Mucopolysaccharidosis, Type Iiib

A number sign (#) is used with this entry because Sanfilippo syndrome B, or mucopolysaccharidosis type IIIB, is caused by homozygous or compound heterozygous mutation in the gene encoding N-alpha-acetylglucosaminidase (NAGLU; 609701) on chromosome 17q21.

Description

Sanfilippo syndrome B is an autosomal recessive lysosomal storage disorder characterized by the accumulation of heparan sulfate. Clinically, patients have progressive neurodegeneration, behavioral problems, mild skeletal changes, and shortened life span. The clinical severity ranges from mild to severe (Chinen et al., 2005).

For a phenotypic description and a discussion of genetic heterogeneity of Sanfilippo syndrome, or mucopolysaccharidosis III, see MPS IIIA (252900).

Clinical Features

Harris (1961) may have reported the earliest case of Sanfilippo syndrome. The same patient was later shown by Neufeld (1973) to have MPS IIIB.

Van Schrojenstein-de Valk and van de Kamp (1987) reviewed 7 patients, aged 30 to 43 years, with a mild variant of Sanfilippo syndrome B. Somatic findings in these patients were unremarkable. Dementia and behavioral disturbances occurred late in the course of the disease. Four of the 7 patients were sibs in family A; 2 were sibs in family B, and the seventh was a double first cousin of these 2.

Yogalingam et al. (2000) reported a patient with an attenuated form of Sanfilippo syndrome B confirmed by genetic analysis (609701.0003; 609701.0010). The patient presented at 18 months of age with failure to thrive, developmental delay, hepatomegaly, and diarrhea. At age 3 he had coarse hair, a protuberant abdomen, soft hepatomegaly, and normal facies. Liver function testing and a skeletal survey were both normal. He was intellectually delayed with hyperactive aggressive behavior but showed no regression. He had had a slowly progressive course but was still alive at age 31. Functional studies showed significant residual NAGLU activity sufficient to metabolize 34% of intracellular 35-S-labeled GAG storage, suggesting that some mutant NAGLU was being correctly sorted to the lysosomal compartment. Yogalingam et al. (2000) suggested that the residual NAGLU activity could explain the attenuated phenotype in their patient.

Biochemical Features

O'Brien (1972) determined that the defect in Sanfilippo syndrome B was absence or decreased activity of alpha-N-acetylglucosaminidase.

Andria et al. (1979) reported 3 sibs with MPS IIIB. Two sibs were severely affected and 1 was mildly affected. The finding of clinical heterogeneity within the same family was unusual. In cell fusion studies with cells from the mild case of Andria et al. (1979) and cells from severe cases, Ballabio et al. (1984) found no complementation, indicating that both mild and severe forms of the disorder are allelic.

Pande et al. (1992) described the daughter of first-cousin parents who had both MPS IIIB and Glanzmann disease (273800). Both disorders map to chromosome 17q21. In this family, there was no genetic linkage between the 2 disorders when studied by analyzing the heterozygotes. While the mother of the proband had NAGLU activity levels in the heterozygous range, the father had normal levels similar to those of a wildtype homozygote. Several family members had abnormally high levels of NAGLU activity, consistent with a 'hyperactive' allele, as had been demonstrated by Vance et al. (1980, 1981) and by Pericak-Vance et al. (1985). Pande et al. (1992) concluded that the father of the proband had an unusual NAGLU genotype: a combination of a hyperactive allele and a defective allele. The findings indicated that normal levels of the NAGLU enzyme can be found in obligate heterozygotes, thus precluding genotype classification on a biochemical basis alone.

Diagnosis

Prenatal Diagnosis

Kleijer et al. (1984) made the prenatal diagnosis of Sanfilippo syndrome B and found that elevated heparan sulfate in the amniotic fluid complemented the enzyme assay.

Minelli et al. (1988) made the prenatal diagnosis of Sanfilippo syndrome B by chorionic villus sampling.

Clinical Management

Vellodi et al. (1992) performed bone marrow transplantation in twin sisters with Sanfilippo syndrome B. The diagnosis was made at the age of 18 months, at which time they were clinically normal, on the basis of abnormal excretion of heparan sulfate in the urine and deficiency of glucosaminidase in the plasma and leukocytes; the diagnosis was suspected because an older brother was affected. The transplant was first done from the haploidentical father; there was no engraftment in either so that a second transplant was carried out with success from the haploidentical mother. Follow-up for 9 years posttransplant showed that neither twin was as handicapped as the untreated brother at the same age; other evidence of beneficial effect was recorded.

Cytogenetics

Wenger et al. (2000) described a child who had Sanfilippo syndrome B with a homozygous mutation in the NAGLU gene, glycogen storage disease (GSD) type Ia (232200), and a presumably balanced translocation between chromosomes 12 and 20. The parents were nonconsanguineous and of Czechoslovakian/Hungarian ancestry; 3 of the 4 grandparents were 'ethnically similar.' The karyotype of the father and a normal brother was 46,XY. The mother was 45,X in lymphoblasts and mosaic 45,X/47,XXX in fibroblasts. Both Sanfilippo syndrome B and GSD Ia map to chromosome 17q21, suggesting a common mechanism. Wenger et al. (2000) stated that it was highly unlikely that the 2 recessive disorders and the de novo translocation in the same patient were unrelated occurrences.

Molecular Genetics

Using SSCP analysis of PCR-amplified segments of genomic DNA from patients with Sanfilippo syndrome B, Zhao et al. (1996) identified several recessive mutations in the NAGLU gene (see, e.g., 609701.0001-609701.0005).

In a mutation screen of 20 patients with Sanfilippo syndrome B, Tessitore et al. (2000) identified 28 mutations, 14 of which were novel, in the NAGLU gene. Of these mutations, 4 were found in homozygosity and only 1 was seen in 2 different patients, showing the remarkable molecular heterogeneity of the disorder.

Tanaka et al. (2002) performed molecular analysis of the NAGLU gene in 7 Japanese patients with Sanfilippo syndrome B from 6 unrelated families; 6 disease-causing mutations were found, of which 2 were novel. Two families were from Okinawa, where more patients with Sanfilippo syndrome were found than in other areas in Japan. Two sibs, who were compound heterozygous for F314L (609701.0011) and R565P (609701.0009), showed an attenuated form. Two patients with a severe phenotype with rapid progression were homozygous for R482W (609701.0012) and R565P, respectively. Tanaka et al. (2002) suggested that the R565P mutation is common in Okinawa. Chinen et al. (2005) identified the homozygous R565P mutation in 5 unrelated Japanese patients from Okinawa, suggesting a founder effect.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. They identified a family (8600486) in which 3 of 4 children, born to parents related as first cousins once removed, had MPS IIIB (severe intellectual disability, autism spectrum disorder, and coarse facial features) and a homozygous missense mutation in the NAGLU gene (609701.0014).

Population Genetics

In series of cases of Sanfilippo syndrome collected in most parts of the world, type A is more frequent than type B. Among 11 patients in Greece, however, Beratis et al. (1986) found that 10 had type B and 1 had type A. Both parents of the latter patient came from the Greek ethnic community of Turkey. All of the type B cases came from east-central Greece and neighboring areas of Thessaly and Macedonia.

Using multiple ascertainment sources, Nelson et al. (2003) obtained an incidence rate for Sanfilippo syndrome (all forms combined) in western Australia for the period 1969 to 1996 of approximately 1 in 58,000 live births; there were a total of 11 cases, including 5 of type A, 5 of type B, and 1 of type C.

Mangas et al. (2008) noted the MPS IIIB is the most common form of MPS among Portuguese. The authors identified a founder mutation (R234C; 609701.0013) in the NAGLU gene, which accounted for 32% of mutant alleles in their study of 11 Portuguese patients with the disorder. Haplotype analysis showed that the R234C mutation arose on a founder haplotype common to both Spanish and Portuguese individuals, suggesting that the mutation had a single and relatively recent origin in the Iberian peninsula.

Animal Model

Ellinwood et al. (2003) reported naturally occurring Sanfilippo syndrome IIIB in Schipperke dogs. Two affected dogs presented at about 3 years of age with progressive ataxia, tremors, and lethargy. Other findings included mildly dystrophic corneas and small peripheral foci of retinal degeneration. Naglu activity was less than 10% of normal values. Postmortem examination showed severe cerebellar atrophy with marked Purkinje cell loss.