eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Krabbe Disease

Author: David H Tegay, DO, FACMG, Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center
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Updated: Dec 4, 2008

Introduction

Background

Krabbe disease is an autosomal recessive sphingolipidosis caused by deficient activity of the lysosomal hydrolase galactosylceramide beta-galactosidase (GALC). GALC degrades galactosylceramide, a major component of myelin, and other terminal beta-galactose–containing sphingolipids, including psychosine (galactosylsphingosine). Increased psychosine levels are believed to lead to widespread destruction of oligodendroglia in the CNS and to subsequent demyelination.^1,2

Krabbe originally described a condition with infantile onset that was characterized by spasticity and a rapidly progressive neurologic degeneration leading to death. Since the original description, numerous cases have been documented that show a wide distribution in age of onset.³

Krabbe disease has the following 4 clinical subtypes, distinguished by age of onset:⁴

• Type 1 - Infantile
• Type 2 - Late infantile
• Type 3 - Juvenile
• Type 4 - Adult

Hallmarks of the classic infantile form include irritability, hypertonia, hyperesthesia, and psychomotor arrest, followed by rapid deterioration, elevated protein levels in cerebrospinal fluid (CSF), neuroradiologic evidence of white matter disease, optic atrophy, and early death.⁵

Studies indicate that early unrelated hematopoietic stem cell transplantation in both the infantile and late-onset forms is associated with at least short-term benefits on neurocognitive parameters, lifespan, and quality of life.^6,7,8,9 Because of this evidence of success, the addition of Krabbe disease to newborn screening panels has occurred in some states and is under consideration in others.¹⁰

Pathophysiology

Galactosylceramide (galactocerebroside) is biosynthesized via galactosylation of ceramide (N- acyl-sphingosine). Galactosylceramide is highly concentrated in the myelin sheath, where it is synthesized in oligodendroglia and Schwann cells; it is practically absent in systemic organs with the exception of the kidneys. Galactosylceramide can be converted to sulfatide by adding a sulfate group. Galactosylceramide degradation is catalyzed by GALC, a lysosomal hydrolase.¹ Psychosine (galactosylsphingosine) is synthesized by direct galactosylation of sphingosine and is also degraded by GALC.^2,11 (Other compounds, such as monogalactosyldiglyceride and lactosylceramide, also are degraded by GALC but are not believed to be involved in the pathogenesis of Krabbe disease.)

Peak synthesis and turnover of galactosylceramide coincides with the peak period of myelin formation and turnover during the first 18 months of life. Myelination continues, albeit at a slower rate, through the first 2 decades of life before reaching a stable state with minimal turnover. GALC activity also increases in relation to this peak.¹

In Krabbe disease, myelin composition is not qualitatively abnormal. However, because of deficient GALC activity (0-5% reference value), galactosylceramide accumulation occurs, particularly during the early period of rapid myelin turnover. This accumulation causes formation of globoid cells (hematogenous often-multinucleated macrophages containing undigested galactosylceramide), which is the histologic hallmark of Krabbe disease. Psychosine also accumulates, and in theory, this highly cytotoxic substance is responsible for the widespread destruction of myelin-producing oligodendroglia.^2,11,12 Rapid destruction of oligodendroglia leads to myelin breakdown, and further myelin production diminishes, causing the following:

• Severe depletion of oligodendroglia
• Globoid cell formation
• Qualitatively normal myelin
• Demyelination
• Severely reduced levels of myelin production
• Lack of increased total galactosylceramide content in the brain⁵

Frequency

United States

Calculated incidence of Krabbe disease is 1 case per 100,000 population.

International

Overall calculated European incidence is 1 case per 100,000 population, with a higher reported incidence in Sweden of 1.9 cases per 100,000 population. An unusually high incidence, 6 cases per 1000 live births, is reported in the Druze community in Israel.^5,13

Mortality/Morbidity

Morbidity in patients with all subtypes arises from the primary progressive neurodegeneration of the central and peripheral nervous systems and secondary effects of the disease (ie, weakness, seizure, loss of protective reflexes, immobility). The sequelae, including infection and respiratory failure, cause most deaths.

Race

Krabbe disease is panethnic, although most reported cases have been among people of European ancestry. Late-onset Krabbe disease may be more common in southern Europe.

Sex

Krabbe disease is inherited as an autosomal recessive trait and equally affects both sexes.¹⁴

Age

Typical age of onset is 3-6 months for the infantile form of Krabbe disease (type 1), 6 months to 3 years for the late infantile form (type 2), 3-8 years for the juvenile form (type 3), and older than 8 years for the adult form (type 4).^4,5,15,16

Clinical

History

Signs and symptoms of early onset and late-onset Krabbe disease are as follows⁵ :

• Early-onset Krabbe disease (preambulatory)^17,18,19
  • Stage 1
    • Irritability
    • Hypertonia
    • Hyperesthesia - Auditory, tactile, and visual
    • Peripheral neuropathy
    • Hyperpyrexia
    • Psychomotor arrest
    • Failure to thrive
    • Vomiting
    • Gastroesophageal reflux
  • Stage 2
    • Hyperreflexia
    • Hyporeflexia
    • Opisthotonus
    • Seizures
    • Psychomotor deterioration
    • Optic atrophy
    • Visual loss
    • Sluggish pupillary light response
  • Stage 3
    • Decerebrate posturing
    • Blindness
    • Deafness
• Late-onset Krabbe disease (postambulatory)^15,16,20
  • Paresthesias
  • Decreased muscle strength
  • Spasticity
  • Ataxia
  • Paresis
  • Psychomotor arrest
  • Psychomotor deterioration
  • Seizures
  • Optic atrophy
  • Visual loss
  • Blindness
• Other signs and symptoms
  • Macular cherry red spots were reported in 1 patient.
  • Head circumference may be diminished, although macrocephaly also has been reported.²¹

Physical

No visceromegaly, dysmorphic features, or skeletal abnormalities are associated with Krabbe disease, nor does the disease cause direct cardiovascular complications. Manifestations of types 1-4 Krabbe disease are as follows:

• Type 1: The infantile or classic form accounts for the vast majority of recognized cases (85-90%) and is considered the prototype of Krabbe disease. The clinical course in patients with the infantile form has the following 3 stages:^1,5
  • Stage 1: Irritability, hypertonia, hyperesthesia, peripheral neuropathy and arrest of psychomotor development occur following normal early development. Onset usually occurs at age 3-6 months. Feeding difficulties, such as vomiting and reflux, may cause failure to thrive.
  • Stage 2: Rapid psychomotor deterioration, increasing hypertonia, opisthotonus, hyperreflexia, and optic atrophy ensue. Seizures may occur.
  • Stage 3: Severe neurologic impairment often ensues within weeks to months with loss of voluntary movements and persistent decerebrate posturing. Patients become blind, deaf, and unaware of external stimuli. This final stage sometimes is termed the burnt-out stage.
• Type 2: Late infantile Krabbe disease follows a similar but less rapid course. After a variable period of normal early development (6 mo to 3 y), the patient develops irritability, hypertonia, ataxia, and psychomotor arrest followed by progressive deterioration and vision loss.
• Type 3: Juvenile Krabbe disease is characterized by later age of onset (3-8 y) and greater variability in the tempo of disease progression. Early normal development is followed by a period of rapid psychomotor regression, although the disease then tends to subside into a slower, but progressive, degeneration.
• Type 4: Age of onset of adult Krabbe disease varies widely (8 y through adulthood). This type has a more varied clinical symptomatology and course of progression. Patients may present with signs of peripheral neuropathy, cerebellar dysfunction, spasticity, and impaired higher cortical functioning. Patients with type 4 disease may experience a rapid degenerative course or endure an indolent progression.^15,16

Causes

• All 4 subtypes are caused by deficient galactosylceramide beta-galactosidase (GALC) activity, which results from mutations to the gene that encodes for the enzyme.²²
• The gene has been mapped to chromosome band 14q31.3²³
• Almost 70 mutations have been identified in the gene responsible for GALC production. Polymorphisms have been identified that may play a considerable role in the resultant phenotypes.^5,22,24
• Genotype-phenotype correlations are being delineated to provide a molecular explanation for the clinical variability seen in patients with Krabbe disease.²⁵

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