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, 16]
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, 17]
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
See the list below:
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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]
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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
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Dysmorphic features
Frontal bossing
Depressed nasal bridge and broad nasal tip
Large low-set ears
Long philtrum
Gingival hypertrophy and macroglossia [1]
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Coarse skin
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Hirsutism
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Cardiovascular - Dilated and/or hypertrophic cardiomyopathy, valvulopathy
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Abdomen
Hepatosplenomegaly
Inguinal hernia
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Skeletal abnormalities
Lumbar gibbus deformity and kyphoscoliosis
Dysostosis multiplex
Broad hands and feet
Brachydactyly
Joint contractures
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Angiokeratoma corporis diffusum (reported infrequently)
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Hydrops fetalis (has been reported)
Causes
All 3 forms of GM1 gangliosidosis are caused by deficiency in acid β -galactosidase activity. [2]
GM1 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 GLB1 gene has been isolated and is located on chromosome band 3p21.33. More than 165 disease-causing types of mutations have been identified in the acid β -galactosidase gene, including missense/nonsense, duplication/insertion, and splice site abnormalities. [21] The wide variety in GLB1 mutations causes the variable symptomology in GM1 gangliosidosis, and the severity and age of onset of disease are directly related to the severity of the genetic mutation. [11]
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]
Complications
Patients with GM1 gangliosidosis are at risk for aspiration pneumonia and recurrent respiratory infections resulting from neurologic compromise.
Congestive heart failure may result secondary to cardiomyopathy.
Atlantoaxial instability can develop because of abnormally shaped cervical vertebrae. If this occurs, patients should be monitored, and they eventually should undergo surgical stabilization to avoid the risk of spinal cord injury.
