Clinical,biochemical and molecular analysis of five Chinese patients with Sandhoff disease.

Sandhoff disease (SD) is a rare autosomal recessive lysosomal storage disorder of sphingolipid metabolism resulting from the deficiency of ß-hexosaminidase (HEX). Mutations of the HEXB gene cause Sandhoff disease. In order to improve the diagnosis and expand the knowledge of the disease, we collected and analyzed relevant data of clinical diagnosis, biochemical investigation, and molecular mutational analysis in five Chinese patients with SD. The patients presented with heterogenous symptoms of neurologic deterioration. HEX activity in leukocytes was severely deficient. We identified seven different mutations, including three known mutations: IVS12-26G > A, p.T209I, p.I207V, and four novel mutations: p.P468PfsX62, p.L223P, p.Y463X, p.G549R. We also detected two different heterozygous mutations c.-122delC and c.-126C > T in the promoter which were suspected to be deleterious mutations. We attempted to correlate these mutations with the clinical presentation of the patients. Our study indicates that the mutation p.T209I and p.P468PfsX62 may link to the infantile form of SD. Our study expands the spectrum of genotype of SD in China, provides new insights into the molecular mechanism of SD and helps to the diagnosis and treatment of this disease.

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

Infantile Sandhoff Disease (iSD) is a subtype of GM2 gangliosidosis, which is never been reported in Sri Lanka. Data of eight children, who were diagnosed with iSD during the period of 2017 to 2021, were analyzed retrospectively. The aim of this study was to analyze genotypic and phenotypic variations of native iSDs. Café-au-lait spots, mitral regurgitation and atrial septal defect were found in our patients but never reported in the literature. We found c.1417 + 5G>A and c.1303_1304insCT p.(Arg435Thrfs*10) novel variants of HEXB gene among the nine different gene mutations that were identified. The commonest HEXB gene variant identified in India was c.850 C4T (p.R284X) but was not noticed among Sri Lankan patients. In contrast to other studies, all our patients died within the age of two years. This is the first Sri Lankan study that expands the clinical and molecular basis of iSD with its novel findings.

Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations.

BACKGROUND: Infantile Sandhoff disease (ISD) is a GM2 gangliosidosis that is classified as a lysosomal storage disorder. The most common symptoms of affected individuals at presentation are neurologic involvement. Here we report clinical course and demographic features in a case series of infantile Sandhoff disease. Enzymatically and some genetically proven cases of ISD were extracted from the Iranian Neurometabolic Registry (INMR) in Children's Medical Center, Iran, Tehran from December 2010 to December 2016. RESULT: Twenty five cases of infantile SD (13 female, 12 male) were included in this study. The age range of patients was 9-24 months with a mean of 15.8 months. The consanguinity rate of parents affected families was about 80%. The mean age of patients at disease onset was 6.4 months and the mean age at diagnosis was 14 months. Patients were diagnosed with a mean delay of 7.8 months. Eleven of patients died due to aspiration pneumonia and intractable seizure. The most common features at presentation (92%) were developmental delay or regression in speech and cognitive domains. Cherry red spots were detected in 17 patients (68%). Organomegaly was detected only in two patients. Enzyme studies showed marked reductions of both Hexosaminidase A and B in all patients. HEXB gene mutation studies performed in eight patients identified 6 different mutations, which five of them were novel. CONCLUSION: Infantile SD should be considered for each child presented with neurologic symptoms such as developmental delay and regression and cherry red spots in ophthalmic examination. Organomegaly is not a frequent clinical finding in infantile SD. Additionally; there are a genetic heterogenisity among Iranian patients.

[Juvenile form of Sandhoff disease: first case reported in Argentina]. / Variante juvenil de la enfermedad de Sandhoff: presentación del primer caso descrito en Argentina.

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.

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).

Early cardiac involvement in an infantile Sandhoff disease case with novel mutations.

INTRODUCTION: Hepatosplenomegaly is often present in infantile Sanshoff disease. However, cardiac involvement is extremely uncommon. CASE REPORT: We describe a 14-month-old female baby who exhibited mitral regurgitation and cardiomegaly at the age of 2months, dilation of the left atrium and left ventricle at age of 6months, followed by regression of developmental milestones after an episode of minor infection at age of 14months. Brain magnetic resonance imaging revealed signal changes over the bilateral thalami, bilateral cerebral white matter and left putamen. An examination of the fundus showed presence of cherry-red spots in both macular areas. The lysosomal enzymatic activities showed a marked reduction of ß-hexosaminidase B (HEXB) activity. Two novel mutations of HEXB gene were identified. One of the mutations was a c.1538 T>C mutation, which predicted a p.L513P amino acid substitution of leucine to proline; the other was a c.299+5 G>A mutation, which was a splice site mutation. CONCLUSION: Cardiac involvement might occur prior to neurological symptoms in infantile Sandhoff disease, and it should be included in the differential diagnoses of metabolic cardiomyopathies in the infantile stage.

Analysis of HEXB gene mutations in an infant with Sandhoff disease / 中华医学遗传学杂志

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.

Infantile Sandhoff disease:a case report and literature review / 临床儿科杂志

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.

Variante juvenil de la enfermedad de Sandhoff: presentación del primer caso descrito en Argentina / Juvenile form of Sandhoff disease: first case reported in Argentina

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.