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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Krabbe Disease

Synonyms: GALC Deficiency, Galactocerebrosidase Deficiency, Galactosylceramidase Deficiency, Globoid Cell Leukodystrophy
, PhD
Director, Lysosomal Diseases Testing Laboratory
Department of Neurology
Jefferson Medical College
Thomas Jefferson University
Philadelphia, Pennsylvania

Initial Posting: ; Last Update: March 31, 2011.

Summary

Disease characteristics. Krabbe disease is characterized by infantile-onset progressive neurologic deterioration and death before age two years (85%-90% of individuals) or by onset between age one year and the fifth decade with slower disease progression (10%-15%). Children with the infantile form appear to be normal for the first few months of life but show extreme irritability, spasticity, and developmental delay before age six months; psychomotor regression progresses to a decerebrate state with no voluntary movement. The onset and progression in the late-onset forms can be quite variable. Individuals can be clinically normal until weakness, vision loss, and intellectual regression become evident. The onset of symptoms and clinical course can be variable even among siblings.

Diagnosis/testing. In almost all individuals with Krabbe disease, galactocerebrosidase (GALC) enzyme activity is deficient (0%-5% of normal activity) in leukocytes isolated from whole heparinized blood or in cultured skin fibroblasts. Testing is most reliable when conducted in a laboratory with demonstrated experience in this assay. Carrier testing by measurement of GALC enzyme activity in leukocytes or in cultured skin fibroblasts is not reliable because of the wide range of enzymatic activities observed in carriers and non-carriers. GALC is the gene most commonly known to be associated with Krabbe disease.

Management. Treatment of manifestations: Only supportive care to control irritability and spasticity in children with infantile-onset Krabbe disease is available in the later stages (II and III).

Prevention of primary manifestations: Hematopoietic stem cell transplantation (HSCT) in presymptomatic infants and older individuals with mild symptoms may improve and preserve cognitive function, but peripheral nervous system function may deteriorate. Significant clinical variability in late-onset forms makes evaluation of treatment effectiveness difficult.

Evaluation of relatives at risk: Testing at-risk infants can reduce morbidity and mortality through early diagnosis and HSCT using umbilical cord blood.

Genetic counseling. Krabbe disease is inherited in an autosomal recessive manner. If both parents are carriers, each child has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Each healthy sib of a proband has a 2/3 chance of being a carrier. For genetic counseling purposes, a carrier frequency of one in 150 may be used for the general population. Carrier detection by molecular genetic testing is possible if the disease-causing mutations have been identified in the family. Prenatal diagnosis is possible either by measurement of GALC enzyme activity or by molecular genetic testing if both disease-causing alleles in an affected family member are known.

Diagnosis

Clinical Diagnosis

Individuals with the infantile form of Krabbe disease can present with any or all of the following features:

  • Irritability
  • Muscle hypertonicity
  • Progressive neurologic deterioration
  • Peripheral neuropathy
  • Evidence of white matter disease on neuroimaging
  • Elevation of cerebrospinal fluid (CSF) protein concentration

While most individuals have the infantile form, older individuals ranging in age from six months to the seventh decade have also been diagnosed with galactocerebrosidase deficiency. They usually present with weakness and vision loss and may experience intellectual regression.

Neuroimaging. Progressive, diffuse, and symmetric cerebral atrophy is observed by neuroimaging.

In the early stage of the disease, CT can be normal; diffuse cerebral atrophy involving both gray and white matter develops later. Diffuse hypodensity of the white matter may be present, particularly in the parieto-occipital region. These findings are nonspecific and are observed in many diseases of white matter.

In general, MRI detects demyelination in the brain stem and cerebellum more clearly than CT at the early stage of the disease; however, some infants have had deceptively normal MRIs when CT had already revealed symmetric hyperdensity involving the cerebellum, thalami, caudate, corona radiata, and brain stem.

Individuals with Krabbe disease who have severe demyelination show high-intensity lesions on T2-weighted images with a loss of diffusional anisotropy and relatively high signal on diffusion-weighted images. Calculation of the T2 value in the central white matter provides objective judgment for demyelinating diseases. It is progressively prolonged in the occipital deep white matter and posterior part of the central semiovale in individuals with late-onset Krabbe disease.

Testing

Galactocerebrosidase (GALC) enzyme activity

  • Symptomatic individuals. Measurement of GALC enzyme activity is best done using the radiolabeled natural substrate galactosylceramide (gal-cer). The in vitro assay using radiolabeled gal-cer utilizes a synthetic buffer and detergent mixture. Some laboratories use the synthetic substrate 6-hexadecanoylamino-4- metylumbelliferyl-beta-D-galactopyranoside (HMGal).

    All individuals with Krabbe disease have very low GALC enzyme activity (0%-5% of normal activity) in leukocytes isolated from whole heparinized blood and cultured skin fibroblasts. This test is most reliable when conducted in a laboratory with demonstrated experience in performing the assay.

    Note: The finding of GALC enzyme activity that is 8%-20% of normal in a healthy individual, in an individual with neurologic disease that is not typical of any form of Krabbe disease, or in an individual identified by newborn screening presents a diagnostic problem and requires additional study. In most instances, such individuals have multiple copies of known polymorphisms in both GALC alleles. However, some individuals with enzyme activity in this range may have a disease-causing mutation on one allele and multiple polymorphic changes on the other allele, and thus may be carriers of Krabbe disease.
  • Carrier testing. Carrier testing by measurement of GALC enzyme activity in leukocytes or cultured skin fibroblasts is not reliable because of the wide range of enzymatic activities observed in carriers and non-carriers. The presence of normal variants (polymorphisms) in the GALC coding region results in amino acid changes that lower GALC enzyme activity but do not result in clinical disease when inherited in the homozygous state or, as far as is known, when inherited together with a disease-causing mutation.

    Note: Although the finding of low GALC enzyme activity in one or both healthy parents of an affected child (due to the presence of polymorphisms in their normal allele) makes prenatal testing using enzyme measurement more difficult, it is accurate when performed in an experienced laboratory.
  • Newborn screening. With improvements in treatment options for presymptomatic individuals, efforts to develop newborn screening methods are underway. A method using dried blood spots and tandem mass spectrometry to measure GALC enzyme activity has been published [Li et al 2004a, Li et al 2004b].

    In August 2006 New York State instituted newborn screening for Krabbe disease; to date over 1,000,000 newborns have been screened.

    Four newborns were identified as being at risk of developing infantile Krabbe disease. The identification of these newborns permitted umbilical cord blood transplantation in three within the first month of life; the parents of the fourth infant did not elect this option. One newborn who underwent transplantation subsequently died of complications of the transplant; the other two are still alive.

    Other high-risk individuals were identified by confirming enzymatic studies [Wenger, unpublished].] and by molecular genetic testing. Their mutations suggest a later-onset disease or possibly no disease; their clinical status is being carefully monitored.

    At this time several other states are considering newborn screening for Krabbe disease; to date none have implemented the program.

Molecular Genetic Testing

Gene. GALC is the gene most commonly known to be associated with Krabbe disease (see Differential Diagnosis).

Clinical testing

    • Infantile Krabbe disease. One mutation (a 30-kb deletion) accounts for approximately 45% of the mutant alleles in individuals of European ancestry [Luzi et al 1995, Rafi et al 1995] and 35% of the mutant alleles in individuals of Mexican heritage [personal experience]. This large deletion results in the classic infantile phenotype when in the homozygous state or in the compound heterozygous state along with another mutation known to cause infantile Krabbe disease.
    • Late-onset Krabbe disease. The c.857G>A mutation is often found in individuals with the late-onset form of Krabbe disease. One copy of this mutation, even in the compound heterozygous state with the 30-kb deletion, always results in late-onset Krabbe disease.
  • Sequence analysis. It is possible to sequence the entire coding region, intron-exon boundaries, and 5'-untranslated region of GALC and identify essentially 100% of the disease-causing mutations and polymorphisms (normal variants).
  • Deletion/duplication analysis. Deletions involving single exons and multiple exons have been detected [Wenger et al 2001].

Table 1. Summary of Molecular Genetic Testing Used in Krabbe Disease

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
GALCTargeted mutation analysis30-kb deletionSee footnote 4
c.857G>ASee footnote 5
Sequence analysisSequence variants 6~100%
Deletion/ duplication analysis 7(Multi)exonic and whole-gene deletions/duplications Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. This large deletion accounts for approximately 45% of the mutant alleles in individuals with infantile Krabbe disease of European ancestry [Luzi et al 1995, Rafi et al 1995] and 35% of the mutant alleles in individuals with infantile Krabbe disease of Mexican heritage [personal experience]. One copy of this large deletion can also be observed in the compound heterozygous state in individuals with late-onset Krabbe disease.

5. Found in individuals with late-onset Krabbe disease: approximately 50% have at least one c.857G>A disease-causing allele.

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Measurement of GALC enzyme activity in leukocytes or another tissue to establish the diagnosis
  • Molecular genetic analysis of the proband to identify both disease-causing alleles to aid in phenotype prediction (especially in those individuals identified in newborn screening), in carrier detection in at-risk family members, and possibly for prenatal diagnosis

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Approximately 85%-90% of individuals with Krabbe disease have the infantile form presenting with extreme irritability, spasticity, and developmental delay before age six months. The remaining 10%-15% have onset between age six months and the seventh decade.

Infantile form. The infantile form typically has three stages:

  • Stage I is characterized by irritability, stiffness, arrest of motor and mental development, and episodes of temperature elevation without infection, possibly caused by involvement of the hypothalamus. The child, apparently normal for the first few months after birth, becomes hypersensitive to auditory, tactile, or visual stimuli and begins to cry frequently without apparent cause. Many infants keep their fists tightly clenched throughout their lives. Slight retardation or regression of psychomotor development as well as vomiting and other feeding difficulties may result in progressive loss of weight leading to emaciation. In some infants, peripheral neuropathy is a presenting feature with no other neurologic symptoms appreciated for several months [Korn-Lubetzki et al 2003]. Seizures may occur as an initial clinical symptom. Infantile spasms rarely occur. The CSF protein concentration is already increased at this stage.
  • Stage II is characterized by rapid and severe motor and mental deterioration. There is marked hypertonicity with extended and crossed legs, flexed arms, and a backward-bent head. Tendon reflexes are hyperactive. Minor tonic or clonic seizures occur. Optic atrophy and sluggish pupillary reactions to light are common. Clinical examination does not always reveal peripheral neuropathy, especially in the early stages when symptoms and signs of central nervous system involvement are overwhelming.
  • Stage III, sometimes reached within a few weeks or months, is the "burnt out" stage. The infant is blind and decerebrate with no voluntary movement. The infant has no contact with his/her surroundings.

The average age of death in children with the infantile form is 13 months; however, some succumb by age eight months from infections and respiratory failure, while others live for more than two years. Even with the best care, it is difficult to extend the life of a severely affected child.

Symptoms and signs are confined to the nervous system. No visceromegaly is present. Head size may be large or small; hydrocephalus has been observed. Macular cherry-red spots were described in one individual.

One infant, diagnosed with Krabbe disease in utero, had normal psychomotor development for the first two months of life but lost deep tendon reflexes by age five weeks, had markedly reduced nerve conduction velocities at age seven weeks, and developed neck muscle weakness at age three months [Lieberman et al 1980]. These findings suggest that careful examination could reveal clinical manifestations of Krabbe disease in an affected infant earlier than the reported age of onset.

Late-onset forms. Individuals with late-onset forms can be clinically normal until almost any age when symptoms of weakness, vision loss, and intellectual regression become evident. The clinical course of older individuals is variable. Individuals with the late-infantile or juvenile form who present after age one year may have nonspecific findings related to walking difficulties, vision loss, and loss of developmental milestones. These individuals regress at an unpredictable rate.

Loonen et al [1985] identified late-infantile (early-childhood) and juvenile (late-childhood) forms in 18 individuals.

In the late-infantile group (onset age 6 months - 3 years), irritability, psychomotor regression, stiffness, ataxia, and loss of vision were the most common initial symptoms. In most cases the course was progressive and resulted in death approximately two years after onset.

In the juvenile group (onset age 3-8 years), children developed loss of vision together with hemiparesis, ataxia, and psychomotor regression. Most children with the juvenile form showed an initial rapid deterioration followed by a more gradual progression lasting for years. None died during the follow-up period that ranged from ten months to seven years [Loonen et al 1985].

Some individuals with onset in adolescence and adulthood present with loss of manual dexterity, burning paresthesia in their extremities, and weakness without intellectual deterioration; others become bedridden and continue to deteriorate mentally and physically [Kolodny et al 1991, Satoh et al 1997, Jardim et al 1999, Wenger 2003].

The adult-onset group includes individuals in whom the diagnosis was first made in adulthood (because the subtle symptoms present earlier in life did not prompt biochemical testing) as well as individuals considered completely normal until symptoms began after age 20 years [Kolodny et al 1991, Satoh et al 1997, Wenger 2003]. An example of the former is an individual reported by Kolodny et al [1991] (case 15) who had been "shaky" in childhood, walked slowly with a stiff and wide-based gait, and had progressive, generalized neurologic deterioration after age 40 years. She died of pneumonia at age 73 years. An example of the latter is a woman who developed slowly progressive spastic paraparesis at age 38 years. Demyelination identified on MRI was confined to the corticospinal tract [Satoh et al 1997].

The phenotypes can differ considerably among individuals with later-onset forms, including siblings, who have the same GALC genotype. Findings in two sisters illustrate this point. At age 28 years, sister 1 had been considered normal until a few years previously when she experienced lower-extremity paresis with episodes of tripping and clumsiness when walking. Heel cord lengthening was performed, but spastic paresis continued with clumsy gait and difficulty rising from a squatting or sitting position. Ten years earlier, nerve conduction studies had shown slowing in motor and sensory fibers. She had no obvious intellectual impairment, was married and had a child, and at age 38 years continues to work. Sister 2 had been considered normal until age four to five years, when she developed progressive weakness in all extremities. She experienced rapid mental deterioration and seizures. At age 36 years, she was significantly intellectually disabled and wheelchair bound, although she could function in a sheltered environment [personal observation].

Electroencephalogram (EEG). While normal in the initial stages, the EEG gradually becomes abnormal. Background activity becomes slow and disorganized, with changes that may be asymmetric.

EMG and NCV. Motor nerve conduction velocities (NCVs) are consistently low. NCV studies have been reported to be normal in some adults with an enzymatically confirmed diagnosis.

Visual and auditory evoked responses, NCV, and EEG are all more frequently and more severely abnormal in individuals with early-infantile onset [Husain et al 2004].

MRI. In general, in the early stage of Krabbe disease MRI detects demyelination in the brain stem and cerebellum more clearly than CT, but some infants have a deceptively normal MRI.

In some cases, CT reveals symmetric hyperdensity involving the cerebellum, thalami, caudate, corona radiata, and brain stem.

On MRI the T1 value is decreased, with normal or slightly decreased T2 in white matter of the centrum semiovale.

T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI showed symmetric high intensity of the pyramidal tract and optic radiation in an adult whose initial clinical manifestations occurred at age 60 years. The T2 value is progressively prolonged in the occipital deep white matter and posterior part of central semiovale in late-onset disease. MRI is also useful for differentiation between dysmyelination and demyelination. Individuals with Krabbe disease with severe demyelination showed high-intensity lesions on T2-weighted images, with a loss of diffusional anisotropy and relatively high signal intensity on diffusion-weighted images [Husain et al 2004].

MRS. Magnetic resonance spectroscopy can also be used to document the demyelination, gliosis, and axonal loss in white matter of individuals with typical and atypical Krabbe disease.

Genotype-Phenotype Correlations

GALC Enzyme Activity

No consistent correlation has been observed between age of onset and residual GALC enzyme activity measured in leukocytes or cultured skin fibroblasts.

Occasionally, some individuals with Krabbe disease have slightly higher than expected GALC enzyme activity. Because the active enzyme consists of a large aggregate containing multiple copies of the 30-kd and 50-kd subunits derived from the same precursor and because many individuals are compound heterozygotes, it is difficult to place much significance on the detection of a small amount of residual enzyme activity.

GALC Mutations

Infantile form. The common 30-kb deletion results in the classic infantile form in the homozygous state or when in the compound heterozygous with another mutation associated with severe disease. Three other mutations associated with the infantile phenotype make up another 15% of the mutant alleles in individuals of European ancestry [Kleijer et al 1997, Wenger et al 1997]. Except for the c.857G>A mutation, all disease-causing mutations listed in Table 2 result in the infantile phenotype when homozygous or compound heterozygous with each other.

Late-onset forms. Many individuals with late-onset disease are compound heterozygotes, having one copy of the c.857G>A mutation and one copy of the common 30-kb deletion. Although having one copy of the c.857G>A allele always results in a milder phenotype, it is not possible to predict the clinical course, as illustrated by the two sisters described in Clinical Description. Five additional families with multiple affected members with the 30-kb del/ c.857G>A genotype have significant intra- and interfamilial clinical variability [Wenger, personal observation].

Only one individual of Japanese heritage with adult-onset disease is known to be homozygous for the c.857G>A mutation. One individual with adult-onset disease had a complex genotype with three mutations on one allele and two on the other [Luzi et al 1996]. Other mutations have been described [Kukita et al 1997].

Prevalence

Krabbe disease occurs in approximately one in 100,000 births in the United States and Europe.

The carrier frequency in individuals with no family history is approximately one in 150.

The disease is pan ethnic; however, no cases have been identified in individuals of Jewish ancestry. A very high incidence of the disease is found in a Druze community in Northern Israel and two Moslem Arab villages located near Jerusalem, where the carrier rate is estimated at one in six [Rafi et al 1996].

Differential Diagnosis

A history of normal development for the first few months after birth followed by psychomotor deterioration differentiates Krabbe disease from non-progressive CNS disorders of congenital or perinatal origin. Differentiation of Krabbe disease from other degenerative diseases is often difficult. Individuals of any age with progressive deterioration of the central or peripheral nervous systems should be tested for Krabbe disease.

The following disorders, ordered by mode of inheritance, should be considered in the differential diagnosis.

Autosomal Recessive

Arylsulfatase A deficiency (metachromatic leukodystrophy, MLD) is characterized by three clinical subtypes that can closely resemble late-onset Krabbe disease: late-infantile MLD (50%-60% of cases) with onset between age one and two years; juvenile MLD (~20%-30%) with onset between age four years and sexual maturity (12-14 years); and adult MLD (~15%-20%) with onset after sexual maturity. All individuals eventually lose motor and intellectual functions. The disease course may be from three to ten or more years in the late infantile-onset form and up to 20 years or more in the juvenile- and adult-onset forms. Death most commonly results from pneumonia or other infection.

MLD is suggested by arylsulfatase A enzyme activity in leukocytes that is less than 10% of normal controls. Because of the high frequency of the so-called pseudodeficiency (Pd) allele, additional studies in all individuals with low arylsulfatase activity are required. The diagnosis of MLD is confirmed by one or more of the following additional tests: molecular genetic testing of ARSA, urinary excretion of sulfatides, and/or finding of metachromatic lipid deposits in nervous system tissue. Several individuals with Krabbe disease who were also homozygous for the Pd allele also had low arylsulfatase A activity, confusing the diagnosis [Wenger, unpublished].

GM1 gangliosidosis. The GM1 gangliosidoses, including Morquio syndrome type B, result from defects in acid β-galactosidase. They are clinically variable, ranging from newborns with nonimmune fetal hydrops to adults with varying degrees of neurologic involvement. In addition to psychomotor retardation, young individuals usually have coarse facial features and hepatosplenomegaly, neither of which is found in individuals with Krabbe disease. Skeletal involvement is variable. Some individuals primarily have dysostosis multiplex with no neurologic involvement, and others have only neurologic problems, such as dysarthria, and mild vertebral changes. Low-acid β-galactosidase enzyme activity in both leukocytes and plasma establishes the diagnosis of GM1 gangliosidosis and Morquio syndrome type B and differentiates them from galactosialidosis, a disorder in which β-galactosidase enzyme activity is low in leukocytes only.

GM2 gangliosidosis. The GM2 gangliosidoses are a group of neurodegenerative disorders caused by the intralysosomal storage of the specific glycosphingolipid GM2 ganglioside. Tay-Sachs disease, the prototype GM2 gangliosidosis, is characterized by loss of motor skills beginning between age three and six months with progressive evidence of neurodegeneration, including seizures, macular cherry-red spots, and blindness. Total incapacitation and death usually occur before age four years. The juvenile, chronic, and adult-onset variants of hexosaminidase A deficiency have later onset, slower progression, and more variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, motor neuron disease, and in some individuals with adult-onset disease, a bipolar form of psychosis.

The diagnosis of hexosaminidase A deficiency relies on the demonstration of absent to near-absent beta-hexosaminidase A (HEX A) enzymatic activity in the serum or white blood cells of a symptomatic individual in the presence of normal or elevated activity of the beta-hexosaminidase B (HEX B) isoenzyme. Mutation analysis of HEXA is used primarily for genetic counseling purposes (1) to distinguish pseudodeficiency alleles from disease-causing alleles in individuals with apparent deficiency of HEX A enzymatic activity identified in population screening programs and (2) to identify specific disease-causing alleles in affected individuals.

Canavan disease is characterized by evidence of developmental delays by age three to five months with severe hypotonia and failure to achieve independent sitting, ambulation, or speech. Hypotonia evolves into spasticity and assistance with feeding becomes necessary. Life expectancy is usually into the second decade. Most individuals with Canavan disease have macrocephaly, which is a variable finding in individuals with Krabbe disease. MRI shows prominent involvement of subcortical white matter. The finding of elevated N-acetylaspartic acid concentration in urine confirms the diagnosis of Canavan disease.

Saposin A deficiency. An infant with abnormal myelination resembling Krabbe disease was found to have a mutation in the saposin A region of the gene PSAP, encoding prosaposin [Spiegel et al 2005]. This heat-stable protein interacts with the enzyme GALC to catalyze the hydrolysis of the natural lipid substrates. The infant with mutations in the saposin A region of PSAP had low GALC enzyme activity when measured in leukocytes, but not in cultured skin fibroblasts.

X-Linked

X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in males:

  • The childhood cerebral form manifests most commonly between age four and eight years. It initially resembles attention deficit disorder; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years.
  • Adrenomyeloneuropathy (AMN) manifests most commonly in the late twenties as progressive paraparesis, sphincter disturbances, and varying degrees of distal sensory loss.
  • "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years; some degree of neurologic disability (most commonly AMN) usually develops later.

Approximately 20% of carrier females develop neurologic manifestations that resemble adrenomyeloneuropathy, but have later onset (age 35 years or later) and milder disease than do affected males.

The plasma concentration of very-long-chain fatty acids (VLCFA) is elevated in more than 99% of males with X-ALD of all ages regardless of the presence or absence of symptoms. The assay has a sensitivity of approximately 85% in female carriers. Mutations in ABCD1 are causative.

Pelizaeus-Merzbacher disease (PMD) is part of the phenotypic spectrum of PLP1-related disorders of central nervous system myelin formation. The phenotypes that can be observed in males with this disorder range from PMD to spastic paraplegia 2 (SPG2); a wide range of phenotypes can be observed in members of the same family. PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment and progresses to severe spasticity and ataxia. Life span is shortened. Molecular genetic testing of PLP1 is diagnostic.

Autosomal Dominant

Alexander disease is a disorder of cortical white matter. Two forms are common, infantile (80% of affected individuals) and juvenile (~14%), although neonatal and adult forms are also recognized. The infantile form presents in the first two years of life typically with megalencephaly, seizures, progressive psychomotor retardation with loss of developmental milestones, and quadriparesis. Affected individuals survive a few weeks to several years. The juvenile form usually presents between age four and ten years, occasionally in the mid-teens. Survival is variable, ranging from the early teens to the 20s-30s. Affected individuals can present with megalencephaly, bulbar/pseudobulbar signs including speech abnormalities, swallowing difficulties, frequent vomiting, lower-limb spasticity, poor coordination (ataxia), gradual loss of intellectual function, and seizures.

Diagnostic criteria based on MRI findings include extensive white matter involvement with frontal preponderance, periventricular rim of low T2 and high T1 signal intensity, and mild signal changes and swelling in the basal ganglia, thalamus, and brain stem [van der Knaap et al 2001]. GFAP, which encodes glial fibrillary acidic protein, is the only gene currently known to be associated with Alexander disease.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Krabbe disease:

  • Neurologic examination
  • EEG
  • Brain MRI and MRS

Treatment of Manifestations

Treatment of individuals with infantile-onset Krabbe disease who are diagnosed in stage II or III is limited to supportive care to control irritability and spasticity.

Prevention of Primary Manifestations

Hematopoietic stem cell transplantation (HSCT) in presymptomatic infants [Escolar et al 2005] and older individuals with mild symptoms [Krivit et al 1998] provides a benefit over symptomatic treatment only. Treated individuals show improved and preserved cognitive function; however, many show progressive deterioration of peripheral nervous system findings.

The availability of suitable donors has changed considerably with the use of umbilical cord blood for HSCT.

The identification of newborns with the potential to develop Krabbe disease by newborn screening (presently in place in New York State) facilitates the initiation of treatment before neurologic damage has occurred. Concerns remain regarding the age at which to start treatment, prediction of clinical course without treatment, and long-term consequences of treatment.

Given the significant clinical variability among individuals with late-onset forms (even those with the same genotype), evaluation of treatment effectiveness is difficult.

Evaluation of Relatives at Risk

If the disease has been identified in an affected family member, it is appropriate to test siblings so that morbidity and mortality can be reduced by early diagnosis and treatment with HSCT using umbilical cord blood [Escolar et al 2005].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Studies using the well-characterized animal models to investigate other treatment options including gene therapy, enzyme replacement therapy, neural stem cell transplantation, substrate reduction therapy, and chemical chaperone therapy are being conducted. However, at this time HSCT (bone marrow transplantation) is the most effective method of therapy in the mouse models of Krabbe disease. None of these other methods is ready for human trials.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

In utero HSCT in fetuses predicted to be affected with Krabbe disease has been tried three times with little success [Bambach et al 1997].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Krabbe disease is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore each carries one mutant allele.
  • While each parent carries one normal and one mutated GALC allele, the measured GALC enzyme activity can range widely in carriers because of polymorphisms in the normal copy of the gene. Although some parents have quite low GALC enzyme activity measured in vitro, none has had clinical disease.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

Offspring of a proband with adult-onset Krabbe disease. The offspring of an individual with adult-onset Krabbe disease are obligate heterozygotes (carriers) for a disease-causing mutation in GALC.

Other family members. Each sib of the proband's parents (aunts and uncles of the proband) and each grandparent is at a 50% risk of being a carrier.

Carrier Detection

At-risk family members

  • As the contribution of each allele is additive, when the GALC enzyme activity of both parents is known it is usually possible to accurately determine carrier status of the sibs of an affected individual by measurement of GALC enzyme activity. When the enzyme activity of the parents is not known or if the individual is not an at-risk sib, carrier testing using GALC enzyme activity is not reliable.
  • When the GALC disease-causing mutations have been identified in the family, accurate carrier detection of at-risk family members is possible using molecular genetic testing.

Reproductive partners of at-risk family members. No reliable carrier detection exists for individuals who do not have a family history of Krabbe disease. The carrier frequency in the general population is approximately one in 150.

Related Genetic Counseling Issues

As stated above, carrier testing of relatives using GALC enzyme activity is not reliable. However, sibs of affected individuals, especially younger sibs, should be tested as soon as possible to either relieve anxiety for the parents or to institute therapy as soon as possible.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Biochemical genetic testing. Prenatal testing is possible for at-risk couples who have had an affected child. Ideally, GALC enzyme activity should be measured in both parents before prenatal testing is undertaken. GALC enzyme activity can be measured directly using either fetal cells obtained by chorionic villus sampling at approximately ten to 12 weeks' gestation, cultured cells from CVS, or cultured amniotic fluid cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. Measurement of GALC enzyme activity for prenatal testing is reliable, and molecular genetic testing is not necessary. It is essential that there be no maternal contamination in the sample used for prenatal analysis.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is also possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed. It is essential that there be no maternal contamination in the sample used for prenatal analysis.

Carrier status documented in only one parent. When one parent is a known heterozygote and the reproductive partner has inconclusive enzymatic activity and no disease-causing GALC mutation has been found on DNA analysis, or when the mother is a known heterozygote and the father is unknown and/or unavailable for testing, options for prenatal testing can be explored in the context of formal genetic counseling.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Hunter's Hope Foundation
    6368 West Quaker Street
    PO Box 643
    Orchard Park NY 14127
    Phone: 877-984-4673 (toll-free); 716-667-1200
    Fax: 716-667-1212
    Email: info@huntershope.org
  • National Library of Medicine Genetics Home Reference
  • Canadian MPS Society
    RPO Parkgate
    PO Box 30034
    North Vancouver British Columbia V7H 2Y8
    Canada
    Phone: 800-667-1846; 604-924-5130
    Fax: 604-924-5131
    Email: info@mpssociety.ca
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    Email: office@ulf.org
  • Hunter James Kelly Research Institute Worldwide Registry
    Phone: 716-667-1200
    Email: info@huntershope.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Krabbe Disease: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
GALC14q31​.3GalactocerebrosidaseGALC homepage - Mendelian genesGALC

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Krabbe Disease (View All in OMIM)

245200KRABBE DISEASE
606890GALACTOSYLCERAMIDASE; GALC

Normal allelic variants. The normal gene is approximately 57 kb in length with 17 exons that code for 669 amino acids. The reference protein NP_000144.2 (Table 2) has 685 amino acids because by convention longer isoforms are chosen as reference sequences. Compared to the 669-amino acid isoform described by Wenger et al, this one uses an alternate start codon that is 48 nucleotides upstream.

The 5' flanking region of the gene is GC rich and contains one potential YY1 element and one potential SP1 binding site. The strongest promoter activity is -176 to -24 upstream of the initiation codon. Inhibitory sequences are immediately upstream of the promoter region and within intron 1 [Luzi et al 1997] (see Table 2).

Pathologic allelic variants. Over 110 disease-causing mutations have been identified (some are summarized in Wenger et al [2001], others unpublished). The more common mutations that have occurred in more than one unrelated individual in either the homozygous or heterozygous state are in Table 2.

Mutations occur in every one of the 17 exons. Missense mutations causing the infantile form of Krabbe disease are found in both subunits, although more seem to be found in the coding region for the 30-kd subunit.

The 30-kb deletion, which always occurs in cis with the c.550C>T polymorphism (normal variant), accounts for approximately 45% of mutant alleles in the population of European ancestry. The 30-kb deletion, starting within the large intron 10 and continuing beyond the end of the gene, probably originated in Sweden and spread throughout Europe, including Spain. This deletion comprises a significant number of mutant alleles in individuals of Mexican, Pakistani, and Indian heritage. This deletion results in the classic infantile form when found in the homozygous state or in the compound heterozygous state with another severe mutation. Several other mutations associated with the infantile phenotype make up another 15% of the mutant alleles in individuals with European ancestry [Kleijer et al 1997, Wenger et al 1997] (see Table 2).

The mutation c.857G>A always results in the later-onset form of Krabbe disease. One copy of this mutation, even when present with the 30-kb deletion as the second allele, results in late-onset Krabbe disease. In all c.857G>A alleles that have been examined it was found in cis configuration with the c.1685T>C polymorphism. Whether pathogenesis requires the presence of both or only one nucleotide change is not known.

A number of small deletions and insertions result in frame shift and premature termination. Even missense mutations very near the 3' end of the coding region that result in amino acid changes near the carboxyl end of the 30-kd subunit result in clinical disease [Rafi et al 1996, Jardim et al 1999]. It is difficult to predict the clinical presentation from the location or type of missense mutation.

Other unique mutations occur within certain ethnic groups [Fu et al 1999]. Unique point mutations resulting in infantile Krabbe disease have been identified in two isolates in the Middle East [Rafi et al 1996]. The Druze in Northern Israel and a Moslem Arab village near Jerusalem each has its own unique missense mutation near the 3' end of the gene. For members of these villages, identification of affected individuals, carrier testing, and prenatal diagnosis can be done by molecular genetic analysis.

Table 2. Common GALC Polymorphisms and Mutations

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
% of All AllelesReference Sequences
Normal
(benign polymorphisms)
c.550C>T
(502C>T)
p.Arg184Cys
(Arg168Cys)
4%-5% NM_000153​.3
NP_000144​.2
c.742G>A
(694G>A)
p.Asp248Asn
(Asp232Asn)
8%-10%
c.1685T>C
(1637T>C)
p.Ile562Thr
(Ile546Thr)
35%-45%
c.[550C>T;1685T>C] 2
(502C>T + 1637T>C) 2
p.[Arg184Cys;Ile562Thr]
(Arg168Cys + Ile546Thr)
<2%
Pathologic 3(30-kb deletion3--40%-50% 4
c.1586C>T
(1538C>T)
p.Thr529Met
(Thr513Met)
5%-8% 4
c.1700A>C
(1652A>C)
p.Tyr567Ser
(Tyr551Ser)
5%-8% 4
c.1472delA
(1424delA)
p.Lys491Argfs*622%-5% 4
c.857G>A
(809G>A) 5
p.Gly286Asp
(Gly270Asp)
1%-2% 4

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions. In this instance, the variant designations conform to the cDNA reference sequence in the HGMD database (see Table A) and some publications.

2. Two mutations in one allele

3. Begins in intron 10 and deletes the remainder of the gene and additional contiguous sequences

4. In individuals of European ancestry

5. One copy of this allele together with another disease-causing mutation results in late-onset disease.

Normal gene product. The 80-kd precursor protein contains six potential glycosylation sites and is proteolytically cut into the active 50-kd and 30-kd subunits. These subunits are not active individually, and galactocerebrosidase (GALC) enzyme activity cannot be generated by mixing together the two subunits. The subunits aggregate into a very high molecular-weight complex that is very hydrophobic. Normally only a very small amount of GALC protein is made in all cell types; however, it appears to be stable and to work efficiently on the natural substrates.

Abnormal gene product. It appears that most disease-causing missense mutations result in the production of protein that is unstable and rapidly degraded. All small and large deletions result either in a frame shift resulting in a premature stop codon, insertion or deletion of amino acids, or deletion of a significant portion of the gene. The polymorphisms listed in Table 2 result in protein that is less active than protein coded for by the most common allele. This reduced activity may result from changes in secondary structure of the mature enzyme or from protein instability. While these effects are measurable in vitro, it is not known what effects the changes have in vivo, especially in the peripheral and central nervous systems.

References

Literature Cited

  1. Bambach BJ, Moser HW, Blakemore K, Corson VL, Griffin CA, Noga SJ, Perlman EJ, Zuckerman R, Wenger DA, Jones RJ. Engraftment following in utero bone marrow transplantation for globoid cell leukodystrophy. Bone Marrow Transplant. 1997;19:399–402. [PubMed: 9051254]
  2. Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W, Kurtzberg J. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med. 2005;352:2069–81. [PubMed: 15901860]
  3. Fu L, Inui K, Nishigaki T, Tatsumi N, Tsukamoto H, Kokubu C, Muramatsu T, Okada S. Molecular heterogeneity of Krabbe disease. J Inherit Metab Dis. 1999;22:155–62. [PubMed: 10234611]
  4. Husain AM, Altuwaijri M, Aldosari M. Krabbe disease: neurophysiologic studies and MRI correlations. Neurology. 2004;63:617–20. [PubMed: 15326231]
  5. Jardim LB, Giugliani R, Pires RF, Haussen S, Burin MG, Rafi MA, Wenger DA. Protracted course of Krabbe disease in an adult patient bearing a novel mutation. Arch Neurol. 1999;56:1014–7. [PubMed: 10448809]
  6. Kleijer WJ, Keulemans JL, van der Kraan M, Geilen GG, van der Helm RM, Rafi MA, Luzi P, Wenger DA, Halley DJ, van Diggelen OP. Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin. J Inherit Metab Dis. 1997;20:587–94. [PubMed: 9266397]
  7. Kolodny EH, Raghavan S, Krivit W. Late-onset Krabbe disease (globoid cell leukodystrophy): clinical and biochemical features of 15 cases. Dev Neurosci. 1991;13:232–9. [PubMed: 1817026]
  8. Korn-Lubetzki I, Dor-Wollman T, Soffer D, Raas-Rothschild A, Hurvitz H, Nevo Y. Early peripheral nervous system manifestations of infantile Krabbe disease. Pediatr Neurol. 2003;28:115–8. [PubMed: 12699861]
  9. Krivit W, Shapiro EG, Peters C, Wagner JE, Cornu G, Kurtzberg J, Wenger DA, Kolodny EH, Vanier MT, Loes DJ, Dusenbery K, Lockman LA. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. 1998;338:1119–26. [PubMed: 9545360]
  10. Kukita Y, Furuya H, Kobayashi T, Sakai N, Hayashi K. Characterization of the GALC gene in three Japanese patients with adult-onset Krabbe disease. Genet Test. 1997;1:217–23. [PubMed: 10464649]
  11. Li Y, Brockmann K, Turecek F, Scott CR, Gelb MH. Tandem mass spectrometry for the direct assay of enzymes in dried blood spots: application to newborn screening for Krabbe disease. Clin Chem. 2004a;50:638–40. [PubMed: 14981030]
  12. Li Y, Scott CR, Chamoles NA, Ghavami A, Pinto BM, Turecek F, Gelb MH. Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening. Clin Chem. 2004b;50:1785–96. [PMC free article: PMC3428798] [PubMed: 15292070]
  13. Lieberman JS, Oshtory M, Taylor RG, Dreyfus PM. Perinatal neuropathy as an early manifestation of Krabbe’s disease. Arch Neurol. 1980;37:446–7. [PubMed: 6248003]
  14. Loonen MC, Van Diggelen OP, Janse HC, Kleijer WJ, Arts WF. Late-onset globoid cell leucodystrophy (Krabbe's disease). Clinical and genetic delineation of two forms and their relation to the early-infantile form. Neuropediatrics. 1985;16:137–42. [PubMed: 4047347]
  15. Luzi P, Rafi MA, Wenger DA. Characterization of the large deletion in the GALC gene found in patients with Krabbe disease. Hum Mol Genet. 1995;4:2335–8. [PubMed: 8634707]
  16. Luzi P, Rafi MA, Wenger DA. Multiple mutations in the GALC gene in a patient with adult-onset Krabbe disease. Ann Neurol. 1996;40:116–9. [PubMed: 8687180]
  17. Luzi P, Victoria T, Rafi MA, Wenger DA. Analysis of the 5' flanking region of the human galactocerebrosidase (GALC) gene. Biochem Mol Med. 1997;62:159–64. [PubMed: 9441867]
  18. Rafi MA, Luzi P, Chen YQ, Wenger DA. A large deletion together with a point mutation in the GALC gene is a common mutant allele in patients with infantile Krabbe disease. Hum Mol Genet. 1995;4:1285–9. [PubMed: 7581365]
  19. Rafi MA, Luzi P, Zlotogora J, Wenger DA. Two different mutations are responsible for Krabbe disease in the Druze and Moslem Arab populations in Israel. Hum Genet. 1996;97:304–8. [PubMed: 8786069]
  20. Satoh JI, Tokumoto H, Kurohara K, Yukitake M, Matsui M, Kuroda Y, Yamamoto T, Furuya H, Shinnoh N, Kobayashi T, Kukita Y, Hayashi K. Adult-onset Krabbe disease with homozygous T1853C mutation in the galactocerebrosidase gene. Unusual MRI findings of corticospinal tract demyelination. Neurology. 1997;49:1392–9. [PubMed: 9371928]
  21. Spiegel R, Bach G, Sury V, Mengistu G, Meidan B, Shalev S, Shneor Y, Mandel H, Zeigler M. A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol Genet Metab. 2005;84:160–6. [PubMed: 15773042]
  22. van der Knaap MS, Naidu S, Breiter SN, Blaser S, Stroink H, Springer S, Begeer JC, van Coster R, Barth PG, Thomas NH, Valk J, Powers JM. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol. 2001;22:541–52. [PubMed: 11237983]
  23. Wenger DA. Krabbe disease: globoid cell leukodystrophy. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, Nestler EJ, eds. The Molecular and Genetic Basis of Neurologic and Psychiatric Disease. Philadelphia: Butterworth-Heinemann; 2003:255-61.
  24. Wenger DA, Rafi MA, Luzi P. Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications. Hum Mutat. 1997;10:268–79. [PubMed: 9338580]
  25. Wenger DA, Suzuki K, Suzuki Y, Suzuki K. Galactosylceramide lipidosis. Globoid cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. McGraw-Hill; 2001:3669-94.

Suggested Reading

  1. De Gasperi R, Friedrich VL, Perez GM, Senturk E, Wen PH, Kelley K, Elder GA, Gama Sosa MA. Transgenic rescue of Krabbe disease in the twitcher mouse. Gene Ther. 2004;11:1188–94. [PubMed: 15164096]
  2. Kondo Y, Wenger DA, Gallo V, Duncan ID. Galactocerebrosidase-deficient oligodendrocytes maintain stable central myelin by exogenous replacement of the missing enzyme in mice. Proc Natl Acad Sci U S A. 2005;102:18670–5. [PMC free article: PMC1317926] [PubMed: 16352725]
  3. Krivit W. Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases. Springer Semin Immunopathol. 2004;26:119–32. [PubMed: 15452666]
  4. Lin D, Fantz CR, Levy B, Rafi MA, Vogler C, Wenger DA, Sands MS. AAV2/5 vector expressing galactocerebrosidase ameliorates CNS disease in the murine model of globoid-cell leukodystrophy more efficiently than AAV2. Mol Ther. 2005;12:422–30. [PubMed: 15996520]
  5. Luzi P, Rafi MA, Zaka M, Rao HZ, Curtis M, Vanier MT, Wenger DA. Biochemical and pathological evaluation of long-lived mice with globoid cell leukodystrophy after bone marrow transplantation. Mol Genet Metab. 2005;86:150–9. [PubMed: 16169269]
  6. Meng XL, Shen JS, Watabe K, Ohashi T, Eto Y. GALC transduction leads to morphological improvement of the twitcher oligodendrocytes in vivo. Mol Genet Metab. 2005;84:332–43. [PubMed: 15781194]
  7. Rafi MA, Zhi Rao H, Passini MA, Curtis M, Vanier MT, Zaka M, Luzi P, Wolfe JH, Wenger DA. AAV-mediated expression of galactocerebrosidase in brain results in attenuated symptoms and extended life span in murine models of globoid cell leukodystrophy. Mol Ther. 2005;11:734–44. [PubMed: 15851012]
  8. Taylor RM, Lee JP, Palacino JJ, Bower KA, Li J, Vanier MT, Wenger DA, Sidman RL, Snyder EY. Intrinsic resistance of neural stem cells to toxic metabolites may make them well suited for cell non-autonomous disorders: evidence from a mouse model of Krabbe leukodystrophy. J Neurochem. 2006;97:1585–99. [PubMed: 16805770]

Chapter Notes

Author Notes

Since 1969 Dr Wenger has been doing research on certain lysosomal storage diseases, primarily Krabbe disease, and in 1973 the diagnostic laboratory was started. Since then, approximately 50,000 individuals have been screened for lysosomal diseases in his laboratory.

Author History

Stephanie Coppola, BS; Jefferson Medical College (2004-2006)
David A Wenger, PhD (2000-present)

Revision History

  • 31 March 2011 (me) Comprehensive update posted live
  • 5 August 2008 (cd) Revision: deletion/duplication analysis available clinically for GALC
  • 3 January 2007 (me) Comprehensive update posted to live Web site
  • 27 September 2004 (me) Comprehensive update posted to live Web site
  • 25 November 2002 (me) Comprehensive update posted to live Web site
  • 19 June 2000 (me) Review posted to live Web site
  • February 2000 (dw) Original submission
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