Krabbe Disease

Clinical characteristics.

Krabbe disease comprises a spectrum ranging from infantile-onset disease (i.e., onset of extreme irritability, spasticity, and developmental delay before age 12 months) to later-onset disease (i.e., onset of manifestations after age 12 months and as late as the seventh decade). Although historically 85%-90% of symptomatic individuals with Krabbe disease diagnosed by enzyme activity alone have infantile-onset Krabbe disease and 10%-15% have later-onset Krabbe disease, the experience with newborn screening (NBS) suggests that the proportion of individuals with possible later-onset Krabbe disease is higher than previously thought. Infantile-onset Krabbe disease is characterized by normal development in the first few months followed by rapid severe neurologic deterioration; the average age of death is 24 months (range 8 months to 9 years). Later-onset Krabbe disease is much more variable in its presentation and disease course.

Diagnosis/testing.

The two diagnostic scenarios are the following:

• Scenario 1. The diagnosis of Krabbe disease, suspected in a symptomatic proband based on clinical findings (by age) and other supportive laboratory, neuroimaging, and electrophysiologic findings, is established by detection of deficient GALC enzyme activity in leukocytes. Abnormal results require follow-up molecular genetic testing of GALC; elevated psychosine levels can also help establish the diagnosis.
• Scenario 2. In an asymptomatic newborn with low GALC enzyme activity on dried blood spot specimens on NBS urgent time-critical measurement of blood psychosine levels and GALC molecular genetic testing is necessary to identify – before age 14 days – those newborns with evidence of infantile-onset Krabbe disease who are candidates for early treatment with hematopoietic stem cell transplantation (HSCT).

Management.

Treatment of manifestations: Treatment of a child who is symptomatic before age six months is supportive and focused on increasing the quality of life and avoiding complications. For older individuals, treatment with HSCT is individualized based on disease burden and manifestations.

Prevention of primary manifestations: Consensus guidelines recommend that asymptomatic newborns identified by either prenatal/neonatal evaluation because of a positive family history of Krabbe disease or an abnormal NBS result undergo additional testing to identify those with infantile-onset Krabbe disease. Those with laboratory findings consistent with infantile-onset Krabbe disease are candidates for HSCT before age 30 days.

Surveillance: Monitor symptomatic individuals with Krabbe disease for development of: hydrocephalus, swallowing difficulties and chronic microaspiration, scoliosis, hip subluxation, and osteopenia, decreased vision, and corneal ulcerations.

Agents/circumstances to avoid: Atypical antipsychotics and multiple medications for seizures can cause over-sedation (affecting cognition, respiratory drive, and rate of neurologic decline). Routine childhood vaccinations can accelerate disease progression.

Evaluation of relatives at risk: Couples who have had one child with molecularly confirmed infantile-onset Krabbe disease may choose prenatal molecular genetic testing in subsequent pregnancies so that newborns with biallelic GALC pathogenic variants can be promptly tested and – if appropriate -- referred for HSCT.

Genetic counseling.

Krabbe disease is inherited in an autosomal recessive manner. 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 the GALC pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible.

Suggestive Findings

The two different scenarios in which Krabbe disease could be suspected in a proband:

• Scenario 1. A symptomatic individual
• Scenario 2. An asymptomatic newborn with a positive result on NBS

Establishing the Diagnosis

Scenario 1

The testing required to establish the diagnosis Krabbe disease in a symptomatic proband. In individuals with some or all of the suggestive findings of infantile-onset Krabbe disease or later-onset Krabbe disease, the diagnosis is established by detection of deficient GALC enzyme activity in leukocytes. Abnormal results require follow-up molecular genetic testing of GALC. For children with infantile-onset Krabbe disease, elevated psychosine levels in dried blood spot specimens confirm the diagnosis; however, in individuals who have later-onset Krabbe disease or have progressed to the later stages of the infantile form of disease, it is not yet known if psychosine concentrations are consistently elevated.

Galactocerebrosidase (GALC) enzyme activity is measured in leukocytes isolated from whole heparinized blood or cultured skin fibroblasts. The substrate used (i.e., radiometric substrate, fluorescent substrate, or mass spectrometry substrate) depends on the laboratory.

• Very low GALC enzyme activity (0%-5% of normal activityl) is observed in all individuals with Krabbe disease who are symptomatic. Note: Low GALC activity can result from pseudodeficiency alleles (benign GALC variants that reduce enzyme activity in vitro but do not cause disease), carrier status for a GALC pathogenic variant, or saposin A deficiency (see Molecular Genetics).
• If GALC enzyme activity in leukocytes is completely normal, no additional biochemical testing is required to exclude Krabbe disease. However, if psychosine was elevated in such cases, a diagnosis of saposin A deficiency should be considered.

Psychosine concentration

• Infantile-onset Krabbe disease. Very elevated concentrations of psychosine (usually >10 nmol/L) are strongly supportive of early symptomatic Krabbe disease [Turgeon et al 2015, Escolar et al 2017, Minter Baerg et al 2018]. Note that psychosine concentrations may drop significantly in the later stages of infantile-onset Krabbe disease and that psychosine may also be elevated in individuals with saposin A deficiency.
• Later-onset Krabbe disease. Psychosine concentrations may not be markedly elevated and may depend on how long the patient has been symptomatic [Escolar et al 2017].

Molecular testing involves single-gene testing. Sequence analysis of GALC and targeted analysis for the common GALC 30-kilobase deletion (30kb del) is performed [Luzi et al 1995, Rafi et al 1995]. Gene-targeted deletion/duplication analysis should also be performed, at least when the suspicion of Krabbe disease is high and only one GALC pathogenic variant has been detected by sequence analysis. See Table 1.

Table 1.

Molecular Genetic Testing Used in Krabbe Disease (Galactosylcerebrosidase Deficiency)

Clinical Description

Historically, 85%-90% of symptomatic individuals with Krabbe disease diagnosed by enzyme activity alone had infantile-onset Krabbe disease (i.e., onset of extreme irritability, spasticity, and developmental delay before age 12 months) and 10%-15% had later-onset Krabbe disease (i.e., onset of manifestations after age 12 months and as late as the seventh decade). In contrast, the vast majority of infants identified through the New York State newborn screening (NBS) program who have low GALC enzyme activity and two presumptive pathogenic GALC variants do not have signs or symptoms of infantile-onset disease [Wasserstein et al 2016]; thus, it is likely that the proportion of individuals with later-onset Krabbe disease is higher than previously thought [Author, personal communication].

Genotype-Phenotype Correlations

Infantile-onset Krabbe disease results from severe loss of galactocerebrosidase activity due to:

• Homozygosity for the common GALC 30-kb deletion;
• Compound heterozygosity for either the common GALC 30-kb deletion and a severe GALC pathogenic variant (most frequently nonsense or frameshift variants, but also some missense variants) or two severe pathogenic variants [Tappino et al 2010].

Later-onset Krabbe disease. The following genotypes have been observed in individuals with later-onset disease:

• p.Gly286Asp+30kb del [Furuya et al 1997, De Gasperi et al 1999]
• p.Gly286Asp+p.Pro318Arg [Tappino et al 2010]
• p.Gly286Asp + another severe allele
• p.Thr112Ala+p.Asp187Val [Luzi et al 1996]
• p.Leu634Ser + another severe allele or homozygous p.Leu634Ser [Hossain et al 2014, Zhang et al 2018]

The p.Gly57Ser variant, a founder variant common in Catania, Italy, is associated with late-onset Krabbe disease in both the homozygous and compound heterozygous states [Lissens et al 2007].

Note that although p.Gly286Asp has been observed in individuals with a milder phenotype, to date it is not possible to predict the clinical course in a given individual.

Nomenclature

The protein encoded by GALC is termed galactocerebrosidase in UniProt, the standard reference for GeneReviews (see Table A). Because additional terms for this protein are used in the published literature, Krabbe disease may also be referred to as:

• Galactosylceramidase deficiency
• Galactosylcerebrosidase deficiency
• β-galactocerebrosidase deficiency

Prevalence

Krabbe disease occurs in approximately one in 250,000 births in the United States [Barczykowski et al 2012] and approximately one in 100,000 births in Europe [Wenger et al 2013]; with the median prevalence varying widely between countries [Tappino et al 2010].

A very high incidence of Krabbe disease is found in a Druze community in northern Israel and two Muslim Arab villages located near Jerusalem where the carrier rate is estimated at one in six [Rafi et al 1996].

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in GALC.

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 individuals) with onset between age one and three years
• Juvenile MLD (~20%-30%) with onset between age four years and sexual maturity (12-14 years)
• Adult MLD (~15%-20%) with onset after sexual maturity

Biallelic pathogenic variants in ARSA are causative.

Hexosaminidase A deficiency results in a group of neurodegenerative disorders caused by the intralysosomal storage of the specific glycosphingolipid, GM2 ganglioside. Tay-Sachs disease, the prototype hexosaminidase A deficiency, is characterized by loss of motor skills beginning between ages 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. Biallelic pathogenic variants in HEXA are causative.

Canavan disease. Neonatal/infantile (severe) 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. Biallelic pathogenic variants in ASPA are causative.

Saposin A deficiency (OMIM 611722). An infant from a consanguineous union who demonstrated abnormal myelination resembling Krabbe disease was found to be homozygous for a pathogenic variant in the saposin A region of PSAP, which codes prosaposin, a heat-stable protein that interacts with the GALC enzyme to catalyze the hydrolysis of the natural lipid substrates [Spiegel et al 2005]. Saposin A deficiency may also be associated with reduced GALC enzyme activity and elevated psychosine concentrations. Biallelic pathogenic variants in PSAP are causative.

X-Linked

X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. The childhood cerebral form of X-ALD is in the differential diagnosis of Krabbe disease. It 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. A hemizygous ABCD1 pathogenic variant is 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. A hemizygous PLP1 pathogenic variant is causative.

Autosomal Dominant

Alexander disease is a progressive disorder of cerebral white matter that predominantly affects infants and children and has variable life expectancy. The later-onset forms present with a slower clinical course. The infantile form comprises about 42% of affected individuals, the juvenile form about 22%, and the adult form about 33%. A neonatal form is also recognized. The neonatal form leads to severe disability or death within two years. The infantile form presents in the first two years of life typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly, frontal bossing, and seizures. 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 bulbar/pseudobulbar signs, poor coordination (ataxia), gradual loss of intellectual function, seizures, normocephaly or megalencephaly, and breathing problems. A heterozygous pathogenic variant in GFAP is causative.

Autosomal dominant leukodystrophy with dysautonomia is a slowly progressive disorder of central nervous system white matter characterized by onset of autonomic dysfunction in the fourth to fifth decade, followed in months to years by pyramidal and cerebellar involvement. Autonomic dysfunction can include bladder dysfunction, constipation, postural hypotension, feeding difficulties, erectile dysfunction, and (less often) impaired sweating. Pyramidal signs are often more prominent in the lower extremities (i.e., spastic weakness, hypertonia, clonus, brisk deep tendon reflexes, and bilateral Babinski signs). Cerebellar signs typically appear at the same time as the pyramidal signs and can include gait ataxia, dysdiadochokinesia, intention tremor, dysmetria, and nystagmus. Although cognitive function is usually preserved or only mildly impaired early in the disease course, dementia and psychiatric manifestations can occur as late manifestations. Affected individuals may survive for decades after onset. Either an LMNB1 duplication or (more rarely) a large heterozygous deletion upstream of the LMNB1 promoter is causative.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of a symptomatic individual diagnosed with Krabbe disease (i.e., Scenario 1), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Neurologic and developmental examination
• Brain stem auditory evoked response to assess hearing and auditory neuropathy
• Brain MRI (DTI preferred) to understand disease progression and anticipate care needs (e.g., atrophy of brain stem is likely associated with apnea and temperature instability).
• Nerve conduction velocity to help understand the peripheral nerve involvement and development of muscle weakness
• Visual evoked potential to help understand the best approach to visual and developmental therapy
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Symptomatic individual. For a child younger than age six months who is in Stage II or III of infantile-onset Krabbe disease (see Clinical Description), treatment is supportive and focused on increasing the quality of life and avoiding complications (Table 2) [Escolar et al 2016].

Table 2.

Treatment of Manifestations in Individuals with Krabbe Disease Who Have NOT Undergone Hematopoietic Stem Cell Transplantation (HSCT)

Older individuals with mild manifestations. Treatment (based on standard practice) is tailored to the manifestations in each individual.

Prevention of Primary Manifestations

Escolar et al [2005] reported that all 11 asymptomatic newborns (diagnosed prenatally or shortly after birth because of a family history of Krabbe disease) who underwent HSCT between ages 12 and 44 days had stable engraftment of donor hematopoietic stem cells that provided a long-term source of GALC enzyme. Follow up over four months to six years has thus far revealed that while most children had normal cognitive ability and receptive language, they eventually developed speech and motor difficulties (including spasticity).

Wasserstein et al [2016] reported outcomes for five infants from four families detected by the New York State newborn screening program. Two of the five were sibs. All but the first-born in the sib pair underwent HSCT between days 24 and 41 of life. Outcomes for the four who underwent HSCT were not ideal, likely due to disease severity at the time of the transplantation. More recently, several newborns identified through other state newborn screening programs have had more positive outcomes [Orsini, personal observation].

Wright et al [2017] reported a 15-year study of outcomes for 18 individuals presumed to have a form of infantile-onset Krabbe disease who underwent HSCT in the first seven weeks of life. Following early HSCT, the long-term outcome of motor function reflected the severity of corticospinal tract involvement at birth. Peripheral nerve disease progressed with time, causing severe muscular atrophy and scoliosis. Compared to children not treated as babies, those treated early with HSCT can live relatively normal lives with variable motor disabilities until the teen years when the disease may progress. Mortality was 25%, slightly less than general mortality for non-malignant diseases. Outcomes following HSCT vary widely: some individuals live completely normal lives, whereas others are disabled (ranging from reliance on walkers for mobility to quadriplegia). The outcomes depend on how early disease is detected, the severity of disease, and progression of the disease prior to treatment.

Asymptomatic newborns with infantile-onset Krabbe disease. Consensus guidelines recommend that asymptomatic newborns identified by either prenatal/neonatal evaluation because of a positive family history of Krabbe disease (see Evaluation of Relatives at Risk) or an abnormal newborn screening result undergo additional testing to identify those with infantile-onset Krabbe disease (see Establishing the Diagnosis, Scenario 2). Those with laboratory findings consistent with infantile-onset Krabbe disease are thus candidates for HSCT before age 14 days [Kwon et al 2018].

Asymptomatic newborns with abnormal newborn screening results presumed to be at risk for later-onset Krabbe disease. No guidelines have been published for monitoring these at-risk individuals and to date there are no validated markers that can predict later disease onset [Wasserstein et al 2016].

Symptomatic individuals with later-onset Krabbe disease. The manifestations of Krabbe disease progress more slowly; thus, individuals with later-onset Krabbe disease diagnosed early enough in the disease course may benefit from HSCT. In a single report by Laule et al [2018] treatment was found to arrest demyelination and axonal loss.

Prevention of Secondary Complications

Symptomatic individuals with Krabbe disease

• Physical therapy can improve strength, mobility, flexibility, and function.
• Erythromycin may be useful as a prophylactic antibiotic and may also improve gastrointestinal motility.
• Annual influenza vaccination is recommended [Anderson et al 2014], although other routine vaccinations are typically avoided (see Agents/Circumstances to Avoid).

Surveillance

Symptomatic individuals with Krabbe disease

Monitor for development of:

• Hydrocephalus and need for VP shunt
• Scoliosis, hip subluxation, and osteopenia (via dual-energy x-ray absorptiometry [DXA] scan)
• Decreased vision and corneal ulcerations
• Swallowing difficulties and chronic microaspiration (via modified barium swallow)

Agents/Circumstances to Avoid

Symptomatic individuals with Krabbe disease

• Atypical antipsychotics and multiple medications for seizures [Author, personal experience], which can: overly sedate patients, further affecting cognition; affect respiratory drive; and accelerate the neurodegenerative cascade
• Routine childhood vaccinations, including live virus vaccines, as the resulting immune response may accelerate disease progression [Escolar et al 2016]
• Prolonged indwelling catheters for urinary retention due to the high risk of infection

Evaluation of Relatives at Risk

Couples who have had one child with molecularly confirmed infantile-onset Krabbe disease may choose prenatal molecular genetic testing in subsequent pregnancies so that newborns with biallelic GALC pathogenic variants can be promptly tested (see Establishing the Diagnosis, Scenario 2) and – if appropriate – referred for HSCT (see Prevention of Primary Manifestations).

Note that because of intrafamilial variability, sibs of an individual with later-onset Krabbe disease may develop the disease at a much earlier age.

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

Therapies Under Investigation

Studies are being conducted using well-characterized animal models to investigate other treatment options including enzyme replacement therapy, neural stem cell transplantation, substrate reduction therapy, and chemical chaperone therapy. To date experimental "combination therapies" (HSCT together with gene therapy) in the GALC-deficient murine model have demonstrated the potential to further advance treatment of GALC deficiency by synergistically increasing the life span of the treated mice [Reddy et al 2013, Rafi et al 2015, Ungari et al 2015].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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 individual are obligate heterozygotes (i.e., carriers of one GALC pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband with later-onset Krabbe disease. The offspring of an individual with later-onset Krabbe disease are obligate heterozygotes (carriers) for a GALC pathogenic variant.

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 of a GALC pathogenic variant.

Carrier Detection

At-risk family members. Carrier testing for at-risk relatives requires prior identification of the GALC pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the GALC pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Biochemical genetic testing. Prenatal testing by GALC enzyme testing is not offered in the United States.

Author Notes

The Program for Neurodevelopment in Rare Disorders Registry
4401 Penn Ave, Plaza building 4th Floor
Pittsburgh, PA 15224
Phone: 412-692-6350
Website: www.chp.edu/research/areas/neurodevelopment

Author History

Michele Caggana, ScD (2018-present)
Stephanie Coppola, BS; Thomas Jefferson University, Pennsylvania (2004-2006)
Maria L Escolar, MD (2018-present)
Joseph J Orsini, PhD (2018-present)
Melissa P Wasserstein, MD (2018-present)
David A Wenger, PhD; Thomas Jefferson University, Pennsylvania (2000-2018)

Revision History

• 11 October 2018 (bp) Comprehensive update posted live
• 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 live
• 27 September 2004 (me) Comprehensive update posted live
• 25 November 2002 (me) Comprehensive update posted live
• 19 June 2000 (me) Review posted live
• February 2000 (dw) Original submission

Literature Cited

• Anderson HM, Wilkes J, Korgenski EK, Pulsipher MA, Blaschke AJ, Hersh AL, Srivastava R, Bonkowsky JL. Preventable infections in children with leukodystrophy. Ann Clin Transl Neurol. 2014;1:370–4. [PMC free article: PMC4063358] [PubMed: 24955379]

• Barczykowski AL, Foss AH, Duffner PK, Yan L, Carter RL. Death rates in the U.S. due to Krabbe disease and related leukodystrophy and lysosomal storage diseases. Am J Med Genet A. 2012;158A:2835–42. [PubMed: 22991292]

• Bascou N, DeRenzo A, Poe MD, Escolar ML. A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life. Orphanet J Rare Dis. 2018;13:126. [PMC free article: PMC6083585] [PubMed: 30089515]

• Debs R, Froissart R, Aubourg P, Papeix C, Douillard C, Degos B, Fontaine B, Audoin B, Lacour A, Said G, Vanier MT, Sedel F. Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review. J Inherit Metab Dis. 2013;36:859–68. [PubMed: 23197103]

• De Gasperi R, Gama Sosa MA, Sartorato E, Battistini S, Raghavan S, Kolodny EH. Molecular basis of late-life globoid cell leukodystrophy. Hum Mutat. 1999;14:256–62. [PubMed: 10477434]

• Escolar ML, Kiely BT, Shawgo E, Hong X, Gelb MH, Orsini JJ, Matern D, Poe MD. Psychosine, a marker of Krabbe phenotype and treatment effect. Mol Genet Metab. 2017;121:271–8. [PMC free article: PMC5548593] [PubMed: 28579020]

• 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]

• Escolar ML, West T, Dallavecchia A, Poe MD, LaPoint K. Clinical management of Krabbe disease. J Neurosci Res. 2016;94:1118–25. [PubMed: 27638597]

• Fiumara A, Barone R, Arena A, Filocamo M, Lissens W, Pavone L, Sorge G. Krabbe leukodystrophy in a selected population with high rate of late onset forms: longer survival linked to c.121G>A (p.Gly41Ser) mutation. Clin Genet. 2011;80:452–8. [PubMed: 21070211]

• Furuya H, Kukita Y, Nagano S, Sakai Y, Yamashita Y, Fukuyama H, Inatomi Y, Saito Y, Koike R, Tsuji S, Fukumaki Y, Hayashi K, Kobayashi T. Adult onset globoid cell leukodystrophy (Krabbe disease): analysis of galactosylceramidase cDNA from four Japanese patients. Hum Genet. 1997;100:450–6. [PubMed: 9272171]

• Gupta A, Poe MD, Styner MA, Panigrahy A, Escolar ML. Regional differences in fiber tractography predict neurodevelopmental outcomes in neonates with infantile Krabbe disease. Neuroimage Clin. 2014;7:792–8. [PMC free article: PMC4375637] [PubMed: 25844309]

• Hossain MA, Otomo T, Saito S, Ohno K, Sakuraba H, Hamada Y, Ozono K, Sakai N. Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form. Gene. 2014;534:144–54. [PubMed: 24252386]

• Husain AM, Altuwaijri M, Aldosari M. Krabbe disease: neurophysiologic studies and MRI correlations. Neurology. 2004;63:617–20. [PubMed: 15326231]

• 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]

• 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]

• 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]

• 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]

• Kwon JM, Matern D, Kurtzberg J, Wrabetz L, Gelb MH, Wenger DA, Ficicioglu C, Waldman AT, Burton BK, Hopkins PV, Orsini JJ. Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease. Orphanet J Rare Dis. 2018;13:30. [PMC free article: PMC5796396] [PubMed: 29391017]

• Laule C, Vavasour IM, Shahinfard E, Mädler B, Zhang J, Li DKB, MacKay AL, Sirrs SM. Hematopoietic stem cell transplantation in late-onset Krabbe disease: no evidence of worsening demyelination and axonal loss 4 years post-allograft. J Neuroimaging. 2018;28:252–5. [PubMed: 29479774]

• 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]

• Lissens W, Arena A, Seneca S, Rafi M, Sorge G, Liebars I., Wenger D, Fiumara A. A single mutation in the GALC gene is responsible for the majority of late onset Krabbe disease patients in the Catania (Sicily, Italy) region. Hum Mutat. 2007;28:742. [PubMed: 17579360]

• 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]

• 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]

• Minter Baerg MM, Stoway SD, Hart J, Mott L, Peck DS, Nett SL, Eckerman JS, Lacey JM, Turgeon CT, Gavrilov D, Oglesbee D, Raymond K, Tortorelli S, Matern D, Mørkrid L, Rinaldo P. Precision newborn screening for lysosomal disorders. Genet Med. 2018;20:847–54. [PubMed: 29120458]

• Orsini JJ, Kay DM, Saavedra-Matiz CA, Wenger DA, Duffner PK, Erbe RW, Biski C, Martin M, Krein LM, Nichols M, Kurtzberg J, Escolar ML, Adams DJ, Arnold GL, Iglesias A, Galvin-Parton P, Kronn DF, Kwon JM, Levy PA, Pellegrino JE, Shur N, Wasserstein MP, Caggana M., New York State Krabbe Disease Consortium. Newborn screening for Krabbe disease in New York State: the first eight years' experience. Genet Med. 2016;18:239–48. [PubMed: 26795590]

• 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]

• 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]

• Rafi MA, Rao HZ, Luzi P, Wenger DA. Long-term improvements in lifespan and pathology in CNS and PNS after BMT plus one intravenous injection of AAVrh10-GALC in Twitcher mice. Mol Ther. 2015;23:1681–90. [PMC free article: PMC4817953] [PubMed: 26329589]

• Reddy AS, Patel JR, Vogler C, Klein RS, Sands MS. Central nervous system pathology progresses independently of KC and CXCR2 in globoid-cell leukodystrophy. PLoS One. 2013;8:e64647. [PMC free article: PMC3670857] [PubMed: 23755134]

• Saavedra-Matiz CA, Luzi P, Nichols M, Orsini JJ, Caggana M, Wenger DA. Expression of individual mutations and haplotypes in the galactocerebrosidase gene identified by the newborn screening program in New York State and in confirmed cases of Krabbe's disease. J Neurosci Res. 2016;94:1076–83. [PubMed: 27638593]

• 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]

• Shah SS, Ebberson J, Kestenbaum LA, Hodinka RL, Zorc JJ. Age-specific reference values for cerebrospinal fluid protein concentration in neonates and young infants. J Hosp Med. 2011;6:22–7. [PMC free article: PMC2978786] [PubMed: 20629018]

• Siddiqi ZA, Sanders DB, Massey JM. Peripheral neuropathy in Krabbe disease: electrodiagnostic findings. Neurology. 2006;67:263–7. [PubMed: 16864819]

• 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]

• Tanner AK, Chin EL, Duffner PK, Hegde M. Array CGH improves detection of mutations in the GALC gene associated with Krabbe disease. Orphanet J Rare Dis. 2012;7:38. [PMC free article: PMC3404939] [PubMed: 22704718]

• Tappino B, Biancheri R, Mort M, Regis S, Corsolini F, Rossi A, Stroppiano M, Lualdi S, Fiumara A, Bembi B, DiRocco M, Cooper DN, Filocamo M. Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease. Hum Mutat. 2010;31:E1894–914. [PMC free article: PMC3052420] [PubMed: 20886637]

• Turgeon CT, Orsini JJ, Sanders KA, Magera MJ, Langan TJ, Escolar ML, Duffner P, Oglesbee D, Gavrilov D, Tortorelli S, Rinaldo P, Raymond K, Matern D. Measurement of psychosine in dried blood spots - a possible improvement to newborn screening programs for Krabbe disease. J Inherit Metab Dis. 2015;38:923–9. [PubMed: 25762404]

• Ungari S, Montepeloso A, Morena F, Cocchiarella F, Recchia A, Martino S, Gentner B, Naldini L, Biffi A. Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy. Mol Ther Methods Clin Dev. 2015;2:15038. [PMC free article: PMC4605225] [PubMed: 26509184]

• Wasserstein MP, Andriola M, Arnold G, Aron A, Duffner P, Erbe RW, Escolar ML, Estrella L, Galvin-Parton P, Iglesias A, Kay DM, Kronn DF, Kurtzberg J, Kwon JM, Langan TJ, Levy PA, Naidich TP, Orsini JJ, Pellegrino JE, Provenzale JM, Wenger DA, Caggana M. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;2016;18:1235–43. [PubMed: 27171547]

• Wenger D, Escolar ML, Luzi P, Rafi MA. Krabbe disease (globoid cell leukodystrophy). In: Valle D, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, ed. The Online Metabolic and Molecular Bases of Inherited Diseases. New York: McGraw-Hill. 2013.

• 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.

• Wenger DA, Luzi P, Rafi MA. Krabbe disease: are certain mutations disease-causing only when specific polymorphisms are present or when inherited in trans with specific second mutations? Mol Genet Metab. 2014;111:307–8. [PubMed: 24388568]

• 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]

• 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.

• Wright MD, Poe MD, DeRenzo A, Haldal S, Escolar ML. Developmental outcomes of cord blood transplantation for Krabbe disease: A 15-year study. Neurology. 2017;89:1365–72. [PMC free article: PMC5649761] [PubMed: 28855403]

• Zhang T, Yan C, Ji K, Lin P, Chi L, Zhao X, Zhao Y. Adult-onset Krabbe disease in two generations of a Chinese family. Ann Transl Med. 2018;6:174. [PMC free article: PMC5994525] [PubMed: 29951496]

• Zuccoli G, Narayanan S, Panigrahy A, Poe MD, Escolar ML. Midbrain morphology reflects extent of brain damage in Krabbe disease. Neuroradiology. 2015;57:739–45. [PubMed: 25859833]