Neurology India, Vol. 58, No. 6, November-December, 2010, pp. 950-951
Letter to Editor
A mutation of HEXB gene in Sandhoff disease presenting as motor neuron disease
Suk-Won Ahn1, Su-Hyun Kim2, Yoon-Ho Hong3, Kwang-Woo Lee2, Jung-Joon Sung2
1 Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, South Korea
Date of Acceptance: 22-Jul-2010
Code Number: ni10265
Sandhoff disease is an autosomal recessive lysosomal storage disorder.  The biochemical defect in Sandhoff disease is a deficiency of β-hexosaminidase activity resulting from a mutation in the HEXB gene, which is located on chromosome 5 and encodes the β-subunit of the hexosaminidase enzymes.,, The clinical course of Sandhoff disease varies greatly, ranging from very severe infantile forms to relatively milder adult-onset variants. , We report the first Korean case of adult-onset Sandhoff disease, which manifested as motor neuron disease.
A 23-year-old woman visited our department with complaints of weakness in all 4 extremities, followed by muscle fasciculations, cramps, dysarthria and dysphagia. Electromyography (EMG) revealed widespread denervation potentials with normal nerve conduction velocities in the cervical, thoracic, lumbar and bulbar regions. Biopsy of the vastus lateralis muscle revealed denervation atrophy of the muscle fibers, indicating the presence of motor neuron disease.  Brain magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), evoked potential (EP) test, jolly test, electroencephalography (EEG), thyroid-function tests and cerebrospinal fluid analysis did not reveal any abnormalities. Because of the early onset of motor neuron disease, we suspected the patient to have a GM2 gangliosidosis or spinal muscular atrophy (SMA) and tested her for β-hexosaminidase A and B activity, and the presence of the survival motor neuron 1 (SMN1 ) gene in leukocytes. Polymerase chain reaction (PCR) for restriction fragment length polymorphism (RFLP) did not reveal an SMN1 deletion, thus ruling out SMA. A fluorometric assay of the peripheral blood revealed a marked reduction in the total β-hexosaminidase (A and B) activity (290.0 nmol/h/mg; reference range, 620-1000 nmol/h/mg). Further, β-hexosaminidase A accounted for 78.5% of the total β-hexosaminidase activity. After obtaining informed consent for genetic research from the patient and her family, we performed HEXB analysis, which resulted in the identification of a compound heterozygote of two mutations in the patient. The first mutation was a 619A-G transition (Ile207Val) in exon 5, and it was also present in the patient's sister [Figure - 1]a. The second mutation was a 1250C-T transition (Pro417Leu) in exon 11, and this was also present in the patient's father, and her father's brother and sisters [Figure - 1]b.
The clinical features in our patient were clearly suggestive of motor neuron disease. The biochemical assay revealed a deficiency of β-hexosaminidase A and B activity , and Sandhoff disease was confirmed by gene analysis. The patient was assumed to have inherited the 619A-G mutation (Ile207Val) from her mother, who died at the age of 30 years; and the 1250C-T mutation (Pro417Leu) from her father. The latter mutation was also detected in her father's relatives. This case is classifiable as an example of delayed-onset Sandhoff disease, which usually manifests as neurological signs and symptoms in adulthood.  The allelic mutations leading to Sandhoff disease are diverse and can result in varying residual levels of the enzymes, which explains the variations in the clinical presentation of the disease. ,,,, Both the mutations found in our patient have been reported earlier but only in cases of infantile or juvenile Sandhoff disease, and neither has been reported to result in a phenotype of motor neuron disease.  Although the gene mutations reported here are not novel, this is the first report of a compound heterozygote of these 2 HEXB mutations in the Korean population, especially, one resulting in a phenotype of motor neuron disease.
Copyright 2010 - Neurology India
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