Schindler Disease, Type I
A number sign (#) is used with this entry because of evidence that Schindler disease types I and III are caused by homozygous or compound heterozygous mutation in the alpha-N-acetylgalactosaminidase gene (NAGA; 104170) on chromosome 22q13.
DescriptionAlpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy; type II, also known as Kanzaki disease (609242), is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder with mild to moderate neurologic manifestations (Desnick and Schindler, 2001).
Clinical FeaturesSchindler Disease, Type I
Van Diggelen et al. (1987, 1988) reported 2 sons of a German couple with remote consanguinity who were affected with type I lysosomal alpha-N-acetylgalactosaminidase deficiency. Starting at age 9 months, the boys showed neurologic symptoms and developmental delay followed by rapid progressive psychomotor deterioration. By the ages 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. The levels of NAGA 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 enzyme 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) reported that the affected German boys demonstrated severe psychomotor retardation, myoclonic seizures, decorticate posture, optic atrophy, blindness, marked long tract signs, and total loss of contact with the environment by ages 3 to 4 years. No visceral 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 consistent with a diagnosis of neuroaxonal dystrophy.
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). Characteristic 'spheroids' were observed histologically and ultrastructurally in terminal axons in gray matter. They concluded that the disorder, which they referred to as Schindler disease, was an autosomal recessive form of infantile axonal dystrophy. Schindler et al. (1989) also characterized the disorder as a neuroaxonal dystrophy.
Wolfe et al. (1995) reported neuropathologic findings from the affected boys reported by van Diggelen et al. (1988). Widespread spheroid formation was observed in terminal and preterminal axons. Neocortical and peripheral autonomic axons contained tubulovesicular and lamelliform membranous arrays, prominent acicular clefts, and electron-dense axoplasmic matrix. Other alterations resembling those in various neuronopathic lysosomal storage diseases were not observed. The findings were remarkably similar to those seen in Seitelberger disease.
Keulemans et al. (1996) reported a distant affected relative of the boys described by van Diggelen et al. (1987). He had normal development until age 7 months, when he developed convulsions. He died at 18 months of hypoxia during a prolonged convulsion causing apnea. During the last 3 months of his life, development had stopped. Keulemans et al. (1996) noted that the original brothers were alive at ages 11 and 12 years, but remained in a persistent vegetative state.
Bakker et al. (2001) reported a 3-year-old boy, born of consanguineous Moroccan parents, with alpha-NAGA deficiency. He showed congenital bilateral cataracts 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. Histopathologic studies were not performed. The proband and his 7-year-old healthy brother had undetectable alpha-NAGA activity in leukocytes and a profound deficiency in fibroblasts. Both patients had blood group O. The parents had alpha-NAGA activity consistent with heterozygosity. Bakker et al. (2001) noted that factors in addition to alpha-NAGA activity must play a role in the phenotype, as the 2 brothers had vastly different phenotypes. Bakker et al. (2001) also commented that NAGA deficiency with neuroaxonal dystrophy had not been reported since 1987, and suggested that the original German boys reported by van Diggelen et al. (1988) may have had 2 disorders: alpha-NAGA deficiency and neuroaxonal dystrophy. Accidental occurrence of 2 independent monogenic diseases may occur in consanguineous families, as was the case for the German boys.
Schindler Disease, Type III
De Jong et al. (1994) reported 2 Dutch sibs with alpha-NAGA deficiency. The proband was an 11-month-old girl with generalized seizures and persistent mild oligosacchariduria. Enzymatic study of plasma, leukocytes, and fibroblasts revealed alpha-NAGA deficiency. Electron microscopy of lymphocytes showed no vacuolization, but incubation of cultured fibroblasts with Helix pomatia lectin showed intracellular N-acetylgalactosamine-containing storage material. A younger asymptomatic brother, who was part of a dizygotic twin pair, had the same enzyme deficiency. De Jong et al. (1994) concluded that these were mild cases of alpha-NAGA deficiency. In a follow-up of the girl reported by de Jong et al. (1994), Keulemans et al. (1996) noted that she had psychomotor retardation since about 1 year of age. The brother remained healthy at age 3 years. Bakker et al. (2001) reported that the brother of the affected girl reported by de Jong et al. (1994) remained without clinical signs and symptoms at age 8 years.
Molecular GeneticsIn the 2 German boys with alpha-N-acetylgalactosaminidase deficiency reported by van Diggelen et al. (1987, 1988), Wang et al. (1990) identified a homozygous glu325-to-lys (E325K) mutation in the NAGA gene (104170.0001). Keulemans et al. (1996) identified a distant affected relative of the 2 boys who had the same homozygous mutation.
In the Dutch girl with type III NAGA deficiency reported by de Jong et al. (1994), Keulemans et al. (1996) identified compound heterozygosity for 2 mutations in the NAGA gene (104170.0001 and 104170.0004). The same genotype was found in the clinically unaffected 3-year-old brother of the proband, and the authors suggested that the brother might be a preclinical case of NAGA deficiency; the brother's twin sister did not have the genotype.
Bakker et al. (2001) identified the homozygous E325K mutation in a 3-year-old Moroccan boy with NAGA deficiency. The same genotype was found in his clinically unaffected 7-year-old brother. A third unaffected sib and both parents were heterozygous for the mutation. 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 of the disorder.
Genotype/Phenotype CorrelationsKeulemans et al. (1996) found that the 3 related German boys with type I NAGA deficiency retained residual NAGA activity in fibroblasts that was higher than NAGA activity in 2 patients with the less severe adult-onset Kanzaki disease. They also noted the absence of visceral lysosomal storage findings in the infantile cases compared to the presence of vacuolization in the milder adult patients. Keulemans et al. (1996) postulated that additional factors or genes must contribute to the phenotype, and even suggested that severe infantile patients may have 2 distinct disorders of NAGA deficiency and neuroaxonal dystrophy.
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 of Keulemans et al. (1996) 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.