GM1 Gangliosidosis

GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder due to biallelic variants in GLB1, with deficiency of beta galactosidase and accumulation of GM1 ganglioside in neurons. It has infantile, late infantile or juvenile, and adult forms.

Pathophysiology. Beta galactosidase removes terminal galactose from GM1 ganglioside, keratan sulphate and oligosaccharides. Deficiency causes neuronal storage and neurodegeneration. Allelic variants in the same gene also cause Morquio syndrome type B (mucopolysaccharidosis IVB), which affects the skeleton without brain disease.

Residual enzyme activity predicts the age of onset.

No disease modifying treatment is established, so care is supportive.

• Infantile form (onset by 6 months): hypotonia, poor feeding, coarse facial features, hepatosplenomegaly, macular cherry red spot, startle response, rapid regression and seizures, and death by 2 to 3 years.
• Dysostosis multiplex: vertebral beaking, kyphosis, and short hands.
• Late infantile or juvenile form (onset 1 to 5 years): ataxia, regression, seizures, spasticity, with less visceral involvement.
• Adult form: dystonia, parkinsonism like features and gait disorder, with mild intellectual disability.
• Cardiomyopathy in some.
• Angiokeratomas in the adult form.

• Beta galactosidase enzyme assay in leukocytes or fibroblasts: low activity, with normal alpha neuraminidase (to exclude galactosialidosis).
• GLB1 sequencing with deletion and duplication analysis.
• Urinary oligosaccharides and keratan sulphate.
• Brain MRI: thalamic hyperdensity on CT, white matter signal change, and basal ganglia involvement.
• Radiographs for dysostosis multiplex, and ophthalmic examination for cherry red spot.
• Echocardiography.

Differential diagnosis.

• Tay-Sachs and Sandhoff disease (GM2 gangliosidosis)
• Niemann-Pick disease type A
• Mucopolysaccharidoses and mucolipidosis
• Galactosialidosis and sialidosis
• Krabbe disease

• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily, and clobazam 0.25 mg/kg daily increasing to 1 mg/kg daily (maximum 40 mg). Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Spasticity and dystonia: baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg), and trihexyphenidyl or botulinum toxin for dystonia under specialist care.
• Feeding and aspiration: thickened feeds and gastrostomy, with omeprazole 0.7 to 1 mg/kg daily for reflux.
• Drooling: glycopyrronium bromide 15 microgram/kg orally three times daily, increasing every 7 days to a maximum of 100 microgram/kg daily (not over 6 mg daily).
• Respiratory care: chest physiotherapy, vaccination and prompt antibiotics for infection.
• Orthopaedic care: bracing and surgery for progressive deformities.
• Palliative care: early involvement in the infantile form, with comfort measures and support.
• Disease modifying therapy: substrate reduction with miglustat and gene therapy are experimental, so offer enrolment in research where possible.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis by enzyme assay or variant testing.

Special groups.

• Adult onset patients: manage dystonia and gait with specialist movement disorder care, and give levodopa for parkinsonism if needed.

Monitoring. Seizures, feeding and respiratory status at each visit. Growth and development every 3 to 6 months, and orthopaedic review yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine, neurology and palliative care. Emergency for status epilepticus, aspiration or respiratory failure.