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Neurobehavioral correlates of CGG amplification were studied in 17 nonretarded adult female carriers of fragile X syndrome. The results revealed a significant relationship between IQ and the number of CGG repeats in the 5' untranslated region of the FMR1 gene. Women with a full mutation (> 200 CGG repeats) scored below average in IQ, visual-spatial perception, visual-spatial organization, and executive function. There were no differences in fine motor dexterity or memory as a function of CGG amplification status. A history of major depressive disorder was identified in 71% of the sample, but incidence of depression was not associated with the degree of CGG amplification. Schizotypal features were noted in 18%. No intellectual or neuropsychological deficit was found in women with a premutation (< 200 CGG repeats). Decrements in IQ, visual-spatial perception, and executive function appear to arise as a consequence of the CGG amplification.

Using label-free quantative proteomics, we have identified 2 potential protein biomarkers that indicate presymptomatic kidney disease in the urine of pediatric patients with type-I diabetes and Fabry disease (n = 20). Prosaposin and GM2 activator protein (GM2AP) were observed to be elevated in the urine of these patient groups compared to age- and sex-matched controls. These findings were validated by development of a rapid MRM-based tandem mass spectrometry test. Prosaposin was observed to be both significantly elevated in the urine of patients with Fabry disease compared to controls (p = 0.02) and reduced after 12 months enzyme replacement therapy (ERT, p = 0.01). Similarly, GM2AP concentrations were observed to be significantly higher compared to controls in the diabetic group (p = 0.049) and the pretreatment Fabry group (p = 0.003). In addition, this observed to be reduced significantly in the Fabry group following 12 months of ERT (p = 0.01). The process of detection of the biomarkers, development into a test and implications for monitoring patients and treatment are discussed.

CATHEPSIN D DEFICIENCY CAUSES JUVENILE-ONSET ATAXIA AND DISTINCTIVE MUSCLE PATHOLOGYThe neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative disorders with the most common phenotype consisting of early-onset progressive motor deterioration, cognitive decline, visual failure, epilepsy, cerebellar ataxia, and premature death. Mutations in the lysosomal protein cathepsin D (CatD/CTSD) underlie one subtype of NCL (CLN10) and were initially associated with a severe, congenital form resulting in early death, 2 with a single juvenileonset CLN10 disease subsequently reported. 3 We report additional novel mutations in cathepsin D in 2 consanguineous pedigrees, both with a juvenile onset of NCL and associated with characteristic muscle pathology.Methods. Ethical approval to undertake this study was given by the National Hospital for Neurology and Neurosurgery/Institute of Neurology ethics committees and informed consent was obtained from all participating family members.Exome sequencing and homozygosity mapping were carried out in a large recessive consanguineous pedigree with complex ataxia and retinitis pigmentosa, which identified a homozygous missense mutation in CTSD in the index case of family A. We subsequently screened a cohort of complex ataxia cases all with associated retinitis pigmentosa and found a further homozygous missense mutation in CTSD in a second family. To support the pathogenicity of these variants, we carried out a kinetic assay of CatD activity in patient fibroblasts and performed detailed pathologic examination of patient muscle biopsies. See appendix e-1 on the Neurology ® Web site at Neurology.org for additional details on the above methods.Results. A summary of the clinical features of both pedigrees is shown in the table and pedigrees are shown in figure e-1.