Krabbe's Disease

Synonyms: Globoid cell leukodystrophy; Globoid cell leukoencephalopathy; Galactosylceramide lipidosis; Galactosylceramidase (GALC) deficiency

An autosomal recessive condition which is often fatal, resulting in lack of the enzyme galatosylceramidase leading to abnormalities of myelin formation affecting both the central and peripheral nervous system. It is a member of the leukodystrophies.

There are two types of presentation

1. Infantile form - the commonest with infants developing features in the first 6 months of life
2. Late-onset form - later presentation including adulthood, more rare but progression is slower

Worldwide it is estimated to affect 1 in 100,000 - 200,000 births although a higher incidence occurs in some certain groups e.g. some Israeli communities. Males and females are equally affected with 80% of cases being diagnosed by 6 months of age.

The mutation in Krabbe disease is located to the human chromosome 14 and more than 40 mutations have been identified.¹ This mutation of the GALC gene leads to a deficiency of galactosylceramidase. Deficiency of this enzyme leads to an inability to breakdown lipids in the myelin leading to reduced myelin production. However, it has been observed that this genotype alone may not account for the phenotype suggesting that other genetic factors may also be important.^1,2

Affected infants are normal at birth.

Symptoms occur at 3-6 months

• Irritability
• Crying
• Fever
• Feeding difficulties
• Limb stiffness
• Delayed achievement of milestones
• Vomiting
• Blindness
• Seizures

Signs

• Cherry red spots
• Protruding ears
• Postural tremor of limbs
• Spasticity
• Hyperreflexia
• Clonus
• Pyramidal paresis of limb or limbs
• Extensor plantar responses
• Unsteadiness of gait
• Psychomotor retardation
• Dysphagia
• Deafness

The late onset forms have similar features but these progress slower and can be milder. Adults commonly present with motor skill problems, paraesthesia, weakness and cognitive deficits.

• Cerebral palsy
• Congenital rubella
• Tay-Sachs disease
• Myotonia congenita

• Galactosylceramidase (GALC) enzyme activity - from blood or skin fibroblasts (activity reduced)
• MRI - demyelination of white matter of brain and more rarely the spinal cord³
• Lumbar puncture will show raised CSF protein
• Nerve conduction - can be normal; but most have some abnormalities e.g. delayed brainstem auditory evoked potentials and visual evoked potentials
• Histology - presence of PAS- positive material extracellularly and cerithin in microglial cells with characteristic "globoid cells" in brain tissue¹
• EEG
• Genetic studies

This can be performed with chorionic villous sampling.¹

• There is no cure yet and thus management is mainly supportive e.g. physiotherapy, anti-convulsants.
• Allogeneic haematopoietic stem cell transplantation in early disease leads to reversal of CNS deterioration.^4,5
• Transplantation of umbilical cord blood from unrelated donors leads to neurological improvement in those who received this therapy before the development of symptoms.⁶

Parents and carers will need education and support. Parents will require counselling before further pregnancies

Poor in infantile forms with death usually before the age of 2 years. However, some cases have been reported to live beyond the teens. In late onset disease cases progress more slower and the spectrum and severity of the illness is also very variable.