This study is consistent with others suggesting a high prevalence of clumsiness in Asperger's syndrome. Our findings also attest to the widespread prevalence of motor impairment in developmental disorders and the problems such co-morbidity poses for attempts to posit discrete and functionally coherent impairments underlying distinct syndromes.

No abstract

We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1(nmf164)) of Niemann-Pick type C1 (NPC) disease: a single nucleotide change (A to G at cDNA bp 3163) that results in an aspartate to glycine change at position 1005 (D1005G). This change is in the cysteine-rich luminal loop of the NPC1 protein and is highly similar to commonly occurring human mutations. Genetic and molecular biological analyses, including sequencing the Npc1(spm) allele and identifying a truncating mutation, confirm that the mutation in Npc1(nmf164) mice is distinct from those in other existing mouse models of NPC disease (Npc1(nih), Npc1(spm)). Analyses of lifespan, body and spleen weight, gait and other motor activities, as well as acoustic startle responses all reveal a more slowly developing phenotype in Npc1(nmf164) mutant mice than in mice with the null mutations (Npc1(nih), Npc1(spm)). Although Npc1 mRNA levels appear relatively normal, Npc1(nmf164) brain and liver display dramatic reductions in Npc1 protein, as well as abnormal cholesterol metabolism and altered glycolipid expression. Furthermore, histological analyses of liver, spleen, hippocampus, cortex and cerebellum reveal abnormal cholesterol accumulation, glial activation and Purkinje cell loss at a slower rate than in the Npc1(nih) mouse model. Magnetic resonance imaging studies also reveal significantly less demyelination/dysmyelination than in the null alleles. Thus, although prior mouse models may correspond to the severe infantile onset forms of NPC disease, Npc1(nmf164) mice offer many advantages as a model for the late-onset, more slowly progressing forms of NPC disease that comprise the large majority of human cases.

No abstract

Abstract. Muscle activity alters the expression of functionally distinct nicotinic acetylcholine receptors (nAChR) via regulation of subunit gene expression. Denervation increases the expression of all subunit genes and promotes the expression of embryonic-type (et213~) nAChRs, while electrical stimulation of denervated muscle prevents this induction. We have discovered that the denervation-induced increases in a, 13, % and ~ subunit gene expression do not persist in muscles that have been denervated for periods extending beyond a couple of months. However, expression of RNA encoding the e-subunit remains elevated suggesting a return to expression of predominantly adult-type (OLe~3~e) nAChR in long-term denervated muscles; a finding confirmed by single channel patch-clamp analysis. Since the nAChR subunit genes are regulated by the MyoD family of muscle regulatory factors, and the genes encoding these factors are also induced following short-term muscle denervation, we determined their level of expression in long-term denervated muscle. Although MyoD and myf-5 RNA levels remained elevated, myogenin and MRF4 RNAs were induced only transiently by muscle denervation. Surprisingly, Id-1, a negative regulator of transcription, was gradually induced in denervated muscle with RNA levels peaking about two months after denervation. It is likely that this maintained level of increased Id expression, in conjunction with the returning levels of myogenin and MRF4 expression, account for the reduced level of embryonic receptors in long-term denervated muscle. These changing patterns of gene expression may have important consequences for the ability of muscle to recover function after denervation.T HE muscle nicotinic acetylcholine receptor (nAChR) t is a pentameric integral membrane protein that functions as a ligand-gated ion channel. During muscle development the levels, distribution, and properties of this receptor change (for review see Brehm and Henderson, 1988;Hall and Sanes, 1993). Many of these changes are correlated with muscle innervation. Before innervation, or after denervation of adult muscle embryonictype nAChRs are expressed throughout the muscle fiber. These receptors are composed of four different subunits with a stoichiometry of tx213-,/~. After innervation of muscle, the ",/ subunit is replaced by an ~ subunit, and these adult-type receptors (et2[3e~) are preferentially expressed at the neuromuscular junction (NMJ).The switch from embryonic to adult-type receptors resuits in a change in their channel properties. Embryonic-

SYNOPSISMost of the previous research reporting abnormalities of rapid re-fixation eye movements (saccades) in patients with schizophrenia has used patients receiving neuroleptic medication. In this study non-neuroleptically medicated schizophrenics were compared with other psychiatric patients using a variety of saccadic paradigms to determine the specificity of saccadic dysfunction. The patient groups consisted of schizophrenics (N = 18), bipolar affectives (N = 18), anxiety neurotics (N = 10) and normal controls (N = 31), none of whom had received neuroleptic medication for the preceding 6 months. Four behavioural paradigms, reflexive, predictive, remembered and ANTI were used to elicit saccades. The primary abnormality in the schizophrenic group was a significantly increased rate of distractibility in the ANTI (saccades made towards the target rather than in an opposite direction) and REM (saccades made prior to the imperative cue) paradigms. The major neuropsychological variable predictive of these errors was Wisconsin card sort perseverative errors. These data, in conjunction with findings from previous neurological research, would seem to provide converging evidence towards dysfunction of prefrontal cortex in schizophrenia.

Rapid eye movements (saccades) were examined in 7 patients with idiopathic Parkinson's disease (PD) and a matched group of normal control subjects. The effect of instructional and stimulus conditions used to elicit saccades was examined using 3 experimental paradigms. Eye movements directly elicited by a novel peripheral target were unimpaired in patients with PD as compared with control subjects. Saccades to a remembered target location, however, were dysmetric in the PD group and showed a characteristic multistepping pattern. The PD impairment was not caused by a loss of information on target location since their final eye position was close to the target at all eccentricities. Peak velocity, duration, and latency did not distinguish between PD patients and controls. These results support the view that for saccades which are not directly elicited by a visual target there is a neural pathway that can be distinguished from structures involved in the generation of visually elicited (or 'reflexive') saccades. The finding that in PD saccades to a remembered target are selectively impaired suggests that structures in the basal ganglia play a crucial role in this alternative pathway.

Saccadic eye movements, fixation, and smooth pursuit were recorded in 17 subjects with amyotrophic lateral sclerosis (ALS) and 11 age-matched controls using a magnetic scleral search coil. Reflexive, remembered and antisaccades, and smooth pursuit at four target velocities were studied. Subjects with ALS showed significantly elevated error rates (distractibility) and latency in the antisaccade and remembered saccade paradigms but no abnormality of reflexive saccades. The frequency of small saccades that intruded on steady fixation (square-wave jerks) was also increased in ALS subjects. Peak velocity gain of smooth pursuit and performance on the Wisconsin Card Sort Test did not differ significantly between the two groups. These findings are consistent with prefrontal dysfunction in ALS and provide an independent source of support for the thesis that the pathology of this condition invades frontal cortex.