-
[show abstract]
[hide abstract]
ABSTRACT: We investigated the predictive power of morphological features in 224 autistic patients and 224 matched-pairs controls. To assess the relationship between the morphological features and autism, we used the receiver operator curves (ROC). In addition, we used recursive partitioning (RP) to determine a specific pattern of abnormalities that is characteristic for the difference between autistic children and typically developing controls. The present findings showed that morphological features are significantly increased in patients with autism. Using ROC and RP, some of the morphological measures also led to strong predictive accuracy. Facial asymmetry, multiple hair whorls and prominent forehead significantly differentiated patients with autism from controls. Future research on multivariable risk prediction models may benefit from the use of morphological features.
Journal of Autism and Childhood Schizophrenia 06/2012; · 3.06 Impact Factor
-
H M Ozgen,
E van Daalen,
P F Bolton,
V K Maloney,
S Huang,
L Cresswell,
M J van den Boogaard,
M J Eleveld,
R van 't Slot,
R Hochstenbach, F A Beemer,
M Barrow,
J C K Barber,
M Poot
[show abstract]
[hide abstract]
ABSTRACT: Autism spectrum disorder (ASD) represents a set of neurodevelopmental disorders with a strong genetic aetiology. Chromosomal rearrangements have been detected in 5-10% of the patients with ASD, and recent applications of array comparative genomic hybridisation (aCGH) are identifying further candidate regions and genes. In this study, we present four patients who implicate microcephalin 1 (MCPH1) in band 8p23.1 as an ASD susceptibility gene. Patient 1 was a girl with a syndromic form of autistic disorder satisfying the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Oligonucleotide aCGH (oaCGH) showed that she had a classic inv dup del(8)(qter-> p23.1::p23.1-> p21.2) containing at least three candidate genes; MCPH1 and DLGAP2 within the 6.9-Mb terminal deletion and NEF3 within the concomitant 14.1-Mb duplication. Three further patients with MCPH1 copy number changes were found using single-nucleotide polymorphism (SNP) array analysis in a cohort of 54 families with ASD patients. Our results show that ASD can be a component of the classical inv dup del(8) phenotype and identify changes in copy number of MCPH1 as a susceptibility factor for ASD in the distal short arm of chromosome 8.
Clinical Genetics 10/2009; 76(4):348-56. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Autism is a complex neurodevelopmental disorder in which the interactions of genetic, epigenetic and environmental influences play a causal role. Despite the compelling evidence for a strong heritability, the etiology and molecular mechanisms underlying autism remain unclear. High phenotypic variability and genetic heterogeneity confounds the identification of susceptibility genes. The lack of robust indicators to tackle this complexity in autism has led researchers to seek for novel diagnostic tools to create homogenous subgroups. Several studies have indicated that patients with autism have higher rates of minor physical anomalies (MPAs) and that MPAs may serve as a diagnostic tool; however, the results have been inconsistent. Using the cumulative data from seven studies on MPAs in autism, this meta-analysis seeks to examine whether the aggregate data provide evidence of a large mean effect size and statistical significance for MPAs in autism. It covers the studies using multiple research methods till June 2007. The current results from seven studies suggested a significant association of MPAs in autism with a robust pooled effect size (d=0.84), and thereby provide the strongest evidence to date about the close association between MPAs and autism. Our results emphasize the importance of MPAs in the identification of heterogeneity in autism and suggest that the success of future autism genetics research will be exploited by the use of MPAs. Implications for the design of future studies on MPAs in autism are discussed and suggestions for further investigation of these important markers are proposed. Clarifying this relation might improve understanding of risk factors and molecular mechanisms in autism.
Molecular psychiatry 08/2008; 15(3):300-7. · 15.05 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The 22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with palatal abnormalities, cardiac defects, a characteristic facial appearance, learning difficulties, and delays in speech and language development. Various behavioral disorders and psychiatric illnesses have also been reported. There is much debate as to whether the behavioral problems are caused by factors such as medical discomfort, facial abnormalities or a lower intelligence, or whether they are independently related to the genetic abnormality ("behavioral phenotype"). We examined the relationship between intelligence level and behavioral problems. A group of 69 children with 22q11DS was compared with 69 children with craniofacial anomalies (CFA) using the child behavior checklist (CBCL). The matches between individual children were based on their total IQ scores. Use of the CBCL norm scores covered the corrections for age and sex. The group of 22q11DS children showed significantly more behavioral problems than the CFA group: this was especially apparent on the CBCL subscales "withdrawn," "anxious/depressed," "delinquent behavior," "aggressive behavior," "somatic complaints," and "social problems." We found no correlation between IQ score and behavioral problems in the 22q11DS group, which was remarkable because, comparable with the general population, intellectual disabilities were a predictor of behavioral problems in the CFA group. 22q11DS children with relatively higher IQs showed more problems of an internalizing than an externalizing nature, whereas the 22q11DS children with lower IQs showed various behavioral problems. The absence of a statistically significant correlation between intelligence and behavior problems in the group of 22q11DS children is tentative evidence for a 22q11DS behavioral phenotype.
American Journal of Medical Genetics Part A 04/2007; 143(6):574-80. · 2.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We report a girl with severe retardation of expressive speech development carrying a small, supernumerary ring chromosome derived from the proximal region of the long arm of chromosome 7. The r(7) chromosome is present in 50% of lymphocytes. We also review the six additional cases with a supernumerary r(7) chromosome reported in the literature. Among these patients, a severe retardation of productive language capabilities is seen as a shared clinical feature, irrespective of the degree of mosaicism as detected in blood. The dysmorphisms in these patients are minor and no shared congenital abnormalities seen. We, therefore, recommend chromosomal investigations in children with unexplained, disproportionately retarded expressive speech performance. Because speech and language acquisition are subject to genetic influences, we investigated whether there are genes on the r(7) chromosome that may affect brain development or function in a dosage-dependent manner. We found that both in our patient and in four patients described by others, the supernumerary r(7) chromosome contains the region from the centromere up to marker D7S613 located at 7q11.23. We speculate that the effects on speech acquisition are mediated by the supernumerary copies of the STX1A and LIMK1 genes, which are both located in this region and known to suppress neurite growth when overexpressed in vitro.
American Journal of Medical Genetics Part A 02/2005; 132A(1):93-100. · 2.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A bifid uvula and nasal speech were observed in a 25-year-old woman who was referred because of psychotic complaints. Fluorescence in situ hybridisation (FISH) research for the 22q11 deletion was carried out and the deletion was found. The 22q11-deletion syndrome (22q11DS) is characterised by somatic abnormalities including cardiovascular defects, velopharyngeal anomalies and typical facial characteristics. There is an increasing interest in the cognitive and psychiatric consequences of 22q11DS. There is a high prevalence of learning disabilities and the delayed development of language and speech. Mild mental retardation or borderline intellectual functioning is often reported. A broad range of psychiatric symptoms have been reported; a consistent finding is the development of a psychosis in a considerable proportion of 22q11DS patients from early adulthood onwards. It is important to consider the possibility of 22q11DS in psychiatric patients, as then early intervention strategies for later psychopathological abnormalities are possible, as well as the provision of genetic counselling.
Nederlands tijdschrift voor geneeskunde 11/2002; 146(43):2033-6.
-
[show abstract]
[hide abstract]
ABSTRACT: Autosomal dominant cerebellar ataxias (ADCAs), or spinocerebellar ataxias (SCAs), are a heterogeneous group of neurodegenerative disorders. Mild CAG repeat expansions in the alpha(1A) voltage-dependent calcium channel gene are associated with SCA type 6 (SCA6).
To obtain further insight into the contribution of SCA6 mutations to the phenotypic variability in Dutch patients with ataxia.
Survey and case series.
Hospitalized care, referral center.
The SCA6 locus was analyzed for CAG repeat expansions in a referred sample of 220 Dutch families with progressive cerebellar ataxia. Clinical characteristics of patients with SCA6 were investigated and correlated with molecular findings.
The diagnosis SCA6 was confirmed in 24 families comprising 30 familial and 4 sporadic cases. Mean +/- SD age at onset was 50.1 +/- 11.1 years. Expanded CAG repeats with sizes 22, 23, and 25 were found. These sizes correlated inversely with age at onset. No intergenerational changes in CAG repeat size were detected. Despite this, 2 families showed clinical anticipation.
This study provides the first detailed description of Dutch patients with SCA6. Clinical analysis identifies SCA6 as a late-onset ataxia in which eye movement abnormalities are prominent and consistent early manifestations. No single clinical sign can be considered specific for SCA6. Some patients have ataxia combined with episodic headaches or nausea, suggesting an overlap among SCA6, eposidic ataxia type 2, and familial hemiplegic migraine. Spinocerebellar ataxia type 6 accounts for approximately 11% of all Dutch families with ADCA. Analysis of SCA6 contributes further to the genetic classification of patients with ADCA, including patients without a clear family history of the disease.
Archives of Neurology 12/2001; 58(11):1839-44. · 7.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study examined (1) the effects of type of malformation, sex of ratee, and sex of rater on facial attractiveness and facial impairment ratings, and (2) the reliability of judgments on facial attractiveness and facial impairment and the association between these two constructs.
A university hospital for children.
Raters were eight volunteers from the student population in a university, four men and four women.
Raters judged frontal and lateral view slides of children with various types of craniofacial malformations both on a 5-point facial attractiveness scale and on a 5-point facial impairment scale.
Main effects were found for type of malformation, sex of ratee, and sex of rater. No interaction effects were found among type of malformation, sex of ratee, and sex of rater. Interrater reliability was moderate to high, both for attractiveness ratings and for impairment ratings. The correlation between facial attractiveness and facial impairment was also moderate to high. CONCLUSIONS; Both condition parameters (type of malformation) as well as social parameters (sex of rater and sex of ratee) seem to influence judgments on attractiveness and impairment. Facial attractiveness and facial impairment can be rated reliably in children with (cerebro)craniofacial dysplasias. Raters consider these concepts to be very similar but not identical.
The Cleft Palate-Craniofacial Journal 08/2001; 38(4):386-92. · 0.82 Impact Factor
-
American Journal of Medical Genetics 04/2001; 99(2):159-60.
-
American Journal of Medical Genetics 02/2001; 99(2):159 - 160.
-
Journal of Inherited Metabolic Disease 12/2000; 23(7):760-4. · 3.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The intrafamilial variability of late-onset glycogen storage disease type II was studied in siblings of 18 patients and in reports in the literature. Siblings of seven of the 18 index cases opted for DNA testing or enzyme studies after being informed by the index case of the availability of testing, and after genetic counselling. Of the 12 siblings tested, five asymptomatic individuals were diagnosed (mean age, 32.8 years; range, 17-53). Intrafamilial variability in the age at onset (more than 10 years difference) or in the clinical symptoms was found in one of seven sibships tested in this study, and also in seven sibships reported in the literature. We advocate that testing should not be offered to healthy siblings of late-onset glycogen storage disease type II patients as a routine, because it is impossible to give a precise prognosis to an individual who is symptom-free, but has been identified with a glycogen storage disease type II genotype, nor is there any therapeutic intervention available.
Neuromuscular Disorders 11/2000; 10(7):467-71. · 2.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Glycerol kinase deficiency (GKD) is an X-linked recessive disorder. There are two types. an isolated form and a complex form. We review the clinical, biochemical and molecular genetic features of GKD. The clinical and biochemical phenotype of isolated GKD may vary from a life-threatening childhood metabolic crisis to asymptomatic adult 'pseudohypertriglyceridaemia', resulting from hyperglycerolaemia. To date 38 patients from 24 families with isolated GKD have been reported. At least 7 of these patients had a metabolic crisis during a catabolic condition. The complex GKD is an Xp21 contiguous gene syndrome involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Clinical features of a patient with complex GKD depend on the loci that are involved. Approximately 100 patients from 78 families with a complex GKD have been reported. Seventeen patients with complex GKD (AHC-GKD-DMD or AHC-GKD) died in the neonatal period or early childhood because of unrecognized or inappropriate management of adrenal dysfunction. Since the outcome of the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis. From molecular genetic investigations of isolated GKD, 7 missense mutations, 2 splice site mutations, I nonsense mutation, 1 Alu Sx insertion and 2 small deletions were reported for isolated GKD in 13 unrelated families. In 4 families consisting of more than one patient with the same biochemical and genetic defect, the phenotypic variability of the isolated GKD was remarkable. The clinical variability in isolated GKD cannot be explained by biochemical or by molecular heterogeneity. Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further.
Journal of Inherited Metabolic Disease 10/2000; 23(6):529-47. · 3.58 Impact Factor
-
Nature Genetics 05/2000; 24(4):342-3. · 35.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Glycogen storage disease type II (GSD H) is an autosomal recessive myopathy. Early and late-onset phenotypes are distinguished - infantile, juvenile and adult. Three mutations in the acid alpha-glucosidase gene are common in the Dutch patient population: IVS1(-13T-->G), 525delT and delexon18. 63% of Dutch GSD II patients carry one or two of these mutations, and the genotype-phenotype correlation is known. To determine the frequency of GSD II, we have screened an unselected sample of neonates for the occurrence of these three mutations. Based on the calculated carrier frequencies, the predicted frequency of the disease is 1 in 40000 divided by 1 in 138 000 for infantile GSD II and 1 in 57 000 for adult GSD II. This is about two to four times higher than previously suggested, which is a reason to become more familiar with the presentation of GSD II in its different clinical forms and to adjust the risk assessment for genetic counselling.
European Journal of HumanGenetics 09/1999; 7(6):713-6. · 4.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Data are collected with the Child Behavior Check List (CBCL) as well as with the Teacher Report Form (TRF) of 40 VCFS children between 4 and 18 years of age. Half of the group shows very high problem scores in the "clinical" range. The average T-score of the VCFS children as a group are over 60 (one standard deviation above the mean) for the "total problem score" and the "internalising score". The highest scores with the subscales are found with "withdrawn" and "social problems". But also "thought problems" and "attention problems" score over 60. The VCFS children show more behavior problems and personality problems than the matched control children with a craniofacial anomaly. The differences are highly statistically significant.
Genetic counseling (Geneva, Switzerland) 02/1999; 10(1):89-93. · 0.50 Impact Factor
-
M G Ausems,
K ten Berg,
M A Kroos,
O P van Diggelen,
R A Wevers,
B J Poorthuis,
K E Niezen-Koning,
A T van der Ploeg, F A Beemer,
A J Reuser,
L A Sandkuijl,
J H Wokke
[show abstract]
[hide abstract]
ABSTRACT: To compare the overall birth prevalence of diagnosed glycogen storage disease type II (GSD II) with the predicted frequency based on mutation screening, in order to determine whether GSD II is an underdiagnosed condition, and to analyze which medical disciplines recognize GSD II.
Retrospective data on all enzymatic diagnoses of GSD II were collected from diagnostic labs throughout the Netherlands, covering the period from January 1, 1972 to December 31, 1996. Age-specific diagnostic incidence rates were calculated for the entire study period. By adding together the diagnostic incidences for all age groups, we calculated the birth prevalence of diagnosed GSD II and compared these figures with the predicted frequency based on mutation screening in a random sample from the general population. The medical specialization of the referring clinicians was also recorded.
GSD II was diagnosed in 154 individuals, including 11 prenatal diagnoses. The birth prevalences of the various phenotypes were 1/101,000 (infantile form), 1/720,000 (juvenile form) and 1/53,000 (adult form). The birth prevalence of the adult and infantile phenotype together was 1/35,000. Eighty-two percent of the patients were diagnosed in university hospitals. Of the patients with infantile GSD II, 71% were diagnosed by a pediatrician, whereas most patients with adult GSD II were diagnosed by a neurologist (80%).
There is no evidence for the underdiagnosis of GSD II in the Netherlands, as the calculated birth prevalences of the disease are consistent with previous predictions based on mutation screening in a random sample of newborns. The worldwide birth prevalence of the disease may well be higher than 1 in 100,000. GSD II is mainly diagnosed in university hospitals.
Community Genetics 02/1999; 2(2-3):91-6. · 1.32 Impact Factor
-
A. B. P. Van Kuilenburg,
P. Vreken,
N. G. G. M. Abeling,
H. D. Bakker,
R. Meinsma,
H. Van Lenthe,
R. A. De Abreu,
J. A. M. Smeitink,
H. Kayserili,
M. Y. Apak, [......],
W. J. Kleijer, F. A. Beemer,
M. Duran,
K. E. Niezen-Koning,
G. P. A. Smit,
C. Jakobs,
L. M. E. Smit,
U. Moog,
L. J. M. Spaapen,
A. H. Van Gennip
[show abstract]
[hide abstract]
ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in
homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic
and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD.
In this group of patients, 7 different mutations have been identified, including 2 deletions [295–298delTCAT, 1897delC], 1
splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence
of the various mutations among DPD patients has shown that the G→A point mutation in the invariant splice donor site is by
far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has
been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations.
A clear correlation between the genotype and phenotype has not been established. An altered β-alanine, uracil and thymine
homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.
Human Genetics 01/1999; 104(1):1-9. · 5.07 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Isolated glycerol kinase deficiency (GKD) is an X linked recessive disorder. The clinical and biochemical picture may vary from a childhood metabolic crisis to asymptomatic adult "pseudohypertriglyceridaemia", the result of hyperglycerolaemia. We performed glycerol kinase (GK) gene analysis to study the molecular heterogeneity and genotype-phenotype correlation in eight males from three families with isolated GKD. All patients had hyperglycerolaemia and glyceroluria. Four patients from two families were essentially free of symptoms. Three patients had gastrointestinal symptoms with ketoacidosis or hypoglycaemia or both. One patient had recurrent convulsions as the only acute sign, without evidence that it was correlated with a catabolic state. Fasting tests in two symptomatic patients of family 1 showed hyperketotic states, together with a tendency to hypoglycaemia. The diagnosis was confirmed by a defective 14C-glycerol incorporation into trichloroacetic acid precipitable macromolecules in intact skin fibroblasts. Mutation screening of the GK gene was performed by amplification and direct sequencing of exons using PCR. Three novel mutations were identified: (1) a deletion starting downstream of exon 9, extending to the 3' end of the gene; (2) a nonsense mutation R413X caused by a C1351T transition; and (3) a missense mutation W503R caused by a T1651C transition. In addition, we found differences from the reported sequence: (1) exon 9 actually consists of two exons, which consequently will change the number of GK gene exons from 19 to 20 exons, and (2) nucleotide differences in exon 19. So far, no genotype-phenotype correlation can be established in these GKD families.
Journal of Medical Genetics 09/1998; 35(8):650-6. · 6.36 Impact Factor
-
Journal of Inherited Metabolic Disease 07/1998; 21(3):276-9. · 3.58 Impact Factor
