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Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886 EISSN: 1998-4022
Vol. 58, Num. 6, 2010, pp. 950-951

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
2 Department of Neurology, Seoul National University Hospital, Seoul, South Korea
3 Department of Neurology, Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
Correspondence Address: Suk-Won Ahn, 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

PMID: 21150067
DOI: 10.4103/0028-3886.73755


Sandhoff disease is an autosomal recessive lysosomal storage disorder. [1] 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.[1],[2],[3] The clinical course of Sandhoff disease varies greatly, ranging from very severe infantile forms to relatively milder adult-onset variants. [4],[5] 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. [6] 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. [3] 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. [4],[5],[6],[7],[8] 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. [8] 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.


1.Cordeiro P, Hechtman P, Kaplan F. The GM2 gangliosidoses databases: Allelic variation at the HEXA, HEXB, and GM2A gene loci. Genet Med 2000;2:319-27.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Mark BL, Mahuran DJ, Cherney MM, Zhao D, Knapp S, James MN. Crystal structure of human beta-hexosaminidase B: Understanding the molecular basis of Sandhoff and Tay-Sachs disease. J Mol Biol 2003;327:1093-109.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Gomez-Lira M, Sangalli A, Mottes M, Perusi C, Pignatti PF, Rizzuto N, et al. A common beta hexosaminidase gene mutation in adult Sandhoff disease patients. Hum Genet 1995;96:417-22.  Back to cited text no. 3  [PUBMED]  
4.Yoshizawa T, Kohno Y, Nissato S, Shoji S. Compound heterozygosity with two novel mutations in the HEXB gene produces adult Sandhoff disease presenting as a motor neuron disease phenotype. J Neurol Sci 2002;195:129-38.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Maegawa GH, Stockley T, Tropak M, Banwell B, Blaser S, Kok F, et al. The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics 2006;118:1550-62.  Back to cited text no. 5    
6.Kim W, Kim JS, Lee KS, Gwoun YJ, Kim JM, Lee KH. Anticipation and phenotypic heterogeneity in korean familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutation. J Clin Neurol 2007;3:38-44.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Gomez-Lira M, Mottes M, Perusi C, Pignatti PF, Rizzuto N, Gatti R, et al. A novel 4-bp deletion creates a premature stop codon and dramatically decreases HEXB mRNA levels in a severe case of Sandhoff disease. Mol Cell Probes 2001;15:75-9.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Fujimaru M, Tanaka A, Choeh K, Wakamatsu N, Sakuraba H, Isshiki G. Two mutations remote from an exon/intron junction in the beta-hexosaminidase beta-subunit gene affect 3'-splice site selection and cause Sandhoff disease. Hum Genet 1998;103:462-9.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]

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