Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype

Abstract

Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetyl-α-D-glucosaminidase (NAGLU). Information on the natural course of MPS IIIB is scarce but much needed in view of emerging therapies. To improve knowledge on the natural course, data on all 52 MPS IIIB patients ever identified by enzymatic studies in the Netherlands were gathered. Clinical data on 44 patients could be retrieved. Only a small number (n = 9; 21%) presented with a classical MPS III phenotype; all other patients showed a much more attenuated course of the disease characterized by a significantly slower regression of intellectual and motor abilities. The majority of patients lived well into adulthood. First signs of the disease, usually mild developmental delay, were observed at a median age of 4 years. Subsequently, patients showed a slowing and eventually a stagnation of development. Patients with the attenuated phenotype had a stable intellectual disability for many years. Molecular analysis was performed in 24 index patients. The missense changes p.R643C, p.S612G, p.E634K, and p.L497V were exclusively found in patients with the attenuated phenotype. MPS IIIB comprises a remarkably wide spectrum of disease severity, and an unselected cohort including all Dutch patients showed a large proportion (79%) with an attenuated phenotype. MPS IIIB must be considered in patients with a developmental delay, even in the absence of a progressive decline in intellectual abilities. A key feature, necessitating metabolic studies, is the coexistence of behavioral problems.

A mild form of Mucopolysaccharidosis IIIB diagnosed with targeted next-generation sequencing of linked genomic regions

“…The p.S612G mutation has been identified in both compound heterozygous and homozygous states, all producing attenuated phenotypes, whereas the p.G79C mutation has been identified in a homozygous state in a severely affected individual. [19][20][21] The patients reported here are mildly affected and this supports the hypothesis that particular mutations, including p.S612G, seem to reduce the clinical severity of the disease. 21,22 Even in the presence of the p.G79C mutation known to produce a severe phenotype, the allele with the p.S612G mutation seems to be able to provide a residual enzyme activity sufficient to mitigate the course of the disease.…”

Early Umbilical Cord Blood-Derived Stem Cell Transplantation Does Not Prevent Neurological Deterioration in Mucopolysaccharidosis Type III

“…Mutation analysis showed compound heterozygosity for the p.R297X (c.889C>T) and the p.S612G (c.1834A>G) mutations. This combination of mutations has been reported previously in two brothers with an attenuated phenotype of MPS IIIB (Valstar et al 2010a). Neurocognitive testing at the age of 21 months demonstrated a normal cognitive development (DQ 94, BSID-II-NL).…”

“…This may erroneously lead to a conclusion of clinical efficacy of the UCBT in this patient. However, the mutation combination in this patient has been reported previously in two brothers (Valstar et al 2010a). One of them died at the age of 41 due to pneumonia.…”

“…The disease course in patient B closely resembles the clinical history of these brothers, and we can therefore conclude that the UCBT in this patient was ineffective. Mutations and mutation combinations conveying an attenuated phenotype have been reported frequently in MPS IIIB (Weber et al 1999;Valstar et al 2010a) and, though more rare, also occur in MPS IIIA (Meyer et al 2008;Valstar et al 2010b).…”

“…Death usually follows in the second or third decade of life. However, in recent years, a remarkably broad phenotypic spectrum, with attenuated patients living well into adulthood and expressing a developmental delay that may remain stable for many years, has been recognized (Valstar et al 2010a). To date, there is no disease-modifying treatment available for any of the subtypes of Sanfilippo disease.…”