AUTHOR INFORMATION

Section 1 of 11

Authored by David H Tegay, DO, FACMG, Clinical Research Scholar, Assistant Professor of Pediatrics and Internal Medicine, Co-Director, Division of Medical Genetics, Stony Brook University Hospital

Coauthored by Shari Fallet, DO, Chief, Division of Genetics, Assistant Clinical Professor of Human Genetics and Pediatrics, Children's Hospital of New Jersey at Newark Beth Israel Medical Center

David H Tegay, DO, FACMG, is a member of the following medical societies: American College of Medical Genetics, American Medical Association, American Osteopathic Association, and American Society of Human Genetics

Edited by Erawati V Bawle, MD, FAAP, FACMG, Director, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, Wayne State University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	David H Tegay, DO, FACMG
Editor's Email:	Erawati V Bawle, MD, FAAP, FACMG

eMedicine Journal, April 18 2006, VOLUME 7, Number 4

INTRODUCTION

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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.

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.

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

• Type 1 - Infantile

• Type 2 - Late infantile

• Type 3 - Juvenile

• Type 4 - Adult

Hallmarks of the classic infantile form are 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.

Recent 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. Because of this evidence of success, the addition of Krabbe disease to newborn screening panels is being considered in a number of states.

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, and 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. Psychosine (galactosylsphingosine) is synthesized by direct galactosylation of sphingosine, and it, too, is degraded by GALC. (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.

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. Rapid destruction of oligodendroglia leads to myelin breakdown, and further myelin production diminishes, causing the following results:

• 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

Frequency:

• In the US: Calculated incidence of Krabbe disease is 1 case per 100,000 people.

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

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, affecting both sexes equally.

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).

CLINICAL

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

• Early-onset Krabbe disease (preambulatory)


• • 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)


• • 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.
  
  
  

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:


• • 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.

Causes:

• All 4 subtypes are caused by deficient GALC activity, which results from mutations to the gene encoding for the enzyme.



• The gene has been mapped to chromosome band 14q31.3



• 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.



• Genotype-phenotype correlations are being delineated to provide a molecular explanation for the clinical variability seen in patients with Krabbe disease.

DIFFERENTIALS

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GM2 Gangliosidoses
Gaucher Disease
Metachromatic Leukodystrophy
Niemann-Pick Disease

Other Problems to be Considered:

Alexander disease
Canavan disease
Encephalitis
Metachromatic leukodystrophy
Multiple sclerosis
Pelizaeus-Merzbacher disease
Tay-Sachs disease
X-linked adrenoleukodystrophy

WORKUP

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Lab Studies:

• Neither routine blood chemistry tests nor urinalysis reveals specific abnormalities in findings.



• 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. Since overlap often exists between unaffected noncarriers and heterozygote carriers, screening for heterozygote carriers by enzyme analysis is unreliable. The level of GALC activity does not help delineate clinical subtypes.



• 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.



• 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- and gamma-globulin levels), and a cell count within the reference range.



• 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 also are available.

Imaging Studies:

• Brain CT scans


• • 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.



• Brain MR spectroscopy may reveal elevated myoinositol- and choline-containing compounds with decreased N-aspartylaspartate in affected white-matter areas.



• 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.

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.

Gray matter may show neuronal degeneration.

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

TREATMENT

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Medical Care:

• Hematopoietic stem cell transplantation should be considered in individuals with late-onset or slowly progressive 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.



• 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 ultimately may 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

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

FOLLOW-UP

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Further Inpatient Care:

• Hematopoietic stem cell transplantation 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- 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.

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

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Medical/Legal 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

TEST QUESTIONS

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CME Question 1: Which of the following statements is correct regarding the parents of a child with Krabbe disease?

A: Parents have a 50% chance of having another affected child with each subsequent pregnancy.
B: Each parent has a 50% chance of carrying the mutation for Krabbe disease.
C: Parents have a 25% chance of having another affected child with each subsequent pregnancy.
D: Parents cannot carry the mutation for Krabbe disease.
E: Parents have the same risk with each subsequent pregnancy as parents in the general population of having another affected child.

The correct answer is C: Krabbe disease is an autosomal recessive disorder. When a couple has a child with Krabbe disease, each parent is an obligate carrier. With each subsequent pregnancy, the couple has a 25% risk of having another affected child, a 50% chance of having a child who is unaffected and a carrier for the disease, and a 25% chance of having a child who is unaffected and is not a carrier.

CME Question 2: Which of the following tests can help confirm the diagnosis of Krabbe disease?

A: Brain MRI (showing evidence of demyelination)
B: Glucosylceramide beta-glucosidase activity level
C: Ganglioside beta-galactosidase activity level
D: Galactosylceramide beta-galactosidase (GALC) activity level
E: Elevated cerebrospinal fluid (CSF) protein levels and abnormal protein electrophoresis results

The correct answer is D: Although patients with Krabbe disease show evidence of demyelination on MRI scans and have CSF abnormalities that include elevated CSF protein levels and abnormal protein electrophoresis results, neither test is specific for the condition or sufficient to confirm the diagnosis. Diagnosis of Krabbe disease requires demonstrating deficient GALC activity at 0-5% of reference range levels.

Pearl Question 1 (T/F): A couple has a child with Krabbe disease. The wife is now 11 weeks pregnant. When the couple asks if any tests can be performed to determine whether the fetus is affected, the physician should tell them that no tests are available to help diagnose Krabbe disease prenatally.

The correct answer is False: Prenatal diagnosis of Krabbe disease by assay of galactosylceramide B-galactosidase activity levels in cultured amniotic fluid or chorionic villus cells is an established procedure. The couple should be told that Krabbe disease can be diagnosed in an 11-week-old fetus.

Pearl Question 2 (T/F): A 24-year-old man had a history of normal early development until age 19 years, when progressive lower extremity spastic paraparesis and vision loss occurred. The physician should reassure the patient that his history precludes a diagnosis of Krabbe disease.

The correct answer is False: The adult-onset form of Krabbe disease is characterized by normal early development, with a variable age of onset of progressive neurologic deterioration. The spectrum of clinical abnormalities can range from slowly progressive weakness and ataxia to rapidly progressive psychomotor degeneration. The differential diagnosis for the patient should include the adult-onset type of Krabbe disease.

Pearl Question 3 (T/F): Measuring the levels of galactosylceramide beta-galactosidase activity in leukocytes is a reliable method for determining whether a person is a carrier for Krabbe disease.

The correct answer is False: As a result of the varying degrees of overlap between unaffected noncarriers and heterozygote carriers, diagnosis using enzyme levels in heterozygote carriers is not always reliable. Direct gene sequencing may provide a more reliable method to detect carriers.

Pearl Question 4 (T/F): An infant was diagnosed prenatally with Krabbe disease after his older brother died from the same disease. No therapy exists to alter the disease course for this infant.

The correct answer is False: Currently, hematopoietic stem cell transplantation is the only treatment known to improve the course of Krabbe disease. This is a viable option in presymptomatic or minimally affected patients and may be a treatment option for both infantile and late-onset patients.

BIBLIOGRAPHY

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