Kerstin Strömland

Autism in thalidomide embryopathy : a population study

Of a population of 100 Swedish thalidomide embryopathy cases, at least four met full criteria for DSM‐III‐R autistic disorder and ICD‐10 childhood autism. Thalidomide embryopathy of the kind encountered in these cases affects fetal development early in pregnancy, probably on days 20 to 24 after conception. It is argued that the possible association of thalidomide embryopathy with autism may shed some light on the issue of which neural circuitries may be involved in autism pathogenesis.

Teratogen update: thalidomide: a review, with a focus on ocular findings and new potential uses

Thalidomide (a-[N-phthalmido]-glutarimide) was synthesized in 1954, in what was then West Germany, by Chemie Grunenthal under the brand name of Contergan and was subsequently licensed in 46 other countries worldwide, covering all continents. It is an odorless white crystalline compound with low solubility in water (McBride, ’77; Stirling et al., ’97). A number of pharmaceutical companies manufactured thalidomide in various concentrations under several trade names (Stirling et al., ’97).Advertisements for the drug claimed that it was helpful in treating anxiety, insomnia, gastritis, and tension and that it was safe and harmless for pregnant women (Lenz, ’88). Additionally, it was an effective antiemetic in pregnancy (McBride, ’77). Thalidomide was first marketed in Germany in October 1957 as an effective, safe, inexpensive sedative, and production in that country reached 14.58 tons by 1960 (Zwingenberger and Wendt, ’96). A liquid form was available for children, and some compounds were sold without prescriptions (Stirling et al., ’97). Routine screening tests found thalidomide to be nontoxic in rodents, and therefore its potent teratogenicity in humans and higher mammals was not anticipated (Brent and Holmes, ’88). In the early 1960s an increasing number of infants were born with hypoplastic limb defects (Lenz,’85). In fall 1961, Lenz, noting these congenital malformations in the German population, suggested a possible correlation with thalidomide taken during pregnancy. He reported his observations at meetings and in the medical literature (Lenz,’61a,b,’62; Lenz and Knapp, ’62). Similar observations were made in England (Smithells, ’62) and Australia (McBride, ’61). Within a few months of the initially reported cases, the drug was withdrawn from commercial sale by Grunenthal (November 1961), and 9 months later was taken off the market in Japan. It was withdrawn from Great Britain in December 1961 (Kida, ’87). The potent teratogenicity appropriately suppressed other uses of thalidomide, such as for anti-inflammatory effects (Somers, ’60, Miller et al., ’60). The U.S. Food and Drug Administration (FDA) had not approved the drug for unrestricted use because of concerns (primarily about possible peripheral neuropathy) raised by Francis Kelsey, an FDA physician. Thus the number of cases of thalidomide embryopathy in the United States was small (Kelsey, ’88). The teratogenic effects of thalidomide contributed to the passage of new regulatory legislation for pharmaceuticals (Stirling et al.,’97). There are many reviews in the literature of various aspects of the thalidomide story (McBride, ’77; Fraser, ’88; Kelsey, ’88; Lenz, ’88; Warkany, ’88; Lenz, ’88).

Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review

Autism is a complex developmental disorder without an established single etiology but with significant contributions from genetic studies, functional research, and neuropsychiatric and neuroradiologic investigations. The purpose of this paper is to review the findings in five studies involving individuals manifesting the characteristic findings of autism spectrum disorder associated with malformations and dysfunctions known to result from early embryogenic defects. These investigations include two associated with teratogens (thalidomide embryopathy, Möbius sequence with misoprostol) and three (most Möbius sequence cases, CHARGE association, Goldenhar syndrome) with no known etiology.

Prenatal Alcohol Exposure and Neurodevelopmental Disorders in Children Adopted From Eastern Europe

OBJECTIVES: The purposes of this investigation were to determine the frequencies of and associations between different neurodevelopmental disorders and to study the potential lasting effects of alcohol on children adopted from eastern Europe. METHODS: In a population-based, prospective, observational, multidisciplinary, cross-sectional, cohort study of 71 children adopted from eastern Europe, children were assessed 5 years after adoption, from pediatric, neuropsychological, and ophthalmologic perspectives. RESULTS: Fetal alcohol spectrum disorders, that is, fetal alcohol syndrome (FAS), partial FAS, and alcohol-related neurodevelopmental disorders, were identified for 52% of children; FAS was found for 30%, partial FAS for 14%, and alcohol-related neurodevelopmental disorders for 9%. Alcohol-related birth defects were found for 11% of children, all of whom also were diagnosed as having FAS. Mental retardation or significant cognitive impairment was found for 23% of children, autism for 9%, attention-deficit/hyperactivity disorder for 51%, and developmental coordination disorder for 34%. CONCLUSIONS: Fetal alcohol spectrum disorders and neurodevelopmental disorders were common in this long-term follow-up study of children adopted from orphanages in eastern Europe. Maternal alcohol consumption during pregnancy has long-lasting adverse effects, causing structural, behavioral, and cognitive damage despite a radically improved environment.

Autistic spectrum disorders in Möbius sequence: a comprehensive study of 25 individuals

The prevalence of autistic disorder was analysed in 25 individuals with Möbius sequence, a disorder with brain-stem dysfunction. The sample consisted of 18 males and seven females (20 participants were aged 2 to 22 years, and five were aged 1, 19 and 23 months, and 55 years old). Participants were recruited after a nationwide call and were part of a multidisciplinary study of individuals with Möbius sequence. They were given a meticulous neuropsychiatric examination including standardized autism diagnostic interviews. Ten individuals had an autistic spectrum disorder. Six of these met all diagnostic criteria for autism. In 23 individuals cognitive development could be assessed. Eight of those 23 patients had clear learning disability and six individuals were functioning in the normal but subaverage range. Autistic spectrum disorder and learning disability occurred in more than a third of the examined patients. Considering the hospital-based nature of the sample, these findings may be overestimates. Nevertheless, awareness of this coexistence is important in the diagnosis and habilitation care of children with Möbius sequence. Moreover, the results provide further support for the notion of a subgroup of autistic spectrum disorders being caused by first trimester brain-stem damage.

The Möbius sequence: A relook

BACKGROUND The constellations of findings often referred to as Mobius syndrome might be better described as Mobius sequence, because the term sequence defines a cascade of secondary events after an embryonic insult from heterogeneous causes. Classic clinical findings include evidence of sixth and seventh cranial nerve involvement, often with associated malformations of limbs, craniofacial structures, and other cranial nerves. METHODS A prospective study was undertaken in Sweden of 25 patients who showed characteristic findings of Mobius sequence. RESULTS Of the patients who did not have strabismus surgery, 10 patients had straight eyes in the primary position, 7 had esotropia, 2 had exotropia, and 1 had hypertropia. All had significant limitation of abduction, except 1 patient with exotropia who showed minimal underaction on abduction but a large limitation of adduction. In the description in these early cases, some patients manifested a clinical pattern resembling a horizontal gaze paresis. Narrowing of the palpebral fissure on adduction similar to that seen in Duane syndrome was observed in a few cases. Two patients had ptosis. Nineteen patients had diminished facial expression bilaterally, often asymmetric, and 6 cases appeared to be unilateral. Seven patients had abnormal tearing. Associated systemic findings included Poland anomaly (2), club feet or other limb anomalies (8), micrognathia (8), tongue malformations (17), cleft palate (5), and speech problems (18). An unusual finding was autism syndrome (6) or autism-like syndrome (1). CONCLUSIONS The associated findings in Mobius sequence may give further clues to the location and timing of the developmental disturbance. The wide range of ocular motility patterns suggests that the previous concept of a lesion solely in the sixth nerve nucleus is an inadequate explanation for these findings.

Thalidomide embryopathy: Revisited 27 years later

Abstract A prospective ophthalmological study was done in 86 out of a total of 100 Swedes with established thalidomide embryopathy. Forty‐six (54%) of all examined individuals had eye findings, which made the eye the second most commonly affected organ in thalidomide embryopathy only surpassed by upper limbs (81%). Forty‐three patients (50%) had ocular motility defects, mostly incomitant strabismus. Facial palsy and abnormal lacrimation each occurred in 17 (20%) individuals. One patient had coloboma of the uvea and optic disc and another two had coloboma of the optic disc. Infrequent anomalies were microphthalmos, congenital glaucoma, lipodermoid, and large refractive errors. The observed ocular motility defects, facial palsy and abnormal lacrimation occurred with early induced defects in thalidomide embryopathy, but not with isolated late occurring anomalies. This suggests that thalidomide exerts its effects on the development of these structures early in the teratogenic period, probably mainly during the fourth week of development.

CHD7 mutation spectrum in 28 Swedish patients diagnosed with CHARGE syndrome

CHARGE syndrome is a disorder characterized by Coloboma, Heart defect, Atresia choanae, Retarded growth and/or development, Genital hypoplasia and Ear anomalies. Heterozygous mutations in the chromodomain helicase DNA‐binding protein 7 (CHD7) gene have been identified in about 60% of individuals diagnosed with CHARGE syndrome. We performed a CHD7 mutation screening by direct exon sequencing in 28 index patients (26 sporadic cases, 1 familial case consisting of a brother and sister and 1 case consisting of monozygotic twins) diagnosed with CHARGE syndrome in order to determine the mutations in a cohort of Swedish CHARGE syndrome patients. The patients without a detectable CHD7 mutation, or with a missense mutation, were further investigated by multiplex ligation‐dependent probe amplification (MLPA) in order to search for intragenic deletions or duplications. Thirteen novel mutations and five previously reported mutations were detected. The mutations were scattered throughout the gene and included nonsense, frameshift and missense mutations as well as intragenic deletions. In conclusion, CHD7 mutations were detected in a large proportion (64%) of cases diagnosed with CHARGE syndrome. Screening for intragenic deletions with MLPA is recommended in cases where mutations are not found by sequencing. In addition, a CDH7 mutation was found in an individual without temporal bone malformation.

Autism spectrum disorders and underlying brain pathology in CHARGE association

The rate of autism spectrum disorders (ASDs) and brain abnormalities was analyzed in 31 individuals (15 males, 16 females; age range 1mo to 31y, mean age 8y 11mo) with CHARGE association, as part of a multidisciplinary study. A meticulous neuropsychiatric examination was performed, including standardized autism diagnostic interviews. Judgement regarding ASDs was impossible in three infants and three patients who were deaf and blind. Five individuals met diagnostic criteria for autism, five for an autistic‐like condition, and seven for autistic traits. Brain abnormalities were indicated in almost three‐quarters of examined individuals, and midline abnormalities of the forebrain in one‐third. Awareness of the coexistence of CHARGE and ASDs is important in habilitation care in CHARGE. Moreover, the results indicate that a subgroup of ASDs may be associated with errors in early embryonic brain development.

Morphometry of the optic nerve and retinal vessels in children by computer-assisted image analysis of fundus photographs.

Abstract• Background: The retinal fundus in childhood has a different morphology than in adulthood. Existing methods are not suitable for evaluation of fundus photographs from children. Therefore, a new method for quantitative analysis of fundus morphology utilizing a personal computer-assisted digital mapping system was developed. • Methods: A CCD flatbed scanner is used to digitize fundus photographs, producing computer images which are analyzed on an IBM/AT computer. Area measurements of the optic disc, excavation and peripapillary crescent are made, as well as determinations of the length, branching, tortuosity and distribution of the retinal vessels on the fundus surface. • Results: Determination of the inter-and intra-observer variability of the computer-assisted image analysis technique demonstrated good reproducibility. The method is demonstrated using fundus photographs of six normal children and six children with the fetal alcohol syndrome. Typical variations in appearance of optic disc and retinal vessels are seen. • Conclusion: The system is unique in measuring both the optic nerve head and the retinal vessels and is therefore especially useful for detailed studies of normal and abnormal development of these structures in children.