Genetic analysis reveals HSP complexity

47 new HSP variants identified

67 variants representing 40 genes were identified in this study in India of 57 people with HSP, including 47 novel variants. 48 (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders.

Abstract

The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts.

Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5-49 years). Based on the phenotype, the cohort could be categorized as ‘pure’ (n = 15, 26.3%) and ‘complicated’ (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4).

67 variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In 9 patients, no genetic variants implicated in spastic paraplegia phenotype were identified.

Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.

SOURCE:  J Neurogenet. 2022 May 2;1-11. doi: 10.1080/01677063.2022.2064463. Online ahead of print. PMID: 35499206

Novel insights into the genetic profile of hereditary spastic paraplegia in India

Sundarapandian Narendiran  1 Monojit Debnath  2 Sumanth Shivaram  1 Ramakrishnan Kannan  3 Shivani Sharma  1 Rita Christopher  4 Doniparthi V Seshagiri  1 Sanjeev Jain  3 Meera Purushottam  3 Sandhya Mangalore  5 Rose Dawn Bharath  5 Parayil Sankaran Bindu  5 Sanjib Sinha  5 Arun B Taly  1 Madhu Nagappa  1

1. Departments of Neurology and Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.

2. Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.

3. Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.

4. Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.

5. National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.

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