Krabbe Disease

Krabbe disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme galactocerebrosidase. Accumulation of galactocerebroside results in destruction of myelin-producing cells throughout the peripheral and central nervous systems, leading to demyelination and clinical symptoms. The disease is classified into infantile-onset (classic) and late-onset subtypes. Clinical manifestations for classic Krabbe disease include irritability, hypertonia, difficulty feeding, failure to thrive, and rapid neurodegeneration. Death occurs from infection or respiratory failure. Diagnosis is made by measuring enzyme activity. There is no cure for Krabbe disease. Management is supportive. Stem cell transplantation is an option for some infants.

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  • Incidence: 
    • 1 case per 250,000 births in the United States
    • 1 case per 100,000 births in Europe
  • Both sexes are affected equally.
  • Panethnic, but higher incidence noted in:
    • European ancestry
    • Druze community in Israel


  • A lysosomal storage disorder
  • Autosomal recessive inheritance
  • Mutation of the galactocerebrosidase gene (GALC) on chromosome 14q31
  • Results in a deficiency of the enzyme GALC


  • Many aspects of the pathophysiology remain unknown.
  • Accumulation of galactocerebroside is toxic to: 
    • Oligodendrocytes in the CNS
    • Schwann cells in the peripheral nervous system (PNS)
  • Results in demyelination and neurologic manifestations
  • Pathologic findings include: 
    • Globoid cells (hallmark): abnormal, multinucleated macrophages
    • Generalized loss of myelin
    • Absence of oligodendroglia
Lysosomal storage pathway diagram

The lysosomal storage pathway:
Krabbe disease results from galactocerebrosidase enzyme deficiency (step 5) and the subsequent buildup of galactocerebroside.

Image by Lecturio.

Clinical Presentation

Time course

  • Infantile (classic):
    • Majority of cases
    • Onset within 6 months
    • Death by approximately 13 months
  • Late-onset subtypes:
    • Onset at ≥ 13 months of age and subdivided into:
      • Late infantile 
      • Juvenile
      • Adult
    • Disease progression varies (usually faster in younger-onset subtypes).

Signs and symptoms

The classic, infantile form progresses through the following stages:

  • Stage 1:
    • Irritability (most common initial symptom)
    • Feeding difficulties
    • Failure to thrive
    • Vomiting
    • Gastroesophageal reflux
    • Hypertonia, rigidity
    • Hyperesthesia—auditory, tactile and visual
    • Peripheral neuropathy
    • Hyperpyrexia
  • Stage 2:
    • Hyporeflexia or hyperreflexia
    • Optic atrophy and blindness
    • Opisthotonus (muscle spasm resulting in a backward arching of the head, neck, and spine)
    • Seizures (do not respond to anticonvulsants)
    • Psychomotor deterioration (rapid and severe)
  • Stage 3:
    • Deafness
    • Decerebrate posturing
    • Severe spasticity
    • Death is often due to infection or respiratory failure.

Diagnosis and Management


  • Prenatal screening is standard in certain locations.
  • Diagnostic testing:
    • Measurement of GALC activity: 
      • Often tested on blood leukocytes or skin fibroblasts
      • Low or absent GALC confirms the diagnosis.
    • Molecular genetic testing for the genetic mutation is also available.
  • Additional testing may show:
    • ↑ CSF protein levels
    • Evidence of demyelination on neuroimaging
Krabbe disease on imaging

A 13-month-old boy with diffuse demyelination (hyperintensity) of the corpus callosum on MRI, characteristic of Krabbe disease

Image: “Krabbe disease on imaging” by Department of Diagnostic Imaging, Institute of Mother and Child, ul. Kasprzaka, 17a, 01-211 Warsaw, Poland. License: CC BY 3.0


  • There is no cure for Krabbe disease.
  • Management is supportive, focused on controlling symptoms.
  • Stem cell transplantation is an option for infants who screen positive and have not yet developed symptoms.

Differential Diagnosis

  • Gaucher disease (GD): lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside. Infantile GD presents within 6 months of life with progressive neurodegeneration, loss of motor skills, hypotonia, hepatosplenomegaly, feeding difficulties, and death before age 3 years. Diagnosis is made with measurement of acid beta-glucosidase activity and confirmed with genetic analysis. Management is supportive.
  • Fabry disease: lysosomal storage disorder caused by alpha-galactosidase A (GLA) deficiency, resulting in glycophospholipid deposition in the vascular endothelium and smooth muscle cells. Clinical manifestations include acroparesthesias, purplish skin lesions, decreased sweating, cerebrovascular and cardiovascular complications, and renal disease. Diagnosis is made with GLA enzyme activity. Management is supportive and can include enzyme replacement and chaperone therapies.
  • Niemann-Pick disease type A (NPD-A): lysosomal storage disorder caused by acid sphingomyelinase enzyme deficiency. The disease is characterized by progressive neurodegeneration starting within a few months of life and resulting in death by age 3. Clinical manifestations include a macular cherry-red spot, difficulty feeding, loss of motor skills, hypotonia, and organomegaly. Diagnosis includes measurement of sphingomyelinase enzyme activity and genetic testing. Management is supportive. 
  • Tay-Sachs disease: autosomal recessive lysosomal storage disorder caused by mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Clinical manifestations include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Diagnosis is made with enzyme activity testing and molecular genetic analysis. Management is supportive.
  • Sandhoff disease (SD): lysosomal storage disorder caused by a deficiency in both HEXA and HEXB. Juvenile SD is characterized by progressive neurodegeneration starting at 6 months of age. Clinical manifestations include organomegaly, skeletal abnormalities, hyperacusis, macular cherry-red spot, blindness, and seizures. Diagnosis is made by measurement of HEXA and HEXB, as well as genetic analysis. Management is supportive. 
  • Pompe disease (glycogen storage disease II): lysosomal and glycogen storage disorder caused by acid alpha glucosidase (GAA) deficiency. There are 3 types of Pompe disease, with variable onset and presentations. Clinical manifestations include failure to thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. The diagnosis is made by measuring enzyme activity and molecular genetic analysis. Management includes supportive measures and enzyme replacement.


  1. Escolar, M. (n.d.). Krabbe disease. UptoDate. Retrieved August 2, 2021, from
  2. Brenda, A.V. (2019). Medscape. Retrieved August 7, 2021, from
  3. NIH Genetic and Rare Diseases Information Center. (n.d.). Krabbe disease. Retrieved August 8, 2021, from
  4. National Organization for Rare Disorders. (n.d.). Krabbe disease. Retrieved August 7, 2021, from
  5. Jain, M., De Jesus, O. (2021). Krabbe disease. StatPearls. Retrieved August 9, 2021, from

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