RESUMEN
Descriptions of the clinical features of Angelman syndrome (AS) have mainly been focused on children. Here, we describe the evolution of the clinical phenotypes of AS in adulthood, using clinical data from 95 individuals (mean age 31.6 years, median 29.0 years, range 18-83 years), with genetically confirmed AS. Data was collected through physical examination and inspection of medical records, combined with questionnaires and interviews. Adults with AS experience substantial debilitating health problems. Constipation, reflux, visual problems, scoliosis, behavioral and sleeping problems occurred frequently and require appropriate attention. Epilepsy was reported in 57% of adults, negatively affecting the level of functioning. Non-convulsive status epilepticus was not observed in the adults, however some individuals developed prolonged episodes of rhythmic shaking while awake. A decline in mobility was noted in the majority of adults. A minority of adults with AS showed microcephaly. Taken together, this first phenotypic study of adults with AS to include in person interviews with care-givers and physical examination of patients, including the eldest adult reported to date, provides important insight in the development of the syndrome into adulthood. This knowledge is required to improve care for adult individuals with AS and to evaluate future therapies for this group.
Asunto(s)
Síndrome de Angelman/diagnóstico , Síndrome de Angelman/epidemiología , Epilepsia/diagnóstico , Epilepsia/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Síndrome de Angelman/complicaciones , Síndrome de Angelman/fisiopatología , Epilepsia/complicaciones , Epilepsia/fisiopatología , Femenino , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/epidemiología , Reflujo Gastroesofágico/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
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, placebo-controlled intervention with a genistein-rich soy isoflavone extract (10mg/kg/day of genistein) followed by an open-label 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 -0.68 mg GAGs/mmol creatinine/mo) and in plasma concentrations of HS (p = 0.01, slope -15.85 ng 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.
Asunto(s)
Genisteína/uso terapéutico , Mucopolisacaridosis III/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios Cruzados , Método Doble Ciego , Femenino , Glicosaminoglicanos/orina , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mucopolisacaridosis III/orina , Adulto JovenRESUMEN
BACKGROUND: 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. METHODS: We aimed to assess cognitive development in all 73 living patients with MPS III in the Netherlands. RESULTS: 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. CONCLUSIONS: 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 trials.
Asunto(s)
Cognición , Mucopolisacaridosis III/patología , Envejecimiento , HumanosRESUMEN
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. INTERPRETATION: 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.
Asunto(s)
Estudios de Asociación Genética , Genotipo , Fenotipo , Adolescente , Adulto , Síntomas Conductuales/etiología , Células Cultivadas , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Epilepsia/etiología , Femenino , Fibroblastos , Trastornos de la Audición/etiología , Humanos , Hidrolasas/genética , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mucopolisacaridosis III/complicaciones , Mucopolisacaridosis III/enzimología , Mucopolisacaridosis III/genética , Mucopolisacaridosis III/patología , Mutación/genética , Embarazo , Análisis de Regresión , Índice de Severidad de la Enfermedad , Piel/patología , Trastornos del Sueño-Vigilia/etiología , Trastornos de la Visión/etiología , Adulto JovenRESUMEN
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.
Asunto(s)
Fenotipo , Algoritmos , Causas de Muerte , Células Cultivadas , Niño , Preescolar , Parto Obstétrico/métodos , Parto Obstétrico/estadística & datos numéricos , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Mucopolisacaridosis III/clasificación , Mucopolisacaridosis III/diagnóstico , Mucopolisacaridosis III/epidemiología , Mucopolisacaridosis III/mortalidad , Embarazo , Sistema de RegistrosRESUMEN
Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N-acetylglucosamine-6-sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported. The clinical phenotype of 12 new MPS IIID patients from 10 families was studied. Mutation analysis of GNS was performed in 16 patients (14 index cases). Clinical signs and symptoms of the MPS IIID patients appeared to be similar to previously described patients with MPS III. Early development was normal with onset of behavioral problems around the age of 4 years, followed by developmental stagnation, deterioration of verbal communication and subsequent deterioration of motor functions. Sequence analysis of the coding regions of the gene encoding GNS (GNS) resulted in the identification of 15 novel mutations: 3 missense mutations, 1 nonsense mutation, 4 splice site mutations, 3 frame shift mutations, 3 large deletions and 1 in-frame small deletion. They include the first missense mutations and a relatively high proportion of large rearrangements, which warrants the inclusion of quantitative techniques in routine mutation screening of the GNS gene.
Asunto(s)
Mucopolisacaridosis III/genética , Sulfatasas/deficiencia , Sulfatasas/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Mutación/genética , Fenotipo , Adulto JovenRESUMEN
AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 functioning.