Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype

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

Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome)

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder caused by a deficiency of one of the enzymes involved in the degradation of heparan sulfate. MPS III is characterized by progressive mental deterioration resulting in severe dementia. A number of potentially disease-modifying therapies are studied. As preservation of cognitive function is the ultimate goal of treatment, assessment of cognitive development will be essential in order to evaluate treatment efficacy. However, no large scale studies on cognitive levels in MPS III patients, using formal psychometric tests, have been reported. We aimed to assess cognitive development in all 73 living patients with MPS III in the Netherlands. Cognitive development could be assessed in 69 patients. In 39 of them developmental level was estimated > 3 months and formal psychometric testing was attempted. A remarkable variation in the intellectual disability was detected. Despite special challenges encountered, testing failed in only three patients. The observed broad variation in intellectual disability, should be taken into account when designing therapeutic trial

Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome)

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder caused by a deficiency of one of the enzymes involved in the degradation of heparan sulfate. MPS III is characterized by progressive mental deterioration resulting in severe dementia. A number of potentially disease-modifying therapies are studied. As preservation of cognitive function is the ultimate goal of treatment, assessment of cognitive development will be essential in order to evaluate treatment efficacy. However, no large scale studies on cognitive levels in MPS III patients, using formal psychometric tests, have been reported. We aimed to assess cognitive development in all 73 living patients with MPS III in the Netherlands. Cognitive development could be assessed in 69 patients. In 39 of them developmental level was estimated > 3 months and formal psychometric testing was attempted. A remarkable variation in the intellectual disability was detected. Despite special challenges encountered, testing failed in only three patients. The observed broad variation in intellectual disability, should be taken into account when designing therapeutic trial

Predicting health-related quality of life of parents of children with inherited metabolic diseases

The aim of this study was to examine medical, socio-demographic and psychosocial determinants of health-related quality of life (HRQoL) of parents of children with metabolic diseases. A survey among parents of children with metabolic diseases (children aged 1-19 years, diagnosed > 1 year before the start of the study, living at home). Parents were approached through the Emma Children's Hospital, and through a national parent and patient association. HRQoL was assessed using the TNO-AZL Questionnaire for Adult's Health Related Quality of Life (TAAQOL), describing 12 domains of HRQoL. Predictor variables were taken from a self-report questionnaire. Univariate and multivariate logistic regression analyses were performed to predict which parents were at risk for HRQoL impairment. Mainly psychosocial determinants were predictive for parental HRQoL. Emotional support was protective for parental HRQOL while loss of friendship was a risk factor for HRQoL impairment. Medical and socio-demographic variables did not consistently predict parental HRQoL. Psychosocial determinants appeared more important in predicting parental HRQoL than medical and socio-demographic variables. Interventions should be focused on supporting parents combining the care for their children with a social life. Further research on this subject is necessary. In the meantime, involved medical specialists should pay structural attention to parental functionin

Genistein in Sanfilippo disease: A randomized controlled crossover trial

Objective: Sanfilippo disease (mucopolysaccharidosis type III [MPS III]) is a rare neurodegenerative metabolic disease caused by a deficiency of 1 of the 4 enzymes involved in the degradation of heparan sulfate (HS), a glycosaminoglycan (GAG). Genistein has been proposed as potential therapy but its efficacy remains uncertain. We aimed to determine the efficacy of genistein in MPS III. Methods: Thirty patients were enrolled. Effects of genistein were determined in a randomized, crossover, placebocontrolled intervention with a genistein-rich soy isoflavone extract (10mg/kg/day of genistein) followed by an openlabel extension study for patients who were on genistein during the last part of the crossover. Results: Genistein resulted in a significant decrease in urinary excretion of total GAGs (p 0.02, slope = 0.68mg GAGs/mmol creatinine/mo) and in plasma concentrations of HS (p 0.01, slope = 15.85ng HS/ml/mo). No effects on total behavior scores or on hair morphology were observed. Parents or caregivers could not predict correctly during which period of the crossover a patient was on genistein. Interpretation: Genistein at 10mg/kg/day effectively reduces urinary excretion of GAGs and plasma HS concentration in patients with MPS III. However, the absolute reduction in GAGs and in HS is small and values after 12 months of treatment remain within the range as observed in untreated patients. No clinical efficacy was detected. Substantially higher doses of genistein might be more effective as suggested by recent studies in animal models. ANN NEUROL 2012; 71: 110-12