Enfermedad de Krabbe

Synonyms: globoid cell leukodystrophy, globoid cell leukoencephalopathy, galactosylceramide lipidosis, galactosylceramidase (GALC) deficiency

This is an autosomal recessive leukodystrophy. There is a lack of the enzyme galatosylceramidase (GALC) leading to abnormalities of myelin formation in both the central and peripheral nervous system. It is often fatal.

Epidemiología

Worldwide it is estimated to affect 1 in 100,000-200,000 births, although a higher incidence occurs in certain groups, eg some Israeli communities.¹² Males and females are equally affected.

Genética

The mutation in Krabbe's disease is located to the human chromosome 14 and more than 40 mutations have been identified.² This mutation of the galactosylceramidase (GALC) gene leads to a GALC deficiency. Deficiency of this enzyme leads to an inability to break down 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.²³

Presentación

There are two types of presentation:

• Infantile form - the most common, with affected infants being normal at birth. 80% of cases develop features and are diagnosed in the first six months of life.

• Late-onset form - later presentation including adulthood; rarer and milder, with slower progression.

Síntomas

These usually occur at 3-6 months:⁴

• Irritabilidad.

• Crying.

• Fiebre.

• Dificultades de alimentación.

• Limb stiffness.

• Delayed achievement of developmental milestones.

• Vómitos.

• Blindness.

• Convulsiones.

Señales

• 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.

• Disfagia.

• Sordera.

Adults commonly present with motor skill problems, paraesthesia, weakness and cognitive deficits.

Diagnóstico diferencial

• Parálisis cerebral

• Congenital rubella

• Tay-Sachs disease

• Myotonia congenita

Investigaciones

• Galactosylceramidase (GALC) enzyme activity - from blood or skin fibroblasts (activity reduced).

• MRI - demyelination of white matter of the brain and, more rarely, the spinal cord.⁵⁶

• Lumbar puncture will show raised CSF protein.

• Nerve conduction - can be normal; however, most have some abnormalities, eg 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 tissue.²

• EEG.

• Estudios genéticos.

Diagnóstico prenatal

This can be performed with chorionic villous sampling.²

Gestión

• There is no cure yet and thus management is mainly supportive, eg physiotherapy, anticonvulsants.

• Allogeneic haematopoietic stem cell transplantation in early disease leads to reversal of CNS deterioration.⁷⁸

• Transplantation of umbilical cord blood from unrelated donors leads to neurological improvement in those who received this therapy before the development of symptoms.⁹

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

Pronóstico

Poor in infantile forms with death usually before the age of 2 years.⁴ However, some cases have been reported to live beyond the teens. In late-onset disease, cases progress slower and the spectrum and severity of the illness are very variable.