Data from Indian ethnicity is limited. Objective: We aim to report the characteristics of patients with SH3TC2-associated neuropathy from an Indian cohort. Patients and Methods: Data of five unrelated subjects with SH3TC2 variations were analyzed. Results: Clinical features included female predominance (n = 4), early-onset neuropathy (n = 2), pes cavus and hammer toes (n = 4), kyphoscoliosis (n = 1), impaired vision and hearing (n = 1), facial muscle weakness (n = 1), impaired kinaesthetic sense (n = 3), tremor (n = 2), and ataxia (n = 1). Four patients had the "CMT" phenotype, while one patient had Roussy-Levy syndrome. All had demyelinating electrophysiology with conduction velocities being "very slow" in one, "slow" in one, "mildly slow" in two, and "intermediate" in one patient. Brain stem auditory evoked potentials were universally abnormal though only one patient had symptomatic deafness. Seven variants were identified in SH3TC2 [homozygous = 3 (c.1412del, c.69del, c.3152G>A), heterozygous = 4 (c.1105C>T, c.3511C>T, c.2028G>C, c.254A>T)]. Except for c.3511C>T variant, the rest were novel. Three patients had additional variations in genes having pathobiological relevance in other CMTs or amyotrophic lateral sclerosis. Conclusion: We provide data on a cohort of patients of Indian origin with SH3TC2 variations and highlight differences from other cohorts. Though the majority were not symptomatic for hearing impairment, evoked potentials disclosed abnormalities in all. Further studies are required to establish the functional consequences of novel variants and their interacting molecular partners identified in the present study to strengthen their association with the phenotype.

Spectrum of Sensory Conduction Abnormalities in Guillain Barre Syndrome.

Background: Sensory nerve conduction parameters in Guillain Barre Syndrome (GBS) are underemphasized. Objective: To describe abnormalities on sensory conduction studies in a large cohort of prospectively evaluated patients of GBS and to correlate with clinico-electrophysiological features. Methods and Materials: Sensory conduction parameters of three nerves (median, ulnar, and sural) were analyzed using standard protocols in 238 patients (M: F 163:75, mean age: 35.76 ± 15.9 years). Electrophysiological subtyping was based on criteria of Hadden et al., and Rajabally et al. Results: Among patients with "typical" GBS who underwent electrophysiological testing within 30 days of symptom-onset (n = 219), 183 (83.5%) had abnormal sensory potentials (one nerve = 52, two nerves = 77, all three nerves = 54). Frequency of abnormalities in sensory potentials increased with duration of illness. Commonest abnormality was reduced amplitude or in-excitable nerves. Mean amplitude and velocity of median and ulnar nerve sensory potentials were significantly lower among those with demyelinating electrophysiology (P < 0.05). Proportion of subjects with reduced amplitude and velocity of median and ulnar nerve sensory potentials was higher among those who required mechanical ventilation (P < 0.05). Frequency of "sural sparing" ranged from 10.5% to 84.5% depending on the criteria used and almost always was significantly associated with demyelinating neuropathy. Conclusion: This prospective study provides comprehensive data on sensory conduction parameters in GBS. Abnormalities are frequent and vary with duration of illness. While median nerve is most frequently and more severely affected, involvement of sural nerve may have prognostic value.

Genetic Spectrum of Inherited Neuropathies in India.

Background and Objectives: Charcot-Marie-Tooth (CMT) disease is the commonest inherited neuromuscular disorder and has heterogeneous manifestations. Data regarding genetic basis of CMT from India is limited. This study aims to report the variations by using high throughput sequencing in Indian CMT cohort. Methods: Fifty-five probands (M:F 29:26) with suspected inherited neuropathy underwent genetic testing (whole exome: 31, clinical exome: 17 and targeted panel: 7). Their clinical and genetic data were analysed. Results: Age at onset ranged from infancy to 54 years. Clinical features included early-onset neuropathy (n=23), skeletal deformities (n=45), impaired vision (n=8), impaired hearing (n=6), facial palsy (n=8), thickened nerves (n=4), impaired cognition (n=5), seizures (n=5), pyramidal signs (n=7), ataxia (n=8) and vocal cord palsy, slow tongue movements and psychosis in one patient each. Twenty-eight patients had demyelinating electrophysiology. Abnormal visual and auditory evoked potentials were noted in 60.60% and 37.5% respectively. Sixty two variants were identified in 37 genes including variants of uncertain significance (n=34) and novel variants (n=45). Eleven patients had additional variations in genes implicated in CMTs/ other neurological disorders. Ten patients did not have variations in neuropathy associated genes, but had variations in genes implicated in other neurological disorders. In seven patients, no variations were detected. Conclusion: In this single centre cohort study from India, genetic diagnosis could be established in 87% of patients with inherited neuropathy. The identified spectrum of genetic variations adds to the pool of existing data and provides a platform for validation studies in cell culture or animal model systems.

Spectrum and Evolution of EEG Changes in Anti-NMDAR Encephalitis.

BACKGROUND: NMDA receptor encephalitis (NMDARE) is the most prevalent autoimmune encephalitis and it encompasses a spectrum of clinical features. It is most commonly associated with alteration in consciousness, seizures, neuro-psychiatric symptoms, and movement disorders. Electroencephalography (EEG) plays a vital role and can give clues to diagnosis in a subset of patients. METHODS: We retrospectively characterized the clinical and EEG findings in our NMDARE patients (n = 48). A total of 131 EEGs were analyzed. RESULTS: We observed that patients with seizures had a younger age of onset (p < 0.001). The most common EEG pattern that was noted was diffuse slowing (n = 20) followed by generalized rhythmic delta activity (n = 9), focal spikes and slowing (n = 8 each). Delta brush pattern was seen in only 3 EEGs. Focal ictal rhythms were seen in 3 EEGs. There was no significant difference in outcomes such as seizure recurrence, modified Rankin score (mRS) at follow up/discharge or relapse between groups of patients who had EEG abnormalities in the first EEG and with those who did not. CONCLUSIONS: NMDARE has varied EEG findings, most of them being non-specific. When combined with clinical presentation, EEG is a useful tool in the diagnosis and management of NMDARE.

PMP22 Gene-Associated Neuropathies: Phenotypic Spectrum in a Cohort from India.

Reports of spectrum of clinical manifestations in PMP22 gene-associated neuropathies (duplication/mutations) are scarce. To identify the frequency of PMP22 gene variations and establish their genotype-phenotype correlation. Patients with suspected genetic demyelinating neuropathy (n = 128) underwent evaluation for copy number variations and point mutations in PMP22 gene by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing respectively. Of these, only 27 patients (M:F:19:8) from 18 families had PMP22 gene-associated neuropathy; they were subsequently analyzed for genotype-phenotype correlation. Twenty-five patients had PMP22 duplication while two patients had PMP22 missense mutations (p.A114V and p.L80P). Age at onset of neuropathy ranged from infancy to 63 years and symptom duration ranged from 2 to 32 years. Cranial nerve dysfunction in the form of ptosis, ophthalmoplegia, bifacial weakness, and sensorineural hearing loss was observed in addition to a number of systemic features. Three patients were asymptomatic. All except one patient were ambulant. Velocity of median nerve and amplitude of evoked motor responses from common peroneal nerve were significantly reduced in male patients. There was significantly worse disability in the late-onset group as compared with the early-onset group. Otherwise, the mean age at onset, frequency of skeletal deformities, patterns of motor weakness, muscle stretch reflexes, sensory impairment, disability rating scales, and electrophysiological parameters were comparable irrespective of gender, onset age, family history and ulnar nerve conduction velocities. The relatively low frequency of PMP22 duplication in the present cohort warrants a more comprehensive search to establish the genetic etiology. Further research into the role of other genetic variants as well as modifier genes and their effect on phenotypic heterogeneity is indicated.

Genetic analysis of ATP7B in 102 south Indian families with Wilson disease.

Wilson disease (WD) is an autosomal recessive disorder, characterized by excessive deposition of copper in various parts of the body, mainly in the liver and brain. It is caused by mutations in ATP7B. We report here the genetic analysis of 102 WD families from a south Indian population. Thirty-six different ATP7B mutations, including 13 novel ones [p.Ala58fs*19, p.Lys74fs*9, p.Gln281*, p.Pro350fs*12, p.Ser481*, p.Leu735Arg, p.Val752Gly, p.Asn812fs*2, p.Val845Ala, p.His889Pro, p.Ile1184fs*1, p.Val1307Glu and p.Ala1339Pro], were identified in 76/102 families. Interestingly, the mutation analysis of affected individuals in two families identified two different homozygous mutations in each family, and thus each affected individual from these families harbored two mutations in each ATP7B allele. Of 36 mutations, 28 were missense, thus making them the most prevalent mutations identified in the present study. Nonsense, insertion and deletion represented 3/36, 2/36 and 3/36 mutations, respectively. The haplotype analysis suggested founder effects for all the 14 recurrent mutations. Our study thus expands the mutational landscape of ATP7B with a total number of 758 mutations. The mutations identified during the present study will facilitate carrier and pre-symptomatic detection, and prenatal genetic diagnosis in affected families.

Autoantibodies in acquired myasthenia gravis: Clinical phenotype and immunological correlation.

BACKGROUND: Data on antibody profile in myasthenia gravis (MG) from India are limited. OBJECTIVES: To investigate antibody profile in patients with MG and their clinical correlates. PATIENTS AND METHODS: Patients of MG (n = 85, M:F::1.1:1, mean age: 39.29 ± 17.3 years, mean symptom duration: 72.94 ± 91.8 months) were evaluated for clinical features, MG foundation of America (MGFA) score, response to treatment, and outcome at last follow-up. Antibodies to acetylcholine receptor (AChR), muscle-specific kinase (MUSK), titin and ryanodine receptor (RYR) were analysed using ELISA. RESULTS: Based on the regional distribution of weakness, the cohort could be categorized as: generalized: 60, ocular: 16 and oculo-bulbar: 9. Sixty patients were followed up for a mean duration of 26.74 ± 13.8 months. Outcome at last follow-up was as follows: remission-22, no remission-33 and dead-5. AChR and MUSK antibodies were detected in 58 and 8 patients, respectively. Frequency of generalized MG, worse MGFA score during the disease course and thymomatous histology significantly correlated with presence of AChR-antibodies, though outcome at last follow-up was comparable between AChR-antibody positive and negative groups. Patients with MUSK antibodies had oculo-bulbar or generalized MG and frequent respiratory crisis, but majority improved or remitted with treatment. Titin antibodies were detected in 31.8% and RYR antibodies in 32.9%. Their presence did not correlate with age at onset of MG, severity or presence of thymoma. CONCLUSION: This report highlights the spectrum of antibodies in MG in an Indian cohort. AChR-antibody positivity correlated with clinical severity. Outcome was good in majority of MUSK antibody-positive MG. The role of other antibodies, complementary vs epiphenomenon, remains open.

Pediatric opsoclonus-myoclonus-ataxia syndrome: Experience from a tertiary care university hospital.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder; there is limited experience regarding its clinical course and therapeutic response. AIMS AND OBJECTIVES: To describe the clinical profile, investigations, and therapeutic outcome in pediatric OMAS. PATIENTS AND METHODS: Fourteen children (age: 27.1 ± 7 months; male: female = 1:2.3) suffering from OMAS seen over a period of 10 years (2006-2015) were included in the study. Their clinicodemographic profile, investigations, therapeutic outcome at follow-up, and relapses were reviewed. RESULTS: Ten children reported antecedent events (respiratory infection: 7; gastrointestinal infection: 1; vaccination: 2). The most common referral diagnosis was acute cerebellitis (n = 8). Hypotonia (n = 9), abnormal behavior (n = 10), and neuroregression (n = 6) were also the frequent manifestations. Brain magnetic resonance imaging, cerebrospinal fluid, and urinary vanillylmandelic acid were normal in all the patients. Seven patients had an underlying tumor (abdomen: 4; thorax: 2; neck: 1) detected by ultrasound (n = 2/14), computed tomography (CT) (n = 6/12), and fluorodeoxyglucose - positron emission tomography (n = 2/2). CT scan identified the tumor in 2 patients where metaiodobenzylguanidine scintigraphy was negative. All patients received steroids for 22.3 ± 20 months (3 months to 5 years). Eight required prolonged immunomodulation (>12 months). Complete remission after follow-up of 31.3 ± 19 months (7 months to 5 years) was noted in 5 patients, whereas the rest had persisting behavioral and cognitive abnormalities. Relapses were noted in 6 patients related to intercurrent infections (n = 5) and discontinuation of steroids (n = 1). The patients presented with isolated symptoms of the full-blown syndrome during their relapses. CONCLUSION: OMAS in children runs an indolent course requiring careful monitoring and long-term immunomodulation. An abnormal behavior is common and the outcome is variable.

Palatal Tremor Revisited: Disorder with Nosological Diversity and Etiological Heterogeneity.

This case series aimed to describe clinicoradiological, electromyographic, and etiological spectra in palatal tremor (essential=1; symptomatic=26). Patients with symptomatic palatal tremor had 2 to 10 Hz arrhythmic electromyographic bursts, a spectrum of changes in inferior olivary nucleus, with/without lesions in Guillain Mollaret triangle, and varied etiologies (genetic=9, vascular=6, trauma=3, infections=3). Exome sequencing showed variations in POLG, WDR81, NDUFS8, TENM4, and EEF2. Clinical phenotypes of patients with POLG, WDR81, and NDUFS8 variations were consistent with that described in literature. We highlight salient magnetic resonance imaging features, electrophysiological observations, and diverse etiologies in a large cohort of palatal tremor.

Fatal Morvan Syndrome Associated With Myasthenia Gravis.

INTRODUCTION: Morvan syndrome is a rare and complex autoimmune disorder affecting multiple sites of neuraxis. CASE REPORT: We present fulminant Morvan syndrome, developing on a background of chronic myasthenia gravis. A 54-year-old gentleman presented with fluctuating ophthalmoplegia and proximal muscles weakness of 7 years duration that remitted with pyridostigmine and prednisolone. He developed insomnia of 2 months duration, worsening of myasthenic symptoms and respiratory distress, dysautonomia, encephalopathy, and peripheral nerve hyperexcitability. Antibodies against contactin-associated protein (CASPR) 2 were detected in serum. Computed tomography of thorax showed a thymic mass. He received intravenous methyl prednisolone and plasmapheresis. Antibodies against CASPR and thymic lesion reduced with immunotherapy. However, he developed persistent hypotension and expired after 11 weeks of hospital stay. CONCLUSIONS: Clinical clues for diagnosis of Morvan syndrome and therapeutic changes faced by the treating team are highlighted in this report. Increased awareness and prompt testing for CASPR2 antibody is warranted so that early immunotherapy can be initiated.

Non-Wilsonian hepatolenticular degeneration: Clinical and MRI observations in four families from south India.

Non-Wilsonian hepatolenticular degeneration (NWHD) is a heterogeneous neurological disorder occurring secondary to chronic acquired liver disease. Genetically determined familial NWHD is rare, poorly understood, and often mistaken for Wilson's disease (WD). We analysed clinical and MRI profiles of NWHD patients who did not have obvious cause for acquired liver disease, such as alcohol intake or hepatitis. Six patients from four families (four males, two females, mean age: 17.0±standard deviation 7.9years), presenting with chronic extrapyramidal disorder resembling WD and imaging (abdominal ultrasound/MRI) evidence of cirrhosis were studied. They lacked Kayser-Fleischer rings or biochemical and/or genetic evidence of WD. Clinical features included dystonia (n=6), parkinsonism (n=3), tremor (n=1), cerebellar ataxia (n=3), orofacial dyskinesia (n=1), behavioural abnormalities (n=3), and cognitive decline (n=1). Brain MRI revealed T1-weighted hyperintensity in the pallidum (n=6), crus cerebri (n=4), putamen (n=1), caudate (n=1), thalamus (n=1), and red nucleus (n=1) with T2-weighted shortening in some of these regions. Additional findings included giant cisterna magna (n=1), face of giant panda sign (n=1) and thin corpus callosum (n=1). Areas of "blooming" on susceptibility weighted images were noted in two patients in the caudate (n=2) and putamen (n=1). The finding of T1 shortening is distinct from that of WD where the majority of lesions are T1-hypointense and T2-hyperintense. Extrapallidal T1-hyperintensity is also an exceptional observation in NWHD. The MRI appearance of intense T1 shortening coupled with the lack of increased susceptibility changes suggests that the most likely mineral deposited is manganese. The association of this neurological disorder and cirrhosis of the liver in the absence of an acquired liver disease is a distinct disease entity. This syndrome may represent a disorder of manganese metabolism resulting in its toxic deposition.

Ictal Generalized EEG Attenuation (IGEA) and hypopnea in a child with occipital type 1 cortical dysplasia - Is it a biomarker for SUDEP?

An interesting association of ictal hypopnea and ictal generalized EEG attenuation (IGEA) as possible marker of sudden unexpected death in epilepsy (SUDEP) is reported. We describe a 5-years-old girl with left focal seizures with secondary generalization due to right occipital cortical dysplasia presenting with ictal hypopnea and IGEA. She had repeated episodes of the ictal apnoea in the past requiring ventilator support and intensive care unit (ICU) admission during episodes of status epilepticus. The IGEA lasted for 0.26-4.68 seconds coinciding with the ictal hypopnea during which both clinical seizure and electrical epileptic activity stopped. Review of literature showed correlation between post-ictal apnoea and post ictal generalized EEG suppression and increased risk for SUDEP. The report adds to the growing body of literature on peri-ictal apnea, about its association with IGEA might be considered as a marker for SUDEP. She is seizure free for 4 months following surgery.

Clinical, hematological, and imaging observations in a 25-year-old woman with abetalipoproteinemia.

Abetalipoproteinemia is an uncommon cause of ataxia and retinitis pigmentosa (RP). Most of the neurological and ocular manifestations occur secondary to deficiency syndromes that is consequent to fat malabsorption from the small intestine. In this report, we have described the phenotype of a young adult female who manifested with recurrent diarrheal illness in her first decade, followed by anemia, RP, and neurological involvement with progressive deafness, cerebellar and sensory ataxia, and subclinical neuropathy in her second decade of life. While RP and sensory ataxia due to vitamin E deficiency are well-recognized features of abetalipoproteinemia, deafness is rarely described. In addition, we have highlighted the abnormal posterior column signal changes in the cervical cord in this patient. Early recognition avoids unnecessary investigations and has a potential to retard the disease progression by replacing some of the deficient vitamins.

Intraneural perineurioma of unilateral radial and median nerves manifesting with long-standing focal amyotrophy in a 14-year-old-boy.

Intraneural perineuriomas are rare tumors of the peripheral nerves with unique immunohistochemical findings. In this report, we highlight the clinical and imaging findings of an adolescent male with histologically proven intraneural perineurioma involving multiple nerves. The salient features included a clinically progressive course, imaging evidence of involvement of long segments of multiple nerves, enlargement of individual fascicles within the affected nerves, and intense contrast enhancement of the enlarged fascicles. The identification of enlarged fascicles with intense contrast enhancement within the affected and distended nerve segments may aid in distinguishing intraneural perineurioma from other tumors affecting the peripheral nerves.

Pattern recognition on brain magnetic resonance imaging in alpha dystroglycanopathies.

Alpha dystroglycanopathies are heterogeneous group of disorders both phenotypically and genetically. A subgroup of these patients has characteristic brain imaging findings. Four patients with typical imaging findings of alpha dystroglycanopathy are reported. Phenotypic features included: global developmental delay, contractures, hypotonia and oculomotor abnormalities in all. Other manifestations were consanguinity (3), seizures (3), macrocephaly (1), microcephaly (3), retinal changes (2) and hypogenitalism (2). Magnetic resonance imaging (MRI) of the brain revealed polymicrogyria, white matter changes, pontine hypoplasia, and subcortical cerebellar cysts in all the patients, ventriculomegaly, callosal abnormalities, and absent septum pellucidum in two and Dandy -Walker variant malformation in three. Magnetic resonace imaging of the first cousin of one the patient had the same characteristic imaging features. Brain imaging findings were almost identical despite heterogeneity in clinical presentation and histopathological features. Pattern recognition of MR imaging features may serve as a clue to the diagnosis of alpha dystroglycanopathy.

Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish.

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5' RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities, and analysis of axon pathway formation demonstrated an overall perturbation of neuronal differentiation. These data confirm loss of spatacsin as the cause of SPG11-linked HSP-TCC in Asian kindreds, expanding the mutation spectrum recognized in this disorder. This study represents the first investigation in zebrafish addressing the function of a causative gene in autosomal recessive HSP and identifies a critical role for spatacsin during early neural development in vivo.