Krabbe disease

INTRODUCTION — Krabbe disease (globoid cell leukodystrophy, OMIM 245200) is a rare autosomal recessive lysosomal disease (table 1) caused by the deficiency of galactocerebrosidase. This topic will review the clinical aspects of Krabbe disease. Other lysosomal diseases are discussed separately. (See "Fabry disease: Neurologic manifestations" and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Metachromatic leukodystrophy" and "Mucopolysaccharidoses: Clinical features and diagnosis" and "Mucopolysaccharidoses: Complications" and "Overview of Niemann-Pick disease".)

PATHOPHYSIOLOGY — Krabbe disease (globoid cell leukodystrophy) is a rare autosomal recessive disorder caused by the deficiency of the enzyme galactocerebrosidase (GALC; also known as galactosylceramidase). Galactocerebrosidase is responsible for the liposomal hydrolysis of galactolipids formed during white matter myelination. The pathologic changes in the peripheral and central nervous system (globoid cell formation and decreased myelin) are hypothesized to result from the toxic nature of accumulated psychosine (galactosylsphingosine), which cannot be degraded because of the galactocerebrosidase deficiency [1,2]. Psychosine accumulation is thought to be toxic to oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system [3]. Many aspects of the pathophysiology of Krabbe disease are unknown.

The main neuropathologic findings in the central nervous system include demyelination with preservation of myelin within the subcortical U-fibers and the presence of gliosis and multinucleated globoid cells within the white matter. The positive staining of globoid cells for CD68, ferritin, and periodic acid Schiff (PAS) suggests a monocytic origin for globoid cells in Krabbe disease. Ultrastructural studies reveal the accumulation of tubular crystalloid inclusions in globoid cells [4,5]. Globoid cells are no longer present in end-stage Krabbe disease due to lack of active demyelination in long-term survivors [6].

GENETICS — The galactosylceramidase (GALC) gene, also known as the galactocerebrosidase gene, is located on chromosome 14q31 [7]. More than 200 GALC pathogenic variants, including numerous small deletions and insertions, have been identified in patients with all clinical types of Krabbe disease [1]. Some pathogenic variants result in the infantile type if found to be homozygous or with another severe pathogenic variant, and a few pathogenic variants can predict a less severe phenotype. However, genotype-phenotype correlations are not well established for Krabbe disease, with the exception of patients who are homozygotes for the most common deletion (large 30 kilobase deletion), or those who have other truncation, frameshift, or nonsense variants [8].

●A 30 kb deletion [1,9] accounts for approximately 40 to 45 percent of the pathogenic alleles in infantile patients in northern Europe and is present in approximately 35 percent of the pathogenic alleles in infantile Mexican patients.

●Approximately one-half of patients with the juvenile or adult phenotype are heterozygous for the large 30 kilobase gene deletion [10]. Other pathogenic variants in these patients may occur in a low-activity GALC allele [10]. As an example, a few reported patients with at least one copy of the 809G>A pathogenic variant have had a juvenile or adult phenotype, regardless of the pathogenic variant in the second allele [11]. A subsequent analysis of Krabbe genotypes found many variants of unknown significance and confirmed that predicting the timing of symptom onset, if any, is extremely difficult in most potentially at risk people [8].

●A 2019 report from a nationwide cohort of patients with Krabbe disease in Denmark, consisting of genotype and phenotype information for 29 patients, included 10 new pathogenic variants [12]. The four new missense variants (c.1142C>T, p.T381I; c.596G>T, p.R199M; c.443G>A, p.G148E; c.1858G>A, p.G620R) and the splice-site variant (c.442+1G>A) were predicted pathogenic in silico and found in patients with the early infantile phenotype, with the exception of the p.G620R in homozygous form, which presented with the late infantile phenotype. The nonsense variants (p.S405*, p.W288*), the insertion (c.293insT), and the two deletions (c.1003_1004del and c.887delA) were predicted as loss-of-function variants and were found in patients manifesting the early infantile phenotype. Two missense variants (p.T529M and p.Y567S) typically found in patients with severe phenotypes were seen in patients with both severe and milder phenotypes.

Obstacles to correlating genotypes with specific phenotypes include the rarity of many pathogenic variants and the need for very long follow-up of patients. As an example, in the experience of the New York State Krabbe Consortium, none of the infants who were homozygotes or compound heterozygotes for p.T96A or p.Y303C, two variants previously associated with later-onset symptoms, have developed any Krabbe symptoms [8]. There are no available data that can predict the risk that these individuals have for developing symptoms beyond their first decade of life.

EPIDEMIOLOGY — Infantile Krabbe disease is rare. The incidence of Krabbe disease was originally estimated to be 1:100,000 [1,7]. Later, evidence from the New York State Krabbe Consortium, based upon screening of around two million infants, indicated an incidence of 1:400,000 [13]. An analysis of mortality records suggested the incidence in the United States was 1:250,000 [14]. However, as many as 1:6000 individuals may have decreased enzyme activity and genotypes of unclear significance [2,8]. The incidence for Krabbe disease is presumably that of the invariably fatal early infantile variant, which is most likely to be listed as a cause of death. The incidence of late-onset cases, which may have prolonged survival with more indolent symptoms, is unknown since milder phenotypes are likely underdiagnosed.

A high incidence (approximately 1:100 to 1:150) of Krabbe disease has been reported in separate inbred regions of Israel, including a Druze community in northern Israel and two Muslim Arab villages near Jerusalem [15].

CLINICAL MANIFESTATIONS AND COURSE — Most patients with Krabbe disease present with symptoms within the first twelve months of life; approximately 10 percent present later in life, including adulthood. A peripheral motor-sensory neuropathy occurs in most patients and may be the initial presenting symptom in later-onset patients. The early-onset forms are dominated by symptoms related to central nervous system dysfunction.

Infantile onset — Symptoms usually develop from ages 2 to 12 months with infantile-onset Krabbe disease [16,17]. Manifestations include irritability, feeding difficulty, reflux, developmental delay, limb spasticity, axial hypotonia, optic atrophy, and decreased growth [16,18-20]. Deep tendon reflexes may be increased early when spasticity predominates but diminish and are lost as neuropathy worsens. Irritability is the most common initial symptom. The median age of onset is four months, though testing such as magnetic resonance imaging (MRI), nerve conduction velocities, auditory brainstem responses (ABR), and visual evoked potentials (VEP) may show abnormalities prior to symptom onset [20]. As patients grow, dysautonomia and orthopedic complications worsen, tonic extensor spasms occur upon stimulation with light, sound, or touch, and seizures may occur. The irritability, unprovoked crying, and tonic extensor spasms that may be triggered by simple interactions such as touch make this a particularly distressing condition for parents and caregivers to manage.

In a study of 88 children with symptom onset prior to six months of age, 77 percent did not have head control or the ability to sit independently after seven months of age [20]. Eighty percent of these patients developed quadriparesis by 12 months of age. Developmental testing showed that no child achieved an age equivalence higher than six months at any point. Receptive language skills were a relative strength, while gross motor skills were the most significant disability. These children regressed rapidly to a decerebrate condition, with most dying before reaching two years of age.

Infantile Krabbe disease can be broken into four stages of disease progression characterized by the presence of various clinical indicators [21]:

●During stage 1, the child is asymptomatic to minimally symptomatic, potentially exhibiting intermittent thumb clasp, slow feeding, or reflux. Children begin to cry frequently without apparent cause.

●In stage 2, neurologic symptoms become more apparent as feeding difficulties worsen and muscle tone changes.

●Stage 3 is characterized by moderate to severe neurologic progression with spastic extremities, clinical seizures, exaggerated startle, and visual tracking difficulties.

●Stage 4 is the final and most advanced state of the disease, indicated by severe weakness and sensory impairment.

Late infantile onset — In late infantile-onset Krabbe disease, patients present between 13 months and 36 months. Initial symptoms include abnormal gait, irritability, slurred speech, or vision difficulties. Clinical indicators include appendicular hypertonia, axial hypotonia, abnormal protective reflexes, abnormal deep tendon reflexes, constipation, and abnormal pupillary response. Visual difficulty, apneic episodes, seizures, and temperature instability are more likely as the disease progresses. The median age of death is six years [22].

Patients typically reach motor milestones such as sitting, crawling, and walking within the normal age range. As measured by developmental testing, receptive and expressive language skills are a relative strength while gross and fine motor skills are a relative weakness.

Juvenile onset — Patients with juvenile-onset Krabbe disease typically present with attention deficit hyperactivity disorder (ADHD), tremors, abnormal gait, or vision loss. Juvenile patients regress at an unpredictable rate, but all become severely incapacitated and die within ten years of diagnosis.

Adult onset — Adult-onset Krabbe disease may be manifested initially by mood and behavioral problems, loss of manual dexterity, burning paresthesias in the extremities, weakness, or peripheral motor sensory neuropathy with loss of distal sensation and muscle atrophy with scoliosis [9,23]. Some adolescents and adults have symptoms confined to weakness without intellectual deterioration, whereas others become bedridden and continue to deteriorate mentally and physically [24].

EVALUATION AND DIAGNOSIS

Approach to the diagnosis — The diagnosis of Krabbe disease should be considered in newborns or older children with suggestive symptoms, and in newborns with positive screening tests.

Symptomatic patients — Symptomatic patients with some or all of the suggestive clinical features of Krabbe disease should be tested for GALC enzyme activity (often available as part of a white cell enzyme panel that will also cover many of the conditions in the differential diagnosis) and, if deficient, undergo molecular genetic testing for pathogenic variants in GALC. (See 'Galactocerebrosidase (GALC) activity' below and 'Molecular genetic testing' below.)

For infants younger than 12 months of age, features suggestive of Krabbe disease include [1]:

●Excessive crying or extreme irritability

●Feeding difficulties

●Gastroesophageal reflux disease

●Leg spasticity

●Fisting

●Axial hypotonia

●Loss of acquired milestones (eg, smiling, cooing, and head control)

●Staring episodes

●Peripheral neuropathy

For children 12 months of age and older, features suggestive of Krabbe disease include [1]:

●Slow development or loss of milestones (eg, sitting without support, walking)

●Slurred speech

●Limb spasticity with truncal hypotonia

●Vision loss, esotropia

●Seizures

●Peripheral neuropathy

For adults, features of Krabbe disease include:

●Changes in mood and behavior

●Dementia

●Burning paresthesia and peripheral neuropathy

●Limb spasticity and gait abnormality

Additional supportive features may include abnormalities on brain and spine on MRI, elevated CSF protein concentration, and abnormal electrodiagnostic studies. (See 'Neuroimaging' below and 'Electrodiagnostic studies' below and 'Cerebrospinal fluid' below.)

Newborn screening — One significant barrier to the rapid and accurate diagnosis of Krabbe disease is that the neurodiagnostic tests (eg, MRI, lumbar puncture, and electrodiagnostic examinations) are difficult to obtain in newborns/infants and may not be rapidly available. The goal of newborn screening is to identify cases as quickly as possible and thereby allow for early treatment with hematopoietic stem cell transplantation (HSCT), which is associated with improved outcomes when performed before the onset of symptoms or in minimally symptomatic patients (see 'Hematopoietic stem cell transplantation' below). Newborn screening for Krabbe disease is being implemented in a number of states, while others have not yet implemented screening procedures. The methods, diagnostic accuracy, and ethical issues related to newborn screening for Krabbe disease are reviewed in the following sections.

●First- and second-tier testing – Most of the states mandating newborn screening for Krabbe disease use tandem mass spectrometry and one state uses fluorometry to directly assay galactocerebrosidase (GALC) activity in dried blood spots for the detection of Krabbe disease [25,26]. However, irrespective of the assay method used, the specificity of low GALC activity is insufficient to confirm the diagnosis of Krabbe disease [1]. Low GALC activity can be result from several causes, including the presence of pseudodeficiency alleles (ie, benign GALC variants), heterozygosity for one GALC pathogenic variant (unaffected carrier), and GALC variants that cause later-onset Krabbe disease.

As GALC activity does not have enough specificity to indicate whether a child will develop Krabbe, it is important to introduce a second tier of screening to identify true cases of Krabbe disease [25]. Different states screening for Krabbe disease have different approaches to this second tier of screening.

•One strategy is to subsequently measure the level of psychosine in newborns with low GALC activity, given the evidence that markedly elevated psychosine in newborns is indicative of infantile Krabbe disease. Newborns with highly elevated psychosine should be evaluated immediately for treatment, while newborns with mildly elevated psychosine require close follow-up. (See 'Psychosine concentration' below.)

•Another strategy is subsequent sequencing of GALC. However, not all screening laboratories have the capability to detect all pathogenic variants of GALC [25]. This, in combination with the frequency of variants with unknown significance, suggests that GALC genotyping as the only second-tier test may not be as reliable as psychosine measurements for identifying cases of infantile Krabbe disease. (See 'Molecular genetic testing' below.)

Ideally, results of second tier testing should be available by the end of the first week of life to allow for subsequent referral for HSCT [27]. (See 'Hematopoietic stem cell transplantation' below.)

●Diagnostic accuracy – In an analysis of nearly five million newborns who were screened across six states from 2006 through October 2019, 1050 infants were picked up as a positive screen [28]. Of the positive screens, 24 infants were confirmed to have Krabbe disease and another 34 infants were identified as high risk in New York. Across states, the false positive rate ranged from zero percent (Tennessee, only one positive screen) to 0.052 percent (Ohio, 214 positive screens). The positive predictive rate across states ranged from 1.3 percent (New York, 545 positive screens) to 100 percent (Tennessee, only one positive screen). The positive predictive rate in New York was 7.5 percent when high-risk candidates were included.

Newborn screening for Krabbe disease was initiated in Illinois in December 2017. Out of 497,147 newborns screened, 288 specimens had low GALC activity and were sent for second-tier testing consisting of psychosine levels, the presence of a 30 kb deletion, and GALC sequencing [29]. Two infants had elevated psychosine levels (10 and 35 nM) and were referred immediately for evaluation and treatment for infantile Krabbe disease; six infants had intermediate psychosine levels (2 to 5 nM) and are under observation as suspected candidates for late-onset Krabbe disease; and 178 infants had pseudodeficiency alleles associated with psychosine levels <2.0 nM.

●Ethical issues – Newborn screening for Krabbe disease has been controversial [30,31]. Since studies suggest that early treatment improves outcomes (see 'Management' below), proponents emphasize the need to identify cases as quickly as possible to allow for early treatment. Any delays in initiating HSCT will lead to diminished outcomes. With the discovery that psychosine is a reliable biomarker for the infantile population [32], the biggest challenge is expeditious referral to experienced transplant centers and assuring that the transplant is done in a timely manner (within the first month of life). As new therapies are developed, it will become imperative to diagnose patients prior to the onset of symptoms.

However, the utility of screening is limited because neither GALC enzyme activity nor knowledge of the genetic variant can always predict phenotype. In addition, prediction of disease onset after the first year is not as well understood. Thus, many children identified as at risk for later-onset Krabbe disease may remain asymptomatic, and referring them for HSCT, itself a high-risk procedure, could lead to harm [30]. Furthermore, while HSCT improves or stabilizes the brain disease, some children may still deteriorate from peripheral nerve disease.

The Krabbe Newborn Screening-Family Perspective Survey found that 165 of 170 (97 percent) survey respondents from families affected by Krabbe disease would support the implementation of Krabbe disease newborn screening in all states [33]. Semistructured interviews were conducted with parents from 11 families who received a false-positive Krabbe disease newborn screening result [34]. They expressed that a lack of understanding of the newborn process and limited information provided by the primary care provider at initial contact contributed to the emotional distress and negative emotions related to the false-positive results. More detailed information provided by a genetic counselor provided some reassurance to the family while awaiting the results of diagnostic studies, suggesting an early role for genetic counseling for newborn screening positive results. The 2020 statement by the Commonwealth of Virginia Newborn Screening Advisory Committee, outlining the reasons for their decision to not include Krabbe disease in the Virginia newborn screening program, raised interesting equity and equality issues [35]. Logistic barriers to rapid diagnosis, lack of availability of stem cell transplantation in Virginia, and variable insurance coverage for out-of-state treatment (with long prior authorization times in particular for Medicaid patients) lead to delayed access to treatment and place lower-income families at a disadvantage [36].

Prenatal testing — Preimplantation genetic testing or prenatal testing may be an option for pregnancies at high genetic risk where both GALC pathogenic variants are known [1,37].

Diagnostic tests

Galactocerebrosidase (GALC) activity — The diagnosis of Krabbe disease can be made by measurement of galactocerebrosidase (GALC) activity in leukocytes isolated from whole blood or cultured skin fibroblasts [38]. Typical values in patients with Krabbe disease are <5 percent of the normal range. However, the residual GALC activity is not an indicator of clinical type or prognosis. Screening of newborn infants with assays of GALC activity in dried blood spots for the detection of Krabbe disease is performed in some states. (See 'Newborn screening' above.)

Molecular genetic testing — Molecular genetic testing is available to confirm the diagnosis of Krabbe disease [1] and is also useful for genetic counseling if parental genotypes are available, despite limited information about genotype-phenotype relationships. Testing involves sequence analysis of GALC and targeted analysis for the 30 kb deletion, which accounts for 35 to 45 percent of pathogenic variants in individuals with Krabbe disease. Gene-targeted deletion/duplication analysis is useful to detect duplications and rare deletions involving single exons and multiple exons, particularly when there is high suspicion for Krabbe disease and sequence analysis has detected only one GALC pathogenic variant. (See 'Genetics' above.)

Psychosine concentration — Psychosine (galactosylsphingosine) has emerged as a rapidly available, predictive biomarker [2]. GALC enzyme activity and blood psychosine can provide accurate and early diagnosis, as substantially elevated psychosine measured during the newborn period is predictable of the infantile form [32]. However, a mildly elevated psychosine level is indeterminate and does not predict the age of onset.

One 2017 study assessed levels of psychosine in affected Krabbe patients as well as infants identified through newborn screening [32]. Psychosine levels obtained from newborns were available for eight affected Krabbe patients (six early infantile cases, one late infantile case, and one juvenile case). Psychosine levels were elevated at birth in all eight cases, and patients who developed infantile Krabbe disease had the highest levels at birth. For 42 patients with an elevated psychosine level of >3 nmol/L measured within the first year, infantile or late infantile Krabbe disease developed in 100 percent. Mildly elevated psychosine levels (0.71 to 3.0 nmol/L) were found in one carrier, one late-infantile case, one juvenile case, and seven cases of newborn screening-positive infants who had not developed Krabbe disease as of publication. The same study also showed that in untreated patients with infantile Krabbe disease, psychosine levels decreased after the first year of life as the disease progressed. Treatment with HSCT markedly dropped psychosine levels; however, in most cases, psychosine levels remained above normal.

A 2020 report described a more sensitive assay for psychosine measurement in newborn screening samples that differentiates infantile from late-onset Krabbe disease and differentiates pathogenic variant and pseudodeficiency carriers [39]. This measurement was therefore recommended as second-tier testing for positive Krabbe disease newborn screening, and a diagnostic algorithm was provided. A psychosine assay in red blood cells was also described, which can be used as part of the diagnostic process.

Neuroimaging — In children with infantile-onset Krabbe disease, the most frequent MRI abnormalities involve the deep cerebral white matter, dentate nucleus, and cerebellar white matter (image 1) [16,20,40-42]. Midbrain atrophy on MRI has been correlated with diminished cognition and gross motor function [43]. Enhancement of multiple cranial nerves and spinal nerve roots has also been reported, as well as thickening of the optic nerves [42,44-47]. MRI scans of the brain may appear normal in up to 25 percent of early-symptomatic infants, based upon the results of the World-Wide Krabbe Registry [16]. Hydrocephalus and spontaneous third ventriculostomy (STV), likely related to chronic increased intracranial pressure, have been described in patients with infantile Krabbe disease and may be associated with worse motor and developmental outcomes [48]. In a study of 75 infantile Krabbe patients, STV was identified in 12. No patients developed STV after undergoing HSCT, though some patients who had developed STV subsequently underwent HSCT.

In those with juvenile- and adult-onset Krabbe disease, brain MRI may show atrophy and increased T2 signal involving the parieto-occipital regions (image 2) and/or corticospinal tracts (image 3), while the dentate and cerebellum are generally spared [40,42,49].

Head computed tomography (CT) scan most often shows increased signal in the basal ganglia or thalamus.

A study specifically focused on diffusion tensor imaging (DTI) found that, compared with controls, newborns with infantile Krabbe disease had significantly reduced fractional anisotropy (FA) across six tracts measured [27]. Decreases in FA of the corticospinal tracts were predictive of cognitive and motor outcomes following HSCT, while decreases in FA of the splenium and uncinate fasciculus correlated with cognitive outcomes only following HSCT. These findings suggest that DTI analysis could be used as a potential biomarker to predict treatment outcomes for patients with infantile Krabbe disease.

Magnetic resonance spectroscopy from deep white matter at TE 135 ms shows reduced N-acetylaspartate, a small lipid peak, and relative elevation of choline and myoinositol [42], a pattern that is nonspecific but has been associated with axonal loss and demyelination.

Electrodiagnostic studies — Neurophysiologic studies are abnormal in a majority of children with infantile-onset Krabbe disease. Nerve conduction studies (NCS) show marked slowing of both motor and sensory nerve conduction velocities in most patients with infantile onset, even in presymptomatic disease, and in 20 percent of those with late-onset disease [50,51]. Electroencephalography is often normal in the early stages of disease, but background activity gradually becomes slow and disorganized, and epileptiform activity develops in a minority [1,51].

Across two natural history studies of 123 Krabbe patients with onset of symptoms ranging from 0 to 36 months, 78 percent of patients evaluated by three months of age had abnormal motor nerve conduction studies, whereas 95 percent of patients between four and six months of age had abnormal motor nerve conduction [20,22]. For patients with onset at less than six months of age, motor nerve conductions studies were abnormal in 100 percent of cases by six months, while sensory nerve conduction studies were abnormal in 100 percent of cases by seven months.

Symptomatic children frequently had abnormalities on auditory brainstem responses (ABR) and visual evoked potentials as well as electroencephalography [20,22]. For patients with onset of symptoms prior to six months of age, 60 percent of patients had abnormal visual evoked potentials prior to three months of age. One hundred percent of patients with symptom onset prior to six months had abnormal visual evoked potentials by 18 months of age. Seventy percent of patients with symptom onset prior to six months had abnormal ABR results by three months of age. By 10 months of age, 100 percent of ABR results were abnormal.

Cerebrospinal fluid — Elevated cerebrospinal fluid (CSF) protein concentration is a characteristic but not universal feature of Krabbe disease, and is thought to occur because of the breakdown of myelin associated with the disorder. In a registry of 25 symptomatic children with early infantile Krabbe disease who had lumbar puncture, elevated CSF protein levels were present in 23 (92 percent) [16]. In one review, CSF protein >61.5 mg/dL was associated with shorter survival [17].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of infantile Krabbe disease is broad and includes a number of neurodegenerative conditions that can present with neurodevelopmental delay and white matter abnormalities on neuroimaging studies (algorithm 1) [1,52,53]:

●Atypical Krabbe disease due to saposin A and PSAP deficiency

●Metachromatic leukodystrophy (see "Metachromatic leukodystrophy")

●GM1 gangliosidoses

●GM2 gangliosidosis

●X-linked adrenoleukodystrophy (see "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy")

●Zellweger spectrum disorders (see "Peroxisomal disorders", section on 'Zellweger spectrum disorders')

●Alexander disease (see "Alexander disease")

●Mitochondrial disorders (see "Mitochondrial myopathies: Clinical features and diagnosis")

●Neuronal ceroid lipofuscinoses (see "Neuronal ceroid lipofuscinosis")

Distinguishing Krabbe disease from these disorders can be difficult, though a definitive diagnosis can usually be made based upon the results of targeted metabolic and/or molecular genetic testing [1,52]. Extreme irritability often precedes the motor signs of infantile Krabbe disease, with increased muscle tone noted next. These symptoms often advance rapidly in the first two to four months of life, helping to distinguish Krabbe disease from these other disorders.

MANAGEMENT — Therapeutic options currently are limited to those who are asymptomatic or minimally symptomatic patients with the infantile form of Krabbe disease. The available evidence, discussed in greater detail below, suggests that hematopoietic stem cell transplantation (HSCT) is beneficial for the infantile form of Krabbe if performed before the onset of symptoms, and is possibly beneficial for patients with late infantile- and juvenile-onset Krabbe disease.

Supportive care (table 2) is currently the only viable option to manage irritability, spasticity, and other debilitating manifestations of Krabbe disease [1,54]. The 2017 consensus statement on the preventive and symptomatic care of patients with leukodystrophies also provides valuable information for the ongoing management of patients with Krabbe disease and other leukodystrophies [55]. (See 'Supportive care' below.)

Hematopoietic stem cell transplantation — Patients should have a thorough evaluation to understand what stage of disease progression they are in. Patients in stage 1 (asymptomatic) and stage 2 (includes minimal symptoms and neurologic symptoms apparent to clinicians) should be quickly referred for transplant.

●Indications and eligibility – Allogeneic HSCT may be used to treat the infantile form of Krabbe disease if transplantation is performed before the onset of symptoms or in minimally symptomatic patients [56]. Early HSCT is associated with longer survival and improved functional abilities. HSCT has become a safer procedure with the development of techniques such as reduced intensity regimens [57]. However, HSCT is not a cure. The procedure requires myelosuppressive therapy and is associated with morbidity and mortality. Therefore, we inform potential candidates and their families of the option of HSCT, being careful to point out its potential benefits and risks.

●Efficacy and adverse effects for early infantile Krabbe disease – Preliminary studies have reported beneficial clinical effects using HSCT to treat the infantile form of Krabbe [56,58-61]. These include a reduction in symptom burden and cognitive decline, but only if transplantation is performed before the onset of symptoms or in minimally symptomatic patients. This report examined the effect of umbilical cord blood transplantation from unrelated donors in 11 asymptomatic (ages 12 to 44 days) and 14 symptomatic newborns (ages 142 to 352 days) with infantile Krabbe disease [56]. All patients received myeloablative chemotherapy prior to transplantation. At a median follow-up of three years, all 11 children who had transplantation as asymptomatic newborns remained alive and demonstrated normal progression of central myelination by MRI [56]. In 10 of these children who had neurocognitive evaluations after transplantation, all had age-appropriate language, and nine had age-appropriate cognitive function. Of some concern, four had mild to moderate delay in gross motor function. These findings contrasted with the disease progression seen in an untreated control group of registry patients, most of whom experienced overwhelming spasticity, blindness, and death by one or two years of age. At a median follow-up of 3.4 years, only 6 of 14 infants who were symptomatic at the time of transplantation had survived; the survival rate for this group was not considered different from survival among the untreated controls [56]. None of the surviving patients from the symptomatic group demonstrated appreciable improvement in any domain of neurocognitive function.

Long-term benefit of HSCT was shown in a later prospective longitudinal study of 18 patients diagnosed with the infantile form of Krabbe disease who were treated within the first seven weeks of life [59]. This study included all of the asymptomatic patients reported above in the earlier study [56]. The median survival was 10.7 years [59]. Three patients died in the periprocedural period. Of 15 patients with at least two years of post-transplantation follow-up, only two patients showed a plateauing of cognitive development. One patient developed normally, while the remaining 10 continued to gain skills, though at a rate slightly below normal. Receptive language was the best-preserved area of development, with 7 of the 15 patients developing skills at a normal rate. The remaining six patients all continued to gain skills. However, despite success with preserving cognitive function and learning, most patients developed worsening motor complications. Three patients were able to walk independently, and seven patients were able to walk with assistive devices. All 13 patients with extensive motor follow-up developed mild to severe spasticity, muscle atrophy, and contractures. Demyelination and degree of atrophy of brain MRI stabilized in most patients; however, nerve conduction tests ultimately worsened, likely reflecting progression of peripheral neuropathy, after briefly improving in most cases following transplant. Overall, asymptomatic patients who underwent transplantation had significantly improved function especially when given the appropriate supports and therapies for their continuing motor disabilities.

A retrospective study reported long-term follow-up (30 to 58 months) of six children with infantile onset-Krabbe disease detected by newborn screening who underwent HSCT between 24 and 40 days of life described different degrees of developmental delay [62]. Lower-extremity weakness and spasticity of variable severity was present in all children, limiting ambulation and mobility. In general, fine motor skills were less impaired than gross motor skills. Nerve conduction studies revealed mixed demyelinating and axonal neuropathies (sensory and motor), present from birth in the infants tested and worsening over time. The contribution of progressive neuropathy to gross and fine motor disability has not been determined.

●Efficacy and adverse effects for later-onset Krabbe disease – There is limited published evidence that patients with later-onset forms of Krabbe disease may benefit from HSCT even after the onset of symptoms [58,63]. A prospective study reported 19 patients with late-infantile Krabbe disease (defined by the authors as onset between 6 and 36 months) receiving HSCT. Patients presenting before 12 months of age with symptomatic onset who received HSCT had poor neurodevelopmental outcomes that were similar to those of untreated early-infantile patients; patients with symptomatic onset at >12 months of age who received HSCT were developmentally delayed but continued to gain skills, with the exception of gross and fine motor skills, which experienced a plateau or regression; patients who were asymptomatic at the time of HSCT had normal to near-normal development, with the exception of gross motor skills [64].

Gene therapy — Studies in Twitcher mice and Krabbe dogs have demonstrated the safety and efficacy of a single injection of an adeno-associated virus (AAV) vector (AAVhu68) expressing GALC into the cisterna magna [65]. This study has led to a human study that is ongoing.

Monitoring — Symptomatic patients diagnosed with Krabbe disease should be evaluated at baseline with a neurologic and developmental examination. Additional evaluations are useful to determine the severity of disease and care needs of the patient and family, if not already performed as part of the diagnostic evaluation. These include [1]:

●Brain stem auditory evoked response to assess hearing and auditory neuropathy

●Brain MRI with diffusion tensor imaging (DTI) to assess disease progression and anticipate possible symptomatic care (eg, brainstem atrophy may be associated with apnea and temperature instability)

●Nerve conduction velocity to assess peripheral nerve involvement and development of muscle weakness

●Visual evoked potentials to inform the approach to visual and developmental therapy

●Genetic counseling

Supportive care — Patients with Krabbe disease may benefit from multispecialty care (eg, audiology, neurology, nutrition, ophthalmology, physical therapy, speech pathology) to monitor and manage the potential complications, as outlined in the table (table 2). These include [1,54]:

●Dental: delayed dentition

●Gastrointestinal: vomiting, reflux, dysphagia, constipation

●Musculoskeletal: weakness, spasticity, contractures, weakness

●Neurologic: neuropathic pain, seizures, hydrocephalus

●Ocular: Corneal ulceration

●Ophthalmologic: Impaired vision, delayed pupillary response, impaired upgaze, palpebral weakness

●Orthopedic: scoliosis, hip subluxation, osteopenia

●Respiratory: excessive airway secretions, chronic aspiration, infections

●Urologic: infections, bladder distention

Patients with Krabbe disease should receive an annual influenza vaccination, but we advise against routine childhood live vaccines since they may worsen disease progression [1,54].

For patients treated with HSCT, post-transplantation care includes prophylaxis and treatment of graft-versus-host disease. (See "Prevention of graft-versus-host disease" and "Treatment of acute graft-versus-host disease" and "Prevention of graft-versus-host disease", section on 'Introduction'.)

Palliative care — Patients with life-threatening illnesses, such as Krabbe disease, may benefit from palliative care. Palliative care is interdisciplinary collaboration directed at improving the quality of life, preventing and relieving suffering, and addressing the physical, psychosocial, and spiritual needs of the child and family. (See "Pediatric palliative care".)

Children with infantile Krabbe disease who are not treated with HSCT or fail HSCT will eventually regress to a decerebrate condition [54]. The focus of care should shift to minimizing suffering for the patient and the family. Elements of end-of-life planning may include home hospice care, pain management, withdrawal of medications for spasticity (as weakness and hypotonia progress), management of end-of-life symptoms, do-not-resuscitate orders, and provision of bereavement support and counseling to the family. (See "Pediatric palliative care", section on 'End-of-life care'.)

Evaluation of family members at risk — Krabbe disease is an autosomal recessive disorder. For siblings of an affected individual, the chance of being affected is 25 percent, the chance of being an asymptomatic carrier is 50 percent, and the chance of being an unaffected noncarrier is 25 percent [1]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Autosomal recessive' and "Genetic counseling: Family history interpretation and risk assessment".)

All siblings of confirmed Krabbe disease cases should be tested for GALC activity, preferably during the prenatal period or in the immediate newborn period. They should also have molecular genetic testing, particularly if the genetic profile of the proband is known. Siblings of patients with the infantile form are likely to present with similar onset. However, the onset is more variable among later-onset phenotypes. Therefore, older asymptomatic siblings of late-onset patients who are galactocerebrosidase deficient should be observed closely, but these patients may not become symptomatic until much later.

Information and support — A number of organizations provide information and support for patients and families affected by Krabbe disease:

●KrabbeConnect

●Partners for Krabbe Research

●The Legacy of Angels Foundation / Krabbe disease

●United Leukodystrophy Foundation

●Hunter's Hope

SUMMARY AND RECOMMENDATIONS

●Pathophysiology and genetics – Krabbe disease (globoid cell leukodystrophy) is a rare autosomal recessive disorder caused by the deficiency of galactocerebrosidase (GALC; also known as galactosylceramidase). The pathologic changes in the peripheral and central nervous system (globoid cell formation and decreased myelin) are hypothesized to result from the toxic nature of accumulated psychosine (galactosylsphingosine), which cannot be degraded because of the GALC deficiency. (See 'Pathophysiology' above and 'Genetics' above.)

●Clinical manifestations – Most patients with Krabbe disease present with symptoms within the first twelve months of life; approximately 10 percent present later in life, including adulthood. A peripheral motor sensory neuropathy occurs in most patients, but the early-onset forms present with symptoms of brain disease that eventually progresses to peripheral nerve involvement. Infantile-onset disease is associated with irritability, developmental delay or regression, limb spasticity, axial hypotonia, and optic atrophy. Deep tendon reflexes may be increased early when spasticity predominates but diminish and are lost as neuropathy worsens. Seizures and tonic extensor spasms eventually appear. Typically, there is rapid regression to a hypotonic condition and death in most cases before two years of age. (See 'Clinical manifestations and course' above.)

●Evaluation and diagnosis – The diagnosis of Krabbe disease in symptomatic patients is made by measurement of GALC activity in leukocytes isolated from whole blood or cultured skin fibroblasts. Typical values in patients with Krabbe disease are <5 percent of normal. The diagnosis should be confirmed by molecular genetic testing. Although controversial, newborn screening for Krabbe disease has been implemented in a number of states. Psychosine levels are the only biomarker that can predict an infantile phenotype. (See 'Approach to the diagnosis' above and 'Diagnostic tests' above.)

●Management – The only available therapy for patients with Krabbe disease is hematopoietic stem cell transplantation (HSCT), which is beneficial for the infantile form if performed when infants are asymptomatic or minimally symptomatic. In lieu of HSCT, management involves monitoring, supportive care, and palliative care for those with progressive and more severe disease. (See 'Management' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Maria Escolar, MD, MS, Robert P Cruse, DO, and Thomas J Langan, MD, who contributed to earlier versions of this topic review.