Whole Exome Sequencing Reveals Novel Candidate Genes in Familial Forms of Glaucomatous Neurodegeneration.

Glaucoma is the largest cause of irreversible blindness with a multifactorial genetic etiology. This study explores novel genes and gene networks in familial forms of primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) to identify rare mutations with high penetrance. Thirty-one samples from nine MYOC-negative families (five POAG and four PACG) underwent whole-exome sequencing and analysis. A set of prioritized genes and variations were screened in an independent validation cohort of 1536 samples and the whole-exome data from 20 sporadic patients. The expression profiles of the candidate genes were analyzed in 17 publicly available expression datasets from ocular tissues and single cells. Rare, deleterious SNVs in AQP5, SRFBP1, CDH6 and FOXM1 from POAG families and in ACACB, RGL3 and LAMA2 from PACG families were found exclusively in glaucoma cases. AQP5, SRFBP1 and CDH6 also revealed significant altered expression in glaucoma in expression datasets. Single-cell expression analysis revealed enrichment of identified candidate genes in retinal ganglion cells and corneal epithelial cells in POAG; whereas for PACG families, retinal ganglion cells and Schwalbe's Line showed enriched expression. Through an unbiased exome-wide search followed by validation, we identified novel candidate genes for familial cases of POAG and PACG. The SRFBP1 gene found in a POAG family is located within the GLC1M locus on Chr5q. Pathway analysis of candidate genes revealed enrichment of extracellular matrix organization in both POAG and PACG.

"Ear of the Lynx" Sign in Hereditary Spastic Paraparesis (HSP) 76.

Background: Hereditary Spastic Paraparesis (HSP) are a group of genetically inherited disorders, clinically and genetically heterogenous and characterized by degeneration of corticospinal tracts, manifesting with progressive spasticity and lower limbs weakness. Most HSPs have an autosomal dominant inheritance. "Ear of the Lynx" sign describes the characteristic abnormality in the forceps minor region of the corpus callosum (CC) on MRI brain. These bear a striking resemblance to the ears of a lynx. This finding has previously been described with hereditary spastic paraparesis 11 and 15, both of which are autosomal recessive HSPs. Cases: We describe this finding in two siblings with novel mutations causing HSP76, an extremely rare autosomal recessive HSP (less than 50 cases described worldwide), which has not been reported previously. Conclusion: This sign suggests the presence of pathogenic genetic mutations and is likely indicative of autosomal recessive HSPs.

Cognition in Trinucleotide Repeat Spinocerebellar Ataxias: A Review.

Spinocerebellar ataxias (SCAs) comprise a group of complex and heterogeneous hereditary neurodegenerative disorders characterized by cerebellar ataxia, with ophthalmoplegia, pyramidal and extrapyramidal features, peripheral neuropathy, motor neuron disease, pigmentary retinopathy, epilepsy, and dementia in varying proportions. Cognitive impairment is not frequent in SCAs but is rarely noticed since it gets camouflaged behind the exorbitant ataxic manifestations of the disease. The exact incidence and extent of cognitive impairment in these rare disorders are not known due to the heterogeneity between different SCA types and different modalities of testing employed in different studies. Through our review, we have summarized the cognitive aspects of SCA and can safely conclude that cognitive dysfunction is common in some SCA types when compared to others. Not only is it important to appreciate its presence as a symptom complex in SCA but also is the need to actively search and treat it to improve the patients' quality of life.

Genetic Testing in Neurology: What Every Neurologist Must Know.

Approximately 80% genes have an active expression in the brain and 40% of known genetic disorders affect the central nervous system. Revolutionary techniques like next-genome sequencing have solved the problem of the diagnostic odyssey in neurological genetic diseases. As several studies have shown the cost-effectiveness of next-genome sequencing compared to the older tests available in our diagnostic armamentarium, it becomes imperative to know about these genetic mutations and the tests available to diagnose them. We have tried to explain the basic concepts of genetics, the selection of available tests and their interpretation for neurophysicians.

SCA2 in the Indian population: Unified haplotype and variable phenotypic patterns in a large case series.

BACKGROUND: Spinocerebellar ataxia-2 is one of the most prevalent SCA type across the world and one of the commonest in India. We aimed to characterize SCA2 patients both clinically and genetically (ATXN2-CAG repeats and its haplotypic background). METHODS: A total of 436 SCA2 patients were recruited consecutively comprising individuals of multiple ethnicities and two large multigenerational families. A detailed clinical evaluation and genetic analysis for CAG repeat length estimation and two marker based haplotype analysis [rs695871 and rs695872 located 177 bp and 106 bp upstream of CAG sequence in Exon 1 of ATXN2] was performed. RESULTS: Generalized limb ataxia and slow saccades were prevalent features in majority of our patients, while hyporeflexia and extrapyramidal features were less commonly observed manifestations. Slow ocular saccades, upper limb ataxia and tremor showed significant associations with age of onset, CAG repeat length and disease duration. We observed a 100% association of C-C haplotype with the expanded ATXN2 repeats. CONCLUSION: This study represents the largest study of SCA2 Indian patients that highlights the clinico-genetic manifestations and haplotype analysis. A significant proportion of patients have not shown the characteristic slow saccades and hyporeflexia thus indicating the influences of other factors in modulation of the disease which warrants further investigations. The observation of CC haplotype in all our SCA2 patients indicates a common origin across all Indian sub populations and that also indicate a common global founder event in the past.

Investigations of Huntington's Disease and Huntington's Disease-Like Syndromes in Indian Choreatic Patients.

BACKGROUND: The diagnostic workup for choreiform movement disorders including Huntington's disease (HD) and those mimicking HD like phenotype is complex. OBJECTIVE: The aim of the present study was to genetically define HD and HD-like presentations in an Indian cohort. We also describe HTT-CAG expansion manifesting as neuroferritinopathy-like disorder in four families from Punjab in India. MATERIALS AND METHODS: 159 patients clinically diagnosed as HD and HD-like presentations from various tertiary neurology clinics were referred to our centre (CSIR-IGIB) for genetic investigations. As a first tier test, CAG-TNR for HTT was performed and subsequently HD-negative samples were screened for JPH3 (HDL2), TBP (SCA17), ATN1 (DRPLA), PPP2R2B (SCA12) and GGGGCC expansion in C9orf72 gene. Four families presenting as neuroferritinopathy-like disorder were also investigated for HTT-CAG expansion. RESULTS: 94 of 159 (59%) patients were found to have expanded HTT-CAG repeats. Pathogenic repeat expansion in JPH3, TBP, ATN1 and C9orf72 were not found in HD negative cases. Two patients were positive for SCA12-CAG expansion in pathogenic length, whereas 5 cases harboured TBP-CAG repeats falling in reduced penetrance range of 41- 48 repeats for SCA17. Four unrelated families, presented with atypical chorea and brain MRI findings suggestive of basal ganglia abnormalities mimicking neuroferritinopathy were found to harbour HTT-CAG expansion. CONCLUSION: We present SCA12 as a new reported phenocopy of HD which should be considered for diagnostic workout along with SCA17 for HD-like syndromes. This study also illustrates the necessity, to consider evolving HD like phenotype, as a clinical diagnosis for cases with initial manifestations depicting neuroferritinopathy.