Krabbe Disease

Updated: Dec 18, 2019
  • Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Overview

Background

Krabbe disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis, 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 central nervous system (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. [4] Since the original description, numerous cases have been documented that show a wide distribution in age of onset.

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

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

Types 2-4 are also referred to collectively as the late-onset subtypes.

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, [6] optic atrophy, and early death. [7]

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. [8, 9, 10, 11] 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. [12]

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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, 13] (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, 13, 14]

A study by White et al (2009) 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. [15] 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 [7]

Animal models of Krabbe disease have been used extensively to study the pathophysiology of this leukodystrophy.

Using a murine model of Krabbe disease, Signorini et al (2019) established that brain isoprostanoid levels were significantly higher in the twitcher mice than in the heterozygous and wild-type mice. Furthermore, isoprostanoid levels were proportionally increased with disease severity. Normally, isoprostanoids are released by the gray and white matter of the brain under nonenzymatic oxidative stress. The findings of this study show the key role of polyunsaturated fatty acid oxidative damage to brain gray and white matter in the pathogenesis and progression of Krabbe disease. [16]

Using cellular and animal models for Krabbe disease, Sural-Fehr et al (2019) reported a mechanism that explains the inactivation of LR-associated signaling pathway IGF-1-PI3K-Akt-mTORC2, which is vital for neuronal function and survival. The study showed that psychosine accumulation in Krabbe disease leads to a dose-dependent and LR-mediated inhibition of the pathway. Specifically, interference with recruitment of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin complex 2 (mTORC2) to LRs leads to uncoupling of IGF-1 receptor phosphorylation from the downstream activation of Akt, also known as protein kinase B. [17]

The role of various inflammatory molecules, including prostaglandin D and AMP-activated protein kinase (AMPK), in Krabbe disease progression has also 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. [18]

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. [19]

Quantitative microproteomics-based characterization of the central and peripheral nervous systems of a mouse model of Krabbe disease revealed that more than 400 protein groups had differences in expression and included proteins involved in inflammation and defense response, lysosomal protein accumulation, demyelination, reduced nervous system development, and cell adhesion. [20]

In addition, autophagy dysregulation has been suggested as a new factor in the molecular pathogenesis of Krabbe disease. Large cytoplasmic aggregates of the protein p62, one of the fundamental autophagy markers, were present in the brain of early and late symptomatic model mice. Therefore, testing autophagy modulation in combination with correction of the GALC deficiency could be a promising therapeutic option. [21]

Overall, however, many aspects concerning the pathophysiology of Krabbe disease are still relatively unknown.

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Epidemiology

Frequency

United States

The calculated incidence of Krabbe disease was originally estimated to be approximately 1 case per 100,000 population. Newer data show that the incidence of Krabbe disease in the United States is 1 case per 250,000 individuals. [22] However, approximately 1 case in 6000 individuals tested via newborn screening shows decreased enzyme activity of unclear significance. [23]

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. [7] An unusually high incidence, 6 cases per 1000 live births, is reported in the Druze community in Israel. [24] Analysis of records among patients with lysosomal storage disorders from a Spanish database revealed that the group including Krabbe disease registered the highest occurrence numbers in the study period (1997-2015). [25]

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. [22] The average age of death among children with infantile Krabbe disease is 13 months.

Age of onset and therefore Krabbe disease subtype determine survival rates. The median survival was 1.5 years in the early infantile group and 9.5 years in the late infantile group. In the juvenile group, 80% of patients were alive at age 16 years. In the adult-onset group, 87.9% of patients were still alive at age 19 years. Survival was statistically significantly shorter in early infantile compared with late infantile, juvenile, and adolescent-onset groups (P< 0.001, log-rank test). [26]

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. [27]

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, 7, 28, 29]

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Prognosis

In patients with type 1 infantile Krabbe disease, the average lifespan is 13 months. Most patients with type 2 disease die within 2 years of disease onset. With both juvenile-onset and adult-onset Krabbe disease, progression of disease and lifespan reduction vary. HSCT results indicate markedly improved short-term survival for individuals who are treated while asymptomatic during the early neonatal period. [10, 30]

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Patient Education

Provide information to the families of patients with Krabbe disease regarding disease manifestations and potential complications. Educate parents regarding the genetic basis of the disease and include information on recurrence risks, carrier identification, and the possibility of prenatal diagnosis during future pregnancies. Educate parents about the risks, benefits and limitations of hematopoietic stem cell transplantation.

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