Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients.

BACKGROUND: The genetic heterogeneity of developmental delay and cognitive impairment is vast. The endocytic network is essential for neural development and synaptic plasticity by regulating the sorting of numerous transmembrane proteins. Disruption of the pathway can lead to neuronal pathology. Endosomal biogenesis relies on two Rab proteins, Rab5 and Rab7, which bind to two hexameric tethering complexes, the endosomal class C core vacuole/endosome tethering complex (CORVET) and the late endosomal/lysosomal homotypic fusion and protein sorting complex (HOPS). Both complexes consist of four core proteins and differ by their specific Rab-binding proteins. OBJECTIVES: To identify the molecular basis of a neurological disease, which consists of global developmental stagnation at 3-8 months, increasing appendicular spasticity, truncal hypotonia and acquired microcephaly, with variable seizure disorder, accompanied by thin corpus callosum, paucity of white matter and delayed myelination in eight patients from four unrelated Ashkenazi-Jewish (AJ) families. METHODS: Exome analysis, homozygosity mapping and Mup1-GFP transport assay in mutant yeast. RESULTS: Homozygosity for a missense mutation, p.Cys846Gly, in one of the endosomal biogenesis core proteins, VPS11, was identified in all the patients. This was shown to be a founder mutation with a carrier frequency of 0.6% in the AJ population. The homologous yeast mutant had moderate impairment of fusion of the late endosome to the vacuole in Mup1-GFP transport assay. CONCLUSIONS: We speculate that in neuronal cells, impairment of fusion of the late endosome to the vacuole would attenuate the degradation of plasma membrane receptors, thereby underlying the progressive neuronal phenotype in our patients. The VPS11 p.Cys846Gly mutation should be added to the AJ carrier screening panel.

Late diagnosis of autism spectrum disorder after initial negative assessment by a multidisciplinary team.

OBJECTIVE: Describe a cohort of children who received a diagnosis of autism spectrum disorder (ASD) after age 6 and after having undergone a comprehensive multidisciplinary assessment before the age of 6, through which they were not diagnosed with ASD. METHODS: Extensive chart review of patients' electronic medical records comprised a representative population-based registry of patients seen during 2004 to 2011. The study focused only on the cohort of children who were diagnosed with ASD after the age of 6 but were not diagnosed with ASD at an earlier age. The charts were reviewed for the number of developmental assessments completed and the clinician's diagnostic impressions. The charts were also examined for documentation of ASD-suggestive features pulled directly from the text of the evaluators' reports. RESULTS: A total of 221 patients (189 males) were diagnosed with ASD after age 6 although their initial comprehensive developmental evaluations before the age of 6 were negative for ASD. The study cohort underwent a total of 1028 developmental evaluations before the age of 6, with initial diagnostic impressions that included language deficits (70%), motor difficulties (67%), attention problems (46%), and cognitive difficulties (42%). Less than half of the cohort had ASD-suggesting features documented in their initial assessment. CONCLUSIONS: Subsequent late diagnosis of ASD after an initial ASD-negative comprehensive assessment is a common clinical experience. Reasons for this scenario may include evolving diagnosis as well as missed and overdiagnosed cases of ASD.

Israeli children with autism spectrum disorder are not macrocephalic.

The prevalence of macrocephaly in autism spectrum disorder is reported to be much higher than in the general population, 12% to 37%. Progressive macrocephaly is even considered a warning sign for the development of autism. We evaluated the prevalence of an abnormal head circumference in children with autism in Israel and compared it with the head circumferences of children with developmental language disorder and children with normal development. We did not find a higher prevalence of macrocephaly among Israeli children with autism spectrum disorder (4.4%). Although children with autism spectrum disorder had a significantly higher rate of a head circumference above the 75th percentile compared with children with developmental language disorder, it was not significantly different compared with normal controls. We conclude that there is no increased prevalence of macrocephaly in Israeli children with autism; this can be attributed to a different genetic background.