The natural history of amyotrophic lateral sclerosis.

Using 42 strength and functional assessments recorded monthly, the natural history of amyotrophic lateral sclerosis (ALS) is described in 167 patients (98 men, 67 women) followed in five medical centers in the western United States. The mean age at onset was 57.4 years, and symptoms were present for 2.64 years before study entry. Although there was a highly variable rate of decline within the group of patients, there were no differences in rate of decline by age or gender. Older patients and women were weaker on entry. Forty-eight patients died during the study. The median survival was 4.0 years for the study cohort but 2.1 years for newly diagnosed cases. Decline in pulmonary function most closely correlated with death. Our results emphasize the importance of considering clinical variability in planning clinical trials. One possible strategy is to identify and stratify patients by rate of decline in pulmonary function since prospectively identifying homogeneous subgroups allows investigators to substantially reduce sample size in therapeutic trials.

DNA deletion associated with hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that causes episodes of focal demyelinating neuropathy following minor trauma to peripheral nerves. We assign the HNPP locus to chromosome 17p11.2 and demonstrate the presence of a large interstitial deletion associated with this disorder in three unrelated pedigrees. De novo deletion is documented in one pedigree. The deleted region appears uniform in all pedigrees and includes the gene for peripheral myelin protein 22 (PMP-22), suggesting that underexpression of PMP-22 may cause HNPP. The deletion in HNPP spans approximately 1.5 Mb and includes all markers that are known to map within the Charcot-Marie-Tooth neuropathy type 1A (CMT1A) duplication. Furthermore, the breakpoints in HNPP and CMT1A map to the same intervals in 17p11.2, suggesting that these genetic disorders may be the result of reciprocal products of unequal crossover.

Relative refractory period: a measure to detect early neuropathy in alcoholics.

The absolute (ARP) and relative refractory period (RRP) of the median sensory nerve was determined in 26 control subjects and 24 alcoholics, nine of whom had symptoms of peripheral neuropathy. Recovery of latency to normal in response to the second stimulus was used to define RRP. A true RRP was calculated by subtracting ARP from measured RRP. Mean ARP for all subjects ranged from 0.75 to 0.80 msec; normal = 0.8 +/- 0.2 msec. The true RRP of control subjects was 2.1 +/- 0.5 msec, and for all alcoholic subjects it was 3.1 +/- 0.5 msec. True RRP for the nine symptomatic alcoholic subjects was 3.6 +/- 0.5 msec and 2.9 +/- 0.4 msec for those who were asymptomatic. Symptomatic and asymptomatic alcoholics differed significantly from one another, as well as from control subjects (P less than 0.001). Routine nerve conduction studies were normal in asymptomatic subjects. Three out of nine symptomatic alcoholics had increases in distal median motor or sensory latency, and three had slight slowing of median nerve conduction velocity. True RRP is more sensitive than routine measures of nerve conduction in the detection of axonal disorders influencing nerve conduction.