Shindler Disease ALPHA-GALACTOSIDASE B; GALBAlternative titles; symbols
N-ACETYL-ALPHA-D-GALACTOSAMINIDASE; NAGALYSOSOMAL ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, INCLUDEDSCHINDLER DISEASE, INCLUDEDNEUROAXONAL DYSTROPHY, SCHINDLER TYPE, INCLUDEDKANZAKI DISEASE, INCLUDEDGene map locus 22q11
TEXT
In a study of man-rodent somatic cell hybrids, de Groot et al. (1978) assayed human N-acetyl-alpha-D-galactosaminidase activity and concluded that alpha-galactosidase B and mitochondrial aconitase (ACO2; 100850), known to be on chromosome 22, are syntenic. They also obtained evidence for direct assignment of alpha-galactosidase B to chromosome 22. Alpha-NAGA was thought to be a more appropriate designation for this enzyme than alpha-galactosidase B by de Groot et al. (1978), who claimed that there was no structural relationship between alpha-gal A (on the X chromosome; GLA; 301500) and so-called alpha-gal B. However, DNA studies (Wang et al., 1990;Wang and Desnick, 1991), described later, led to a different conclusion. In man-rodent cell hybrids, Geurts van Kessel et al. (1979, 1980) studied chronic myeloid leukemia cells to determine the site of the break on 22q relative to markers assigned to chromosomes 22 and 9. Alpha-NAGA remained with the Ph-1 chromosome, whereas ACO2 went with chromosome 9. Thus, the former is probably in band 22q11, whereas the latter is between it and 22qter.
Wang et al. (1990) isolated a full-length 2.2-kb cDNA and a genomic cosmid clone containing the entire NAGA gene. Sequence analysis revealed striking similarities between the NAGA locus and exons 1-6 of alpha-galactosidase A, suggesting that the 2 genes evolved by duplication and divergence from a common ancestral locus. Wang and Desnick (1991) also pointed to remarkable amino acid identity between the NAGA and GLA genes.
In 2 sons of a German couple with remote consanguinity, van Diggelen et al. (1987, 1988) described the clinical and biochemical features of lysosomal alpha-N-acetylgalactosaminidase deficiency. The boys showed neurologic abnormalities starting at age 9 months, followed by progressive psychomotor deterioration. By the age of 2.5 and 4 years, they had 'largely lost their previously acquired motor and language skills.' Growth had been normal. Computerized tomographic scans were normal, and there was no organomegaly, obvious coarsening of the facies, or skeletal dysplasia. A uniquely abnormal pattern of urinary oligosaccharides was demonstrated by thin-layer chromatography. Among the carbohydrate-hydrolyzing lysosomal enzymes, only alpha-NAGA had not previously been associated with a disorder. The levels of this enzyme were very low in cultured fibroblasts, leukocytes and plasma, whereas these levels were normal in a healthy brother. Both parents had low normal or reduced activity. A major neutral oligosaccharide from the urine of 1 patient was identified as the blood group A determinant, a trisaccharide with terminal alpha-N-acetylgalactosamine. The concentration of this product in the urine of the older boy, who was a secretor and had blood group A, was 5 times normal. The younger boy, who had blood group O, did not excrete this trisaccharide. Schindler et al. (1988) described the clinical findings as consisting of severe psychomotor retardation with myoclonic seizures, decorticate posture, optic atrophy, blindness, marked long tract signs, and total loss of contact with the environment. No features of other lysosomal storage diseases were present. Ultrastructural examination of peripheral nerves was unremarkable, whereas the rectal mucosa contained dystrophic autonomic axons with 'tubulovesicular' material. A unique pattern of abnormal urinary oligosaccharides/glycopeptides was found by thin-layer chromatography. Wang et al. (1988) pointed out that the brothers reported by van Diggelen et al. (1987) had a clinical course and neuropathologic findings similar to those in Seitelberger disease, the infantile form of neuroaxonal dystrophy (256600). The characteristic 'spheroids' were observed histologically and ultrastructurally in terminal axons in gray matter. This disorder, which they referred to as Schindler disease, must represent, therefore, a form of infantile axonal dystrophy, the first in which a specific enzymatic defect has been identified. The disorder is autosomal recessive. Schindler et al. (1989) also characterized the disorder as a neuroaxonal dystrophy. They pointed out that although the disorder is caused by deficiency of a lysosomal enzyme, no lysosomal storage could be identified. It has been proposed that the dystrophic axons in infantile neuroaxonal dystrophy result from defective retrograde axonal transport. How deficiency of alpha-N-acetylgalactosaminidase might lead to a similar problem is not clear. Using PCR amplification and sequence analysis of PCR product from type I and type II offspring of consanguineous matings, Wang et al. (1990) demonstrated single basepair mutations in the homozygous state in both type I and type II. (Type I is classic Schindler disease; type II is an adult disorder with angiokeratoma as a prominent feature (104170.0002). Type II might appropriately be called Kanzaki disease (Kanzaki et al., 1989).)
Keulemans et al. (1996) reported the genotypes of 5 more patients with NAGA deficiency. One of them, related to the first reported German family (van Diggelen et al., 1987), had classic Schindler disease and the same homozygous mutation, i.e., glu325to-lys (104170.0001). The only manifestations in another patient, a 5-year-old Dutch girl whose family was clinically described by de Jong et al. (1994), were convulsions during fever and psychomotor retardation starting after the age of 1 year. She had 2 different mutations: glu325-to-lys inherited from her father and ser160-to-cys (104170.0004) inherited from her mother. The same genotype was found in a clinically unaffected 3.5-year-old brother of the proband. Keulemans et al. (1996) suggested that the brother might be a preclinical case of NAGA deficiency detected through screening. A homozygous nonsense mutation, glu193-to-ter, was found in 2 adult Spanish sibs who had angiokeratoma, lymphedema, and vacuolization in dermal cells, but no neurologic signs. These sibs, previously reported by Chabas et al. (1994), were clinically similar to the original patient described by Kanzaki et al. (1989). Although at the metabolic level the patients with NAGA deficiency are similar, extreme differences between the infantile form(s) and the adult form (Kanzaki disease) suggested to Keulemans et al. (1996) that other factors or genes contribute to the clinical heterogeneity.
Bakker et al. (2001) reviewed the 11 known patients with alpha-NAGA deficiency. The patients, who were from 7 families of German, Japanese, Dutch, Spanish, French/Italian/Albanian, and Moroccan descent, showed extreme clinical heterogeneity from no clinical symptoms to infantile neuroaxonal dystrophy. They reiterated the suggestion that alpha-NAGA deficiency is not a single disease entity but that factors other than alpha-NAGA contribute to the phenotype variation. They further speculated that severe infantile patients have a double disease: neuroaxonal dystrophy in addition to alpha-NAGA deficiency, without causal relationship.
ALLELIC VARIANTS(selected examples)
.0001 SCHINDLER DISEASE [NAGA, GLU325LYS]
In the first cases described with Schindler disease (15,16:van Diggelen et al., 1987, 1988), Wang et al. (1990) found a G-to-A transition at nucleotide 973 of the NAGA gene, resulting in substitution of lysine for glutamic acid as residue 325 (E325K).
Bakker et al. (2001) reported homozygosity of the E325K mutation in the 3-year-old son of consanguineous Moroccan parents. He showed congenital bilateral cataract and an abnormal oligosaccharide pattern in urine suggestive of alpha-NAGA deficiency. At the age of 12 months he showed slightly delayed neuromotor development, which became more prominent in the next 2 years. NMR of the brain showed diffuse white matter abnormalities with a secondary, symmetrical demyelinization. The proband and his 7-year-old healthy brother had undetectable alpha-NAGA activity in leukocytes and a profound deficiency in fibroblasts. The parents had alpha-NAGA activity consistent with heterozygosity. Mutation analysis revealed homozygosity of the E325K mutation in the proband and his healthy brother, whereas a third sib and both parents were heterozygous. The family demonstrated the extreme clinical heterogeneity of alpha-NAGA deficiency, as the homozygous brother at the age of 7 years showed no clinical or neurologic symptoms.
.0002 KANZAKI DISEASE [NAGA, ARG329TRP]
In a 46-year-old Japanese woman with disseminated angiokeratoma, Kanzaki et al. (1989) demonstrated numerous cytoplasmic vacuoles in cells of the kidney and skin. Enzyme activities against synthetic and natural substrates were normal in leukocytes and fibroblasts. Her urine contained a large amount of sialylglycoaminoacids, with predominant excretion of an O-glycoside-linked glycoaminoacid. No information was provided on the patient's family. The enzyme studies excluded Fabry disease (301500), fucosidosis (230000), galactosialidosis (256540), and the various mucolipidoses and mucopolysaccharidoses. Desnick (1991) recounted reading an abstract by Kanzaki et al. (1988) in which the presence of angiokeratoma attracted his attention because of his longtime work with Fabry disease; the possibility that this disorder was related to Schindler disease was suggested by the excretion of large amounts of glycopeptides in the urine. A collaboration thereafter led to the demonstration that indeed there is deficiency of alpha-galactosidase B in Kanzaki disease also (Wang et al., 1990). Even though the disorder was much milder, with no neurodegeneration and no neuroaxonal dystrophy, the deficiency of enzymes seemed to be of the same order as in type I Schindler disease. In the laboratory of Desnick (1991), a substitution of tryptophan for arginine-329 was demonstrated as the basic defect (Wang et al., 1994). Again, it is remarkable that a change so close to that in Schindler disease could cause such a different phenotype. This situation is comparable to that of the Hurler and Scheie forms of mucopolysaccharidosis I and to the allelic mild and severe forms of many lysosomal storage diseases. Kanzaki et al. (1991) provided further evidence that there are 2 forms of alpha-N-acetylgalactosaminidase deficiency with sialopeptiduria: a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral lysosomal inclusions, and an adult-onset form with angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides, and the absence of detectable neurologic involvement. Kanzaki et al. (1993) gave an extensive description of the 46-year-old Japanese woman with the adult form of lysosomal alpha-N-acetylgalactosaminidase deficiency. The angiokeratomas first appeared on her lower torso when she was 28 years old and later became diffusely distributed. Her 2 unaffected children had half-normal enzyme levels, consistent with autosomal recessive inheritance. The woman had mild intellectual impairment and peripheral neuroaxonal degeneration. She was the product of a first-cousin marriage and worked in a hospital as a nurse's aide. Endoscopic examination demonstrated telangiectasia on the gastric mucosa. Dilated blood vessels were present on the ocular conjunctiva and dilated vessels with corkscrewlike tortuosity were observed in the fundi.
To identify the mutation causing this phenotypically distinct adult-onset form of NAGA deficiency, Wang et al. (1994) used reverse transcription, amplification, and sequencing of the NAGA transcript. The change was a C-to-T transition at nucleotide 985, resulting in an R329W amino acid substitution. The base substitution was confirmed by hybridization of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Wang et al. (1994) showed that in transiently expressed COS-1 cells, both the E325K (infantile-onset) and R329W (adult-onset) precursors were processed to the mature form; however, the E325K mutant polypeptide was more rapidly degraded than the R329W subunit, thereby providing a basis for the distinctly different infantile- and adult-onset phenotypes.
.0003 KANZAKI DISEASE [NAGA, GLU193TER ]
Keulemans et al. (1996) showed by PCR and sequence analysis that the Spanish brother and sister with manifestations of Kanzaki disease described by Chabas et al. (1994) were homozygous for an E193X mutation in exon 5 leading to complete loss of NAGA protein.
.0004 NAGA DEFICIENCY, MILD FORM [NAGA, SER160CYS ]
Keulemans et al. (1996) reported that a Dutch girl with NAGA deficiency and mild neurologic manifestations was heterozygous for the E325K (104170.0001) mutation and a C-to-G change at nucleotide 11017 (numbering according to Yamauchi et al., 1990) in exon 4, leading to a substitution of serine for cysteine at residue 160. The same genotype was found in the 3-year-old asymptomatic brother of the proband, who was presumed by the authors to be presymptomatic.
SEE ALSO
Wang et al. (1990)
REFERENCES
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