a) Parametri Genetici delle Neuropatie Sensomotorie Ereditarie (HMSN)

v) LEUCODISTROFIA A CELLULE GLOBOIDALI o MORBO DI KRABBE
 (GLOBOID CELL LEUKODYSTROPHY or KRABBE's DISEASE)

DESCRIPTION

In the early infantile form of Krabbe disease, onset occurs at 4 to 6 months of age.
Definitive diagnosis of this disorder, which clinically can be so similar to several other encephalopathies of infancy, is made by finding characteristic 'globoid cells' in brain tissue.
These cells, derived from monocyte-macrophage stem cells of the bone marrow, contain accumulated psychosine as well as galactosylceramide.
The disorder is due to mutations of the gene encoding glycosylceramidase (GALC).

CLINICAL FEATURES

Nelson et al. (1963) observed 3 affected sibs.
A somewhat similar state 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).
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.
First-cousin parents were noted by Van Gehuchten (1956). Many have described affected sibs.

Suzuki (1972) described 2 patients with morphologically and enzymatically proved Krabbe disease who survived unusually long--into the teens in the oldest--and might represent an allelic form.
Kolodner (1989) described such cases, the oldest case in his experience being that of an 84-year-old woman. Crome et al. (1973) described a late-onset variety.
>From complementation studies by somatic cell hybridization, Loonen et al. (1985) concluded that the early-infantile and late-onset forms of GLD are allelic.
They proposed that there are 2 late-onset forms : a late-infantile or early-childhood form, and a late-childhood or juvenile 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 feature of Krabbe disease. Their communication concerned a total of 11 affected children seen in Israel, all of Arab origin and 4 from related Druze families.
Arroyo et al. (1991) described Krabbe disease in all 3 of monozygotic triplets.
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.

Phelps et al. (1991) reported 4 cases with late 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. Lyon et al. (1991) reviewed 50 cases.

BIOCHEMICAL FEATURES

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 aetiologic 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.

Ben-Yoseph et al. (1978) studied tissue from 4 cases of Krabbe disease and showed that catalytically deficient galactosylceramide beta-galactosidase enzyme immunologically identical to normal enzyme was present in normal quantities.
Thus, the mutation is in the structural gene. 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.

Wenger and Louie (1991) discussed pseudodeficiency of galactocerebrosidase comparable to the pseudodeficiency of arylsulfatase A ; both are hard to distinguish from the bona fide deficiency which may signify a presymptomatic person who will present with adult-onset clinical disease. Kolodny et al. (1991) reviewed the clinical and biochemical features of 15 cases of late-onset Krabbe disease.

GENETIC MAPPING

By study of mouse-man somatic hybrid cells, Rushton and Dawson (1977) concluded that the genes for all the glycosphingolipid beta-galactosidases are on chromosome 12, but could not answer the question of the number of separate beta-galactosidases.
They studied the activities of galactosylceramide, lactosylceramide and GM1-ganglioside beta-galactosidases.

The 'twitcher' mouse mutation results in an autosomal recessive leukodystrophy that is similar histopathologically to Krabbe disease (Duchen et al., 1980).
Lyerla et al. (1989) found that in somatic cell hybrids made by fusing fibroblasts from the 'twitcher' mouse and normal human fibroblasts, the presence of human chromosome 17 was associated with expression of galactocerebrosidase activity.
Thus, they suggested that the Krabbe disease mutation is located on human chromosome 17.
Studies by Zlotogora et al. (1990) showed, however, that the Krabbe disease mutation is located on human chromosome 14. Although the enzyme defect had been known for a long time, attempts to purify GALC and to produce monospecific antibodies had not been successful. Because it was impossible to map the GALC gene by molecular genetic methods, Zlotogora et al. (1990) undertook linkage analysis with RFLPs, focusing first on chromosome 17.
When no evidence of linkage was found there, they took advantage of the homology between the mouse and human chromosomes and the report that the twitcher locus is on mouse chromosome 12 (Sweet, 1986), a chromosome that has large regions of homology with human chromosome 14.
A multipoint lod score of 3.40 was found with marker D14S24. It appears that the GALC locus lies somewhere in the region 14q21-q31. By isotopic in situ hybridization, Cannizzaro et al. (1994) placed GALC at 14q31.

MOLECULAR GENETICS

In addition to being a major lipid in myelin, galactosylceramide is an important constituent of kidney and epithelial cells of small intestine and colon.
Chen et al. (1993) used degenerate PCR primers, derived from N-terminal aminoacid sequence from the 51-kD band from human brain, to amplify cat testes RNA for GALC, and used the resulting product to screen human testes and brain libraries.
Two overlapping clones containing the total protein coding region were obtained.

Sakai et al.(1994) were the first to purify galactocerebrosidase (EC 3.2.1.46) from human lymphocytes and to clone a cDNA for it.
The deduced aminoacid sequence matched all aminoacid sequences determined. The 3,780-nucleotide sequence included 2,007 nucleotides that encoded a single chain peptide of 669 amino acid residues with a 26-amino acid N-terminal signal peptide and 6 potential asparagine-linked glycosylation sites.
A glu369-to-ter nonsense mutation was identified in a patient with typical Krabbe disease.

Luzi et al. (1995) determined that the human GALC gene contains 17 exons spanning about 60kb of genomic DNA. GALC has a GC-rich promoter region similar to the genes of otherlysosomal proteins.

Rafi et al. (1995) described a mutation of the GALC gene leading to the loss of exons 11-17. The deletion was associated with a C-to-T transition at position 502 of the cDNA leading to replacement of arginine by cysteine.
Expression of the 502/del mutation in COS-1 cells resulted in no measurable GALC activity above that in mock transfected cells. Rafi et al. (1995) indicated that, while not yet confirmed by expression studies, 3 missense mutations and 1 single nucleotide insertion had been identified in patients with infantile Krabbe disease.

POPULATION GENETICS

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.

ANIMAL MODEL

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) cloned the canine GALC cDNA and demonstrated that the 2,007-bp open reading frame is 88% identical to that in human, and the deduced amino acid sequence about 90% identical.
However, the 3-prime-untranslated region is about 1 kb shorter than that in the human.
The disease-causing mutation in the canine GALC gene was demonstrated to be an A-to-C transversion at cDNA position 473 (Y158S).

ALLELIC VARIANTS

.0001 KRABBE DISEASE [GALC, GLU369TER]

In a patient with typical Krabbe disease, Sakai et al. (1994) identified a GAA-to-TAA mutation in codon 369, predicting a change of a glutamic acid residue to a termination codon. The patient was homozygous.

.0002 KRABBE DISEASE, INFANTILE [GALC, EX11-17DEL]

Rafi et al. (1995) stated that although most patients with globoid cell leukodystrophy have the severe infantile form, patients up to 50 years of age have been diagnosed in their laboratory.
They reported that a large deletion, together with a polymorphic C-to-T transition at position 502 of the cDNA (counting from the A of the initiation codon), was responsible for a large number of disease-causing alleles in patients with Krabbe disease.
Of 48 patients evaluated, 10 were found to be homozygous for the 502/del allele, 5 were heterozygous for this allele, 21 were heterozygous for the 502 mutation (presence of the deletion could not be confirmed), and 1 infantile patient was homozygous for the 502 mutation but at least 1 allele was not deleted. No patient was found to have the deletion without the 502 mutation.
The deletion of the entire coding region located beyond exon 10 was first detected by failure to PCR amplify any cDNA sequences from that part of the gene. Intron 10 is the largest intron in the GALC gene and is estimated to be about 12 kb in length.
In the patients with deletions, PCR amplification was successful for detecting only about 5 kb into intron 10. The large deletions starting within intron 10 result in the loss of coding information from 7 exons which represent about 15% of the 50-kD subunit and all of the 30-kD subunit.
Normally, these 2 subunits are produced from the 80-kD precursor protein (Chen and Wenger, 1993).
The occurrence of the deletion on the 502 allele and not on the normal allele indicates that the deletion event may have happened only once.
The large deletion occurred particularly in patients with infantile Krabbe disease who have northern European ancestry; however, 1 homozygous patient had a Hispanic surname.
Since more people have the 502 mutation and are carriers of classic Krabbe disease, it must be a polymorphism.
However, the change from arginine to cysteine could result in improper folding of the GALC subunits due to abnormal disulfide bond formation.

.0003 KRABBE DISEASE, LATE INFANTILE [GALC, PRO302ALA]

In a Japanese patient with the late infantile form of Krabbe disease, Tatsumi et al. (1995) found heterozygosity for a missense mutation causing substitution of alanine for proline at codon 302.

.0004 KRABBE DISEASE, LATE INFANTILE [GALC, VAL550GLY]

In a non-Japanese patient with the late infantile form of Krabbe disease, Tatsumi et al. (1995) found a missense mutation resulting in substitution of glycine for valine at codon 550 of the GALC gene. The mutation was present in homozygous state.

.0005 KRABBE DISEASE, INFANTILE [GALC, ASP-ASN, 1582G-A]

Zlotogora et al. (1991) identified 12 Krabbe disease patients from the Moslem Arab population located near Jerusalem and 6 patients from a Druze kindred. Rafi et al. (1996) demonstrated that different mutations are responsible for Krabbe disease in these 2 populations.
The Arab patients were homozygous for a G-to-A transition at nucleotide 1582, which changed the codon for aspartic acid to one for asparagine.
There was also a polymorphism at cDNA position 1637 (T-to-C transition).
All sequences were numbered from the A of the initiation codon.
The Druze patients showed a T-to-G transversion at cDNA position 1748 in homozygous state.
This change resulted in the replacement of isoleucine by serine. The authors did not indicate the codon number of either mutation.

.0006 KRABBE DISEASE, INFANTILE [GALC, ILE-SER, 1748T-G]

See Rafi et al. (1996).

SEE ALSO

Andrews et al. (1971) ; Austin (1963) ; Austin et al. (1970) ; Eto et al. (1983) ; Farrell et al. (1973) ; Hoogerbrugge et al. (1988) ; Kobayashi et al. (1982) ; Kodama et al. (1982) ; Krabbe (1916) ; Lieberman et al. (1980) ; Martin et al. (1981) ; Petersen et al. (1978) ; Svennerholm et al. (1981) ; Tanaka and Suzuki (1976) ; Tsutsumi et al. (1982) ; Vanier et al. (1981) ; Wenger et al. (1974)

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    Am. J. Hum. Genet. 47: 37-44, 1990. 

61. Zlotogora, J.; Cohen, T. : 
    Krabbe disease and protruding ears. (Letter) 
    Am. J. Med. Genet. 28: 759-760, 1987.

62. Zlotogora, J.; Levy-Lahad, E.; Legum, C.; Iancu, T. C.; Zeigler, M.; 
    Bach, G. : 
    Krabbe disease in Israel. 
    Isr. J. Med. Sci. 27: 196-198, 1991.

63. Zlotogora, J.; Regev, R.; Zeigler, M.; Iancu, T. C.; Bach, G. : 
    Krabbe disease: increased incidence in a highly inbred community. 
    Am. J. Med. Genet. 21: 765-770, 1985.