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:
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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]
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Juvenile (type 2): The juvenile subtype is marked by a slightly later age of onset and clinical variability in the classic physical features.
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. There are several possible mechanisms by which the gangliosidoses may cause their pathological hallmarks. Accumulation of toxic asialo-compound and lyso-compound GM1 ganglioside derivatives is believed to be neuropathic. [1] In addition, the ganglioside meganeurites and ectopic dendrites could alter the electrical properties of the neuron, leading to neural dysfunction. [10] Recently, inflammation has been investigated as having a major role in pathogenesis and could explain some of the neuronal dysfunction. [11, 10]
Emerging evidence suggests that mitochondrial function may be diminished in lysosomal storage disorders, resulting in alterations in mitochondrial mass, morphology, and function. [12] Altered mitochondrial morphology could lead to a reduced availability of ATP at synapses, leading to some of the impaired neurotransmission and neuronal degradation seen in lysosomal storage disorders. [13, 12]
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. [14]
Mortality/Morbidity
The infantile form of GM1 gangliosidosis (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. [15, 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) of GM1 gangliosidosis 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.
Prognosis
Infantile (type 1): Death usually occurs during the second year of life because of infection and cardiopulmonary failure. [1]
Juvenile (type 2): Death usually occurs before the second decade of life. [1]
Adult (type 3): Phenotypic variability is marked, but progressive development of neurologic sequelae usually leads to a shortened lifespan. [1]
Patient Education
Families of patients with GM1 gangliosidosis require education regarding the disease manifestations and potential complications.
A discussion of the genetic basis of the disorder should include recurrence risks and methods of carrier identification.
Genetic counseling should be available for at-risk couples to explain risk and options in future pregnancies, including prenatal diagnosis.
Lysosomes are cytoplasmic organelles that are found in nearly all animal cells. They contain various active hydrolytic enzymes (hydrolases) that are used to break down biological molecules.
When there is a genetic defect in a lysosomal enzyme, the activity of the enzyme may be altered, resulting in the accumulation of materials meant for degradation. [13] This results in a lysosomal storage disease such as Pompe disease, mucopolysaccharidoses, oligosaccharidoses, Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy.
In addition to ineffective enzymes, there are also disorders that result from deficiency of activator proteins, as in GM2 gangliosidosis.
In the case of GM1 gangliosidosis, gangliosides fail to have their terminal galactose removed, and the deficient activity of β-galactosidase results in accumulation of gangliosides in neurons, causing the brain pathology and neurodegeneration in this disorder. [13]
