GM1 gangliosidosis in adults: Clinical and molecular analysis of 16 Japanese patients

Abstract

Clinical findings were compared with the results of molecular analysis in 16 Japanese patients from 10 unrelated families with the adult/chronic form of GM1 gangliosidosis. Age of onset ranged from 3 to 30 years. Major clinical manifestations were gait and speech disturbances caused by persistent muscle hypertonia. Dystonic postures and movements, facial grimacing, and parkinsonian manifestations were commonly seen. Cerebellar signs, myoclonus, severe intellectual impairment, dysmorphism, or visceromegaly were not observed. A common single-base substitution, 51Ile(ATC)----Thr(ACC), reported in a previous study of ours, was confirmed in 14 patients by the Bsu36I restriction site analysis; one was a compound heterozygote with another mutation (457Arg[CGA]----Gln[CAA]) and the others were homozygotes of this mutation. Clinically, the compound-heterozygous patient showed more severe neurological manifestations and a more rapid clinical course than those of homozygotes. The homozygotes showed considerable variations in the age of onset and subsequent clinical course. The 51Ile----Thr mutant allele expressed a significant amount of beta-galactosidase activity, whereas the 457Arg----Gln mutant allele expressed extremely low activity in human GM1 gangliosidosis fibroblasts. We conclude that these gene mutations causing different residual enzyme activities are related to the severity of clinical manifestations, but some other genetic or environmental factors contribute to clinical heterogeneity. The Bsu36I restriction site analysis was performed in 7 families and provided clear results for the diagnosis of heterozygotes as well as homozygotes of this specific clinical form of GM1 gangliosidosis. The technique is applicable to prenatal diagnosis and genetic counseling.

Clinical Findings and Natural History in Ten Unrelated Families with Juvenile and Adult GM1 Gangliosidosis

“…Severe motor disability and significant complaints of dysphagia probably contributed to muscle wasting seen in 9/12 patients. This value is higher than the series of Japanese patients with the adult form where only 3/16 had muscular atrophy (Yoshida et al 1992), but the socioeconomic conditions present in our sample might explain this discordance, rather than ethnic and genetic factors.…”

Acute Dystonia with Thalamic and Brainstem Lesions after Initial Penicillamine Treatment in Wilson’s Disease

“…In these patients, the lesions responsible were in the contralateral caudate, lentiform nucleus, particularly the putamen, thalamus, or a combination of these structures. In addition, dystonia can also occur in some metabolic diseases such as glutaric aciduria type 1, Niemann pick disease type c and GM1 gangliosidosis [7][8][9].…”

Six novel ?-galactosidase gene mutations in Brazilian patients with GM1-gangliosidosis

“…Gene mutations are heterogeneous in infantile patients and result in an almost complete deficiency of β-galactosidase [Nishimoto et al, 1991;Yoshida et al, 1991;Boustany et al, 1993]. Common mutations have been found in the other clinical forms of β-galactosidase deficiency [Oshima et al, 1991;Nishimoto et al, 1991;Yoshida et al, 1992]. In general, GM1-gangliosidosis is considered a rare disorder with an incidence of approximately 1 case: 100,000-200,000 live births [Beattie and Harvey, 1992;Whitley, 1993], but the precise number of patients in the total population has not been determined.…”