Petter Strømme

Prevalence Estimation of Williams Syndrome

There are limited population-based data on the occurrence of Williams syndrome. We estimated its prevalence combining data from two investigations. One was an epidemiologic study originally designed to assess the prevalence and etiology of mental retardation among 30,037 Norwegian children born between 1980 and 1985 and living in Akershus County on January 1, 1993. The other investigation was a national survey of Williams syndrome. In the first study, 213 children were referred for evaluation, whereas the second study comprised 57 cases with Williams syndrome born between 1970 and 1992, who were referred for evaluation from all Norwegian counties. The epidemiologic study revealed three children with Williams syndrome, whereas one additional case complying with our demographic criteria was identified in the national survey, thus giving a prevalence of 1 in 7500. In all cases, a typical chromosome 7q11.23 deletion was detected. We also conclude that Williams syndrome is not an uncommon cause of mental retardation, with a prevalence of approximately 6% of patients with genetic etiology. (J Child Neurol 2002;17:269-271).

Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome–linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.

Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX

Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless related homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations.

Prevalence of psychiatric diagnoses in children with mental retardation: data from a population-based study

The main purpose of the study was to estimate the prevalence of psychiatric diagnoses in children with mental retardation (MR) (IQ≤70). All children born between 1980 and 1985 (N=30037) in Akershus County, Norway, were screened for possible MR and assessed with either IQ tests or standardized developmental tests. A total of 178 children, 79 with severe mental retardation (SMR) (IQ<50) and 99 with mild mental retardation (MMR) (IQ 50 to 70) were included for further study. Psychiatric symptomatology was assessed as a standard part of the neurodevelopmental examination, which included a semistructured parent interview, a clinical child interview, and retrieval of the charts of previous child psychiatric examinations. Psychiatric diagnoses were classified according to the International Classification of Disease (ICD‐10). In total, 65 (37%) of the total population with MR (95% confidence intervals 29 to 44) were registered to have psychiatric diagnoses, the most common being hyperkinesia (n=28) and pervasive developmental disorder (n=15). Psychiatric diagnoses were present in 42% of the population with SMR and 33% of the population with MMR (p=0.4). Of all children found to have a psychiatric diagnosis, approximately one‐third had previously been examined by a child psychiatrist and indicated a previously unrecognized need for these services to children with MR.

Aetiology in severe and mild mental retardation: a population-based study of Norwegian children.

The aetiology of mental retardation (MR) was studied in a population‐based series of Norwegian children derived from 30 037 children born between 1980 and 1985. The study included 178 children, 79 with severe MR (SMR) (IQ<50) and 99 with mild MR (MMR) (IQ 50 to 70). Aetiology was divided into two main groups: biopathological and unspecified. The biopathological group comprised 96% of SMR and 68% of MMR, and was subdivided into prenatal (70% and 51%), perinatal (4% and 5%), and postnatal damage (5% and 1%), and a group of undetermined timing of the damaging event (18% and 11%). Single‐gene disorders accounted for 15 of the 63 children with genetic disorders, including X‐linked recessive in six. During the course of the study, at least 27 (15%) children had their aetiological diagnosis revised. Gestational age <32 weeks, birthweight <1500g, and Apgar scores 0 to 2 at 1 and 5 minutes implied a significantly increased risk of MR, but contributed to only 4% of the children in the study. Decreased birthweight (1500 to 2499 g) and Apgar scores 3 to 6 at 1 and 5 minutes showed increased probability of MR. Despite extensive investigations, 4% of SMR and 32% of MMR were not identified with any biological markers and were considered as unspecified MR, several most probably representing the lower end of the normal IQ distribution in the population.

X-linked myoclonic epilepsy with spasticity and intellectual disability Mutation in the homeobox gene ARX

ObjectiveTo describe a new syndrome of X-linked myoclonic epilepsy with generalized spasticity and intellectual disability (XMESID) and identify the gene defect underlying this disorder. MethodsThe authors studied a family in which six boys over two generations had intractable seizures using a validated seizure questionnaire, clinical examination, and EEG studies. Previous records and investigations were obtained. Information on seizure disorders was obtained on 271 members of the extended family. Molecular genetic analysis included linkage studies and mutational analysis using a positional candidate gene approach. ResultsAll six affected boys had myoclonic seizures and TCS; two had infantile spasms, but only one had hypsarrhythmia. EEG studies show diffuse background slowing with slow generalized spike wave activity. All affected boys had moderate to profound intellectual disability. Hyperreflexia was observed in obligate carrier women. A late-onset progressive spastic ataxia in the matriarch raises the possibility of late clinical manifestations in obligate carriers. The disorder was mapped to Xp11.2–22.2 with a maximum lod score of 1.8. As recently reported, a missense mutation (1058C>T/P353L) was identified within the homeodomain of the novel human Aristaless related homeobox gene (ARX). ConclusionsXMESID is a rare X-linked recessive myoclonic epilepsy with spasticity and intellectual disability in boys. Hyperreflexia is found in carrier women. XMESID is associated with a missense mutation in ARX. This disorder is allelic with X-linked infantile spasms (ISSX; MIM 308350) where polyalanine tract expansions are the commonly observed molecular defect. Mutations of ARX are associated with a wide range of phenotypes; functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms.

Mental retardation in Norway: prevalence and sub‐classification in a cohort of 30 037 children born between 1980 and 1985

Objectives: We wanted to determine the prevalence and subcategories of mental retardation (MR) defined as IQ ≤ 70 in Akershus county, which rated by average yearly income, had the second highest socioeconomic status (SES) in Norway. Methods: The study population consisted of 30 037 children born between 1980 and 1985. Cases were ascertained from multiple sources and psychometrically assessed, predominantly with the Wechsler tests, which were standardized in Norway in 1978. The cases were divided into four groups: profound (IQ <20), severe (IQ 20‐34), moderate (IQ 35‐49), and mild (IQ 50–70) MR, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV). The median age was 10.8 y. The frequency and degree of parental consanguinity were registered, and the average inbreeding coefficient was calculated. Results: Altogether, 185 had IQ ≤ 70, giving a prevalence of MR of 6.2/1000. Prevalences for profound, severe, moderate, and mild MR were 0.8, 0.4, 1.5 and 3.5/1000, respectively. In two, possibly three, cases the parents were second cousins, giving an average inbreeding coefficient of 20‐30 × 10‐5. Conclusions: The low prevalence of MR, particularly mild MR, could partly be explained by high SES, old standardization of IQ‐test, and low inbreeding coefficient. The proportion of profound MR was considerably higher than estimated by DSM‐IV.

Postmortem Findings in Two Patients with the Carbohydrate-deficient Glycoprotein Syndrome

The postmortem findings in a pair of twins with the carbohydrate‐deficient glycoprotein syndrome are reported. Rapidly progressive olivopontocerebellar atrophy associated with retinopathy, were the most significant findings within the central nervous system. Additional observations were cerebral infarction, evidence of immune deficiency, steatosis and cirrhosis of the liver, pericarditis, renal cysts and fibrosis of the testes.

Apple peel intestinal atresia in siblings with ocular anomalies and microcephaly

Strømme P, Dahl E, Flage T, Stene‐Johansen H. Apple peel intestinal atresia in siblings with ocular anomalies and microcephaly.

Renal cysts in the carbohydrate-deficient glycoprotein syndrome

The carbohydrate-deficient glycoprotein (CDG) syndrome is a newly described genetic disorder with autosomal recessive inheritance and multiple organ involvement. We describe five patients with the CDG syndrome who all had abnormal renal structure. In two patients autopsy disclosed multiple microcysts. A hyperechogenic pattern strongly suggesting microcysts was demonstrated in all patients that were available for ultrasound examination, while a large single cyst was also seen in one patient. Based on these findings and the reports of others, renal cysts appear to be common in the CDG syndrome.