The possibility that organophosphorus (OP) compounds contribute to motor neuron disease (MND) is supported by association of paraoxonase 1 polymorphisms with amyotrophic lateral sclerosis (ALS) and the occurrence of MND in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphorylation. We evaluated a consanguineous kindred and a genetically unrelated nonconsanguineous kindred in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting. Affected subjects resembled those with OPIDN and those with Troyer Syndrome due to SPG20/spartin gene mutation (excluded by genetic linkage and SPG20/spartin sequence analysis). Genome-wide analysis suggested linkage to a 22 cM homozygous locus (D19S565 to D19S884, maximum multipoint LOD score 3.28) on chromosome 19p13 to which NTE had been mapped (GenBank AJ004832). NTE was a candidate because of its role in OPIDN and the similarity of our patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for disease-specific NTE mutation c.3034A-->G that disrupted an interspecies conserved residue (M1012V) in NTE's catalytic domain. Affected subjects in the nonconsanguineous family were compound heterozygotes: one allele had c.2669G-->A mutation, which disrupts an interspecies conserved residue in NTE's catalytic domain (R890H), and the other allele had an insertion (c.2946_2947insCAGC) causing frameshift and protein truncation (p.S982fs1019). Disease-specific, nonconserved NTE mutations in unrelated MND patients indicates NTE's importance in maintaining axonal integrity, raises the possibility that NTE pathway disturbances contribute to other MNDs including ALS, and supports the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds.

Background: Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary movements that occur spontaneously while at rest and following caffeine or alcohol consumption. Previously, we and others identified a locus for autosomal dominant PDC on chromosome 2q33-2q35. Objective: To identify the PDC gene. Design: Analysis of PDC positional candidate genes by exon sequencing and reverse transcription-polymerase chain reaction. Setting: Outpatient clinical and molecular genetic laboratory at a university hospital. Patients: Affected (n = 12) and unaffected (n =26) subjects from 2 unrelated families with PDC and 105 unrelated control subjects. Results: We identified missense mutations in the myofibrillogenesis regulator gene (MR-1) in affected subjects in 2 unrelated PDC kindreds. These mutations were absent in control subjects and caused substitutions of valine for alanine at amino acid positions 7 and 9. The substitutions disturb interspecies conserved residues and are predicted to alter the MR-1 gene's aminoterminal ␣ helix. The MR-1 exon containing these mutations (exon 1) was expressed only in the brain, a finding that explains the brain-specific symptoms of subjects with these mutations. Conclusions: Although MR-1 gene function is unknown, the precedence of ion channel disturbance in other episodic neurologic disorders suggests that the pathophysiologic features of PDC also involve abnormal ion localization. The discovery that MR-1 mutations underlie PDC provides opportunities to explore this condition's pathophysiologic characteristics and may provide insight into the causes of other paroxysmal neurologic disorders as well as the neurophysiologic mechanisms of alcohol and caffeine, which frequently precipitate PDC attacks.

The areas under the linear loss modulus versus temperature curves (loss area, LA) and tan δ versus temperature curves (TA) were evaluated for a number of acrylic, methacrylic, styrenic and butadiene based copolymers and interpenetrating polymer networks, IPNs, as a function of crosslink density and comliosition, and were compared with values predicted by group contribution analysis. The LAs of the sequential IPNs, cross‐poly(n‐butyl methacrylate)‐inter‐crosspolystyrene, were found to exhibit up to 30% larger LAs than the poly(n‐butyl metacrylate‐stat‐styrene) copolymers, which had LAs slightly less than the values predicted from the group contribution analysis. At constant chemical composition (50% n‐butyl methacrylate, 50% styrene), LA equals 14.4 GPa K for the IPN, attributed to a synergistic effect resulting from the IPN's microheterogeneous morphology, as compared with 10.7 GPa K for the single phase, miscible copolymer. Increases in the LA with increased concentration of polymer, network II were also observed for cross‐poly(ethyl acrylate)‐inter‐crosspolystyrene and cross‐polybutadiene‐inter‐cross‐polystyrene IPNs. On the other hand, cross‐polybutadiene‐inter‐cross‐poly(methyl methacrylate) IPNs had LAs much lower than were predicted by the group contribution analysis, which were attributed to lower miscibility in this system relative to the other systems evaluated. In general, decreased crosslink densities and lower concentrations of network II increased TA. These findings demonstrate how the morphology of a multiphase polymeric material can affect LA and TA, with significant increases In damping capability over the average of the component polymer values.

Interpenetrating polymer networks (IPN's) have been synthesized by swelling a cross-linked rubbery polymer (I) with a second plastic monomer (II or III or II-co-III) plus initiator and cross-linking agent and polymerizing the second monomer in situ. IPN's have also been produced by inverting the order of preparation. According to the overall compositions, IPN's of elastomeric or leathery or plastic behavior have been obtained. Polymers employed were poly(ethyl acrylate) (I), polystyrene (II), and poly(methyl methacrylate) (III). Like most other types of polymer blends, IPN's exhibit a complex twophase morphology. The electron micrographs show a characteristic cellular structure of about 1000-A diameter simultaneously with a fine structure with phase domains of the order of 100 A. In the midrange leathery materials the cell walls are composed of the second network polymer. The fine structure is observed most clearly within the cell walls, and probably originates through a second, later phase separation as polymerization continues beyond the initial cellular formation stage. Increasing compatibility of the two polymers is attained as methyl methacrylate mers replace styrene mers in the plastic component. This leads to the disappearance of the cellular envelopes but retention of the fine 100-A domain structure. Inverting the sequence of preparation (swelling monomer I into network II or III) showed that the network synthesized first controls the morphology of the IPN's, comprizing the more continuous phase.

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