Mutation screening in neurofibromatosis type 1 (NF1) families has long been hampered by the complexity of the NF1 gene. By using a novel multi-track screening strategy, 67 NF1 families (54 two-generation, 13 three-generation) with a de novo mutation in the germline of the first generation were studied with two extragenic and 11 intragenic markers. The pathological lesion was identified in 31 cases. Loss of heterozygosity (LOH) in the affected individual revealed a gross gene deletion in 15 of the two-generation families; in 12 (80%) of them, the deletion was maternally derived. Eleven patients with a gross deletion exhibited developmental delay, ten had dysmorphic features and six manifested a learning disability. No gross deletion was apparent in any of the 13 three-generation families, suggesting that such lesions are subject to more intense selection. In these families, the new mutation was of paternal origin in 11 kindreds and the underlying mutational event could be characterised in three of them.

Spinocerebellar ataxia 8 (SCA8) is caused by a CTG repeat expansion in an untranslated region of a recently cloned gene on 13q21. The pathogenic role of this trinucleotide repeat was evaluated by examining 154 Finnish ataxia patients and 448 controls. Expansions ranging from 100 to 675 repeats were present in 9 (6%) unrelated patients and in 13 (3%) controls. There was a threefold excess of shorter expansions (<204 repeats) in the ataxia series, and the expansions tended to cluster in patients with a family history for the disease. Clinical and genetic data were subsequently collected from 15 patients. Common initial symptoms included gait instability, dysarthria, and tremor. A marked cerebellar atrophy in magnetic resonance imaging or computed tomography was found in all patients. Pyramidal affection was often seen, and various kinds of cognitive impairment were evident in 40% of patients. Disease progression was slow, and fluctuation of symptoms was commonly observed. A maternal penetrance bias was not seen, nor was there any clear‐cut negative correlation between age of onset and repeat number. Meiotic but not mitotic instability of the repeat expansion was evident. Haplotype analysis suggests multiple origins for the Finnish spinocerebellar ataxia 8 repeat expansions. Ann Neurol 2000;48:354–361

The 3p deletion syndrome is a rare disorder caused by deletions of different sizes in the 3p25-pter region. It is characterized by growth retardation, developmental delay, mental retardation, dysmorphism, microcephaly, and ptosis. The phenotype of individuals with deletions varies from normal to severe. Most cases occur de novo, but a few familial cases have been reported. We describe two families with terminal 3p deletions and extremely variable clinical features. In family A, the mother and daughter were extremely mildly affected whereas the son had more severe clinical features. In family B, the mother was normal and her son was affected, having some symptoms that had not been described in the 3p deletion syndrome before. The deletions were characterized by genome-wide SNP array analysis and were 9 and 1.1 Mb in size. Sequencing analysis of the CHL1, CNTN4, and CRBN genes did not reveal any masked recessive alleles that might explain the more severe phenotypes in the probands. In family A, the 9 Mb deletion can be considered causal for the 3p deletion syndrome in the proband, but the extremely mild phenotype in the other family members remains unexplained. In family B, the 1.1 Mb terminal deletion encompasses only the CHL1 gene, which is insufficient to cause 3p deletion symptoms; thus the clinical features observed in this family may have a different cause. The variable penetrance of 3p deletions creates challenges in genetic counseling, as the phenotype of the offspring cannot be predicted based on chromosomal and/or genome-wide array analytical findings.

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These data suggest that Fabry disease affects arterial function and structure by disturbing peripheral endothelial function and promoting intima-media thickening.