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

Krabbe Disease

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

Differential Diagnoses

Gaucher Disease
GM2 Gangliosidoses
Metachromatic Leukodystrophy
Niemann-Pick Disease

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.^4,25,26
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.²⁵
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.⁵
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.⁵

Imaging Studies

Brain CT scans^5,27 may reveal the following:
- 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.²⁸
Brain MR spectroscopy may reveal elevated myoinositol-containing and choline-containing compounds with decreased N -aspartylaspartate in affected white-matter areas.²⁸
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.²⁹

Other Tests

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.

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.^5,30
Gray matter may show neuronal degeneration.
Peripheral nerves demonstrate demyelination, endoneural fibrosis, fibroblast proliferation, and perivascular histiocyte-macrophage aggregation.¹⁹

Treatment

Medical Care

Hematopoietic stem cell transplantation 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. Long-term posttransplant neurocognitive and survival outcomes are unknown; however, short-term results are encouraging. Decreased survival and neurocognitive benefit is seen in symptomatic individuals. Overall 5-year survival rates for umbilical cord blood transplantation in individuals with lysosomal storage disease approaches 68%. Three-year posttransplant survival rates for patients with the infantile form of Krabbe disease range from 43% when symptomatic to 100% when asymptomatic prior to transplant.^6,7,8,9
Symptomatic treatment for some neurologic sequelae is available but has no significant effect on the clinical course.
Research continues into enzyme replacement therapy, gene therapy, and neural stem cell transplantation, although this has not yet advanced to the point of clinical trials.

Consultations

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 of the multiple neurologic sequelae
Ophthalmologist
Audiologist

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.

Medication

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

Follow-up

Further Inpatient Care

Hematopoietic stem cell transplantation 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 mutation, family members at risk for carrying the mutation may wish to be tested.

Complications

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

Prognosis

Type 1: In patients with type 1 infantile Krabbe disease, the average lifespan is 13 months.
Type 2: Most patients die within 2 years of disease onset.
Types 3 and 4: With both juvenile-onset and adult-onset Krabbe disease, progression of disease and lifespan reduction vary.
Hematopoietic stem cell transplantation results indicate markedly improved short-term survival for individuals who are treated while asymptomatic during the early neonatal period.^8,31

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.

Miscellaneous

Medicolegal Pitfalls

Failure to counsel the families of patients concerning the 25% risk of Krabbe disease occurring in each child of parental carriers
Failure to counsel parents concerning prenatal diagnosis options
Failure to provide rapid diagnosis, discussion, and consideration of referral to a center with expertise in hematopoietic stem cell transplantation when appropriate

References

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Keywords

Krabbe disease, galactocerebrosidase deficiency, galactosylceramide beta-galactosidase deficiency, GALC deficiency, globoid cell leukodystrophy, Krabbe's disease, infantile irritability, hypertonia, hyperesthesia, psychomotor arrest, galactosylceramide lipidosis, diffuse infantile familial sclerosis, myelin sheath disorders, sphingolipidosis, hematopoietic stem cell transplantation, respiratory failure, gastroesophageal reflux, GERD

Contributor Information and Disclosures

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
David H Tegay, DO, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association, American Society of Human Genetics, and Federation of American Societies for Experimental Biology
Disclosure: Nothing to disclose.

Medical Editor

Erawati V Bawle, MD, FAAP, FACMG, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, Wayne State University School of Medicine
Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia
David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

Further Reading