Objective
Myotonias are inherited disorders of the skeletal muscle excitability. Nondystrophic forms are caused by mutations in genes coding for the muscle chloride or sodium channel. Myotonia is ...either relieved or worsened by repeated exercise and can merge into flaccid weakness during exposure to cold, according to causal mutations. We designed an easy electromyography (EMG) protocol combining repeated short exercise and cold as provocative tests to discriminate groups of mutations.
Methods
Surface‐recorded compound muscle action potential was used to monitor muscle electrical activity. The protocol was applied on 31 unaffected control subjects and on a large population of 54 patients with chloride or sodium channel mutations known to cause the different forms of myotonia.
Results
In patients, repeated short exercise test at room temperature disclosed three distinct abnormal patterns of compound muscle action potential changes (I‐III), which matched the clinical symptoms. Combining repeated exercise with cold exposure clarified the EMG patterns in a way that enabled a clear correlation between the electrophysiological and genetic defects.
Interpretation
We hypothesize that segregation of mutations into the different EMG patterns depended on the underlying pathophysiological mechanisms. Results allow us to suggest EMG guidelines for the molecular diagnosis, which can be used in clinical practice. Ann Neurol 2006
The time it takes a sound to travel from source to ear differs between the ears and creates an interaural delay. It varies systematically with spatial direction and is generally modeled as a pure ...time delay, independent of frequency. In acoustical recordings, we found that interaural delay varies with frequency at a fine scale. In physiological recordings of midbrain neurons sensitive to interaural delay, we found that preferred delay also varies with sound frequency. Similar observations reported earlier were not incorporated in a functional framework. We find that the frequency dependence of acoustical and physiological interaural delays are matched in key respects. This suggests that binaural neurons are tuned to acoustical features of ecological environments, rather than to fixed interaural delays. Using recordings from the nerve and brainstem we show that this tuning may emerge from neurons detecting coincidences between input fibers that are mistuned in frequency.
Hereditary spastic paraplegia (HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. We found that patients from a chromosome ...16q24.3–linked HSP family are homozygous for a 9.5 kb deletion involving a gene encoding a novel protein, named Paraplegin. Two additional Paraplegin mutations, both resulting in a frameshift, were found in a complicated and in a pure form of HSP. Paraplegin is highly homologous to the yeast mitochondrial ATPases, AFG3, RCA1, and YME1, which have both proteolytic and chaperon-like activities at the inner mitochondrial membrane. Immunofluorescence analysis and import experiments showed that Paraplegin localizes to mitochondria. Analysis of muscle biopsies from two patients carrying Paraplegin mutations showed typical signs of mitochondrial OXPHOS defects, thus suggesting a mechanism for neurodegeneration in HSP-type disorders.
Detecting interaural time difference (ITD) is crucial for sound localization. The temporal accuracy required to detect ITD, and how ITD is initially encoded, continue to puzzle scientists. A ...fundamental question is whether the monaural inputs to the binaural ITD detectors differ only in their timing, when temporal and spectral tunings are largely inseparable in the auditory pathway. Here, we investigate the spectrotemporal selectivity of the monaural inputs to ITD detector neurons of the owl. We found that these inputs are selective for instantaneous frequency glides. Modeling shows that ITD tuning depends strongly on whether the monaural inputs are spectrotemporally matched, an effect that may generalize to mammals. We compare the spectrotemporal selectivity of monaural inputs of ITD detector neurons in vivo, demonstrating that their selectivity matches. Finally, we show that this refinement can develop through spike timing-dependent plasticity. Our findings raise the unexplored issue of time-dependent frequency tuning in auditory coincidence detectors and offer a unifying perspective.
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci ...causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Q270K mutation of the skeletal muscle Na + channel α subunit (Nav1.4) causes atypical paramyotonia with a striking sensitivity to cold. Attacks of paralysis and a drop
in the compound muscle ...action potential (CMAP) are exclusively observed at cold. To understand the pathogenic process, we
studied the consequences of this mutation on channel gating at different temperatures. WT or Q270K recombinant Nav1.4 channels
fused at their C-terminal end to the enhanced green fluorescent protein (EGFP) were expressed in HEK-293 cells. Whole-cell
Na + currents were recorded using the patch clamp technique to examine channel gating at 30°C and after cooling the bathing solution
to 20°C. Mutant channel fast inactivation was impaired at both temperatures. Cooling slowed the kinetics and enhanced steady-state
fast inactivation of both mutant and WT channels. Mutant channel slow inactivation was fairly comparable to that of the WT
at 30°C, but became clearly abnormal at 20°C. Cooling enhanced slow inactivation in the WT by shifting the voltage dependence
toward hyperpolarization, but induced the opposite effect in the mutant. Destabilization of mutant channel slow inactivation
in combination with defective fast inactivation is expected to increase the susceptibility to prolonged membrane depolarization,
and can ultimately lead to membrane inexcitability and paralysis at cold. Thus, abnormal temperature sensitivity of slow inactivation
can be a determinant pathogenic factor, and should therefore be more widely considered in thermosensitive Na + channelopathies.
Little is known about the genetic factors modulating the progression of Huntington's disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of ...HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington's Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Stüve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, ...camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality. Clinical overlap with Schwartz-Jampel type 2 syndrome (SJS2) has suggested that SWS and SJS2 could be allelic disorders. Through studying a series of 19 families with SWS/SJS2, we have mapped the disease gene to chromosome 5p13.1 at locus
D5S418 (
Z
max=
10.66 at θ=
0) and have identified null mutations in the leukemia inhibitory factor receptor (
LIFR or gp190 chain) gene. A total of 14 distinct mutations were identified in the 19 families. An identical frameshift insertion (653_654insT) was identified in families from the United Arab Emirates, suggesting a founder effect in that region. It is interesting that 12/14 mutations predicted premature termination of translation. Functional studies indicated that these mutations alter the stability of
LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells. We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the
LIFR gene on chromosome 5p13.
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