KRABBE DISEASE

Krabbe Disease — a fatal leukodystrophy where a 30-day treatment window after birth determines whether presymptomatic stem cell transplant can preserve neurological function or the opportunity is permanently lost.

Whole genome sequencing identifies all GALC variants — including the 30kb deletion common in European populations — enabling carrier screening, prenatal diagnosis, and the critical early identification that makes presymptomatic HSCT possible.

GALC

About this condition

Krabbe Disease

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in GALC (galactosylceramidase) on chromosome 14q31.3. GALC deficiency leads to accumulation of psychosine (galactosylsphingosine), which is directly toxic to oligodendrocytes and Schwann cells — the myelin-producing cells of the central and peripheral nervous systems. Progressive demyelination produces the devastating clinical phenotype. Infantile Krabbe disease affects approximately 1 in 100,000 births, with higher prevalence in Scandinavian populations.

Infantile Krabbe disease presents at 3-6 months of age with irritability, progressive spasticity, developmental regression, optic atrophy, and peripheral neuropathy. Untreated, it follows a rapid and uniformly fatal course — most affected children die before age 2. Late-onset forms (juvenile and adult) present with progressive spastic paraparesis, peripheral neuropathy, and cognitive decline, and can be misdiagnosed as multiple sclerosis, hereditary spastic paraplegia, or other demyelinating conditions.

Presymptomatic hematopoietic stem cell transplantation (HSCT) — performed before 30 days of life in infantile Krabbe disease — can substantially alter the disease trajectory, preserving cognitive function and extending life by years to decades. However, this narrow treatment window requires that affected newborns be identified before symptom onset. New York State began universal newborn screening for Krabbe disease in 2006, and several additional states have since added it. For populations without universal NBS, carrier screening and prenatal diagnosis through molecular GALC genotyping represent the only pathway to presymptomatic identification.

The 30kb deletion in GALC (c.1161+6532_polyA del) accounts for approximately 40-50% of disease alleles in European populations. Standard exon-sequencing panels may miss this large deletion — whole genome sequencing detects it directly.

Gene locus: GALC (14q31.3)

Enzyme assay screens detect low GALC activity but cannot distinguish infantile from late-onset forms. The GALC genotype determines disease severity and HSCT eligibility — information that enzyme activity alone does not provide.

The 30kb GALC deletion is missed by exon-sequencing panels — whole genome sequencing reads it directly

The most common GALC pathogenic allele in European populations is a ~30kb genomic deletion (c.1161+6532_polyA del) that removes exons 11-17 and extends into the 3' flanking region. This large structural variant is not detectable by standard exon-sequencing panels or Sanger sequencing of individual exons — it requires either deletion/duplication analysis (MLPA) or whole genome sequencing, which reads across the deletion breakpoints directly. A patient carrying one GALC point mutation and one 30kb deletion will appear heterozygous (carrier) on exon sequencing alone, potentially delaying the diagnosis of an affected infant during the critical treatment window.

Identifying carriers before pregnancy enables delivery planning at HSCT-capable centers — the 30-day window is not negotiable

Presymptomatic HSCT for infantile Krabbe disease must be performed before approximately 30 days of life to achieve optimal outcomes. This means that at-risk pregnancies must be identified prenatally, that delivery must occur at or near a center capable of immediate HSCT workup, and that a donor search must begin before birth. None of this is possible if the first indication of Krabbe disease is the newborn screening result — which in many states takes 5-7 days and is followed by confirmatory testing. Carrier screening through whole genome sequencing identifies at-risk couples preconceptionally, providing the full pregnancy duration for delivery and transplant planning.

Krabbe Disease — a fatal leukodystrophy where a 30-day treatment window after birth determines whether presymptomatic stem cell transplant can preserve neurological function or the opportunity is permanently lost.

Krabbe Disease

Enzyme assay screens detect low GALC activity but cannot distinguish infantile from late-onset forms. The GALC genotype determines disease severity and HSCT eligibility — information that enzyme activity alone does not provide.

The 30kb GALC deletion is missed by exon-sequencing panels — whole genome sequencing reads it directly

Identifying carriers before pregnancy enables delivery planning at HSCT-capable centers — the 30-day window is not negotiable

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