Krabbe Disease 

Updated: May 03, 2017
Author: Reem Saadeh-Haddad, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

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 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 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, 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]

 

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]

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

Epidemiology

Frequency

United States

The calculated incidence of Krabbe disease was originally estimated to be approximately 1 case per 100,000 population. However, newer data show that the incidence of Krabbe disease in the United States is 1 case per 250,000 individuals.[17] However, approximately 1 case in 6000 individuals tested via newborn screening shows decreased enzyme activity of unclear significance.[18]

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, 19]

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

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.[20]

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, 21, 22]

 

Presentation

History

Signs and symptoms of early onset and late-onset Krabbe disease are described below.[6]

Infantile Krabbe disease[23, 24, 25]

Stage 1 includes the following:

  • Irritability

  • Hypertonia

  • Hyperesthesia - Auditory, tactile, and visual

  • Peripheral neuropathy

  • Hyperpyrexia

  • Psychomotor arrest

  • Failure to thrive

  • Vomiting

  • Gastroesophageal reflux

Stage 2 includes the following:

  • Hyperreflexia

  • Hyporeflexia

  • Opisthotonus

  • Seizures

  • Psychomotor deterioration

  • Optic atrophy

  • Visual loss

  • Sluggish pupillary light response

  • Rapid and severe psychomotor deterioration

Stage 3 includes the following:

  • Decerebrate posturing

  • Blindness

  • Deafness

  • No voluntary movement 

  • No interaction with the environment

Late-onset Krabbe disease[21, 22, 26, 27]

Symptoms include the following:

  • Paresthesias

  • Decreased muscle strength

  • Spasticity

  • Ataxia

  • Paresis

  • Psychomotor arrest

  • Psychomotor deterioration

  • Seizures

  • Optic atrophy

  • Visual loss

  • Blindness

  • Unpredictable rate of regression

Macular cherry red spots were reported in 1 patient. Head circumference may be diminished, although macrocephaly also has been reported.[28]

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 Krabbe Disease

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 3 stages.[1, 6]

Stage 1 includes 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.

In stage 2, rapid psychomotor deterioration, increasing hypertonia, opisthotonus, hyperreflexia, and optic atrophy ensue. Seizures may occur.

In 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 Krabbe Disease

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, eventually followed by death.

Type 3 Krabbe Disease

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 Krabbe Disease

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.[21, 22]

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.[29] . Measurement of GALC activity shows 0%-5% of normal activity in leukocytes or cultured skin fibroblasts. All individuals with deficient GALC enzyme activity have symptoms, which are confirmed with either physical examination or imaging findings that are consistent with the diagnosis of leukodystrophy.

The gene has been mapped to chromosome band 14q31.3.[30]

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.[6, 29, 31] There are two common mutations. A 30kb deletion has been reported in 40%-45% of individuals with infantile forms of Krabbe disease in northern Europe and in 35% of infantile Krabbe cases among Mexican patients.[32, 33] This deletion results in the infantile form of Krabbe, whether in the homozygous or the heterozygous state. However, when it is coupled with the c.857G>A mutation, it always results in the late-onset form of Krabbe disease.[20] This c.857G>A variant is common in those with late-onset Krabbe.

Genotype-phenotype correlations are being delineated to provide a molecular explanation for the clinical variability seen in patients with Krabbe disease.[34] However, there is no known correlation between enzyme activity and age of onset.

 

DDx

Differential Diagnoses

  • Alexander Disease

    This neurodegenerative disease can present in infancy with megalencephaly, seizures, progressive psychomotor delays, and quadriparesis. Older individuals can present with megalencephaly, speech abnormalities, ataxia, swallowing difficulties, vomiting, intellectual deterioration, and seizures. This condition is X-linked.

  • Canavan disease

    Canavan disease is also characterized by developmental delays with hypotonia noted in the first few months of life. Hypotonia progresses to hypertonia. Canavan is known to result in macrocephaly. Testing shows elevation of N-acetylaspartic acid.

  • GM2 Gangliosidoses

    These neurodegenerative conditions are caused by an accumulation of glycosphingolipid GM2 in the lysosome. Tay Sachs is the prototype and characterized by developmental delays and progressive neurodegeneration noted in the first few months of life. Seizures, maculary cherry red spots, and blindness are seen.

  • Metachromatic Leukodystrophy

    There are subtypes based on age of presentation in MLD that resemble Krabbe. All individuals eventually progress to loss of motor and intellectual function.

  • Sphingomyelinase Deficiency

 

Workup

Laboratory Studies

Routine blood chemistries and urinalysis do not provide any significant abnormalities that assist in establishing a diagnosis of Krabbe disease.

Galactosylceramide beta-galactosidase (GALC) activity measurement can help confirm a diagnosis of Krabbe disease when GALC activity levels are 0-5% of reference values in peripheral blood leukocytes, cultured fibroblasts, cultured amniocytes, and chorionic villi. Because overlap is often observed between unaffected noncarriers and heterozygote carriers, screening for heterozygote carriers by enzyme analysis is unreliable. The level of GALC activity does not absolutely delineate clinical subtypes.[5, 34, 35, 36]

After establishing a diagnosis of Krabbe disease by GALC assay, molecular analysis to provide GALC genotyping can help detect heterozygous carriers and identify candidates for prenatal testing.[34]

CSF analysis in patients with Krabbe disease reveals highly elevated protein levels in patients with types 1 and 2 Krabbe disease, an abnormal protein electrophoresis pattern (elevated albumin and alpha2-globulin levels, decreased beta1-globulin and gamma-globulin levels), and a cell count within the reference range.[6]

Assay of GALC activity levels in cultured amniocytes or chorionic villi has helped provide successful prenatal diagnoses. Accurate interpretation requires that parental GALC activity levels be determined. Molecular diagnostic procedures are also available.[6, 37]   

In 2006, Krabbe disease was added to the New York State newborn screening panel. Subsequently, the Krabbe Consortium of New York State has published an article delineating a model for the implementation of newborn screening for Krabbe disease.[38] This model involves a multidisciplinary, standardized approach to the initial evaluation as well as long-term follow-up of infants at risk. Some of the components include the following:

  • A standardized clinical evaluation protocol (including screening and confirmatory enzyme and genetic testing)

  • Criteria for hematopoietic stem cell transplantation for the early infantile phenotype

  • A clinical database and registry

  • A study of the developmental and functional outcomes

Imaging Studies

Brain CT scans[6, 39] may reveal progressive, diffuse, symmetric cerebral atrophy usually develops, involving both gray and white matter. White matter may appear diffusely hypodense, predominantly in the parieto-occipital region. Focal areas of altered signal intensity have been reported.

Brain MRI is a more sensitive modality with which to detect high-intensity areas of demyelination in the brainstem and cerebellum.[40] The Loes MRI severity scale has been historically used for evaluation of children with Krabbe disease. It was originally devised for measuring the degree of brain abnormality in X-linked adrenoleukodystrophy. Statistically significant correlations are noted between whole brain imaging assessment (total Loes score) and 3 clinical test scores (ie, mental development, gross motor skills, and fine motor skills).[41] These results suggest that Loes MRI scoring may also be useful in evaluating neurological outcomes in Krabbe disease.

Brain MR spectroscopy may reveal elevated myoinositol-containing and choline-containing compounds with decreased N -aspartylaspartate in affected white-matter areas.[40, 42]

Diffusion tensor imaging is being investigated as a sensitive and noninvasive quantitative imaging technique for assessing and monitoring white-matter development in patients who have received hematopoietic stem cell transplants.[43]

Other Tests

Electroencephalography

Electroencephalography (EEG) reveals a nonspecific slowing and disorganization of background rhythm and may show evidence of epileptogenic activity. Electromyography (EMG) changes often are consistent with peripheral neuropathy. Tests for brainstem-evoked auditory responses (BEAR) and visual-evoked potentials (VEP) show only nonspecific abnormalities.

Genetic Testing

The testing strategy always begins with measurement of the GALC activity, as described above. This can be used to confirm the diagnosis. Molecular genetic analysis is important, as it allows identification of carriers within a family, helps identify at-risk pregnancies, and, in some cases, predicts the phenotype based on detected genotype. As an example, if the late-onset c.857G>A allele is identified, a later-onset presentation may be expected. Thus, testing follows a 2-step approach, as follows:

  • Targeted testing for the 30-kb deletion if the presentation is infantile Krabbe disease; targeted testing for the c.857G>A allele if the presentation is late-onset Krabbe disease
  • If two pathogenic variants are not detected with testing above, sequencing and deletion/duplication of the gene, also called GALC, should be performed.

Procedures

Lumbar puncture is helpful, especially to help identify elevated CSF protein levels and an abnormal protein electrophoretic pattern. Skin biopsy to quantitate GALC activity in cultured fibroblasts is not necessary for diagnosis because GALC activity levels can be detected in peripheral blood leukocytes. Brain biopsy was, is, and will continue to be the last resort for diagnosis. Brain biopsy has rarely been necessary since the advent of enzymatic and molecular testing.

Histologic Findings

White matter demonstrates gliosis, demyelination, secondary axonal degeneration, severely diminished numbers of oligodendroglial cells, and multinucleated macrophages with abundant cytoplasm (globoid cells) that cluster around blood vessels.[6, 44]

Gray matter may show neuronal degeneration.

Peripheral nerves demonstrate demyelination, endoneural fibrosis, fibroblast proliferation, and perivascular histiocyte-macrophage aggregation.[25]

 

Treatment

Medical Care

Following the emergence of hematopoietic stem cell transplantation (HSCT) as a potential treatment for Krabbe disease, newborn screening has been implemented in New York State with additional states scheduled to follow suit. Numerous studies in human and animal models have shown varying degrees of benefit with HSCT, with greatest benefit occurring in patients who are asymptomatic or mildly symptomatic and when transplanted within the 1st month of life.[43, 45]

HCST should be considered in individuals with late-onset or slowly progressive Krabbe disease and in individuals with infantile-onset disease, in the early neonatal asymptomatic period. Short-term benefits with HSCT are reported in the medical literature, including a suggestion of delayed progression and improved survival; however, transplantation mortality rates are 15%.

Data on long-term posttransplant neurocognitive and survival outcomes are accumulating. Positive long-term effects of HSCT in presymptomatic infants includes an apparent increase in length of survival, improvements in quality of life versus those that are not transplanted, and an attenuated degree of neurologic complications, with some retaining normal receptive language skills and developing ambulation (although usually requiring assistive devices).

Limitations of HSCT include the persistent development of neurologic deficits, most of which are progressive in nature, including microcephaly, spasticity, growth restriction, and developmental delay (both verbal and motor) with regression. Ultimately, lack of curative effect is associated with HSCT.[45]

Symptomatic treatment for some neurologic sequelae is available but has no significant effect on the clinical course.

Research continues into treatments targeting inflammatory markers,[46] enzyme replacement therapy, gene therapy, and neural stem cell transplantation, although this has not yet advanced to the point of clinical trials.

Consultations

The following consultations are indicated:

  • Clinical geneticist - For initial evaluation and diagnosis, for counseling families regarding recurrence risk, and to help provide prenatal testing if desired in future pregnancies
  • Neurologist - For symptomatic therapy and documentation of the multiple neurologic sequelae
  • Ophthalmologist
  • Audiologist
  • Social worker

Diet

No known dietary modifications significantly alter the clinical course of Krabbe disease. Infants may ultimately require tube feedings for adequate energy intake; however, nutritional support does not change the disease course; therefore, some families may choose to forgo invasive alimentation methods.

Activity

Neurologic sequelae may preclude adequate physical activity. Patients may benefit from physical and occupational therapy.

Long-Term Monitoring

Treatment of symptomatic individuals with infantile-onset Krabbe disease who are already at stage 2 or 3 is limited to supportive care.

 

Medication

Medication Summary

No medications that alter the natural history of Krabbe disease are currently available. Early hematopoietic stem cell transplantation (HSCT) is the only treatment that has been shown to significantly alter the disease progression.

 

Follow-up

Further Inpatient Care

Hematopoietic stem cell transplantation (HSCT) in patients with Krabbe disease should be considered only at an experienced center and follow-up care coordinated with the transplant team.

Deterrence/Prevention

Provide genetic counseling for at-risk couples to explain reproductive options. Prenatal diagnosis, if feasible and desired, can be beneficial in future pregnancies by providing reassurance in the case of an unaffected fetus or by allowing an informed exploration of options, such as termination of pregnancy or, potentially, early stem cell therapy, in the case of an affected fetus.

If molecular testing in a patient with Krabbe disease identifies the causative mutations, family members at risk for carrying the mutation may wish to be tested. The mode of inheritance for Krabbe disease is autosomal-recessive. Therefore, two causative mutations in the GALC gene result in disease. The parents of an affected child are obligate carriers. Each subsequent child of this couple has a 25% risk of also being affected. There is a 50% risk that a child of this couple is unaffected but a carrier. There is a 25% chance that another child of this couple will be unaffected and not a carrier. Each sibling of this couple may be carriers and may desire to know this information to determine the risk posed to their future children. Thus, genetic counseling is an important and integral component to the workup of a child with Krabbe disease.

Prenatal testing is best discussed prior to pregnancy. Options, including preimplantation genetic diagnosis to prenatal diagnosis, can be discussed at length with the family so that they can make the best decision for themselves.

Complications

Irreversible neurologic deterioration and death can occur. Patients are at risk for aspiration pneumonia and recurrent respiratory infections caused by neurologic compromise.

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.[9, 47]

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.