Krabbe disease 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, ... Krabbe disease 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).
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 ... - 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 subarachnoideal 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.
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 ... 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.
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 ... 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).
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. ... 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.
Individuals with the infantile form of Krabbe disease can present with any or all of the following features:...
Diagnosis
Clinical DiagnosisIndividuals with the infantile form of Krabbe disease can present with any or all of the following features:Irritability Muscle hypertonicity Progressive neurologic deterioration Peripheral neuropathy Evidence of white matter disease on neuroimaging Elevation of cerebrospinal fluid (CSF) protein concentration While most individuals have the infantile form, older individuals ranging in age from six months to the seventh decade have also been diagnosed with galactocerebrosidase deficiency. They usually present with weakness and vision loss and may experience intellectual regression.Neuroimaging. Progressive, diffuse, and symmetric cerebral atrophy is observed by neuroimaging. In the early stage of the disease, CT can be normal; diffuse cerebral atrophy involving both gray and white matter develops later. Diffuse hypodensity of the white matter may be present, particularly in the parieto-occipital region. These findings are nonspecific and are observed in many diseases of white matter.In general, MRI detects demyelination in the brain stem and cerebellum more clearly than CT at the early stage of the disease; however, some infants have had deceptively normal MRIs when CT had already revealed symmetric hyperdensity involving the cerebellum, thalami, caudate, corona radiata, and brain stem. Individuals with Krabbe disease who have severe demyelination show high-intensity lesions on T2-weighted images with a loss of diffusional anisotropy and relatively high signal on diffusion-weighted images. Calculation of the T2 value in the central white matter provides objective judgment for demyelinating diseases. It is progressively prolonged in the occipital deep white matter and posterior part of the central semiovale in individuals with late-onset Krabbe disease.TestingGalactocerebrosidase (GALC) enzyme activity Symptomatic individuals. Measurement of GALC enzyme activity is best done using the radiolabeled natural substrate galactosylceramide (gal-cer). The in vitro assay using radiolabeled gal-cer utilizes a synthetic buffer and detergent mixture. Some laboratories use the synthetic substrate 6-hexadecanoylamino-4- metylumbelliferyl-beta-D-galactopyranoside (HMGal). All individuals with Krabbe disease have very low GALC enzyme activity (0%-5% of normal activity) in leukocytes isolated from whole heparinized blood and cultured skin fibroblasts. This test is most reliable when conducted in a laboratory with demonstrated experience in performing the assay. Note: The finding of GALC enzyme activity that is 8%-20% of normal in a healthy individual, in an individual with neurologic disease that is not typical of any form of Krabbe disease, or in an individual identified by newborn screening presents a diagnostic problem and requires additional study. In most instances, such individuals have multiple copies of known polymorphisms in both GALC alleles. However, some individuals with enzyme activity in this range may have a disease-causing mutation on one allele and multiple polymorphic changes on the other allele, and thus may be carriers of Krabbe disease.Carrier testing. Carrier testing by measurement of GALC enzyme activity in leukocytes or cultured skin fibroblasts is not reliable because of the wide range of enzymatic activities observed in carriers and non-carriers. The presence of normal variants (polymorphisms) in the GALC coding region results in amino acid changes that lower GALC enzyme activity but do not result in clinical disease when inherited in the homozygous state or, as far as is known, when inherited together with a disease-causing mutation. Note: Although the finding of low GALC enzyme activity in one or both healthy parents of an affected child (due to the presence of polymorphisms in their normal allele) makes prenatal testing using enzyme measurement more difficult, it is accurate when performed in an experienced laboratory.Newborn screening. With improvements in treatment options for presymptomatic individuals, efforts to develop newborn screening methods are underway. A method using dried blood spots and tandem mass spectrometry to measure GALC enzyme activity has been published [Li et al 2004a, Li et al 2004b]. In August 2006 New York State instituted newborn screening for Krabbe disease; to date over 1,000,000 newborns have been screened. Four newborns were identified as being at risk of developing infantile Krabbe disease. The identification of these newborns permitted umbilical cord blood transplantation in three within the first month of life; the parents of the fourth infant did not elect this option. One newborn who underwent transplantation subsequently died of complications of the transplant; the other two are still alive. Other high-risk individuals were identified by confirming enzymatic studies [Wenger, unpublished].] and by molecular genetic testing. Their mutations suggest a later-onset disease or possibly no disease; their clinical status is being carefully monitored. At this time several other states are considering newborn screening for Krabbe disease; to date none have implemented the program.Molecular Genetic Testing Gene. GALC is the gene most commonly known to be associated with Krabbe disease (see Differential Diagnosis). Clinical testing Targeted mutation analysis Infantile Krabbe disease. One mutation (a 30-kb deletion) accounts for approximately 45% of the mutant alleles in individuals of European ancestry [Luzi et al 1995, Rafi et al 1995] and 35% of the mutant alleles in individuals of Mexican heritage [personal experience]. This large deletion results in the classic infantile phenotype when in the homozygous state or in the compound heterozygous state along with another mutation known to cause infantile Krabbe disease. Late-onset Krabbe disease. The c.857G>A mutation is often found in individuals with the late-onset form of Krabbe disease. One copy of this mutation, even in the compound heterozygous state with the 30-kb deletion, always results in late-onset Krabbe disease. Sequence analysis. It is possible to sequence the entire coding region, intron-exon boundaries, and 5'-untranslated region of GALC and identify essentially 100% of the disease-causing mutations and polymorphisms (normal variants). Deletion/duplication analysis. Deletions involving single exons and multiple exons have been detected [Wenger et al 2001].Table 1. Summary of Molecular Genetic Testing Used in Krabbe DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityGALCTargeted mutation analysis
30-kb deletionSee footnote 2Clinicalc.857G>ASee footnote 3Sequence analysisSequence variants 4~100%Deletion/ duplication analysis 5Exonic, multiexonic, and whole-gene deletions/duplications Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. This large deletion accounts for approximately 45% of the mutant alleles in individuals with infantile Krabbe disease of European ancestry [Luzi et al 1995, Rafi et al 1995] and 35% of the mutant alleles in individuals with infantile Krabbe disease of Mexican heritage [personal experience]. One copy of this large deletion can also be observed in the compound heterozygous state in individuals with late-onset Krabbe disease.3. Found in individuals with late-onset Krabbe disease: approximately 50% have at least one c.857G>A disease-causing allele. 4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a probandMeasurement of GALC enzyme activity in leukocytes or another tissue to establish the diagnosis Molecular genetic analysis of the proband to identify both disease-causing alleles to aid in phenotype prediction (especially in those individuals identified in newborn screening), in carrier detection in at-risk family members, and possibly for prenatal diagnosis In individuals with infantile Krabbe disease, targeted mutation analysis for the 30-kb deletion should be performed first. If two mutations are not detected, sequence analysis should be performed, followed by deletion/duplication analysis.Because approximately 50% of individuals with late-onset Krabbe disease have at least one copy of the c.857G>A allele, targeted mutation analysis should be performed first. If two mutations are not detected, targeted mutation analysis for the 30-kb deletion should follow. If two mutations are not identified, sequence analysis should be performed, followed by deletion/duplication analysis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersAll individuals with a deficiency of GALC enzyme activity have symptoms (unless identified by newborn screening or family history) and findings (e.g., magnetic resonance imaging showing changes in the white matter) consistent with some type of leukodystrophy.
Approximately 85%-90% of individuals with Krabbe disease have the infantile form presenting with extreme irritability, spasticity, and developmental delay before age six months. The remaining 10%-15% have onset between age six months and the seventh decade....
Natural History
Approximately 85%-90% of individuals with Krabbe disease have the infantile form presenting with extreme irritability, spasticity, and developmental delay before age six months. The remaining 10%-15% have onset between age six months and the seventh decade.Infantile form. The infantile form typically has three stages: Stage I is characterized by irritability, stiffness, arrest of motor and mental development, and episodes of temperature elevation without infection, possibly caused by involvement of the hypothalamus. The child, apparently normal for the first few months after birth, becomes hypersensitive to auditory, tactile, or visual stimuli and begins to cry frequently without apparent cause. Many infants keep their fists tightly clenched throughout their lives. Slight retardation or regression of psychomotor development as well as vomiting and other feeding difficulties may result in progressive loss of weight leading to emaciation. In some infants, peripheral neuropathy is a presenting feature with no other neurologic symptoms appreciated for several months [Korn-Lubetzki et al 2003]. Seizures may occur as an initial clinical symptom. Infantile spasms rarely occur. The CSF protein concentration is already increased at this stage. Stage II is characterized by rapid and severe motor and mental deterioration. There is marked hypertonicity with extended and crossed legs, flexed arms, and a backward-bent head. Tendon reflexes are hyperactive. Minor tonic or clonic seizures occur. Optic atrophy and sluggish pupillary reactions to light are common. Clinical examination does not always reveal peripheral neuropathy, especially in the early stages when symptoms and signs of central nervous system involvement are overwhelming. Stage III, sometimes reached within a few weeks or months, is the "burnt out" stage. The infant is blind and decerebrate with no voluntary movement. The infant has no contact with his/her surroundings. The average age of death in children with the infantile form is 13 months; however, some succumb by age eight months from infections and respiratory failure, while others live for more than two years. Even with the best care, it is difficult to extend the life of a severely affected child.Symptoms and signs are confined to the nervous system. No visceromegaly is present. Head size may be large or small; hydrocephalus has been observed. Macular cherry-red spots were described in one individual.One infant, diagnosed with Krabbe disease in utero, had normal psychomotor development for the first two months of life but lost deep tendon reflexes by age five weeks, had markedly reduced nerve conduction velocities at age seven weeks, and developed neck muscle weakness at age three months [Lieberman et al 1980]. These findings suggest that careful examination could reveal clinical manifestations of Krabbe disease in an affected infant earlier than the reported age of onset.Late-onset forms. Individuals with late-onset forms can be clinically normal until almost any age when symptoms of weakness, vision loss, and intellectual regression become evident. The clinical course of older individuals is variable. Individuals with the late-infantile or juvenile form who present after age one year may have nonspecific findings related to walking difficulties, vision loss, and loss of developmental milestones. These individuals regress at an unpredictable rate. Loonen et al [1985] identified late-infantile (early-childhood) and juvenile (late-childhood) forms in 18 individuals. In the late-infantile group (onset age 6 months - 3 years), irritability, psychomotor regression, stiffness, ataxia, and loss of vision were the most common initial symptoms. In most cases the course was progressive and resulted in death approximately two years after onset. In the juvenile group (onset age 3-8 years), children developed loss of vision together with hemiparesis, ataxia, and psychomotor regression. Most children with the juvenile form showed an initial rapid deterioration followed by a more gradual progression lasting for years. None died during the follow-up period that ranged from ten months to seven years [Loonen et al 1985].Some individuals with onset in adolescence and adulthood present with loss of manual dexterity, burning paresthesia in their extremities, and weakness without intellectual deterioration; others become bedridden and continue to deteriorate mentally and physically [Kolodny et al 1991, Satoh et al 1997, Jardim et al 1999, Wenger 2003].The adult-onset group includes individuals in whom the diagnosis was first made in adulthood (because the subtle symptoms present earlier in life did not prompt biochemical testing) as well as individuals considered completely normal until symptoms began after age 20 years [Kolodny et al 1991, Satoh et al 1997, Wenger 2003]. An example of the former is an individual reported by Kolodny et al [1991] (case 15) who had been "shaky" in childhood, walked slowly with a stiff and wide-based gait, and had progressive, generalized neurologic deterioration after age 40 years. She died of pneumonia at age 73 years. An example of the latter is a woman who developed slowly progressive spastic paraparesis at age 38 years. Demyelination identified on MRI was confined to the corticospinal tract [Satoh et al 1997].The phenotypes can differ considerably among individuals with later-onset forms, including siblings, who have the same GALC genotype. Findings in two sisters illustrate this point. At age 28 years, sister 1 had been considered normal until a few years previously when she experienced lower-extremity paresis with episodes of tripping and clumsiness when walking. Heel cord lengthening was performed, but spastic paresis continued with clumsy gait and difficulty rising from a squatting or sitting position. Ten years earlier, nerve conduction studies had shown slowing in motor and sensory fibers. She had no obvious intellectual impairment, was married and had a child, and at age 38 years continues to work. Sister 2 had been considered normal until age four to five years, when she developed progressive weakness in all extremities. She experienced rapid mental deterioration and seizures. At age 36 years, she was significantly intellectually disabled and wheelchair bound, although she could function in a sheltered environment [personal observation].Electroencephalogram (EEG). While normal in the initial stages, the EEG gradually becomes abnormal. Background activity becomes slow and disorganized, with changes that may be asymmetric. EMG and NCV. Motor nerve conduction velocities (NCVs) are consistently low. NCV studies have been reported to be normal in some adults with an enzymatically confirmed diagnosis. Visual and auditory evoked responses, NCV, and EEG are all more frequently and more severely abnormal in individuals with early-infantile onset [Husain et al 2004].MRI. In general, in the early stage of Krabbe disease MRI detects demyelination in the brain stem and cerebellum more clearly than CT, but some infants have a deceptively normal MRI. In some cases, CT reveals symmetric hyperdensity involving the cerebellum, thalami, caudate, corona radiata, and brain stem.On MRI the T1 value is decreased, with normal or slightly decreased T2 in white matter of the centrum semiovale.T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI showed symmetric high intensity of the pyramidal tract and optic radiation in an adult whose initial clinical manifestations occurred at age 60 years. The T2 value is progressively prolonged in the occipital deep white matter and posterior part of central semiovale in late-onset disease. MRI is also useful for differentiation between dysmyelination and demyelination. Individuals with Krabbe disease with severe demyelination showed high-intensity lesions on T2-weighted images, with a loss of diffusional anisotropy and relatively high signal intensity on diffusion-weighted images [Husain et al 2004].MRS. Magnetic resonance spectroscopy can also be used to document the demyelination, gliosis, and axonal loss in white matter of individuals with typical and atypical Krabbe disease.
No consistent correlation has been observed between age of onset and residual GALC enzyme activity measured in leukocytes or cultured skin fibroblasts....
Genotype-Phenotype Correlations
GALC Enzyme Activity No consistent correlation has been observed between age of onset and residual GALC enzyme activity measured in leukocytes or cultured skin fibroblasts.Occasionally, some individuals with Krabbe disease have slightly higher than expected GALC enzyme activity. Because the active enzyme consists of a large aggregate containing multiple copies of the 30-kd and 50-kd subunits derived from the same precursor and because many individuals are compound heterozygotes, it is difficult to place much significance on the detection of a small amount of residual enzyme activity.GALC Mutations Infantile form. The common 30-kb deletion results in the classic infantile form in the homozygous state or when in the compound heterozygous with another mutation associated with severe disease. Three other mutations associated with the infantile phenotype make up another 15% of the mutant alleles in individuals of European ancestry [Kleijer et al 1997, Wenger et al 1997]. Except for the c.857G>A mutation, all disease-causing mutations listed in Table 2 result in the infantile phenotype when homozygous or compound heterozygous with each other. Late-onset forms. Many individuals with late-onset disease are compound heterozygotes, having one copy of the c.857G>A mutation and one copy of the common 30-kb deletion. Although having one copy of the c.857G>A allele always results in a milder phenotype, it is not possible to predict the clinical course, as illustrated by the two sisters described in Clinical Description. Five additional families with multiple affected members with the 30-kb del/ c.857G>A genotype have significant intra- and interfamilial clinical variability [Wenger, personal observation]. Only one individual of Japanese heritage with adult-onset disease is known to be homozygous for the c.857G>A mutation. One individual with adult-onset disease had a complex genotype with three mutations on one allele and two on the other [Luzi et al 1996]. Other mutations have been described [Kukita et al 1997].
A history of normal development for the first few months after birth followed by psychomotor deterioration differentiates Krabbe disease from non-progressive CNS disorders of congenital or perinatal origin. Differentiation of Krabbe disease from other degenerative diseases is often difficult. Individuals of any age with progressive deterioration of the central or peripheral nervous systems should be tested for Krabbe disease. ...
Differential Diagnosis
A history of normal development for the first few months after birth followed by psychomotor deterioration differentiates Krabbe disease from non-progressive CNS disorders of congenital or perinatal origin. Differentiation of Krabbe disease from other degenerative diseases is often difficult. Individuals of any age with progressive deterioration of the central or peripheral nervous systems should be tested for Krabbe disease. The following disorders, ordered by mode of inheritance, should be considered in the differential diagnosis. Autosomal RecessiveArylsulfatase A deficiency (metachromatic leukodystrophy, MLD) is characterized by three clinical subtypes that can closely resemble late-onset Krabbe disease: late-infantile MLD (50%-60% of cases) with onset between age one and two years; juvenile MLD (~20%-30%) with onset between age four years and sexual maturity (12-14 years); and adult MLD (~15%-20%) with onset after sexual maturity. All individuals eventually lose motor and intellectual functions. The disease course may be from three to ten or more years in the late infantile-onset form and up to 20 years or more in the juvenile- and adult-onset forms. Death most commonly results from pneumonia or other infection. MLD is suggested by arylsulfatase A enzyme activity in leukocytes that is less than 10% of normal controls. Because of the high frequency of the so-called pseudodeficiency (Pd) allele, additional studies in all individuals with low arylsulfatase activity are required. The diagnosis of MLD is confirmed by one or more of the following additional tests: molecular genetic testing of ARSA, urinary excretion of sulfatides, and/or finding of metachromatic lipid deposits in nervous system tissue. Several individuals with Krabbe disease who were also homozygous for the Pd allele also had low arylsulfatase A activity, confusing the diagnosis [Wenger, unpublished]. GM1 gangliosidosis. The GM1 gangliosidoses, including Morquio syndrome type B, result from defects in acid β-galactosidase. They are clinically variable, ranging from newborns with nonimmune fetal hydrops to adults with varying degrees of neurologic involvement. In addition to psychomotor retardation, young individuals usually have coarse facial features and hepatosplenomegaly, neither of which is found in individuals with Krabbe disease. Skeletal involvement is variable. Some individuals primarily have dysostosis multiplex with no neurologic involvement, and others have only neurologic problems, such as dysarthria, and mild vertebral changes. Low-acid β-galactosidase enzyme activity in both leukocytes and plasma establishes the diagnosis of GM1 gangliosidosis and Morquio syndrome type B and differentiates them from galactosialidosis, a disorder in which β-galactosidase enzyme activity is low in leukocytes only. GM2 gangliosidosis. The GM2 gangliosidoses are a group of neurodegenerative disorders caused by the intralysosomal storage of the specific glycosphingolipid GM2 ganglioside. Tay-Sachs disease, the prototype GM2 gangliosidosis, is characterized by loss of motor skills beginning between age three and six months with progressive evidence of neurodegeneration, including seizures, macular cherry-red spots, and blindness. Total incapacitation and death usually occur before age four years. The juvenile, chronic, and adult-onset variants of hexosaminidase A deficiency have later onset, slower progression, and more variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, motor neuron disease, and in some individuals with adult-onset disease, a bipolar form of psychosis. The diagnosis of hexosaminidase A deficiency relies on the demonstration of absent to near-absent beta-hexosaminidase A (HEX A) enzymatic activity in the serum or white blood cells of a symptomatic individual in the presence of normal or elevated activity of the beta-hexosaminidase B (HEX B) isoenzyme. Mutation analysis of HEXA is used primarily for genetic counseling purposes (1) to distinguish pseudodeficiency alleles from disease-causing alleles in individuals with apparent deficiency of HEX A enzymatic activity identified in population screening programs and (2) to identify specific disease-causing alleles in affected individuals.Canavan disease is characterized by evidence of developmental delays by age three to five months with severe hypotonia and failure to achieve independent sitting, ambulation, or speech. Hypotonia evolves into spasticity and assistance with feeding becomes necessary. Life expectancy is usually into the second decade. Most individuals with Canavan disease have macrocephaly, which is a variable finding in individuals with Krabbe disease. MRI shows prominent involvement of subcortical white matter. The finding of elevated N-acetylaspartic acid concentration in urine confirms the diagnosis of Canavan disease. Saposin A deficiency. An infant with abnormal myelination resembling Krabbe disease was found to have a mutation in the saposin A region of the gene PSAP, encoding prosaposin [Spiegel et al 2005]. This heat-stable protein interacts with the enzyme GALC to catalyze the hydrolysis of the natural lipid substrates. The infant with mutations in the saposin A region of PSAP had low GALC enzyme activity when measured in leukocytes, but not in cultured skin fibroblasts. X-LinkedX-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in males: The childhood cerebral form manifests most commonly between age four and eight years. It initially resembles attention deficit disorder; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years. Adrenomyeloneuropathy (AMN) manifests most commonly in the late twenties as progressive paraparesis, sphincter disturbances, and varying degrees of distal sensory loss. "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years; some degree of neurologic disability (most commonly AMN) usually develops later. Approximately 20% of carrier females develop neurologic manifestations that resemble adrenomyeloneuropathy, but have later onset (age 35 years or later) and milder disease than do affected males.The plasma concentration of very-long-chain fatty acids (VLCFA) is elevated in more than 99% of males with X-ALD of all ages regardless of the presence or absence of symptoms. The assay has a sensitivity of approximately 85% in female carriers. Mutations in ABCD1 are causative.Pelizaeus-Merzbacher disease (PMD) is part of the phenotypic spectrum of PLP1-related disorders of central nervous system myelin formation. The phenotypes that can be observed in males with this disorder range from PMD to spastic paraplegia 2 (SPG2); a wide range of phenotypes can be observed in members of the same family. PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment and progresses to severe spasticity and ataxia. Life span is shortened. Molecular genetic testing of PLP1 is diagnostic. Autosomal DominantAlexander disease is a disorder of cortical white matter. Two forms are common, infantile (80% of affected individuals) and juvenile (~14%), although neonatal and adult forms are also recognized. The infantile form presents in the first two years of life typically with megalencephaly, seizures, progressive psychomotor retardation with loss of developmental milestones, and quadriparesis. Affected individuals survive a few weeks to several years. The juvenile form usually presents between age four and ten years, occasionally in the mid-teens. Survival is variable, ranging from the early teens to the 20s-30s. Affected individuals can present with megalencephaly, bulbar/pseudobulbar signs including speech abnormalities, swallowing difficulties, frequent vomiting, lower-limb spasticity, poor coordination (ataxia), gradual loss of intellectual function, and seizures. Diagnostic criteria based on MRI findings include extensive white matter involvement with frontal preponderance, periventricular rim of low T2 and high T1 signal intensity, and mild signal changes and swelling in the basal ganglia, thalamus, and brain stem [van der Knaap et al 2001]. GFAP, which encodes glial fibrillary acidic protein, is the only gene currently known to be associated with Alexander disease. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Infantile onsetLate-infantile onsetJuvenile onsetAdult onset
To establish the extent of disease in an individual diagnosed with Krabbe disease:...
Management
Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Krabbe disease:Neurologic examination EEG Brain MRI and MRS Treatment of ManifestationsTreatment of individuals with infantile-onset Krabbe disease who are diagnosed in stage II or III is limited to supportive care to control irritability and spasticity. Prevention of Primary ManifestationsHematopoietic stem cell transplantation (HSCT) in presymptomatic infants [Escolar et al 2005] and older individuals with mild symptoms [Krivit et al 1998] provides a benefit over symptomatic treatment only. Treated individuals show improved and preserved cognitive function; however, many show progressive deterioration of peripheral nervous system findings. The availability of suitable donors has changed considerably with the use of umbilical cord blood for HSCT.The identification of newborns with the potential to develop Krabbe disease by newborn screening (presently in place in New York State) facilitates the initiation of treatment before neurologic damage has occurred. Concerns remain regarding the age at which to start treatment, prediction of clinical course without treatment, and long-term consequences of treatment.Given the significant clinical variability among individuals with late-onset forms (even those with the same genotype), evaluation of treatment effectiveness is difficult.Evaluation of Relatives at RiskIf the disease has been identified in an affected family member, it is appropriate to test siblings so that morbidity and mortality can be reduced by early diagnosis and treatment with HSCT using umbilical cord blood [Escolar et al 2005]. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationStudies using the well-characterized animal models to investigate other treatment options including gene therapy, enzyme replacement therapy, neural stem cell transplantation, substrate reduction therapy, and chemical chaperone therapy are being conducted. However, at this time HSCT (bone marrow transplantation) is the most effective method of therapy in the mouse models of Krabbe disease. None of these other methods is ready for human trials. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherIn utero HSCT in fetuses predicted to be affected with Krabbe disease has been tried three times with little success [Bambach et al 1997].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Krabbe Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGALC14q31.3
GalactocerebrosidaseGALC homepage - Mendelian genesGALCData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Krabbe Disease (View All in OMIM) View in own window 245200KRABBE DISEASE 606890GALACTOSYLCERAMIDASE; GALCNormal allelic variants. The normal gene is approximately 57 kb in length with 17 exons that code for 669 amino acids. The reference protein NP_000144.2 (Table 2) has 685 amino acids because by convention longer isoforms are chosen as reference sequences. Compared to the 669-amino acid isoform described by Wenger et al, this one uses an alternate start codon that is 48 nucleotides upstream. The 5' flanking region of the gene is GC rich and contains one potential YY1 element and one potential SP1 binding site. The strongest promoter activity is -176 to -24 upstream of the initiation codon. Inhibitory sequences are immediately upstream of the promoter region and within intron 1 [Luzi et al 1997] (see Table 2). Pathologic allelic variants. Over 110 disease-causing mutations have been identified (some are summarized in Wenger et al [2001], others unpublished). The more common mutations that have occurred in more than one unrelated individual in either the homozygous or heterozygous state are in Table 2. Mutations occur in every one of the 17 exons. Missense mutations causing the infantile form of Krabbe disease are found in both subunits, although more seem to be found in the coding region for the 30-kd subunit.The 30-kb deletion, which always occurs in cis with the c.550C>T polymorphism (normal variant), accounts for approximately 45% of mutant alleles in the population of European ancestry. The 30-kb deletion, starting within the large intron 10 and continuing beyond the end of the gene, probably originated in Sweden and spread throughout Europe, including Spain. This deletion comprises a significant number of mutant alleles in individuals of Mexican, Pakistani, and Indian heritage. This deletion results in the classic infantile form when found in the homozygous state or in the compound heterozygous state with another severe mutation. Several other mutations associated with the infantile phenotype make up another 15% of the mutant alleles in individuals with European ancestry [Kleijer et al 1997, Wenger et al 1997] (see Table 2).The mutation c.857G>A always results in the later-onset form of Krabbe disease. One copy of this mutation, even when present with the 30-kb deletion as the second allele, results in late-onset Krabbe disease. In all c.857G>A alleles that have been examined it was found in cis configuration with the c.1685T>C polymorphism. Whether pathogenesis requires the presence of both or only one nucleotide change is not known.A number of small deletions and insertions result in frame shift and premature termination. Even missense mutations very near the 3' end of the coding region that result in amino acid changes near the carboxyl end of the 30-kd subunit result in clinical disease [Rafi et al 1996, Jardim et al 1999]. It is difficult to predict the clinical presentation from the location or type of missense mutation.Other unique mutations occur within certain ethnic groups [Fu et al 1999]. Unique point mutations resulting in infantile Krabbe disease have been identified in two isolates in the Middle East [Rafi et al 1996]. The Druze in Northern Israel and a Moslem Arab village near Jerusalem each has its own unique missense mutation near the 3' end of the gene. For members of these villages, identification of affected individuals, carrier testing, and prenatal diagnosis can be done by molecular genetic analysis.Table 2. Common GALC Polymorphisms and Mutations View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)% of All AllelesReference SequencesNormal (benign polymorphisms)c.550C>T (502C>T)p.Arg184Cys (Arg168Cys)4%-5% NM_000153.3 NP_000144.2c.742G>A (694G>A)p.Asp248Asn (Asp232Asn)8%-10%c.1685T>C (1637T>C)p.Ile562Thr (Ile546Thr)35%-45%c.[550C>T;1685T>C] 2(502C>T + 1637T>C) 2p.[Arg184Cys;Ile562Thr] (Arg168Cys + Ile546Thr)<2%Pathologic 3(30-kb deletion) 3--40%-50% 4c.1586C>T (1538C>T)p.Thr529Met (Thr513Met)5%-8% 4c.1700A>C (1652A>C)p.Tyr567Ser (Tyr551Ser)5%-8% 4c.1472delA (1424delA)p.Lys491Argfs*622%-5% 4c.857G>A (809G>A) 5p.Gly286Asp (Gly270Asp)1%-2% 4See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions. In this instance, the variant designations conform to the cDNA reference sequence in the HGMD database (see Table A) and some publications. 2. Two mutations in one allele3. Begins in intron 10 and deletes the remainder of the gene and additional contiguous sequences4. In individuals of European ancestry5. One copy of this allele together with another disease-causing mutation results in late-onset disease.Normal gene product. The 80-kd precursor protein contains six potential glycosylation sites and is proteolytically cut into the active 50-kd and 30-kd subunits. These subunits are not active individually, and galactocerebrosidase (GALC) enzyme activity cannot be generated by mixing together the two subunits. The subunits aggregate into a very high molecular-weight complex that is very hydrophobic. Normally only a very small amount of GALC protein is made in all cell types; however, it appears to be stable and to work efficiently on the natural substrates. Abnormal gene product. It appears that most disease-causing missense mutations result in the production of protein that is unstable and rapidly degraded. All small and large deletions result either in a frame shift resulting in a premature stop codon, insertion or deletion of amino acids, or deletion of a significant portion of the gene. The polymorphisms listed in Table 2 result in protein that is less active than protein coded for by the most common allele. This reduced activity may result from changes in secondary structure of the mature enzyme or from protein instability. While these effects are measurable in vitro, it is not known what effects the changes have in vivo, especially in the peripheral and central nervous systems.