GM<sub>2</sub> gangliosidosis with hexosaminidase A and B defect: Report of a family with motor neuron disease‐like phenotype

Federico, Antonio; Ciacci, G.; D'Amore, I; Pallini, R; Palmeri, Silvia; Rossi, Alessandro; Rizzuto, N.; Guazzi, G. C.

doi:10.1007/bf01799737

Cited by 16 publications

(2 citation statements)

References 7 publications

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“…For example, we have previously shown that the juvenile-onset form ofSandhoffdisease can be biochemically differentiated from the infantile-onset form by the amount of residual Hex A activity in established fibroblast cell lines (10). Further, there have been three reports describing an adult-onset form of the disease (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The disorder in these patients was limited to a motor neuron disease, presumably owing to only a partial deficiency of 13-hexosaminidase.…”

Section: Introductionmentioning

confidence: 99%

Structure and distribution of an Alu-type deletion mutation in Sandhoff disease.

Neote

McInnes²,

Mahuran³

et al. 1990

J. Clin. Invest.

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Sandhoff disease is a recessively inherited lysosomal storage disease resulting from a deficiency of 1-hexosaminidase activity. The enzyme occurs in two major forms, fl-hexosaminidase A, composed of an a-and j-subunit and ft-hexosaminidase B, composed of two 13-subunits. Both isozyme activities are deficient in Sandhoff disease, owing to mutations of the HEXB gene encoding the common ,8-subunit. We have cloned and fully characterized a deletion at the HEXB gene from fibroblasts of a patient with the infantile form of Sandhoff disease. The deletion removes -16 kb of DNA including the HEXB promoter, exons 1-5 and part of intron 5. It most likely arose from recombination between two Alu sequences, with the breakpoints occurring at the midpoint between the left and right arms in each case and regenerating an intact Alu element in the deletion sequence. The deletion allele accounts for 27% of the Sandhoff mutant alleles we analyzed. Two cell lines were shown to be homozygous for the deletion and both had the infantile form of the disease. Four additional patients were compound heterozygotes with other mutations, all of whom displayed a different clinical phenotype. Finally, the mutant allele was present in different ethnic backgrounds, suggesting that it may have been subject to genetic drift. (J. Clin. Invest.

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Section: Introductionmentioning

confidence: 99%

Structure and distribution of an Alu-type deletion mutation in Sandhoff disease.

Neote

McInnes²,

Mahuran³

et al. 1990

J. Clin. Invest.

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“…However, some families are reported in which affected cases are present in two generations (parents and sons). This condition of 'pseudodominance' can occur in auto somal recessive diseases when one of parents is affected and the other is heterozygote, a condition possible in societies with high carrier frequency, in which persons with iate-onset diseases are not identified before mar riage and have no genetic counselling [2][3][4]. Diseases such as adrenoleucodystrophy adrenomyeloneuropathy and a lysosomal disorder, Fabry's disease, have X-linked inheritance [5].…”

Section: The Diagnostic Suspicionmentioning

confidence: 99%

Diagnosis and Pathogenesis of Late-Onset Genetic Metabolic Encephaloneuromyopathies

Federico¹

1991

Dev Neurosci

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The strategy of clinical investigations for the diagnosis of the late-onset neurometabolic diseases is reported. The criteria for the diagnostic suspicion are inheritance and multisystem involvement. The different clinical signs that are the basis for further biological investigations are reviewed. The diagnostic confirmation will be obtained by laboratory analyses, some of which can be easily performed in all hospitals. The pathogenesis of late-onset neurometabolic encephaloneuromyopathies and the clinical consequences of heterozygosity are reported. Finally these disorders are discussed as a useful model for understanding the pathogenesis of some of the most common neurological diseases and of the normal functions of many molecules in the nervous system.

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Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

Navon

Khosravi

Melki

et al. 1997

Annals of Neurology

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Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

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GM₂ gangliosidosis with hexosaminidase A and B defect: Report of a family with motor neuron disease‐like phenotype

Cited by 16 publications

References 7 publications

Structure and distribution of an Alu-type deletion mutation in Sandhoff disease.

Structure and distribution of an Alu-type deletion mutation in Sandhoff disease.

Diagnosis and Pathogenesis of Late-Onset Genetic Metabolic Encephaloneuromyopathies

Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

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GM2 gangliosidosis with hexosaminidase A and B defect: Report of a family with motor neuron disease‐like phenotype

Cited by 16 publications

References 7 publications

Structure and distribution of an Alu-type deletion mutation in Sandhoff disease.

Structure and distribution of an Alu-type deletion mutation in Sandhoff disease.

Diagnosis and Pathogenesis of Late-Onset Genetic Metabolic Encephaloneuromyopathies

Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

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GM₂ gangliosidosis with hexosaminidase A and B defect: Report of a family with motor neuron disease‐like phenotype