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Neuronal Ceroid Lipofuscinosis (NCL) are a group of lysosomal storage disorders characterised by progressive neurodegeneration caused by an accumulation of ceroid lipopigment in lysosomes of neurons and other cell types. Adult-onset NCL (Kufs disease) differs from childhood forms by its later onset and preserved vision. Type A (Kufs A) presents as progressive myoclonus epilepsy (PME), while Type B (Kufs B) manifests as dementia with motor involvement. Both subtypes have distinct causative genes. We have described 3 siblings with genetically confirmed novel pathogenic CLN5 subtype who presented with developmental regression, drug-refractory myoclonic epilepsy, and dementia (Kufs A). We have presented 3 siblings with adult onset NCL with Kufs A (not Kufs B) phenotype, which has been rarely documented. Genotypic-phenotypic variations are increasingly being reported for NCL. We have described three patients from a family with CLN5 subtype who had prominent drug refractory myoclonic epilepsy, which is extremely rare. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The pink circles represent the upregulated genes, and the cyan circles denote interacting genes of the network gl To understand differential disease severity within recovered, we looked further into the transcriptomic profile between mild, moderate, severe and mortality (Supporting Information S1; Figure 2A). Moderate and severe patients' comparisons with mild revealed a distinct DEG profile, with 17 upregulated and two downregulated genes in moderate, whereas only six upregulated genes in severe compared to mild. Human-host transcriptomic analysis reveals unique early innate immune responses in different sub-phenotypes of COVID-19. [Extracted from the article]

The diagnostic workup for choreiform movement disorders including Huntington’s disease (HD) and those mimicking HD like phenotype is complex.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.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.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.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. [ABSTRACT FROM AUTHOR]