No abstract

Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.

No 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.

Lipoid congenital adrenal hyperplasia (LCAH), a rare disorder of steroid biosynthesis, is the most severe form of CAH. We report novel molecular findings of three unrelated infants with LCAH diagnosed at our center. A known missense mutation c.653C>T (p.A218V) and two novel mutations [premature termination c.441G>A (or p.W147X) and frameshift deletion c.del815G (or p.R272PfsX35)] were identified after complete sequencing of the STAR gene. Prenatal diagnosis was carried out for the family with mutation c.815delG by molecular testing wherein the fetus was found to be homozygous for the mutation. This is the first report of molecular diagnosis and prenatal testing for LCAH from India. Conflict of interest:None declared.