Mucopolysaccharidosis type IIIA: clinical spectrum and genotype-phenotype correlations.
OBJECTIVE
Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies.


METHODS
Clinical history and molecular defects of all 110 MPS IIIA patients identified by enzymatic studies in the Netherlands were collected and included in this study.


RESULTS
First clinical signs, mainly consisting of delayed speech development and behavioral problems, were noted between the ages of 1 and 6 years. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The clinical course varied remarkably and could be correlated with the molecular defects. The frequent pathogenic mutations p.R245H, p.Q380R, p.S66W, and c.1080delC were associated with the classical severe phenotype. Patients compound heterozygous for the p.S298P mutation in combination with 1 of the mutations associated with the classical severe phenotype had a significantly longer preservation of psychomotor functions and a longer survival. Two patients homozygous for the p.S298P mutation, and 4 patients from 3 families heterozygous for 3 missense variants not reported previously (p.T421R, p.P180L, and p.L12Q), showed a remarkably attenuated phenotype.


CONCLUSIONS
We report the natural history and mutational analysis in a large unbiased cohort of MPS IIIA patients. We demonstrate that the clinical spectrum of MPS IIIA is much broader than previously reported. A significant genotype-phenotype correlation was established in this cohort.
Department of Pediatrics and Amsterdam Lysosome Center Sphinx, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Marlies J
MJ
Valstar
Sanne
S
Neijs
Hennie T
HT
Bruggenwirth
Renske
R
Olmer
George J G
GJ
Ruijter
Ron A
RA
Wevers
Otto P
OP
van Diggelen
Ben J
BJ
Poorthuis
Dicky J
DJ
Halley
Frits A
FA
Wijburg
D000293:Adolescent; D000328:Adult; D001526:Behavioral Symptoms / Q000209:etiology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000209:etiology; D005260:Female; D005347:Fibroblasts; D056726:Genetic Association Studies; D005838:Genotype; D006311:Hearing Disorders / Q000209:etiology; D006801:Humans; D006867:Hydrolases / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009084:Mucopolysaccharidosis III / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011247:Pregnancy; D012044:Regression Analysis; D012720:Severity of Illness Index; D012867:Skin / Q000473:pathology; D012893:Sleep Wake Disorders / Q000209:etiology; D014786:Vision Disorders / Q000209:etiology; D055815:Young Adult
D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase