Alternative titles; symbols
SNOMEDCT: 189979005, 192782005; ICD10CM: E75.23; ORPHA: 206436, 206443, 206448, 487; DO: 10587;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q31.3 | Krabbe disease | 245200 | Autosomal recessive | 3 | GALC | 606890 |
A number sign (#) is used with this entry because Krabbe disease (KRB) is caused by homozygous or compound heterozygous mutation in the galactosylceramidase gene (GALC; 606890) on chromosome 14q31.
Krabbe disease (KRB) is an autosomal recessive lysosomal disorder affecting the white matter of the central and peripheral nervous systems. Most patients present within the first 6 months of life with 'infantile' or 'classic' disease manifest as extreme irritability, spasticity, and developmental delay (Wenger et al., 2000). There is severe motor and mental deterioration, leading to decerebration and death by age 2 years. Approximately 10 to 15% of patients have a later onset, commonly differentiated as late-infantile (6 months to 3 years), juvenile (3 to 8 years), and even adult-onset forms. The later-onset forms have less disease severity and slower progression. These later-onset patients can be clinically normal until weakness, vision loss and intellectual regression become evident; those with adult onset may have spastic paraparesis as the only symptom. Disease severity is variable, even within families (summary by Tappino et al., 2010).
Infantile Form
Hofman et al. (1987) described cherry red spots in an infant with Krabbe disease who died at age 18 months. Spots were subtle but evident at age 13 months and became prominent at 17 months. Zlotogora and Cohen (1987) pointed to protruding ears as a dysmorphic feature of Krabbe disease. Their report concerned a total of 11 affected children seen in Israel, all of Arab origin and 4 from related Druze families. Lyon et al. (1991) reviewed 50 cases.
Tappino et al. (2010) reported 30 unrelated patients with Krabbe disease ascertained over a 30-year period. Twenty-one patients had the infantile form, with onset between 1 and 5 months of age. Four patients had onset between 8 and 11 months, 4 had onset around 4 years of age, and 1 had adult onset at age 26 years. Those with the infantile and late-infantile forms presented with psychomotor regression, muscular hypertonia and spasticity, truncal hypotonia, and irritability; 2 had seizures, and 2 had nystagmus. Brain imaging, when performed, showed white matter changes and/or hypomyelination, and 6 patients had calcifications. Peripheral nerve conduction velocities were slowed. Residual GALC enzyme activity ranged from 0 to 22% of normal.
In a retrospective analysis of 26 Italian or Tunisian patients with Krabbe disease, Fiumara et al. (2011) found that 9 (34%) had the classic early infantile form with onset before age 6 months. All but 1 were born of consanguineous parents; family history of another child adopted from Brazil was not available. All presented between 2 and 5 months of age with unprovoked inconsolable crying, opisthotonus, and hemiplegia. There was rapid progressive motor deterioration with generalized hypertonia and hyperreflexia. Four patients had horizontal nystagmus, 7 had optic nerve atrophy, and 4 had seizures. Brain MRI showed symmetric cerebral and cerebellar demyelination, as well as changes in the basal nuclei and corpus callosum. Generalized brain atrophy with dilatation of the ventricles and subarachnoid spaces was evident later over the course of the disease. GALC activity levels ranged between 0.39 and 5.8% of normal. Death occurred between 6 and 29 months of age.
Late-Onset Form
Suzuki (1972) described 2 patients with morphologically and enzymatically proven Krabbe disease who survived into childhood and into the teens. Crome et al. (1973) also described a 'late-onset' variety.
From complementation studies by somatic cell hybridization, Loonen et al. (1985) concluded that the early infantile and later onset forms of GLD are allelic. They proposed that there are 2 later onset forms: a late infantile or early childhood form, and a late childhood or juvenile form.
Kolodner (1989) described several cases with a later onset, the oldest case in his experience being that of an 84-year-old woman. Phelps et al. (1991) reported 4 cases with later onset--at ages 4 years and 9 months, 8 years, 5 years, and 5 years. Two of the patients were sibs; the 2 others were each born of a consanguineous mating. One of the patients, although showing minor abnormalities at age 5, was not evaluated medically until the age of 16 and was still working as a baker at the age of 19 years.
Verdru et al. (1991) described globoid cell leukodystrophy in a 19-year-old daughter of consanguineous parents. Clinical examination showed postural tremor of the right upper limb, pyramidal paresis of the left lower limb, and extensive plantar responses bilaterally. There were no signs of peripheral nerve involvement or intellectual impairment when she was first seen. By 9 months later, however, the signs had progressed and there was clinical evidence of peripheral nerve involvement. The patient had almost complete deficiency of galactosylceramide beta-galactosidase. A brother had had normal psychomotor development until the age of 14 months, when he began to have a toppling gait. He became progressively spastic and blind, developed seizures, and died at the age of 4 years.
Kolodny et al. (1991) reviewed the clinical and biochemical features of 15 cases of late-onset Krabbe disease. Turazzini et al. (1997) described 2 brothers with adult-onset Krabbe disease. A 39-year-old man presented with a 2-year history of persisting unsteadiness of gait with weakness of the legs. A younger brother, 29 years old, was asymptomatic but showed tetra-hyperreflexia with bilateral ankle clonus. Both brothers showed MRI changes of demyelination in the white matter of the brain, while nerve conduction was completely normal. Both patients showed deficiency of galactosylceramide beta-galactosidase comparable to that found in the infantile form.
Tappino et al. (2010) reported that 3 of 4 patients with juvenile onset presented with gait disturbances and frequent falls due to spasticity and ataxia, and the fourth presented with decreased visual acuity. Brain imaging showed white matter changes, and 2 had decreased peripheral nerve conduction velocities. Residual GALC enzyme activity ranged from 0 to 13% of normal. One man presented at age 26 years with gait disturbances, frequent falls, and spasticity; he had 5% residual GALC enzyme activity.
In a retrospective analysis of 26 Italian or Tunisian patients with Krabbe disease, Fiumara et al. (2011) found that 17 (66%) had the late-onset form, including 6 with late infantile, 9 with early juvenile, and 2 with adult onset. Fourteen of the patients came from the same area of Sicily, north of Catania. Nine patients died between 6 and 12 years. The first signs were hemiplegia in 12 and visual impairment in 3, followed by rapid deterioration in motor abilities within 3 to 24 months. All patients showed white matter abnormalities at onset, affecting the parietooccipital areas, corpus callosum, and corticospinal tracts, with later involvement of the internal and external capsules, subcortical U fibers, pyramidal tracts, and brainstem. Four patients showed impairment of the auditory and visual evoked potentials. Six of 12 patients studied showed mixed demyelinating and axonal sensorimotor neuropathy. Molecular studies showed that 4 patients were homozygous for a founder G41S mutation (606890.0010), and 4 were compound heterozygous for G41S and another mutation. Three of those homozygous were alive in their forties, although significantly handicapped; 1 had onset at age 3 years and 2 had onset at age 23 years. The fourth homozygous patient had onset at age 4 years and was alive at age 27. There was no correlation between age at onset, disease severity, genotype, and GALC enzyme activity, which ranged from 1 to 6% among those homozygous for G41S. However, considering the whole study, presence of the G41S mutation was associated with a more protracted disease course.
Neurophysiologic Studies
Husain et al. (2004) reported neurophysiologic studies of 20 patients with early-onset Krabbe disease and 6 patients with late-onset Krabbe disease. Of early-onset patients, all had abnormal nerve conduction studies (NCS), 88% had abnormal brainstem auditory evoked potentials (BAEP), 65% had abnormal EEG, and 53% had abnormal flash visual evoked potentials (VEP). Of late-onset patients, 20% had abnormal nerve conduction studies, 40% had abnormal BAEP, 33% had abnormal EEG, and all had normal flash VEP. The abnormalities correlated well with disease severity measured by MRI.
Siddiqi et al. (2006) found that 25 of 27 children with Krabbe disease, aged 1 day to 8 years, showed abnormal motor and/or sensory nerve conduction studies with uniform slowing of conduction velocities. Motor and sensory responses were abnormal in 82% of patients. The severity of the demyelination on NCS correlated with clinical severity of the disease. There were no conduction blocks, indicating uniform rather than focal demyelination of peripheral nerves. Marked NCS abnormalities were found in a 1-day-old and 2 3-week-old neonates, indicating that peripheral neuropathy occurs very early in Krabbe disease and that nerves are likely affected even in intrauterine life. Siddiqi et al. (2006) concluded that nerve conduction studies are a sensitive tool to screen for Krabbe disease. In an accompanying paper, Siddiqi et al. (2006) found that nerve conduction studies improved in 7 (60%) of 12 patients after hematopoietic stem cell transplantation followed for an average of 18 months. However, some patients showed further decline after an initial improvement. There was greater improvement if the transplant was performed earlier in life.
Krabbe disease is an autosomal recessive disorder. First-cousin parents were noted by Van Gehuchten (1956). Nelson et al. (1963) observed 3 affected sibs. Arroyo et al. (1991) described Krabbe disease in all 3 of monozygotic triplets.
Although deficiency of cerebroside-sulfatide sulfotransferase was earlier reported in Krabbe disease (Bachhawat et al., 1967), Suzuki and Suzuki (1970) found deficiency of galactocerebroside beta-galactosidase which they thought was etiologic and better accounted for the morphologic and biochemical features of the disorder. Suzuki and Suzuki (1971) demonstrated an intermediate level of activity of galactocerebroside beta-galactosidase in serum, white cells, and fibroblasts of heterozygotes. Young et al. (1972) found deficiency of the same enzyme, galactocerebrosidase, in a case with late onset.
In postmortem brain tissue from 4 infants with Krabbe disease, Hatton et al. (2022) identified accumulation of alpha-synuclein, particularly in globoid cells of the medulla oblongata, crus cerebri and cerebral cortex. In 2 cases, frozen brain tissue was available for aggregation testing, and the alpha-synuclein exhibited aggregation into fibrils, demonstrating prion-like capabilities.
D'Agostino et al. (1963) concluded that the initial histologic manifestation of the disease is the presence of PAS-positive material extracellularly and cerithin in microglial cells, which later appear as globoid cells. Definitive diagnosis of this disorder, which clinically can be so similar to several other encephalopathies of infancy, is made by finding these characteristic 'globoid cells' in brain tissue (Martin et al., 1981). These cells, derived from monocyte-macrophage stem cells of the bone marrow, contain accumulated psychosine as well as galactosylceramide.
Differential Diagnosis
Wenger and Louie (1991) discussed pseudodeficiency of galactocerebrosidase comparable to the pseudodeficiency of arylsulfatase A (250100); both are hard to distinguish from the bona fide GALC deficiency which may signify a presymptomatic person who will present with adult-onset clinical disease.
Prenatal Diagnosis
Harzer et al. (1987) demonstrated the feasibility of prenatal enzymatic diagnosis using chorionic villi. Harzer and Schuster (1989) warned against the use of uncultured chorionic villi in the prenatal enzymatic diagnosis; this material is subject to uncontrolled contamination with maternal enzyme.
Krivit et al. (1998) reported on their experience using allogeneic hematopoietic stem cell transplantation in the treatment of Krabbe disease. They treated 5 children, 1 with the infantile type and 4 with late-onset disease. Four of the patients had clinical CNS abnormalities before transplantation. In all 4 cases, CNS deterioration was reversed. In the patient with the infantile form of the disease, the expected decline in CNS function had not occurred by the age of 16 months, 14 months posttransplantation. The authors concluded that CNS manifestations of Krabbe disease can be reversed or prevented by allogeneic hematopoietic stem cell transplantation.
Escolar et al. (2005) assessed the safety and efficacy of transplantation of umbilical cord blood from unrelated donors in 11 asymptomatic newborns and 14 symptomatic infants with infantile Krabbe disease. All were prepared with myeloablative chemotherapy. The rates of donor-cell engraftment and survival were 100% and 100%, respectively, among the asymptomatic newborns and 100% and 43%, respectively, among symptomatic infants. Surviving patients showed durable engraftment of donor-derived hematopoietic cells with restoration of normal blood galactocerebrosidase levels. Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild to moderate delays in expressive language and mild to severe delays in gross motor function. Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement.
Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.
Thompson-Stone et al. (2021) reported recommendations from the Krabbe Disease Newborn Screening Council for follow-up of positive newborn screening. Infants with newborn screening showing low GALC activity and a high psychosine level (10 or higher nmol/L) were recommended to enter an early infantile Krabbe disease pathway with immediate family counseling and referral for disease modifying therapy such as hematopoietic stem cell transplantation. Infants with newborn screening showing low GALC activity and an intermediate level of psychosine (2 to less than 10 nmol/L) were recommended to enter an at-risk infantile Krabbe disease pathway with long-term follow-up and monitoring. Infants with newborn screening showing low GALC activity and normal psychosine levels were recommended to enter a low-risk pathway with some degree of follow-up based on additional testing or clinical findings.
Studies by Zlotogora et al. (1990) showed that the Krabbe disease mutation is located on human chromosome 14. Zlotogora et al. (1990) undertook linkage analysis with RFLPs, focusing first on chromosome 17, based on a study by Lyerla et al. (1989). When no evidence of linkage was found there, they took advantage of the homology between the mouse and human chromosomes: the 'twitcher' mouse mutation results in an autosomal recessive leukodystrophy that is similar histopathologically to Krabbe disease (Duchen et al., 1980). Sweet (1986) found that the 'twitcher' locus is on mouse chromosome 12, a chromosome that has large regions of homology with human chromosome 14. A multipoint lod score of 3.40 was found with marker D14S24 (14q21-q31). Cannizzaro et al. (1994) mapped the GALC gene (606890) to chromosome 14q31.
In a study in Catania in Sicily, Fiumara et al. (1990) found that 7 of 10 cases seen in a 12-year period were of the late infantile form, suggesting an unusually high frequency of the gene in Sicily. Of the 7 with the late infantile form, 2 were sibs born of first-cousin parents and 1 of the others was the product of a first-cousin marriage.
Zlotogora et al. (1985) found a frequency of 6 per 1,000 live births in a large Druze isolate in Israel. The isolate numbered about 8,000 persons. The Druze religion dates from the 11th century when it was founded in Egypt with subsequent expansion into Syria and Lebanon.
In 2 different inbred communities in Israel with Krabbe disease, Rafi et al. (1996) identified 2 different founder mutations in the GALC gene: 1 in a Moslem Arab population (606890.0003) and 1 in a Druze population (606890.0004).
Tappino et al. (2010) noted that the median prevalence of Krabbe disease is estimated to be about 1 in 100,000 (1.0 x 10(-5)) with wide variations between countries: 1.35 in the Netherlands, 1.21 in Portugal, 1.00 in Turkey, 0.71 in Australia, and 0.40 in Czech Republic.
Sakai et al. (1994) identified homozygosity for a nonsense mutation in the GALC gene (606890.0001) in a patient with typical Krabbe disease.
Rafi et al. (1995) analyzed the GALC gene in 2 patients with infantile Krabbe disease and identified homozygosity for a 30-kb deletion (606890.0002) that was found to be associated with a 502C-T transition on the same allele, which they designated '502/del.' The transition was determined to be a polymorphism. Rafi et al. (1995) studied an additional 46 patients with infantile Krabbe disease and identified 8 who were homozygous for the 502/del allele and 5 who were compound heterozygotes for 502/del allele and a second mutant allele, including 3 missense mutations and 1 single nucleotide insertion, which had not yet been confirmed by expression studies.
De Gasperi et al. (1996) analyzed the GALC gene in 9 families with late-onset GLD and in 1 patient with classic Krabbe disease. They reported that 5 of the patients were compound heterozygotes for the deletion (606890.0002) first reported by Rafi et al. (1995) and another mutation in the GALC gene. Most of the novel mutations identified appeared to be private family mutations.
In a review of the molecular genetics of Krabbe disease, Wenger et al. (1997) stated that more than 40 mutations had been identified in patients with all clinical types of globoid cell leukodystrophy.
Among 30 unrelated Italian patients with Krabbe disease, Tappino et al. (2010) identified 33 different mutations in the GALC gene, including 14 novel mutations (see, e.g., 606890.0005-606890.0009). The 15 novel mutations included 4 missense mutations in highly conserved residues, 7 frameshift mutations, 3 nonsense mutations, and 1 splice site mutation. Thus, 73% of the newly described mutations were expected to affect mRNA processing. In silico analysis predicted that the missense mutations had a high probability of being deleterious. The common 30-kb deletion (606890.0002) accounted for 18% of mutant alleles, and 4 patients had a founder mutation (G553R; 606890.0005). Otherwise, most of the mutations were private. There were no clear genotype-phenotype correlations, but some missense mutations were associated with milder phenotypes (see, e.g., G286D; 606890.0008).
De Gasperi et al. (1996) noted that it was not always possible to make conclusions about the phenotype from the genotype. Most difficult to explain was the phenotype of 5 late-onset patients who carried on both alleles mutations that completely abolished enzyme activity. They concluded that these observations point to the possibility that other genetic factors besides mutations in the galactocerebrosidase gene may contribute to the phenotype in late-onset GLD. Wenger et al. (1997) noted that some mutations clearly resulted in the infantile type if found in homozygous state or in compound heterozygous state with another severe mutation, but it is difficult to predict the phenotype of novel mutations or mutations found in apparent heterozygous state (when a second mutated allele has not been identified). A high frequency of polymorphic changes on apparent disease-causing alleles also complicated the interpretation of the effects of mutations. The molecular characterization of the naturally occurring mouse, dog, and monkey models will permit their use in therapeutic trials.
In a review of GALC mutations causing Krabbe disease, Furuya et al. (1997) found that those in the adult-onset form occurred in the N- or C-terminus, whereas those in the infantile form occurred in the central domain.
Xu et al. (2006) investigated mutations of the GALC gene in 17 unrelated Japanese patients with Krabbe disease and reviewed the mutations previously reported in 11 Japanese patients. The authors found that 12del3ins and I66M + I289V, which had been identified only in Japanese individuals to date, accounted for 37% of the mutant alleles; with 2 additional mutations, G270D and T652P, these accounted for up to 57% of mutations in Japanese patients. Xu et al. (2006) observed a tendency for the I66M + I289V, G270D, and L618S mutations to be associated with a mild phenotype.
In a retrospective analysis of 26 patients with Krabbe disease, Fiumara et al. (2011) found that 17 (66%) had the late-onset form, including 6 with late-infantile, 9 with early juvenile, and 2 with adult onset. Fourteen of the patients came from the same area of Sicily, north of Catania. Molecular studies showed that 4 patients were homozygous for a founder G41S mutation (606890.0010), and 4 were compound heterozygous for G41S and another mutation. There was no correlation between age at onset, disease severity, genotype, and GALC enzyme activity, which ranged from 1 to 6% among those homozygous for G41S. However, considering the whole study, presence of the G41S mutation was associated with a more protracted disease course.
A somewhat similar disorder was described in 3 adult sibs by Ferraro (1927), but this may be a genetically distinct condition. See discussion of Menkes (1963) and of Norman et al. (1961). Korn-Lubetzki and Nevo (2003) provided an interesting history of the first descriptions of Krabbe disease by Krabbe (1916) and others.
Duchen et al. (1980) described an autosomal recessive leukodystrophy of the mouse, 'twitcher,' which is very similar histopathologically and may be homologous. Kobayashi et al. (1980) demonstrated that the 'twitcher' mouse is an enzymatically authentic model of human GLD, as are disorders in sheep and dog. Igisu and Suzuki (1984) studied the 'twitcher' mouse.
Ichioka et al. (1987) studied the effects of bone marrow transplantation in the twitcher mouse. Hoogerbrugge et al. (1988) showed that transplantation of enzymatically normal congenic bone marrow in the twitcher mouse results in increased galactosylceramidase levels in the CNS. There was a gradual disappearance of globoid cells, the histologic hallmark of Krabbe disease, and the appearance of foamy macrophages capable of metabolizing the storage product. By immunohistochemical labeling, it was shown that these macrophages in the CNS were of donor origin. Extensive remyelination was observed in the CNS. In further studies, Hoogerbrugge et al. (1988) found that bone marrow transplantation in the twitcher mouse resulted in an increase in the galactosylceramidase activity in the CNS to 15% of normal donor levels with a prevention of paralysis of the hind legs and a prolonged survival from 30-40 days to more than 100 days in some instances.
In addition to the 'twitcher' mouse, West Highland white terriers and Cairn terriers have a naturally occurring form of Krabbe disease (Victoria et al., 1996). Wenger et al. (1999) showed successful transduction of cultured skin fibroblasts from a West Highland white terrier with GLD and normal canine bone marrow, using a retroviral vector containing the human GALC cDNA.
Tohyama et al. (2000) crossbred twitcher mice with acid beta-galactosidase knockout mice (GM1-gangliosidosis; 230500) and found that the acid beta-galactosidase gene dosage exerts an unexpected and paradoxical influence on the twitcher phenotype. Twitcher mice with an additional complete deficiency of acid beta-galactosidase (galc-/-, bgal-/-) had the mildest phenotype among twitcher mice of all genotypes, with the longest life span and nearly rescued central nervous system pathology. In contrast, twitcher mice with a single functional acid beta-galactosidase gene (galc-/-, bgal+/-) had the most severe disease, with the shortest life span and brain levels of psychosine even higher than those of twitcher mice. The double knockout mice showed a massive accumulation of lactosylceramide in all tissues as expected, but only a half-normal amount of galactosylceramide in brain. The authors hypothesized that the acid beta-galactosidase gene may function as a modifier gene for the phenotypic expression of galactosylceramidase deficiency.
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