Atypical presentation of late-onset Sandhoff disease : A case report

Sandhoff disease is a rare type of hereditary (autosomal recessive) GM2-gangliosidosis, which is caused by mutation of the HEXB gene. Disruption of the β subunit of the hexosaminidase (Hex) enzyme affects the function of both the Hex-A and Hex-B isoforms. The severity and the age of onset of the disease (infantile or classic; juvenile; adult) depends on the residual activity of the enzyme. The late-onset form is characterized by diverse symptomatology, comprising motor neuron disease, ataxia, tremor, dystonia, psychiatric symptoms and neuropathy. A 36-year-old female patient has been presenting progressive, symmetrical lower limb weakness for 9 years. Detailed neurological examination revealed mild symmetrical weakness in the hip flexors without the involvement of other muscle groups. The patellar reflex was decreased on both sides. Laboratory tests showed no relevant alteration and routine electroencephalography and brain MRI were normal. Nerve conduction studies and electromyography revealed alterations corresponding to sensory neuropathy. Muscle biopsy demonstrated signs of mild neurogenic lesion. Her younger brother (32-year-old) was observed with similar symptoms. Detailed genetic study detected a known pathogenic missense mutation and a 15,088 base pair long known pathogenic deletion in the HEXB gene (NM_000521.4:c.1417G>A; NM_000521:c.-376-5836_669+1473del; double heterozygous state). Segregation analysis and hexosaminidase enzyme assay of the family further confirmed the diagnosis of late-onset Sandhoff disease. The purpose of this case report is to draw attention to the significance of late-onset Sandhoff disease amongst disorders presenting with proximal predominant symmetric lower limb muscle weakness in adulthood.

Novel homozygous HEXB mutation identified in a consanguineous Iranian pedigree with Sandhoff disease

Background Sandhoff disease is a rare neurodegenerative and autosomal recessive disorder, characterized by a defect in ganglioside metabolism. It is caused by mutations in the HEXB gene for the β-subunit of β-N-acetyl hexosaminidase. Results In the present study, an Iranian 14- month -old girl with an 8- month history of unsteady walking and involuntary movements is described. Biochemical testing showed defects in the normal activity of beta-hexosaminidase protein. Following sequencing of HEXB gene, a novel homozygous p.A278V mutation was identified in the patient’s DNA. Conclusions The p.A278V mutation is pathogenic because of amino acid change and changing in biochemical activity. this mutation has not been reported previously, but based on In silico analysis and structural analysis, was predicted to be disease causing.

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

ABSTRACTBackgroundSingle Nucleotide Polymorphisms (SNPs) in the HEXB gene are associated with a neurodegenerative disorder called Sandhoff disease (SD) (GM2 gangliosidosis-O variant). This study aimed to predict the possible pathogenic SNPs of this gene and their impact on the protein using different bioinformatics tools.MethodsSNPs retrieved from the NCBI database were analyzed using several bioinformatics tools. The different algorithms collectively predicted the effect of single nucleotide substitution on both structure and function of beta subunit beta subunit of both hexosaminidase A and hexosaminidase B proteins.ResultsForty nine mutations were found to be extremely damaging to the structure and function of the HEXB gene protein.ConclusionAccording to this study, forty two novel nsSNP in HEXB are predicted to have possible role in Sandhoff disease using different bioinformatics tools, beside two SNPs found to have effect on miRNAs binding site affecting expression of HEXB gene. Our findings may assist in genetic study and diagnosis of Sandhoff disease.