PEDBASE.org - The Pediatric Database - Detailed information of GM1 GANGLIOSIDOSES

GM1 GANGLIOSIDOSES

DEFINITION:

A lysosomal storage disease characterized by the accumulation of lipids (GM1 gangliosides) in the CNS and peripheral tissues resulting in 3 clinical variants.

EPIDEMIOLOGY:

incidence: rare (about 50 cases reported)
age of onset:
- infancy (Type I) -> adulthood (Type III)
risk factors:
- familial - autosomal recessive
  - chrom.#: 3p21.33
  - gene: beta-galactosidase A
- M = F

PATHOGENESIS:

1. Background

beta-galactosidase A is a lysosomal hydrolase which catalyzes the removal of galactose from gangliosides (ceramide plus neuramidic acid), galactose-containing mucopolysaccharides, and glycoproteins

2. Genetic Defect

genetic defect -> deficiency of beta-galactosidase A activity
accumulation of GM1 gangliosides in the CNS (especially the basal ganglia) and galactosyl oligosaccharides and keratan-sulfate degradation products in somatic cells (visera)
in the Type I variant, the deposition of GM1 gangliosides is extensive but less extensive in the Type II variant; in the Type III variant, deposition occurs primarily in the basal ganglia
the deposition of substances in the peripheral tissues decreases from variants I -> III
three clinical variants:
Type I - Infantile Form

Type II - Juvenile Form

Type III - Adult Form

CLINICAL FEATURES:

1. Type I (Infantile Form)

early onset (newborn), rapid course, severe bony abnormalities
death between 6-24 months

1. CNS Manifestations

psychomotor retardation (severe)
- noted from birth
- hypotonic -> decerebrate rigidity
- hypoactive with poor grasp
- usually never able to sit or crawl
- generalized hyperreflexia, poor muscle strength
mental retardation (severe)
tonic clonic seizures - after 1 year of age

2. Gastrointestinal Manifestations

poor appetite, weak suck, failure to thrive, growth retardation
hepatomegaly/hepatosplenomegaly
umbilical and inguinal hernias

3. Musculoskeletal Manifestations

1. Facial

frontal bossing
depressed nasal bridge
large low-set ears
coarse facial features
gum hypertrophy
mild macroglossia
facial edema

2. Other

dorsolumbar kyphoscoliosis
stiff joints with flexion contractures at elbows and knees

4. Ophthalmologic Manifestations

diffuse corneal clouding
cherry-red spot (in 50% of cases)
retinal vascular tortuosity and hemorrhage
optic atrophy -> early blindness
nystagmus and strabismus

5. Other Manifestations

1. Respiratory

recurrent bronchopneumonia

2. Cardiovascular

PAT, cardiomegaly

3. Genitourinary

scrotal edema

4. Integument

thick, hirsute, rough

2. Type II (Infantile Form)

later onset (6-20 months), slower course with milder bony abnormalities
death between 3-10 years

1. CNS Manifestations

psychomotor retardation
- normal development during 1st year of life
- ataxia usually the initial symptom followed by choreoathetoid movements
- generalized moderate muscular weakness with hyper-reflexia
- hypotonia -> progressive spasticity -> decerebrate rigidity
- loss of speech
dulling of the sensorium, lack of socialization, lethargy, severe mental retardation
tonic clonic seizures begin after 16 months of age

2. Ophthalmologic Manifestations

optic atrophy -> blindness
nystagmus, strabismus

3. Other Manifestations

1. Respiratory

recurrent bronchopneumonia

3. Type III (Adult Form)

late onset (teens), lack of visceral involvement
death after 20 years of age (up to 4th decade)

1. CNS Manifestations

gait disturbances (ataxia), dysarthria, spasticity
slowly progressive dystonia affected the face and limbs
mild mental impairment

INVESTIGATIONS:

1. Diagnostic

deficiency of acid beta-galactosidase activity in leukocytes and cultured skin fibroblasts (also brain and liver samples)
prenatal
- deficiency of acid beta-galactosidase activity in cultured chorionic villi or amniocytes

2. Imaging Studies

1. Skeletal X-Rays

1. Dysostosis Multiplex

moderate in Infantile Form and mild in the Juvenile and Adult Forms
affects vertebrae, upper extremities, sella turcica, calvarium, and long bones

2. CT/MRI

Type I - generalized atrophy with dilated ventricles
Type III - atrophy of the basal ganglia

3. Urine

elevated excretion of keratan sulfate

4. Pathology

1. Electron Microscopy

1. Neuronal Lipidosis

neuronal cytoplasmic inclusions consisting of a single membrane-bound organelle (secondary lysosomes) containing GM1 ganglioside and displacing the nuclei to the periphery
neural tissues affected
- CNS - cortex, brainstem, spinal cord (Types I&II)
  - basal ganglia (Type III)
- PNS - autonomic plexus

2. Peripheral Lipidosis

pathology similar to that seen in the neural tissues
tissues affected
- visceral organs, fibroblasts, epithelial cells
- foam cells found in samples from lungs, bone marrow, and liver

MANAGEMENT:

1. Supportive

no treatment for underlying disorder
multidisciplinary approach
- Paediatrics, Neurology, Ophthalmology, Orthopedics
- genetic counselling

2. REFERENCES:

Takano, T. and Y. Yamanouchi, Human Genetics 92:403-404 (1993)

Pediatric Database - GM1 GANGLIOSIDOSES

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