What is Lego's disease?

Krabbe Disease (KD): Understanding Lego's Disease

Lego's disease is actually Krabbe disease (KD), a rare lysosomal storage disorder caused by deficiency of the enzyme galactocerebrosidase (GALC), which leads to progressive damage to the white matter of the peripheral and central nervous systems. 1

Disease Overview

Krabbe disease is inherited in an autosomal recessive pattern and is characterized by:

• Incidence: Approximately 1:100,000 newborns in Europe and the United States 1
• Enzyme deficiency: Galactocerebrosidase (GALC), which normally cleaves galactosyl moieties from substrates including galactosylceramide and psychosine 1
• Pathology: Accumulation of myelin fragments and galactosylceramide in multinucleated macrophages (globoid cells) around blood vessels of affected white matter 1

Clinical Presentations

Early Infantile-Onset KD (EIKD)

• Onset: First months of life
• Symptoms:
  • Progressive irritability
  • Spasms upon noise stimulation
  • Recurrent unexplained fever
  • Blindness and deafness
  • Rapid progression to frequent seizures
  • Hyperpyrexia and hypersalivation
  • Complete loss of social contact
  • Loss of bulbar functions
• Prognosis: Death typically occurs within the first 2 years due to respiratory complications 1
• Distinctive feature: Peripheral neuropathy is always present 1

Late-Onset KD (LOKD)

• Onset: Variable age of onset
• Initial symptoms:
  • Visual impairment
  • Ataxia
  • Irritability
• Diagnostic findings: Only a small percentage show abnormal neurophysiologic studies, compared to EIKD where abnormalities are common 1

Diagnostic Approach

1. Biochemical testing: Demonstration of low GALC activity in leukocytes or dried blood spots (DBS) 1

2. Confirmatory testing: Molecular analysis of the GALC gene to identify mutations 1

3. Neurophysiologic studies: In EIKD, abnormalities are common:

   • 100% show abnormal nerve conduction studies
   • ~90% have abnormal brainstem auditory evoked responses
   • 65% have abnormal electroencephalogram
   • 53% have abnormal flash visual evoked potentials 1

4. Imaging: Cranial MRI may show demyelination of white matter; diffusion tensor imaging can help identify early involvement of motor tracts in asymptomatic neonates 1

Treatment Options

The only available therapy is early allogeneic hematopoietic stem cell (HSC) or cord blood transplantation, which is most effective when performed before symptom onset. 1

Treatment outcomes:

• Presymptomatic infants who receive transplantation may continue to show psychomotor development and gain milestones
• Symptomatic infants typically show only minimal neurologic improvement after transplantation
• Overall mortality rate of approximately 15% has been reported for presymptomatic infants receiving transplantation
• Despite successful engraftment, most transplanted infants develop some neurological disease related to KD 1

Management Algorithm

1. Diagnostic confirmation:

   • Demonstrate GALC deficiency in leukocytes
   • Perform mutation analysis of the GALC gene 1

2. For patients predicted to have EIKD:

   • Consider early bone marrow/stem cell transplantation from cord blood, preferably before 30 days of age 1

3. For symptomatic patients:

   • Provide supportive care
   • Monitor for respiratory complications
   • Manage seizures and other neurological symptoms

4. For all diagnosed patients:

   • Regular neurological assessments
   • Monitoring for disease progression
   • Genetic counseling for family members

Important Caveats

• Genotype-phenotype correlation is limited in KD, though homozygosity for the 30-kb deletion may predict EIKD 1
• There is variability in presentation even with the same genotype 1
• Early diagnosis and intervention are critical, as treatment is most effective before symptom onset 1
• Newborn screening for KD has been implemented in some regions (e.g., New York State) to enable early detection and intervention 1