1. O’Keefe JA, Robertson-Dick EE, Hall DA, Berry-Kravis E. {{Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome}}. {Cerebellum (London, England)}. 2015 Aug 23.
Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a « premutation » (PM) size CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Cerebellar gait ataxia is the primary feature in some FXTAS patients causing progressive disability. However, no studies have quantitatively characterized gait and mobility deficits in FXTAS. We performed quantitative gait and mobility analysis in seven FMR1 PM carriers with FXTAS and ataxia, six PM carriers without FXTAS, and 18 age-matched controls. We studied four independent gait domains, trunk range of motion (ROM), and movement transitions using an instrumented Timed Up and Go (i-TUG). We correlated these outcome measures with FMR1 molecular variables and clinical severity scales. PM carriers with FXTAS were globally impaired in every gait performance domain except trunk ROM compared to controls. These included total i-TUG duration, stride velocity, gait cycle time, cadence, double-limb support and swing phase times, turn duration, step time before turn, and turn-to-sit duration, and increased gait variability on several measures. Carriers without FXTAS did not differ from controls on any parameters, but double-limb support time was close to significance. Balance and disability scales correlated with multiple gait and movement transition parameters, while the FXTAS Rating Scale did not. This is the first study to quantitatively examine gait and movement transitions in FXTAS patients. Gait characteristics were consistent with those from previous cohorts with cerebellar ataxia. Sensitive measures like the i-TUG may help determine efficacy of interventions, characterize disease progression, and provide early markers of disease in FXTAS.
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2. Hobson JA, Tarver L, Beurkens N, Peter Hobson R. {{The Relation between Severity of Autism and Caregiver-Child Interaction: a Study in the Context of Relationship Development Intervention}}. {Journal of abnormal child psychology}. 2015 Aug 23.
The aim of this study was to examine the relations between severity of children’s autism and qualities of parent-child interaction. We studied these variables at two points of time in children receiving a treatment that has a focus on social engagement, Relationship Development Intervention (RDI; Gutstein 2009). Participants were 18 parent-child dyads where the child (16 boys, 2 girls) had a diagnosis of autism and was between the ages of 2 and 12 years. The severity of the children’s autism was assessed at baseline and later in treatment using the autism severity metric of the Autism Diagnostic Observation Schedule (ADOS; Gotham et al. Journal of Autism and Developmental Disorders, 39, 693-705 2009). Although the ADOS was designed as a diagnostic measure, ADOS calibrated severity scores (CSS) are increasingly used as one index of change (e.g., Locke et al. Autism, 18, 370-375 2014). Videotapes of parent-child interaction at baseline and later in treatment were rated by independent coders, for a) overall qualities of interpersonal relatedness using the Dyadic Coding Scales (DCS; Humber and Moss The American Journal of Orthopsychiatry, 75, 128-141 2005), and b) second-by-second parent-child Co-Regulation and Intersubjective Engagement (processes targeted by the treatment approach of RDI). Severity of autism was correlated with lower quality of parent-child interaction. Ratings on each of these variables changed over the course of treatment, and there was evidence that improvement was specifically related to the quality of parent-child interaction at baseline.
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3. Frederikse PH, Nandanoor A, Kasinathan C. {{Fragile X Syndrome FMRP Co-localizes with Regulatory Targets PSD-95, GABA Receptors, CaMKIIalpha, and mGluR5 at Fiber Cell Membranes in the Eye Lens}}. {Neurochemical research}. 2015 Aug 23.
Fmr1 and FMRP underlie Fragile X Syndrome (FXS) and are linked with related autism spectrum disorders (ASD). Fmr1 also has an essential role in eye and lens development. Lenses express FMRP along with gamma-aminobutyric acid (GABA) receptors (GABARs), post-synaptic density protein 95 (PSD-95), Tyr-phosphatase STEP, CaMKIIalpha and Alzheimer’s disease Abeta precursor protein, which are verified targets of FMRP regulation in neurons and outline major topics in FXS/ASD research. PSD-95 as well as CaMKIIalpha transcripts undergo polypryimidine tract binding protein dependent alternative splicing in lens, consistent with PSD-95 translation in lens. At least 13 GABAR subunits and GAD25/65/67 GABA metabolism enzymes are expressed in lenses beginning in embryonic development, matching neural development. Interestingly, GABAergic drugs (e.g. baclofen) studied as FXS/ASD therapeutics are shown to resolve developmental vision defects in experimental myopia. Here, we demonstrated that FMRP co-localizes at fiber cell membranes with PSD-95, GABAAdelta, GABAAbeta3, GABBR1, STEP, CaMKIIalpha, and mGluR5 in young adult lenses. GAD65 and GABA detection was greatest at the peri-nuclear lens region where fiber cell terminal differentiation occurs. These findings add to an extensive list of detailed parallels between fiber cell and neuron morphology and their lateral membrane spine/protrusions, also reflected in the shared expression of genes involved in the morphogenesis and function of these membrane structures, and shared use of associated regulatory mechanisms first described as distinguishing the neuronal phenotype. Future studies can determine if GABA levels currently studied as a FXS/ASD biomarker in the brain, and generated by GAD25/65/67 in a comparable cell environment in the lens, may be similarly responsive to Fmr1 mutation in lens. The present demonstration of FMRP and key regulatory targets in the lens identifies a potential for the lens to provide a new research venue, in the same individual, to inform about Fmr1/FMRP pathobiology in brain as well as lens.
