Observational Prospective Natural History of Patients with Sanfilippo Syndrome Type B.

OBJECTIVE: To evaluate the natural course of disease progression in patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB), identify potential end points for future therapy trials, and characterize biomarkers related to the disease. STUDY DESIGN: A prospective, multicenter study was conducted. Baseline, 6-month, and 12-month assessments included neurodevelopmental status (Bayley Scales of Infant Development, Third edition), adaptive status (Vineland Adaptive Behavior Scales, Second Edition), volumetric brain magnetic resonance imaging, cerebrospinal fluid heparan sulfate, and urine glycosaminoglycan (GAG) measurements. RESULTS: Nineteen patients aged 1.6-31.7 years were enrolled. Over 12 months, cognition, adaptive behavior, and cortical gray matter volume (GMV) declined in most patients. For patients diagnosed at <6 years, although there was no overall mean change over 12 months, there were 10%-48%, 3%-66%, and 1%-14% decreases in cognitive development quotient score, Vineland Adaptive Behavior Scales, Second Edition development quotient score, and cortical GMV in 8/12, 9/11, and 10/11 patients, respectively. Mean urine GAG and cerebrospinal fluid heparan sulfate levels were stable, but patients diagnosed at <6 years (n = 14) had higher levels than those ≥6 years at diagnosis (n = 4), which was likely associated with age as they also were generally younger. CONCLUSIONS: Cognition, adaptive behavior, and cortical GMV measures sensitively tracked deterioration in patients with mucopolysaccharidosis type IIIB aged ≤8.6 years. Biomarkers may have prognostic value, but their sensitivity to disease progression requires further investigation. These findings should help evaluate enzyme replacement and gene therapy agents for this rare, devastating, neurodegenerative disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01509768.

Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency.

Disclaimer:This diagnostic guideline is intended as an educational resource and represents the opinions of the authors, and is not representative of recommendations or policy of the American College of Medical Genetics and Genomics (ACMG). The information should be considered a consensus based on expert opinion, as more comprehensive levels of evidence were not available in the literature in all cases. BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease. The underlying metabolic defect is deficiency of the enzyme acid sphingomyelinase that results in progressive accumulation of sphingomyelin in target tissues. ASMD manifests as a spectrum of severity ranging from rapidly progressive severe neurovisceral disease that is uniformly fatal to more slowly progressive chronic neurovisceral and chronic visceral forms. Disease management is aimed at symptom control and regular assessments for multisystem involvement. PURPOSE AND METHODS: An international panel of experts in the clinical and laboratory evaluation, diagnosis, treatment/management, and genetic aspects of ASMD convened to review the evidence base and share personal experience in order to develop a guideline for diagnosis of the various ASMD phenotypes. CONCLUSIONS: Although care of ASMD patients is typically provided by metabolic disease specialists, the guideline is directed at a wide range of providers because it is important for primary care providers (e.g., pediatricians and internists) and specialists (e.g., pulmonologists, hepatologists, and hematologists) to be able to identify ASMD.Genet Med advance online publication 13 April 2017.