Clinical, biochemical and mutation profile in Indian patients with Sandhoff disease

Abstract

Sandhoff disease (SD) is an autosomal recessive neurodegenerative lysosomal storage disorder caused by mutations in HEXB gene. Molecular pathology is unknown in Indian patients with SD. The present study is aimed to determine mutations spectrum and molecular pathology leading to SD in 22 unrelated patients confirmed by the deficiency of β-hexosaminidase-A and total-hexosaminidase in leukocytes. To date, nearly 86 mutations of HEXB have been described, including five large deletions. Over all we have identified 13 mutations in 19 patients, eight of which were novel, including two missense mutations [c.611G>A (p.G204E), c. 634A>T (p.H212Y)], two nonsense mutations [c.333G>A (p.W111X), c.298C>T (p.R100X)], one splice site mutation c.1082+5 G>T, two small in-frame deletions [c.534_541delAGTTTATC (p.V179RfsX10), c.1563_1573delTATGGATGACG (p.M522LfsX2)] and one insertion c.1553_1554insAAGA (p.D518EfsX8). We have also identified previously known, five sequence variations leading to amino acid changes [c.926G>A (p.C309Y), c.1597C>T (p.R533C)], one nonsense mutation c.850 C>T (p.R284X), one splice site mutation c.1417+1 G-A and one insertion c.1591_1592insC (p.R531TfsX22). Mutation was not identified in three patients. We observed from this study that mutation c.850C>T (p.R284X) was identified in 4/19 (21%) patients which is likely to be the most common mutation in the country. This is the first study providing insight into the molecular basis of SD in India.

Infantile onset Sandhoff disease: clinical manifestation and a novel common mutation in Thai patients

“…Pattern of generalized tonic-clonic seizures and myoclonic seizures exacerbated by loud noise was consistent with previous observation [3]. Unlike TSD, mild hepatosplenomegaly can be noted in SD as also found in one patient of the present cohort (patient-3) [24]. Cardiac involvement including cardiomegaly, valvulopathies, hypertrophic/dilated cardiomyopathy is an uncommon finding, it is rare but could be a presenting feature of infantile SD and even ahead of neurological manifestation [25,26].…”

“…HEXB gene is the only gene known to cause SD with approximately 107 variants described with the vast majority being missense and nonsense variants [29]. Most of the HEXB pathologic variants are family-specific but common HEXB variant have been observed in certain ethnic groups such as c.850C>T (p.Arg284*) in Indian population [24], c.171delG (p.Trp57CysfsX6) in Spanish descendants [30], and c.115delG (p.Val39fs) in northern Saskatchewan population of Canada [27]. Possible genotype-phenotype correlation has been suggested, for example c.626C>T (p.Thr209Ile) and c.1404delT (p.P468PfsX62) are likely linked to the infantile form of SD [31].…”

Comprehensive Analysis of HEXB Protein Reveal Forty Two Novel nsSNPs That May Lead to Sandhoff disease (SD) Using Bioinformatics

“…The difference in charge and size could possibly have some detrimental effects on external interactions and interactions with internal molecules. The same mutation was previously reported in many countries in patients with Sandoff disease (13,(46)(47)(48). Zampieri et al(2012) found that the activity of the affected protein is considerably diminished or completely absent compared to the normal protein, and they predicted the mutant residue C533 could form a disulphide bond with C551 which normally forms this bond with C534, and that could result in severe misfolding of the C terminal loop of the protein (49).…”

Clinical Presentation and Genetic Heterogeneity Including Two Novel Variants in Sri Lankan Patients With Infantile Sandhoff Disease

“…Cherry-red spots on fluoroscopy examination and hyperacusis are the essential clinical clues to diagnosing SD. 2,9 Here, cherry-red spots in all eight cases helped early suspicion of iSD, but hyperacusis was present only in three cases.…”