Deciphering the natural history of SCA7 in children.

BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1).

In a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)-and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The prevalence rate for clinical ASD was 10.9%, which is clearly higher than in the general population. This prevalence rate is presumably more accurate than in previous studies that examined children with NF1 with an ASD presumption or solely based on screening instruments. The combined observational- and screening based classifications demonstrated the highest positive predictive value for DSM-IV diagnosis, highlighting the importance of using both instruments in children with NF1.

A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands.

NF1 mutations are the underlying cause of neurofibromatosis type 1 (NF1), a neuro-cardio-facio-cutaneous syndrome (NCFC). Because of the clinical overlap between NCFCs, genetic analysis of NF1 is necessary to confirm a clinical diagnosis NF1. This report describes the clinical and genetic findings of 18 years of NF1 molecular diagnostics in the Netherlands. A pathogenic mutation was found in 59.3% (1178/1985) of the index patients, mostly de novo (73.8%). The majority of the index patients (64.3%) fulfilled the National Institute of Health NF1 criteria, a pathogenic mutation was found in 80.9% of these patients. Seventy-four percent of the index patients with an NF1 pathogenic mutation and not fulfilling the NF1 criteria is <12 years, in agreement with the fact that some NF1 symptoms appear after puberty. Genotype-phenotype correlations were studied for 527 index patients. NF1 patients with a type 1 microdeletion have a sixfold higher risk of special education vs NF1 patients with an intragenic mutation. No evidently milder NF1 phenotype for patients with a missense mutation was observed. Forty-six prenatal analyses were performed in 28 (2.4%) families, of which 29 (63%) showed heterozygosity for the familial pathogenic mutation. This indicates that there is a need for prenatal NF1 testing.

Genome-wide linkage scan in affected sibling pairs identifies novel susceptibility region for venous thromboembolism: Genetics In Familial Thrombosis study.

BACKGROUND: Venous thromboembolism (VTE) is a multicausal disorder involving environmental and genetic risk factors. In many thrombophilic families the clustering of thrombotic events cannot be explained by known genetic risk factors, indicating that some remain to be discovered. OBJECTIVES: We aimed to identify novel thrombosis susceptibility alleles in a large panel of small thrombophilic families: the Genetics In Familial Thrombosis (GIFT) study. PATIENTS/METHODS: In the GIFT study, 201 families were recruited consisting of 438 siblings with an objectively confirmed VTE at a young age. Multipoint linkage analysis (402 SSR markers) and fine mapping were performed, followed by genotyping of tagging SNPs in positional candidate genes. RESULTS: Established genetic risk factors such as factor V Leiden, ABO blood group non-O, prothrombin 20210A, fibrinogen gamma 10034T and deficiencies of antithrombin, protein C and protein S were more frequent in GIFT patients than in unselected VTE patients. Linkage supported the presence of novel thrombosis susceptibility loci on 7p21.3-22.2 (LOD score = 3.23) and Xq24-27.3 (LOD score = 1.95). Simulation analysis showed that the chr7 signal was genome-wide statistically significant (P = 0.022). Tagging SNPs (n = 157) in eight positional candidate genes (LOD drop 1.5 regions) were genotyped in GIFT patients and 332 healthy controls. Five chr7 SNPs associated with VTE. SNP THSD7A rs2074597 was responsible for part of the chr7 signal. CONCLUSIONS: The GIFT panel is rich in established genetic risk factors for VTE, but genetic factors remain unidentified in many families. Genome-wide linkage failed to identify the previously established genetic risk factors for VTE, but identified a novel VTE susceptibility locus on chr7.