1/45. Enzyme studies in GM2 gangliosidiosis, and their application in prenatal diagnosis. Assay of hexosaminidase a and B enzymes in four cases with developmental regression and cherry red spot on fundus examination confirmed that three cases had tay-sachs disease, and one case had sandhoff disease. prenatal diagnosis was carried out by hexosaminidase enzyme assay in amniotic fluid and cells in one family, and chorionic villus sample in the second family. The fetus was diagnosed to be unaffected in one, and affected in the other family. Assay of hexosaminidase a and B is useful for specific diagnosis of GM2 gangliosidosis, and for prenatal diagnosis to reduce the burden of these disorders. ( info) |
| INTRODUCTION: sandhoff disease is a GM2 gangliosidosis that may present within the first 6 months of life with developmental regression. This is the first report of a pedigree from Southeast Asia. CLINICAL PICTURE: All the affected siblings presented in the first year of life with developmental regression, spasticity, seizures and loss of vision. The diagnosis was confirmed by an enzymatic deficiency in both beta-hexosaminidase a and B. CONCLUSION: As the disorder is autosomal recessive, and no curative therapy is currently available, genetic counselling is necessary to prevent the burden of this devastating disease. We review the potential strategies of treatment for sandhoff disease. ( info) |
3/45. A novel 4-bp deletion creates a premature stop codon and dramatically decreases HEXB mRNA levels in a severe case of sandhoff disease. We present the molecular genetic analysis of an infantile-onset sandhoff disease patient. Genomic dna amplification, heteroduplex analysis, cloning and sequencing revealed a 4-bp deletion in exon 4 (497 DeltaAGTT). The result is a frameshift mutation that leads to a stop codon in exon 5. This mutation is associated with a dramatic decrease of HEXB mRNA levels. ( info) |
4/45. Late-onset GM2 gangliosidosis presenting as burning dysesthesias. Two brothers with a painful neuropathy as a component of late-onset GM2 gangliosidosis of the Sandhoff type are presented. A dramatic response of the severe dysesthesias to amitriptyline and gabapentin is described. Symptomatic sensory neuropathy may be a component of late-onset GM2 gangliosidosis. ( info) |
| Little information is available on molecular defects involved in adult sandhoff disease presenting as motor neuron disease phenotype. We studied enzyme activities of beta-hexosaminidase (Hex) and the HEXB gene encoding the beta-subunit of Hex in a family of the Japanese case. Enzyme assay with 4-methylumbelliferyl-2-acetamido-2-deoxy-beta-D-glucopyranoside revealed a reduction in Hex A and B activity in proband's leukocytes. Although the activity of both in the mother were intermediate between those of controls and the proband, only Hex B reduction determined with heat inactivation was found in the father. Analysis of HEXB gene demonstrated two novel point mutations. The first mutation, IVS2-1G>A, was located at the 3'-splice acceptor site of intron 2 derived from the mother, causing exon 3 skipping. The resultant mRNA encoded a shorter beta-chain, which may not form an active enzyme. The second mutation was a G-to-A transition in exon 13 (c.1598G>A) derived from the father and resulted in arginine-to-histidine substitution at amino acid position 533 (R533H). Expression of R533H mutation in COS-1 cells demonstrated a lack of normal Hex activity, indicating that this mutation is pathological. Compound heterozygosity of these two mutations may trigger the development of adult sandhoff disease with a motor neuron disease phenotype. ( info) |
| We report a female premature infant with bronchopulmonary dysplasia and Sandhoff disease. The clue for diagnosis was the fundoscopy examination. We discuss this rare disease with unusual presentation of intrauterine growth retardation, premature delivery, and bronchopulmonary dysplasia. ( info) |
7/45. GM2 gangliosidosis variant B1 neuroradiological findings. Variant B1 is a rare type of GM2 gangliosidosis. Clinically, it shows a wide spectrum of forms ranging from infantile to juvenile. We report the first magnetic resonance imaging (MRI) findings from three patients affected by GM2 gangliosidosis variant B1, two presenting with the infantile form and one with the juvenile form. The MRI appearances of the two patients with the infantile form disease are congruent with those reported for the early-onset type of both Tay-Sachs and Sandhoff diseases, and are characterized by early involvement of the basal ganglia and thalamus with cortical atrophy appearing later. In contrast, the patient with the juvenile form of variant B1 showed progressive cortical and white-matter atrophy of the supratentorial structures and, to a lesser extent, the infratentorial structures. No basal ganglia or thalamic anomalies were observed. Because in the adult forms of both Tay-Sachs and Sandhoff diseases a progressive cerebellar atrophy represents the only abnormality detectable, it appears that an MRI pattern peculiar to GM2 gangliosidosis can be defined. This pattern ranges from the basal ganglia injury associated with the early and severe demyelination process noted in the infantile form of the disease, to cerebellar atrophy with no supratentorial anomalies in the adult form. An "intermediate" MRI picture, with cortical atrophy and mild cerebellar atrophy, but without basal ganglia impairment, can be observed in the juvenile form. In addition, our investigations suggest that MRI abnormalities in GM2 gangliosidosis correlate with the clinical form of the disease rather than with the biochemical variant of the enzymatic defect. ( info) |
8/45. Infantile Sandhoff's disease: multivoxel magnetic resonance spectrosecopy findings. Sandhoff's disease is a rare, genetic lysosomal storage disease leading to delayed myelination or demyelination. Although neuroimaging findings in this disease have been reported previously, magnetic resonance spectroscopy findings have not been reported. In this report, we present magnetic resonance imaging and magnetic resonance spectrscopy features of two cases with Sandhoff's disease. magnetic resonance spectroscopy revealed findings indicating widespread demyelination in both cases and neuroaxonal loss and anaerobic metabolism in the second case. magnetic resonance spectroscopy could provide useful information in the explanation of the clinical picture of cases with Sandhoff's disease. ( info) |
9/45. An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds. sandhoff disease is caused by mutations affecting the beta subunit of lysosomal beta-hexosaminidase (EC 3.2.1.52) and displays a wide spectrum of clinical phenotypes. We report a 57-year-old patient with a very mild phenotype, although residual hexosaminidase a activity in his cultured fibroblasts was less than 3% of normal activity, a level observed in juvenile onset patients. Northern and Western blot analyses confirmed a similar low level of beta subunit-mRNA and mature beta-protein, respectively. Two mutations of the HEXB gene were identified in this patient, a partial 5' gene deletion (a null allele), and a C T transition 8 nucleotides downstream from the intron 10/exon 11 junction affecting the splicing of the beta subunit-mRNA. In their homozygous forms, the 5' deletion has been previously shown to result in a severe infantile phenotype, and the C T transition in a juvenile phenotype. The genotype and the low level of residual hexosaminidase a activity would be expected to produce a juvenile Sandhoff phenotype in this patient, as well as in four of his six clinically normal siblings. The biochemical basis of his mild phenotype is uncertain, but may result from genetic variations in the rna splicing machinery. ( info) |
| Juvenile sandhoff disease (McKusick 268800) is a rare lysosomal storage disorder with only 12 cases recorded in the literature. This condition is also referred to as the subacute form of hexosaminidase deficiency. We describe 9 new cases of Pakistani origin and compare these with the other published cases. ataxia and speech abnormalities were the commonest presentation. constipation and urinary incontinence were frequent and may be due to autonomic neuropathy. Cherry-red spot was not noted in any of our cases. Increased lower limb reflexes were the commonest physical finding. Significant delay in diagnosis may be due to the nonspecific presentation of this condition. Diagnosis was on the basis of hexosaminidase deficiency. Residual enzyme activity did not correlate with the clinical picture. Emerging therapies make early diagnosis of this disorder important. ( info) |