Krabbe Disease

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disease due to deficiency of galactocerebrosidase (GALC, 14q31), which leads to accumulation of psychosine (galactosylsphingosine) and widespread oligodendrocyte and Schwann cell death, causing demyelination in the central and peripheral nervous system. Incidence is about 1 in 100,000 in the United States and Europe (higher in Druze and Scandinavian communities). Infantile onset accounts for about 85 to 90% and later onset forms for the remainder.

• Early infantile (onset 0 to 6 months): Stage 1: irritability, hyperirritability to stimuli, feeding difficulty, vomiting, mild developmental slowing, and stiffness; Stage 2: rapid motor and mental regression, spasticity, opisthotonus, seizures, optic atrophy and blindness, absent reflexes (peripheral neuropathy), and fever of unknown origin; Stage 3: decerebrate posturing and a vegetative state, with death by about 2 years
• Late infantile, juvenile, and adult onset: progressive spastic paraparesis, ataxia, visual loss, peripheral neuropathy, and cognitive decline; slower course
• Characteristic imaging: symmetrical white matter changes in the parieto occipital areas and corticospinal tracts, with optic nerve and cranial nerve thickening; CSF protein markedly elevated; nerve conduction studies show slowed velocities

1. Galactocerebrosidase enzyme activity (leucocytes or dried blood spots; reduced to below 5% in infantile disease).
2. GALC sequencing (with identification of pseudodeficiency alleles that cause low enzyme activity without disease; the 30 kb deletion is the commonest pathogenic allele in Europeans), and psychosine measurement in dried blood spot for second tier newborn screening (elevated in infantile disease).
3. MRI brain and nerve conduction studies; CSF protein.
4. Newborn screening now exists in several US states (using enzyme assay and psychosine), which has enabled pre-symptomatic therapy.

• Haematopoietic stem cell transplantation (umbilical cord blood or bone marrow): the only disease modifying therapy for pre-symptomatic infants (treated within the first month of life, ideally before 30 days of age) and mildly symptomatic later onset patients; it preserves cognition and survival but does not fully halt motor and peripheral nerve disease; it is not effective after symptom onset in infantile disease. Newborns with high risk genotype and enzyme levels are referred urgently to a transplant centre.
• Symptomatic care: antiepileptic drugs, baclofen and botulinum toxin for spasticity, irritability control (gabapentin, propranolol; treat reflux), feeding support (gastrostomy), physiotherapy, orthopaedic care (hip dislocation), respiratory care, and palliative care.
• Experimental: gene therapy (AAV9 and lentiviral approaches), substrate reduction, and chaperone therapy.
• Genetic counselling: 25% recurrence risk, carrier testing, prenatal diagnosis, and preimplantation testing; interpret psychosine and genotype for later onset prediction.