Biomedical subjects

Christopher M Gomez

Publications and source records attributed to Christopher M Gomez.

23 records · Page 2Linked to original sources

PubMed2003

Dominantly inherited ataxias.

The autosomal dominant ataxias continue to bewilder us as the enormity of their genetic heterogeneity continues to unfold. The Human Genome Organization website now lists 22 such ataxias, not including dentatorubral-pallidoluysian atrophy. The early genetic discoveries in this field included several disorders caused by CAG repeat expansions within coding regions of the respective genes. More recent discoveries have included unstable expansions of nucleotide repeats in noncoding regions of genes as well as point mutations that have formed the basis of progressive dominant ataxias. This article summarizes the clinical and genetic features of the currently identified dominant ataxias.

Genes, Dominant↗

PubMed2002

Active calcium accumulation underlies severe weakness in a panel of mice with slow-channel syndrome.

Mutations affecting the gating and channel properties of ionotropic neurotransmitter receptors in some hereditary epilepsies, in familial hyperekplexia, and the slow-channel congenital myasthenic syndrome (SCCMS) may perturb the kinetics of synaptic currents, leading to significant clinical consequences. Although at least 12 acetylcholine receptor (AChR) mutations have been identified in the SCCMS, the altered channel properties critical for disease pathogenesis in the SCCMS have not been identified. To approach this question, we investigated the effect of different AChR subunit mutations on muscle weakness and the function and viability of neuromuscular synapses in transgenic mice. Targeted expression of distinct mutant AChR subunits in skeletal muscle prolonged the decay phases of the miniature endplate currents (MEPCs) over a broad range. In addition, both muscle strength and the amplitude of MEPCs were lower in transgenic lines with greater MEPC duration. SCCMS is associated with calcium overload of the neuromuscular junctional sarcoplasm. We found that the extent of calcium overload of motor endplates in the panel of transgenic mice was influenced by the relative permeability of the mutant AChRs to calcium, on the duration of MEPCs, and on neuromuscular activity. Finally, severe degenerative changes at the motor endplate (endplate myopathy) were apparent by electron microscopy in transgenic lines that displayed the greatest activity-dependent calcium overload. These studies demonstrate the importance of control of the kinetics of AChR channel gating for the function and viability of the neuromuscular junction.

Animals↗

PubMed2002

Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7.

Infantile- and juvenile-onset spinal cerebellar ataxia (SCA) is associated with expansion of 130 to more than 200 CAG-repeats in the SCA2 and SCA7 genes. Routine clinical assays for SCA2 and SCA7, which use polymerase chain reaction (PCR) and denaturing PAGE (polyacrylamide gel electrophoresis), will not reliably detect such large expansions. An assay based on separation of PCR products on an agarose gel, blotting, and hybridization with a (CAG)6 oligonucleotide probe was used to test DNA from individuals more than 10 years of age who had a possible diagnosis of SCA. Among 25 cases, the PCR-blot assay confirmed the presence of SCA2 expansions between 230 and 500 repeats in four unrelated individuals, but did not detect any cases of extreme expansion in the SCA7 gene. The PCR-blot assay provides reliable detection of extreme expansion mutations. Routine incorporation of this assay in clinical laboratories may reveal that infantile-juvenile forms of SCA2 and SCA7 are more prevalent than previously recognized.

Age of Onset↗

PubMed2002

Spinocerebellar ataxia in monozygotic twins.

CONTEXT: Although phenotypic heterogeneity in autosomal dominant spinocerebellar ataxia (SCA) has been explained in part by genotypic heterogeneity, clinical observations suggest the influence of additional factors. OBJECTIVES: To demonstrate, quantitate, and localize physiologic abnormalities attributable to nongenetic factors in the development of hereditary SCA. DESIGN: Quantitative assessments of ocular motor function and postural control in 2 sets of identical twins, one with SCA type 2 and the other with episodic ataxia type 2. SETTING: University laboratory. MAIN OUTCOME MEASURES: Saccadic velocity and amplitude, pursuit gain, and dynamic posturography. RESULTS: We found significant differences in saccade velocity, saccade metrics, and postural stability between each monozygotic twin. The differences point to differential involvement between twins of discrete regions in the cerebellum and brainstem. CONCLUSIONS: These results demonstrate the presence of quantitative differences in the severity, rate of progression, and regional central nervous system involvement in monozygotic twins with SCA that must be owing to the existence of nongermline or external factors.

Adult↗

PubMed2002

Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms.

We investigated the basis for a novel form of the slow-channel congenital myasthenic syndrome presenting in infancy in a single individual as progressive weakness and impaired neuromuscular transmission without overt degeneration of the motor endplate. Prolonged low-amplitude synaptic currents in biopsied anconeus muscle at 9 years of age suggested a kinetic disorder of the muscle acetylcholine receptor. Ultrastructural studies at 16 months, at 9 years, and at 15 years of age showed none of the typical degenerative changes of the endplate associated with the slow-channel congenital myasthenic syndrome, and acetylcholine receptor numbers were not significantly reduced. We identified a novel C-to-T substitution in exon 8 of the delta-subunit that results in a serine to phenylalanine mutation in the region encoding the second transmembrane domain that lines the ion channel. Using Xenopus oocyte in vitro expression studies we confirmed that the deltaS268F mutation, as with other slow-channel congenital myasthenic syndrome mutations, causes delayed closure of acetylcholine receptor ion channels. In addition, unlike other mutations in slow-channel congenital myasthenic syndrome, this mutation also causes delayed opening of the channel, a finding that readily explains the marked congenital weakness in the absence of endplate degeneration. Finally, we used serial morphometric analysis of electron micrographs to explore the basis for the progressive weakness and decline of amplitude of endplate currents over a period of 14 years. We demonstrated a progressive widening and accumulation of debris in the synaptic cleft, resulting in loss of efficacy of released neurotransmitter and reduced safety factor. These studies demonstrate the role of previously unrecognized mechanisms of impairment of synaptic transmission caused by a novel mutation and show the importance of serial in vitro studies to elucidate novel disease mechanisms.

Adolescent↗