ABSTRACT
Objective@#To detect potential mutations of HEXB gene in an infant with Sandhoff disease (SD).@*Methods@#Genomic DNA was extracted from peripheral blood sample of the infant. All coding exons (exons 1 to 14) and splicing sites of the HEXB gene were subjected to PCR amplification and direct sequencing.PubMed Protein BLAST system was employed to analyze cross-species conservation of the mutant amino acid. PubMed BLAST CD-search was performed to identify functional domains destroyed by thecandidate mutations. Impact of the mutations was analyzed with software including PolyPhen-2, Mutation Taster and SIFT. Whole-exome sequencing was carried out to identify additional mutations.@*Results@#The infant was found to carry compound heterozygous mutations c. 1652G>A(p.Cys551Tyr) and c. 1389C>G (p.Tyr463*) of the HEXB gene. The c. 1389C>G (p.Tyr463*) mutation may lead to destruction of two functional domains in β subunit of the Hex protein. The c. 1652G>A(p.Cys551Tyr)mutation, unreported previously, was predicted to be probably damaging by Bioinformatic analysis.@*Conclusion@#Compound heterozygous mutations c. 1652G>A(p.Cys551Tyr) and c. 1389C>G (p.Tyr463*) in the HEXB gene probably underlie the disease in this patient.
ABSTRACT
La enfermedad de Sandhoff es una patología neurodegenerativa, de almacenamiento lisosomal, causada por mutaciones en el gen HEXB. Existen tres formas clínicas: infantil, juvenil y adulta. Previamente, fue identificada una población endogámica en la provincia de Córdoba, Argentina, que presentaba una alta incidencia de la enfermedad; todos los casos correspondieron a la forma infantil. En este trabajo, se presenta por primera vez el caso de un paciente argentino con la variante juvenil de la enfermedad de Sandhoff. El paciente es un niño de 7 años que, a partir de los 2, presentó ataxia, trastorno del habla y retraso global en el desarrollo. El diagnóstico se confirmó con la detección de valores residuales de enzima hexosaminidasa y con la identificación de dos mutaciones ya descritas en estado de heterocigosis: c.796T>G (p.Y266D) y c.1615C>T (p.R539C).
Sandhoff disease is a neurodegenerative, lysosomal and autosomal recessive disease caused by mutations in the HEXB gene. Three forms are recognized: infantile, juvenile and adult. Previously, an endogamous population in Córdoba, Argentina, was identified with a high incidence of Sandhoff disease, all reported cases were of the infantile type. In this work, we describe a child with the juvenile form of Sandhoff disease, the first case reported in Argentina. The patient is a 7-year-old boy presenting with ataxia, speech disturbances and global developmental delay, symptoms starting at the age of 2 years. Diagnosis was based on the hexosaminidase deficiency. Sequencing of genomic DNA revealed compound heterozygosity for two HEXB gene mutations: c.796T>G (p.Y266D) and c.1615C>T (p.R539C), both already reported.
Subject(s)
Humans , Male , Child , Sandhoff Disease/diagnosis , Argentina , Sandhoff Disease/classificationABSTRACT
Objective To summarize the clinical manifestations, diagnosis, and treatment of infantile Sandhoff disease. Methods The clinical data of one case with infantile Sandhoff disease were reviewed retrospectively. The related literatures were reviewed. Results The girl aged 1 year and 2 months suffered from psychomotor regression and intractable convulsions. The parents were consanguineous marriage. The fundus microscopy showed fundus erythema. Brain magnetic resonance imaging showed an abnormal signal of long T2WI and identical T1WI at left pons, white matter edema, and diffuse demyelination. No abnormal karyotype was observed. A chromosome microarray suggested multiple large homozygous chromosomes segments. The second generation gene sequencing showed deletion of c.1263_1268delTGAAGT:P. (Glu422_Val423del) deletion in exon 11 and a shear mutation of c.1614_2A>G:P? in intron 13 of HEXB gene which were carried by her parents respectively . The activity of HexA, HexA & HexB were 84 and 112 nmol?mg?1?h?1, respectively. Finally, this girl was diagnosed of infantile Sandhoff's disease. After treatment with valproate, levetiracetam combined with antiepileptic and glucocorticoids, episodes of convulsions were decreased gradually, and the reaction was better than before. In 5 months of follow up, the condition was stable, and no progression and no seizures exist. Her mother got pregnant again and received an amniocentesis on her 21+6 weeks of pregnancy, and results suggest that the fetus had the same mutation as this girl. Conclusions Sandhoff's disease is a type of rare hereditary lysosomal disease, characterized by progressive neurological impairment. Currently there are no effective treatments. Genetic testing is helpful in the diagnosis and prenatal diagnosis.