Arja Voutilainen

A dominant gene for developmental dyslexia on chromosome 3

Developmental dyslexia is a neurofunctional disorder characterised by an unexpected difficulty in learning to read and write despite adequate intelligence, motivation, and education. Previous studies have suggested mostly quantitative susceptibility loci for dyslexia on chromosomes 1, 2, 6, and 15, but no genes have been identified yet. We studied a large pedigree, ascertained from 140 families considered, segregating pronounced dyslexia in an autosomal dominant fashion. Affected status and the subtype of dyslexia were determined by neuropsychological tests. A genome scan with 320 markers showed a novel dominant locus linked to dyslexia in the pericentromeric region of chromosome 3 with a multipoint lod score of 3.84. Nineteen out of 21 affected pedigree members shared this region identical by descent (corrected p<0.001). Previously implicated genomic regions showed no evidence for linkage. Sequencing of two positional candidate genes, 5HT1F andDRD3, did not support their role in dyslexia. The new locus on chromosome 3 is associated with deficits in all three essential components involved in the reading process, namely phonological awareness, rapid naming, and verbal short term memory.

A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32

Developmental dyslexia is a distinct learning disability with unexpected difficulty in learning to read despite adequate intelligence, education, and environment, and normal senses. The genetic aetiology of dyslexia is heterogeneous and loci on chromosomes 2, 3, 6, 15, and 18 have been repeatedly linked to it. We have conducted a genome scan with 376 markers in 11 families with 38 dyslexic subjects ascertained in Finland. Linkage of dyslexia to the vicinity of DYX3 on 2p was confirmed with a non-parametric linkage (NPL) score of 2.55 and a lod score of 3.01 for a dominant model, and a novel locus on 7q32 close to the SPCH1 locus was suggested with an NPL score of 2.77. The SPCH1 locus has previously been linked with a severe speech and language disorder and autism, and a mutation in exon 14 of the FOXP2 gene on 7q32 has been identified in one large pedigree. Because the language disorder associated with the SPCH1 locus has some overlap with the language deficits observed in dyslexia, we sequenced the coding region of FOXP2 as a candidate gene for our observed linkage in six dyslexic subjects. No mutations were identified. We conclude that DYX3 appears to be important for dyslexia susceptibility in many Finnish families, and a suggested linkage of dyslexia to chromosome 7q32 will need verification in other data sets.

Two translocations of chromosome 15q associated with dyslexia

Developmental dyslexia is characterised by difficulties in learning to read. As reading is a complex cognitive process, multiple genes are expected to contribute to the pathogenesis of dyslexia. The genetics of dyslexia has been a target of molecular studies during recent years, but so far no genes have been identified. However, a locus for dyslexia on chromosome 15q21 (DYX1) has been established in previous linkage studies. We have identified two families with balanced translocations involving the 15q21-q22 region. In one family, the translocation segregates with specific dyslexia in three family members. In the other family, the translocation is associated with dyslexia in one family member. We have performed fluorescence in situ hybridisation (FISH) studies to refine the position of the putative dyslexia locus further. Our results indicate that both translocation breakpoints on 15q map within an interval of approximately 6-8 Mb between markers D15S143 and D15S1029, further supporting the presence of a locus for specific dyslexia on 15q21.

Familial dyslexia: neurocognitive and genetic correlation in a large Finnish family.

Neuropsychological findings of individuals with dyslexia (n=24) from a large, three‐generation Finnish family are presented. We have previously performed whole genome linkage scanning in this family and found that dyslexia in this kindred segregates with a single locus in the pericentromeric area of chromosome 3. Those included in the analyses were carefully evaluated for general cognitive ability, reading and spelling skills, and reading‐related neurocognitive skills. The neurocognitive type of dyslexia segregating in this family consisted of deficits in phonological awareness, verbal short‐term memory, and rapid naming. Severe dyslexia also seemed to be connected with a general language difficulty and was most common in the eldest generation.

Duchenne-like muscular dystrophy in two sisters with normal karyotypes: evidence for autosomal recessive inheritance

Two sisters, products of a consanguineous marriage (with a total of 12 children) showed muscle weakness at ages 7 and 6 yrs, respectively. The symptoms progressed rapidly and the patients were confined to wheelchairs at ages of 12 and 11 yrs, respectively. They had mild facial weakness and pseudohypertrophy of the calves, but neither cardiomyopathy nor mental retardation. Serum CK activities exceeded upper normal limit by 70 to 85‐fold. Muscle biopsies were compatible with muscular dystrophy. Both girls had a normal karyotype. The healthy mother had mild CK elevations in two out of three occasions, but the muscle biopsy was normal. Three out of the six unaffected sibs had mild CK elevations. The findings support the concept of severe progressive muscular dystrophy with autosomal recessive inheritance. The condition is clinically indistinguishable from Duchenne muscular dystrophy.

A nationwide register study of the characteristics, incidence and validity of diagnosed Tourette syndrome and other tic disorders

The aim of this study was to describe the characteristics and incidence rates of diagnosed tic disorders in the Finnish Hospital Discharge Register, including changing incidence rates between 1991 and 2010. We also aimed to validate the diagnoses of Tourettes syndrome recorded in the register.

Neurocognitive performance of children with higher functioning Autism Spectrum disorders on the NEPSY-II

This study examined patterns of strengths and weaknesses in the neurocognitive performance of children with higher functioning autism spectrum disorder (ASD). The participants were 30 children with higher functioning ASD ranging from 6 to 11 years, and 60 typically developing (TD) children, who were matched with the children with higher functioning ASD in terms of age, gender, and maternal education. The TD children were drawn from the Finnish standardization sample for the NEPSY-II. The cognitive abilities of the children with higher functioning ASD were assessed with the WISC-III, and the neurocognitive performance of the children with higher functioning ASD and TD children on the NEPSY-II was compared. The children with higher functioning ASD were found to have strengths in verbal reasoning skills with respect to the population mean and weaknesses in set-shifting, verbal fluency, and narrative memory in comparison with the TD children. Minor weaknesses were also observed in facial memory and fine and visuomotor skills.

Obstetric and Neonatal Adversities, Parity, and Tourette Syndrome: A Nationwide Registry.

OBJECTIVE To determine the relationships between parity, obstetric adversities, neonatal factors, and Tourette syndrome in a large nationwide cohort. STUDY DESIGN This nationwide, register-based, nested case-control study identified all children diagnosed with Tourette syndrome born between 1991 and 2010 from the Finnish Hospital Discharge Register (n = 767). Each case was matched to 4 controls. Information on parity, obstetric, and neonatal factors was obtained from the Finnish Medical Birth Register. Conditional logistic regression was used to determine the relationship between parity, obstetric, and neonatal factors, and Tourette syndrome. RESULTS Nulliparity was associated with increased odds for Tourette syndrome (OR 1.7, 95% CI 1.4-2.2), and 3 or more previous births was associated with decreased odds for Tourette syndrome (OR 0.5, 95% CI 0.3-0.9) compared with parity 1-2. Birth weight 4000-4499 g was associated with decreased odds for Tourette syndrome (OR 0.7, 95% CI 0.5-0.9). Low birth weight, gestational age, weight for gestational age, Apgar score at 1 minute, induced labor, birth type or presentation, neonatal treatment, or maternal blood pressure were not associated with Tourette syndrome. CONCLUSIONS Increasing parity and high birth weight are associated with decreased odds for Tourette syndrome.

Sluggish cognitive tempo in children and adolescents with higher functioning autism spectrum disorders: Social impairments and internalizing symptoms

Sluggish cognitive tempo (SCT) was introduced in 1980s in the field of attention deficit hyperactivity disorder (ADHD). Studies indicate that symptoms of SCT are separate from symptoms of ADHD and independently associated with multiple domains of functioning in clinical groups and in typical development. We assessed whether similar pattern would apply to higher functioning autism spectrum disorders (ASD). Children with higher functioning ASD (N = 55; 5-15 years) were divided into the ASD+High SCT (n = 17), the ASD+Medium SCT (n = 18) and the ASD+Low SCT (n = 20) groups based on parent-rated daydreaming and slowness on the Five to Fifteen questionnaire (FTF). The groups were compared on SCT-related impairments found in previous studies: social skills, academic functioning, psychiatric symptoms, and processing speed. Assessment methods were the FTF, the Development and Well-Being Assessment, and the Coding subtest of the WISC-III. The ADHD symptoms were statistically controlled due to the overlap between SCT and ADHD. The ASD+High SCT and ASD+Medium SCT groups were significantly more likely to have the most pronounced social impairments, and the ASD+High SCT group had significantly higher rate of internalizing disorders compared to the ASD+Low SCT group. Our results suggest that children with higher functioning ASD and high or medium levels of SCT symptoms could be at higher risk for psychosocial impairments than children with higher functioning ASD with low levels of SCT symptoms. Co-occurring ADHD symptoms do not explain the finding. Recognizing SCT symptoms in higher functioning ASD would be important to targeting preventive support.

Are There Differences in Neurocognition and Social Cognition Among Adolescents with Schizophrenia, a Pervasive Developmental Disorder, and Both Disorders?

Schizophrenia (SCH) and pervasive developmental disorders (PDDs) belong to different diagnostic categories. There is, however, overlap between these 2 diagnostic groups. The aim of this preliminary study was to evaluate some aspects of neurocognitions and social cognitions in adolescents with SCH (n = 10, 2 boys and 8 girls; age range = 13.3–17.7 years), a PDD (n = 15, 7 boys and 8 girls; age range = 13.3–18.0 years), or both disorders (n = 8, 5 boys and 3 girls; age range = 13.5–18 years). Eight subtests (Information, Similarities, Arithmetic, Comprehension, Picture Completion, Coding B, Block Design, and Object Assembly) of the Wechsler Intelligence Scale for Children-Third Version and 2 subtests (Theory of Mind [ToM] and Affect Recognition) of the NEPSY-II were administered. Adolescents with both disorders and those with a PDD only performed better on visual processing tasks than did adolescents with SCH only. On the other hand, adolescents with both disorders as well as those with SCH only experienced more problems with processing speed than did adolescents with a PDD only. Adolescents with SCH only performed significantly more poorly with verbal ToM tasks compared with those with a PDD only. Adolescents with both disorders performed as well as those with SCH only. All in all, our preliminary findings support the current idea that SCH and PDDs are separate disorders.