Krabbe Disease

Updated: Dec 11, 2014
  • Author: David H Tegay, DO, FACMG; Chief Editor: Luis O Rohena, MD  more...
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Overview

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, 3]

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. [4]

Krabbe disease has the following 4 clinical subtypes, distinguished by age of onset: [5]

  • 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. [6]

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. [7, 8, 9, 10] 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. [11]

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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, 12] (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 is thought to be a highly cytotoxic substance and responsible for the widespread destruction of myelin-producing oligodendroglia. [2, 12, 13]

A study by White et al found that psychosine's cytotoxic effects on oligodendroglia and Schwann cells was mediated through disruption of the architecture and composition of lipid rafts (cell membrane regions characterized by high cholesterol and sphingolipid concentration), followed by altered protein kinase C (PKC) function. [14] Psychosine was found to accumulate preferentially in white matter, with associated regional cholesterol increases causing alterations of lipid raft (LR) markers flotillin-2 and caveolin-1. PKC is an important signaling molecule in numerous cell pathways, including cell differentiation, proliferation and apoptosis. PKC isozymes are LR-dependent molecules that link psychosine-induced LR disruption to reduced PKC function and altered cell signaling activity, possibly driving demyelination and apoptosis in oligodendrocytes and Schwann cells.

The 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 brain [6]

The role of various inflammatory molecules, including prostaglandin D and AMP-activated protein kinase (AMPK), in Krabbe disease progression has been explored in animal models. Upregulation of hematopoietic prostaglandin D synthase (HPGDS) causes increased prostaglandin D (PGD2) levels in microglial cells in response to progressive demyelination and is thought to be involved in inducing astrocytic gliosis through astrocytic PGD2 receptors (DP1). Blockage of HPGDS signaling pathways in the mouse twitcher model of Krabbe disease resulted in downregulation of astrocytic gliosis and demyelination, reduction in symptomatology, and decreased oligodendrocyte death. [15]

AMPK plays a role in regulation of energy homeostasis and response to metabolic stress and is believed to possess anti-inflammatory properties. Psychosine has been shown to down-regulate AMPK activity in oligodendrocytes and astrocytes. Activation of AMPK, in animal models, resulted in restoration of lipid metabolism and decreased inflammation. [16]

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Epidemiology

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. [6, 17]

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. [18]

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. [19]

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). [5, 6, 20, 21]

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