Peripheral neuropathy in a family with Sandhoff disease and SH3TC2 deficiency.

Abstract

OBJECTIVE: To report clinical findings of peripheral neuropathy in a family with Sandhoff disease and SH3TC2 deficiency. BACKGROUND: Sandhoff disease is a lysosomal storage disease caused by a deficiency of beta-hexosaminidase. Affected individuals present with a wide spectrum of clinical manifestations ranging from psychomotor impairment and death in the infantile form to motor neuron disease and autonomic dysfunction in the adult form. We present a family with predominantly sensory neuropathy that was found to have Sandhoff disease and deficiency of SH3TC2. DESIGN/METHODS: We assessed a 46-year-old male who experienced parethesia with loss of sensation in his hands and feet for thirty years. An evaluation of his 57 year old sister showed a similar pattern of sensory, motor, and autonomic involvement, with symptom onset in her 20’s. Whole exome sequencing was performed at the NIH Intramural Sequencing Center, National Human Genome Research Institute, and the National Institutes of Health. RESULTS: The two affected siblings were found to have a common mutation in both HEXB and SH3TC (P417L and R954X, respectively) in addition to being heterozygous for a 16kb deletion of the HEXB gene. The two unaffected siblings both had the SH3TC mutation though neither was heterozygous for both HEXB mutations. Elevated creatine, low total hexosaminidase activity, and increased fraction of HEXA activity were observed in the affected siblings. A nerve biopsy revealed evidence of a severe demyelinating neuropathy and a reduction in SH3TC2 staining. CONCLUSIONS: Although the P417L mutation is common in Sandhoff disease patients, the early and severe sensory findings are not a typical presentation of the disease. Our data suggest that the SH3TC2 deficiency is modifying the HEXB phenotype. The identification of a family with mutations in both SH3TC2 and HEXB helps in our understanding of the biological processes that may be common to these two diseases. Study Supported by: Disclosure: Dr. Bakar has nothing to disclose. Dr. Lanman has nothing to disclose. Dr. Grunseich has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Schindler has nothing to disclose. Dr. Mankodi has nothing to disclose. Dr. Traslavina has nothing to disclose. Dr. Lehky has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Maragakis has received personal compensation for activities with Advanced Technologies and Regenerative Medicine LLC. Dr. Tifft has nothing to disclose. Dr. Fischbeck has nothing to disclose.