Clinical and Molecular Spectrum of Degenerative Cerebellar Ataxia: A Single Centre Study.

Background: Cerebellar ataxia is a disabling neurological symptom with extreme clinical and etiological heterogeneity. Objective: To study the clinical and molecular characteristics in patients with degenerative cerebellar ataxia. Materials and Methods: In this study, 150 South-Indian patients with degenerative cerebellar ataxia underwent a phenotype guided, sequential tiered testing. Phenotypic features studied included cerebellar symptoms, pyramidal and extrapyramidal features, and ophthalmic and systemic findings. Tier one included conventional tests such as short PCR/fragment analysis for spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7, 8, 12, 17, and 36 and TP-PCR for Friedreich ataxia (FA). Tier two testing comprised next-generation sequencing (NGS)-based strategies reserved for select undiagnosed cases. Results: The clinical features were highly overlapping and had limited specificity, except in autosomal recessive ataxias and SCA 34. The overall diagnostic yield of our study was 49.3%. SCA 1, 2, and 3 were noted in 13 (12.6%), 12 (11.6%) and 14 (13.5%), respectively, out of the 103 tested, and FA was noted in 17/55 (30.9%) patients. SCA subtypes 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. Targeted Sanger sequencing and NGS revealed some rare diagnoses in 17 among the 18 patients tested. Whole exome sequencing uncovered a novel genotype-phenotype association in a sibling-pair with ataxia, dysmorphism, and retinopathy. Conclusion: SCA 1, 2, 3 and FRDA were the most common causes of ataxia. SCA 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. NGS testing revealed several rare forms of ataxia. Clinical features based testing is cost-effective, achieves good genotype-phenotype correlation, and prioritizes variants for further studies.

Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.

BACKGROUND: Mitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochon drial DNA (mtDNA) and nuclear genome or both have been reported in mitochondrial diseases suggesting common pathophysiological pathways. Considering the clinical heterogeneity of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) phenotype including focal neurological deficits, it is important to look beyond mitochondrial gene mutation. METHODS: The clinical, histopathological, biochemical analysis for OXPHOS enzyme activity, and electron microscopic, and neuroimaging analysis was performed to diagnose 11 patients with MELAS syndrome with a multisystem presentation. In addition, whole exome sequencing (WES) and whole mitochondrial genome sequencing were performed to identify nuclear and mitochondrial mutations. RESULTS: Analysis of whole mtDNA sequence identified classical pathogenic mutation m.3243A > G in seven out of 11 patients. Exome sequencing identified pathogenic mutation in several nuclear genes associated with mitochondrial encephalopathy, sensorineural hearing loss, diabetes, epilepsy, seizure and cardiomyopathy (POLG, DGUOK, SUCLG2, TRNT1, LOXHD1, KCNQ1, KCNQ2, NEUROD1, MYH7) that may contribute to classical mitochondrial disease phenotype alone or in combination with m.3243A > G mutation. CONCLUSION: Individuals with MELAS exhibit clinical phenotypes with varying degree of severity affecting multiple systems including auditory, visual, cardiovascular, endocrine, and nervous system. This is the first report to show that nuclear genetic factors influence the clinical outcomes/manifestations of MELAS subjects alone or in combination with m.3243A > G mutation.

Leber's Hereditary Optic Neuropathy-Specific Mutation m.11778G>A Exists on Diverse Mitochondrial Haplogroups in India.

Purpose: Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the most common maternally inherited mitochondrial disorders. Three mitochondrial DNA point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% of males and approximately 10% of females carrying these mutations develop optic neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic background and environmental modifiers, are likely to contribute toward the observed incomplete penetrance and gender bias. We aimed to investigate whether mtDNA haplogroup influences LHON clinical expression in Indian patients harboring the m.11778G>A mutation. Methods: Detailed clinical assessment and complete mitochondrial genome sequencing was undertaken in 64 LHON families harboring the m.11778G>A mutation. Mitochondrial haplogroup was assigned based on evolutionarily conserved mtDNA variations. Results: A total of 543 individuals (295 male, 248 female) from 64 unrelated families harboring the m.11778G>A mutation were recruited to the study. The overall disease penetrance was 27.07% (146 of 543) and higher in males (37.9%; 112 of 295) than females (13.7%; 34 of 248). The mtDNA haplogroup analysis revealed that all affected probands belonged to different mtDNA haplogroups. No association between the m.11778G>A mutation and the background mtDNA haplogroup was detected. Conclusions: The first detailed study of Indian LHON patients confirm that the m.11778G>A-related LHON in India coexists with multiple different mtDNA haplogroups, unlike the preferential association of west Eurasian haplogroup J and the reported increased clinical penetrance with the J2 subhaplogroup. However, we observed variable penetrance of LHON in different Indian mtDNA haplogroup backgrounds, indicating their possible influence on clinical expression. These data suggest that a similar heterogeneity, resulting from the mtDNA haplogroup, might also exist in other mitochondrial diseases among Indian populations.

Pattern of vascular dementia in India: study of clinical features, imaging, and vascular mechanisms from a hospital dementia registry.

Vascular dementia (VaD) is heterogeneous in its clinical, imaging, and etiological characteristics. Although VaD is common in India, its pattern is not completely known. In a hospital-based cohort, we aimed to characterize VaD by its subtypes and study patterns of risk factors and clinical, and neuropsychological profiles. Vascular mechanisms, known to have racial and genetic variations were identified. NINDS-AIREN criteria were used to diagnose VaD. Patients were subtyped into subcortical, cortical, cortical-subcortical, and strategic infarct dementia. Vascular mechanisms were detected by vascular imaging, cardiac evaluation, and laboratory tests. In the 42 consecutive patients with VaD, subcortical dementia was the most common type (52.4%), followed by cortical-subcortical (26.2%), strategic infarcts in (14.3%), and cortical dementia (7.1%). Stroke (81%), hypertension (71.4%), and diabetes (35.7%) were important risk factors. Small artery disease was the underlying vascular mechanism in 42.9%; intracranial large artery disease, in 16.7%; extracranial disease, in 2.3%; cardioembolism, in 2.3%; multiple mechanisms, in 19%; and unknown, in 16.7%. Subtypes were similar in risk factor profile and neuropsychological features but differed in clinical characteristics and vascular mechanisms. Gait disorder (59.1% vs. 0%) and urinary symptoms (77.3% vs. 16.7%) were more common in subcortical dementia than in strategic infarct dementia (P < .05). Small artery disease was most common in subcortical dementia (72.7%). Intracranial large artery disease was associated with all subtypes. The pattern of VaD demonstrated in our study is a reflection of mechanisms of cerebrovascular disease in India. Outcome depends on underlying mechanisms and thus is likely to differ from that in other ethnic populations.

A characteristic analysis of longitudinally extensive transverse myelitis in South Indian population: A cohort study 145 – 151

This study described the clinical and paraclinical features of south Indian patients with longitudinally extensive transverse myelitis (LETM) and contrasted the findings betweenaquaporin-4 positive versus negative patients. The subjects were recruited between2010 and 2013.The distinctive features among71 LETM patients were compared and it was observed that 56% of the total subjects were found to be AQP4-Ab positive. The ratio of female tomale was found to be higher in the AQP4-Ab positive group. Magnetic resonance imaging showed holocord involvement more commonly in AQP4-Abnegative than positive group. The presence of hypointense lesions did not correlate with severity. The main distinctive features between AQP4-Abpositive and negative cases include older onset age, higher proportion of female, low frequency of conus involvement and higher prevalence of coexisting autoimmune disorders in AQP4-Ab positive cases. Therewas no difference in attack severity, onset of optic neuritis, and spasms between the two groups. Our results suggest that the clinical and spinal cord neuro-imaging information can aid in distinguishing between the positive and negative group of patients with LETM. The early detection of AQP4-Ab positive status predicts the recurrence of LETM or occurrence of optic neuritis duringthe study period.

Fulminant Subacute Sclerosing Panencephalitis Presenting with Acute Ataxia and Hemiparesis in a 15-Year-Old Boy

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a delayed and fatal manifestation of measles infection. Fulminant SSPE is a rare presentation in which the disease progresses to death over a period of 6 months. The clinical features are atypical and can be misleading. CASE REPORT: We report herein a teenage boy who presented with acute-onset gait ataxia followed by right hemiparesis that evolved over 1 month, with left-hemispheric, delta-range slowing on the electroencephalogram (EEG). Magnetic resonance imaging disclosed multiple white-matter hyperintensities, suggesting a diagnosis of acute disseminated encephalomyelitis. He received intravenous steroids, and within 4 days of hospital admission he developed unilateral slow myoclonic jerks. Repeat EEG revealed Rademecker complexes, pathognomonic of SSPE, and an elevated titer of IgG antimeasles antibodies was detected in his cerebrospinal fluid. The disease progressed rapidly and the patient succumbed within 15 days of hospitalization. The diagnosis of SSPE was confirmed by autopsy. CONCLUSIONS: This case illustrates the difficulty of recognizing fulminant SSPE when it manifests with asymmetric clinical and EEG abnormalities.