Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands
Child; Female; Humans; Male; Adult; Middle Aged; Mutation; Netherlands; Phenotype; adolescent; Preschool; infant; Models; Q3 Literature Search; Age of Onset; DNA Mutational Analysis; Acetyltransferases/chemistry/deficiency/genetics; DNA/genetics; Genotype; Missense; Molecular; Mucopolysaccharidosis III/classification/enzymology/genetics/physiopathology
Mucopolysaccharidosis IIIC (MPS IIIC, Sanfilippo C syndrome) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). We performed a clinical study on 29 Dutch MPS IIIC patients and determined causative mutations in the recently identified HGSNAT gene. Psychomotor development was reported to be normal in all patients during the first year of life. First clinical signs were usually noted between 1 and 6 years (mean 3.5 years), and consisted of delayed psychomotor development and behavioral problems. Other symptoms included sleeping and hearing problems, recurrent infections, diarrhoea and epilepsy. Two sisters had attenuated disease and did not have symptoms until the third decade. Mean age of death was 34 years (range 25-48). Molecular analysis revealed mutations in both alleles for all patients except one. Altogether 14 different mutations were found: two splice site mutations, one frame shift mutation due to an insertion, three nonsense mutations and eight missense mutations. Two mutations, p.R344C and p.S518F, were frequent among probands of Dutch origin representing 22.0% and 29.3%, respectively, of the mutant alleles. This study demonstrates that MPS IIIC has a milder course than previously reported and that both severity and clinical course are highly variable even between sibs, complicating prediction of the clinical phenotype for individual patients. A clear phenotype-genotype correlation could not be established, except that the mutations p.G262R and p.S539C were only found in two sisters with late-onset disease and presumably convey a mild phenotype.
2008
Ruijter GJ; Valstar MJ; van de Kamp JM; van der Helm RM; Durand S; van Diggelen OP; Wevers RA; Poorthuis BJ; Pshezhetsky AV; Wijburg FA
Molecular Genetics And Metabolism
2008
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1016/j.ymgme.2007.09.011" target="_blank" rel="noreferrer">10.1016/j.ymgme.2007.09.011</a>
The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature
Humans; infant; Disease Progression; Mutation; Survival Analysis; Child Development; infant; Premature; AIM; IM; Blood Chemical Analysis; alpha-Glucosidases/ge [Genetics]; alpha-Glucosidases/me [Metabolism]; Brain/pa [Pathology]; Cardiomegaly/di [Diagnosis]; Cardiomegaly/et [Etiology]; Glycogen Storage Disease Type II/co [Complications]; Glycogen Storage Disease Type II/mo [Mortality]; Glycogen Storage Disease Type II/pp [Physiopathology]; Netherlands/ep [Epidemiology]; Newborn/gd [Growth & Development]
OBJECTIVE: Infantile Pompe's disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies. METHODS: A total of 20 infantile patients diagnosed by the collaborative Dutch centers and 133 cases reported in literature were included in the study. Information on clinical history, physical examination, and diagnostic parameters was collected. RESULTS: The course of Pompe's disease is essentially the same in the Dutch and the general patient population. Symptoms start at a median age of 1.6 months in both groups. The median age of death is 7.7 and 6 months, respectively. Five percent of the Dutch patients and 8% of all reported patients survive beyond 1 year of age. Only 2 patients from literature became older than 18 months. A progressive cardiac hypertrophy is characteristic for infantile Pompe's disease. The diastolic thickness of the left ventricular posterior wall and cardiac weight at autopsy increase significantly with age. Motor development is severely delayed and major developmental milestones are generally not achieved. For the Dutch patient group, growth deviates significantly from normal despite start of nasogastric tube feeding. Levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, or creatine kinase-myocardial band isoenzyme are typically elevated, although aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase increase significantly with age. The patients have fully deleterious mutations. Acid alpha-glucosidase activity is severely deficient. CONCLUSIONS: Survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies of infantile Pompe's disease. Mutation analysis and measurement of the alpha-glucosidase activity should be part of the enrollment program. [References: 111]
2003
van den Hout HM; Hop W; van Diggelen OP; Smeitink JA; Smit GP; Poll-The BT; Bakker HD; Loonen MC; de Klerk JB; Reuser AJ; Van der Ploeg AT
Pediatrics
2003
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1542/peds.112.2.332" target="_blank" rel="noreferrer">10.1542/peds.112.2.332</a>
Juvenile hyaline fibromatosis: clinical heterogeneity in three patients
Child; Female; Humans; Male; Family Health; Preschool; infant; Fibromatosis; Hyalin/metabolism; Joint Diseases/pathology; Fibroma/genetics/metabolism/pathology; Gingival/pathology; Skin Neoplasms/genetics/metabolism/pathology; Skin/metabolism/pathology/ultrastructure
BACKGROUND: Systemic hyalinoses are genetic generalized fibromatoses characterized by an accumulation of hyalin in the dermis. Two distinctive syndromes are recognized in the literature: infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF). ISH and JHF are sometimes difficult to separate since they show significant overlap. OBSERVATIONS: We report on 3 children from two unrelated families suffering from JHF. The first child is severely handicapped by joint contracture, massive hyperplasia of the gingivae, diffuse skin papules and subcutaneous nodules occupying the scalp, face, perianal area, palms, soles and chest. At the same age, the second child only shows pearly skin papules on the face, groin and perianal area and gingival hyperplasia without joint stiffness or any other subjective complaint. The third patient, a brother of the second child, developed mild skin abnormalities by the end of the first year. The occurrence in siblings and consanguinity in the second family suggests autosomal recessive inheritance. Histological skin examination in the 3 cases showed hyaline deposition in the dermis and abnormal ultrastructure of fibroblasts. Biochemical findings showed mucopolysaccharide abnormalities in both families. CONCLUSION: Our patients do not only illustrate the different expressions of JHF but also show some overlap with ISH, suggesting a common cause for both disorders. Genetic studies will finally answer this question.
1999
Mancini GM; Stojanov L; Willemsen R; Kleijer WJ; Huijmans JG; van Diggelen OP; de Klerk JB; Vuzevski VD; Oranje AP
Dermatology (basel, Switzerland)
1999
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1159/000018058" target="_blank" rel="noreferrer">10.1159/000018058</a>