GM1 Gangliosidosis

Updated: Dec 11, 2014
  • Author: David H Tegay, DO, FACMG; Chief Editor: Luis O Rohena, MD  more...
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Overview

Background

GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder characterized by the generalized accumulation of GM1 ganglioside, oligosaccharides, and the mucopolysaccharide keratan sulfate (and their derivatives). Deficiency of the lysosomal hydrolase, acid β -galactosidase, causes GM1 gangliosidosis and Morquio disease type B (ie, mucopolysaccharidosis type IVB). [1] Three clinical subtypes of GM1 gangliosidosis are recognized, classified by age of onset, as follows:

  • Infantile (type 1): The classic infantile subtype combines the features of a neurolipidosis (ie, neurodegeneration, macular cherry-red spots) with those of a mucopolysaccharidosis (ie, visceromegaly, dysostosis multiplex, coarsened facial features). This form of G M1 gangliosidosis most frequently presents in early infancy and may be evident at birth. [2]
  • Juvenile (type 2): The juvenile subtype is marked by a slightly later age of onset and clinical variability in the classic physical features.
  • Adult (type 3): The adult subtype is marked by normal early neurologic development with no physical stigmata and subsequent development of a slowly progressive dementia with parkinsonian features, extrapyramidal disease, and dystonia. [3, 4, 5]
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Pathophysiology

Acid β -galactosidase is a lysosomal hydrolase that catalyzes the removal of the terminal β -linked galactose from glycoconjugates (eg, GM1 ganglioside), generating GM2 ganglioside. It also functions to degrade other β -galactose–containing glycoconjugates, such as keratan sulfate.

Enzyme activity is markedly reduced in patients with GM1 gangliosidosis. Deficiency of acid β -galactosidase results in the accumulation of glycoconjugates in body tissues and their excretion in urine. GM1 ganglioside and its derivative asialo-GM1 ganglioside (GA1), glycoprotein-derived oligosaccharides, and keratan sulfate are found at elevated intracellular concentrations. [1, 6, 7, 8, 9]

Gangliosides are normal components of cell membranes, particularly neurons, and GM1 is the major ganglioside in the vertebrate brain. Accumulation of toxic asialo-compound and lyso-compound GM1 ganglioside derivatives is believed to be neuropathic. [1]

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Epidemiology

Frequency

United States

GM1 gangliosidosis is a rare disorder, and data concerning incidence are not widely available. The estimated incidence is 1:100,000-200,000 live births. [2]

International

An unusually high incidence of 1 case per 3700 live births has been reported in the population of Malta. [10]

Mortality/Morbidity

The infantile form (type 1) typically presents between birth and age 6 months with progressive organomegaly, dysostosis multiplex, facial coarsening, and rapid neurologic deterioration within the first year of life. Death usually occurs during the second year of life because of infection (usually due to pneumonia that results from recurrent aspiration) and cardiopulmonary failure.

The juvenile form (type 2) typically presents at age 1-2 years with progressive psychomotor retardation. Little visceromegaly and milder skeletal disease are present compared to the infantile form. Death usually occurs before the second decade of life.

The adult form (type 3) typically presents during childhood or adolescence as a slowly progressive dementia with prominent parkinsonian features and extrapyramidal disease, particularly dystonia. Marked phenotypic variability may occur. Age at death may widely vary.

Race

GM1 gangliosidosis is found in all races, although specific alleles can be identified in certain ethnic groups. A high frequency of GM1 gangliosidosis has been reported from Southern Brazil, and a large number of Japanese patients with the adult form have been reported. [11, 1]

Sex

All 3 types of GM1 gangliosidosis are inherited as autosomal recessive traits and have equal sex distributions.

Age

The infantile form (type 1) typically presents from birth to age 6 months, the juvenile form (type 2) typically presents in children aged 1-3 years, and the adult form (type 3) typically presents during childhood or adolescence.

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