eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

GM1 Gangliosidosis

Author: David H Tegay, DO, FACMG, Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center
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Updated: Jun 8, 2009

Introduction

Background

G_M1 gangliosidosis is an autosomal recessive lysosomal storage disorder characterized by the generalized accumulation of G_M1 ganglioside, oligosaccharides, and the mucopolysaccharide keratan sulfate (and their derivatives). Deficiency of the lysosomal hydrolase, acid b -galactosidase, causes G_M1 gangliosidosis and Morquio disease type B (ie, mucopolysaccharidosis type IVB).¹ Three clinical subtypes of G_M1 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

Pathophysiology

Acid β -galactosidase is a lysosomal hydrolase that catalyzes the removal of the terminal β -linked galactose from glycoconjugates (eg, G_M1 ganglioside), generating G_M2 ganglioside. It also functions to degrade other β -galactose–containing glycoconjugates, such as keratan sulfate. Enzyme activity is markedly reduced in patients with G_M1 gangliosidosis. Deficiency of acid β -galactosidase results in the accumulation of glycoconjugates in body tissues and their excretion in urine. G_M1 ganglioside and its derivative asialo-G_M1 ganglioside (GA1), glycoprotein-derived oligosaccharides, and keratan sulfate are found at elevated intracellularconcentrations.¹

Gangliosides are normal components of cell membranes, particularly neurons, and G_M1 is the major ganglioside in the vertebrate brain. Accumulation of toxic asialo-compound and lyso-compound G_M1 ganglioside derivatives is believed to be neuropathic.¹

Frequency

United States

G_M1 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.⁶

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

G_M1 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.^7,1

Sex

All 3 types of G_M1 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.

Clinical

History

• Infantile G _M1 gangliosidosis: In the most common infantile form, coarse facial features, hepatosplenomegaly, generalized skeletal dysplasia (dysostosis multiplex), macular cherry-red spots, and developmental delay/arrest (followed by progressive neurologic deterioration) usually occur within the first 6 months of life. Nonimmune hydrops has been reported. An increased incidence of Mongolian spots has also been reported. A wide spectrum of variability is observed in the appearance and progression of the typical dysmorphic features. As many as 50% of affected infants have a macular cherry-red spot.^1,2
• Juvenile: The juvenile form is characterized by a later age of onset, less hepatosplenomegaly (if any), fewer cherry-red spots (if any), dysmorphic features, or skeletal changes (vertebral dysplasia may be detected radiographically).^1,2
• Adult: The adult form is characterized by normal early neurologic development, with variable age of clinical presentation. Slowly progressing dementia with parkinsonian features and extrapyramidal disease is common. Intellectual impairment may be initially absent or mild but progresses with time. Generalized dystonia with speech and gait disturbance is the most frequently reported early feature. Typically, no hepatosplenomegaly, cherry-red spots, dysmorphic features, or skeletal changes are present aside from scoliosis (mild vertebral changes may be revealed with radiography), but short stature is common.^4,5

Physical

• Neurologic findings
  • Developmental delay, arrest, and regression
  • Generalized hypotonia initially, developing into spasticity
  • Exaggerated startle response
  • Hyperreflexia
  • Seizures
  • Extrapyramidal disease (adult subtype)
  • Generalized dystonia (adult subtype)⁵
  • Ataxia (adult subtype)
  • Dementia (adult subtype)
  • Speech and swallowing disturbance (adult subtype)⁴
• Ophthalmologic findings
  • Macular cherry-red spots
    • Present in as many as 50% of affected infants
    • May be found in other genetic disorders (eg, mucolipidosis type I, Niemann-Pick disease, Krabbe disease, Tay-Sachs disease)
  • Optic atrophy
  • Corneal clouding
• Dysmorphic features
  • Frontal bossing
  • Depressed nasal bridge and broad nasal tip
  • Large low-set ears
  • Long philtrum
  • Gingival hypertrophy and macroglossia¹
• Coarse skin
• Hirsutism
• Cardiovascular - Dilated and/or hypertrophic cardiomyopathy, valvulopathy
• Abdomen
  • Hepatosplenomegaly
  • Inguinal hernia
• Skeletal abnormalities
  • Lumbar gibbus deformity and kyphoscoliosis
  • Dysostosis multiplex
  • Broad hands and feet
  • Brachydactyly
  • Joint contractures
• Angiokeratoma corporis diffusum (reported infrequently)
• Hydrops fetalis (has been reported)
• Prominent dermal melanocytosis (Mongolian spots)^8,9

Causes

• All 3 forms of G_M1 gangliosidosis are caused by deficiency in acid b -galactosidase activity.²
• G_M1 gangliosidosis is an autosomal recessive disease; therefore, affected individuals inherit 2 copies of the nonfunctioning gene. Carriers (ie, individuals with 1 functioning and 1 nonfunctioning gene) have no clinical manifestations.
  • The gene has been isolated and is located on chromosome band 3p21.33. Various types of mutations have been identified in the acid b -galactosidase gene, including missense/nonsense, duplication/insertion, and splice site abnormalities.¹⁰
  • Genotype and phenotype correlations are being delineated to provide a molecular explanation for clinical variability. The amount of residual enzyme activity has some correlation with disease subtype and severity.¹

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