ABSTRACT
More than 140 different mutations have been reported in the Cu/Zn superoxide dismutase-1 (SOD1) gene in patients with amyotrophic lateral sclerosis (ALS), some occurring as founder mutations. Occasionally, specific mutations are associated with a particular phenotype. We evaluated a possible genotype-phenotype correlation and looked for a founder effect in nine patients from six unrelated families with ALS, all carrying the G41S mutation, originating from north-west Tuscany in central Italy. Mutational analysis of the SOD1 gene was carried out by direct sequencing. A haplotype study was carried out using eight polymorphic markers flanking the SOD1 gene. The clinical pattern of the nine familial ALS (FALS) patients was characterized by spinal onset with early upper and lower motor neuron involvement, appearance of bulbar signs within one year, and death a few months later. Mean age at onset was 49.3 years and mean duration of disease was 0.9 years. Genotyping revealed a common haplotype for the G41S allele. We provide the first evidence that the G41S mutation in Italy originates from a common founder. In addition, our findings strengthen the data reported previously and indicate that the G41S mutation is consistently associated with a uniform and dramatic, fast-progressing phenotype.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/physiopathology , Point Mutation , Superoxide Dismutase/genetics , Adult , Aged , Disease Progression , Family Health , Female , Founder Effect , Haplotypes , Humans , Italy , Male , Middle Aged , Pedigree , Phenotype , Severity of Illness Index , Superoxide Dismutase-1ABSTRACT
BACKGROUND: In obsessive-compulsive disorder (OCD) patients, functional abnormalities in basal ganglia/precentral circuitries cause cortical hyperexcitability and lack of inhibitory control. These loops can be partly explored by median-nerve somatosensory evoked potentials (SEPs), which functionally reflect the brain responsiveness to somatosensory stimuli. In healthy humans, SEPs' amplitude during voluntary finger movements is lower than during muscular relaxation (i.e., sensory gating). Cortical hyperexcitability in OCD could be eventually responsible for a reduction of sensory gating. This might have pathophysiologic implications for motor compulsions. METHODS: Median-nerve SEPs were recorded in 11 OCD patients and 9 healthy volunteers during muscle relaxation ("Relax") or finger movements of the stimulated hand ("Move"). Latencies and amplitudes of pre- and postcentral SEP components were compared between groups during "Relax" and "Move" conditions. RESULTS: In OCD patients, the responsiveness to sensory stimuli was enhanced for precentral SEPs. Sensory gating ("Relax" vs. "Move") in control subjects involved both pre- and postcentral SEPs, the former being reduced in amplitude by approximately 60%. In OCD patients, sensory gating was spatially restricted to precentral SEP components and was significantly reduced compared with control subjects (approximately 30%). CONCLUSIONS: Enhanced precentral SEPs and hypofunctioning of centrifugal sensory gating in OCD might reflect the inability to modulate sensory information due to a "tonic" high level of cortical excitability of motor and related areas, likely resulting from basal ganglia dysfunction. This might offer new insights into the pathophysiology of OCD.
Subject(s)
Evoked Potentials, Somatosensory/physiology , Movement/physiology , Muscle Relaxation/physiology , Obsessive-Compulsive Disorder/physiopathology , Somatosensory Cortex , Adult , Electric Stimulation/methods , Electroencephalography/methods , Female , Fingers/physiopathology , Humans , Male , Median Nerve/radiation effects , Middle Aged , Psychomotor Performance/physiology , Reaction Time/physiology , Statistics, NonparametricABSTRACT
In a drug-resistant epilepsy patient with continuous forearm/hand positive myoclonia due to a focal cortical dysplasia of the right motor cortex, cortical jerk-related and electromyographic activity were recorded for 15 min before and after 1 Hz rTMS (15 min, 10% below the resting excitability threshold) of the right motor cortex. A stable negative cortical spike, time-locked with contralateral muscle jerks (60 > 100 microV), was detected only at perirolandic electrodes (maximal amplitudes: block 1 = 21.3 microV, block 2 = 22 microV, block 3 = 25.9 microV). After rTMS, only 20 muscle jerks accomplished the criterion of > 100 microV; blind back-averaging of these disclosed a topographically similar cortical spike, but with amplitude reduced by at least 50% (11.2 microV). This represents in vivo evidence of the possibility to selectively modulate the activity of an epileptic focus by intervening with local low-frequency rTMS.
