Mucopolysaccharidosis, Type Iiia

A number sign (#) is used with this entry because mucopolysaccharidosis type IIIA (MPS3A) is caused by homozygous or compound heterozygous mutation in the gene encoding N-sulfoglucosamine sulfohydrolase (SGSH; 605270) on chromosome 17q25.

Description

The Sanfilippo syndrome, or mucopolysaccharidosis III, is an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate (Esposito et al., 2000). The disorder is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. Type A has been reported (van de Kamp et al., 1981) to be the most severe, with earlier onset and rapid progression of symptoms and shorter survival.

Genetic Heterogeneity of Mucopolysaccharidosis Type III

MPS III includes 4 types, each due to the deficiency of a different enzyme: heparan N-sulfatase (type A); alpha-N-acetylglucosaminidase (type B; 252920); acetyl CoA:alpha-glucosaminide acetyltransferase (type C; 252930); and N-acetylglucosamine 6-sulfatase (type D; 252940).

Clinical Features

In the Sanfilippo syndrome, of which 4 enzymatically distinct forms are recognized, only heparan sulfate is excreted in the urine. The clinical features are severe mental defect with relatively mild somatic features (moderately severe claw hand and visceromegaly, little or no corneal clouding or skeletal, e.g., vertebral, change). The presenting problem may be marked overactivity, destructive tendencies, and other behavioral aberrations in a child of 4 to 6 years of age. Maroteaux et al. (1966) reported a kindred in which 3 separate consanguineous marriages resulted in a total of 4 cases. The radiologic findings in the skeleton are relatively mild and include persistent biconvexity of the vertebral bodies and very thick calvaria. Kresse et al. (1971) recognized 3 forms of Sanfilippo syndrome by cocultivation experiments on fibroblasts. Type A has deficiency of heparan sulfate sulfatase (EC 3.10.1.1.) (Kresse and Neufeld, 1972). Neufeld (1987) suggested that for the sake of simplicity the enzyme deficient in this disorder be termed heparan sulfatase.

Van de Kamp (1979) studied 75 cases of Sanfilippo syndrome identified in the Netherlands. Of these, 32 were type A, 18 were type B, and 12 were type C. Six had died before enzymatic studies for classification were performed. The author concluded that the clinical picture was more severe in type A than in types B and C, with shorter life expectancy. The incidence at birth was thought to be about 1 in 24,000. Van de Kamp et al. (1981) reiterated the milder course in type B with less severe dementia, and the earlier onset, greater severity, and earlier death in type A. They studied 73 patients (36 with type A, 23 with type B, 14 with type C).

Lindor et al. (1994) described an adult sister and brother with milder manifestations of MPS IIIA than in most cases. The family came to attention because of psychiatric manifestations in the sister at age 24 requiring admission to a closed psychiatric ward. A brother, then 30 years old, had required special education from the first grade and had worn hearing aids from the age of 7. The parents were nonconsanguineous, the mother being of French and Irish ancestry and the father of German ancestry. Neither sib had strikingly coarse facial characteristics.

Valstar et al. (2010) retrospectively reviewed the clinical features of 92 patients with MPS IIIA, including 32 living and 60 deceased individuals. There was wide phenotypic variability, and patients could be divided into 3 main groups: a severe, intermediate, and attenuated phenotype. Those with a severe phenotype became completely dependent of care and wheelchair-bound in their teenage years, whereas those with the intermediate phenotype had a slower regression of abilities and could live into adulthood. Those with the attenuated form reached much higher developmental levels and could achieve some speech and walking, lasting well into adulthood. Among the whole cohort, most had normal development in the first year of life, with onset of clinical symptoms at a mean age of 2.5 years. Symptoms included developmental delay, delayed speech development and behavioral problems. Behavioral problems included restlessness, temper tantrums, and crying fits, but these tended to decline with age as neurologic deterioration progressed. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The median age at death was 18 years, most commonly due to pneumonia.

Diagnosis

Toone and Applegarth (1988) used an enzymatic method to identify heterozygotes by studying leukocytes or fibroblasts. Stone et al. (1990) found that in an assay at 55 degrees C heterozygous carriers could be distinguished with complete certainty from normal controls. Twenty-one obligate carriers in 12 families were studied.

For the sulfamidase assay in chorionic villi and amniotic fluid cells, Kleijer et al. (1996) used an artificial substrate and a 2-step assay. Unequivocal assignment of the fetal status in 5 affected pregnancies and 7 pregnancies with a normal outcome confirmed the reliability of the test, which in every respect was more convenient than the conventional method using (35)S-radiolabeled heparin.

Clinical Management

Severe behavioral disturbance is a very common feature of Sanfilippo syndrome, and one of the more difficult aspects of the disorder to manage. Robertson et al. (1998) described a series of 6 patients with MPS III who had cerebrospinal shunts inserted in an attempt to ameliorate behavior that had proved refractory to conventional treatment. Symptoms improved significantly in all 6.

Sivakumur and Wraith (1999) found that bone marrow transplantation did not affect the prognosis favorably, even though neurologic manifestations were not evident.

McDowell et al. (1993) described a family in which sibs with comparable deficiencies of sulfamidase had rather different clinical severity and disease progression. The cases underscored the need for caution in counseling and the limitations of using sibs as controls in evaluating the outcome of treatment.

Population Genetics

In British Columbia, between 1952 and 1986, 4 cases of MPS IIIA were observed, giving a frequency of 1 in 324,617 live births (Lowry et al., 1990).

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 was a total of 11 cases, including 5 of type A, 5 of type B, and 1 of type C.

In the Netherlands, the incidence of MPS IIIA is estimated at 1.16 to 0.88 per 100,000 live births (Poorthuis et al., 1999).

Khan et al. (2017) analyzed the epidemiology of the mucopolysaccharidoses in Japan and Switzerland and compared them to similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II (309900), accounting for 55% of all MPS. MPS I (see 607014), III, and IV (see 253000) accounted for 15%, 16%, and 10%, respectively. MPS VI (253200) and VII (253220) were more rare and accounted for 1.7% and 1.3%, respectively. A retrospective epidemiologic data collection was performed in Switzerland between 1975 and 2008 (34 years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12%, 24%, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3% and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS was also reported to be higher in these countries.

Molecular Genetics

For a discussion of the molecular genetics of Sanfilippo syndrome A, and a listing of disease-causing allelic variants of the N-sulfoglucosamine sulfohydrolase gene (SGSH), see 605270.

Genotype/Phenotype Correlations

Valstar et al. (2010) retrospectively reviewed the clinical features of 92 patients with MPS IIIA, including 32 living and 60 deceased individuals. There was wide phenotypic variability that correlated with genotype. In particular, those with 1 or more S298P (605270.0013) mutant alleles had an attenuated phenotype, with a significantly longer preservation of psychomotor functions and a longer survival. The most frequent pathogenic mutations were R245H (605270.0001), Q380R, S66W (605270.0003), and 1080delC, all of which were associated with the classic severe phenotype.

Animal Model

Fischer et al. (1998) identified sulfamidase deficiency in 2 adult wire-haired dachshund littermates. Clinical and pathologic features paralleled the human disorder. Both dogs exhibited progressive neurologic disease without apparent somatic involvement. Pelvic limb ataxia was observed when the dogs were 3 years old and gradually progressed within 1 to 2 years to severe generalized spinocerebellar ataxia. Mentation remained normal throughout the course of the disease. A positive toluidine blue spot test of urine indicated a mucopolysaccharide storage disorder in both dogs; the diagnosis of MPS IIIA was confirmed by documentation of urinary excretion and tissue accumulation of heparan sulfate and decreased sulfamidase activity in fibroblasts and hepatic tissue.

To identify the molecular defect in the type A Sanfilippo syndrome identified by Fischer et al. (1998), Aronovich et al. (2000) determined the nucleotide sequence of the normal canine heparan sulfate sulfamidase gene and cDNA, using PCR-based approaches. The coding region showed 89% amino acid sequence homology with human HSS. All exon-intron borders were conserved. The authors identified a 3-bp deletion, 737-739delCCA, resulting in loss of threonine at position 246 in both alleles of an affected animal. The same mutation was found in 1 allele of a healthy littermate. The canine model should be useful in the evaluation of gene therapy for this disorder.

Bhattacharyya et al. (2001) described a spontaneous mouse mutant of MPS IIIa resulting from an asp31-to-asn (D31N) mutation in the murine sulfatase gene. Affected mice die at about 10 months of age exhibiting a distended bladder and hepatosplenomegaly. Brain sections show distended lysosomes, some with typical zebra body morphology, and many containing periodic-acid Schiff positive storage material. Urinalysis revealed an accumulation of heparan sulfate. Assays of a variety of lysosomal hydrolases in brain, liver, and kidney extracts uncovered a specific defect in sulfamidase activity, which was reduced by about 97%.

Hemsley and Hopwood (2005) found that the MPS IIIA mouse developed impaired open-field locomotor activity at 3 weeks of age. Abnormalities in tests of gait, grip strength, and in the assessment of the negative geotaxis response were observable from about 15 weeks of age. Behavioral changes were often detected in male MPS IIIA mice before they appeared in females. The authors postulated that axonal degeneration was responsible for the deficits. The observations provided insight into the chronology of pathologic changes within the murine MPS IIIA brain.

In brain tissue of MPS IIIA mice, Settembre et al. (2008) observed increased autophagosomes resulting from impaired autophagosome-lysosome fusion. Cells showed a decreased ability to degrade aggregation-prone proteins. There was also an accumulation of ubiquitin-positive inclusions and increased numbers of dysfunctional mitochondria. Similar findings were observed in a mouse model of another lysosomal storage disorder, multiple sulfatase deficiency (MSD; 272200). The findings were consistent with these diseases being disorders of autophagy, which may be a common mechanism in neurodegenerative lysosomal storage diseases.

Hassiotis et al. (2014) studied the development of cerebellar pathology in a canine model of MPS3A (Huntaway dog model) and observed that Purkinje cells were present in affected dogs aged up to and including 30.9 months; however, by 40.9 months, only approximately 12% remained, coincident with the onset of clinical signs. Primary and secondary substrate accumulation and inflammation were detected as early as 2.2 months, and axonal spheroids were observed from 4.3 months in deep cerebellar nuclei and later (11.6 months) in cerebellar white matter tracts. Degenerating neurons and apoptotic cells were not observed at any time. Hassiotis et al. (2014) suggested that cell-autonomous mechanisms may contribute to Purkinje cell death in the MPS3A dog.