Anna Hudson

Eight patients with a homogeneous syndrome of progressive symmetric spinobulbar spasticity were studied. Clinical features were limited to those associated with dysfunction of the descending motor tracts and included spastic quadriparesis, pseudobulbar affect, spastic dysarthria, hyper-reflexia and bilateral Babinski signs. Lower motor neuron findings were absent and higher cognitive function preserved. Median age of onset was 50.5 yrs and median disease duration was 19 yrs. Neuropathologic features (including morphometric analysis) in the single autopsied case confirmed the selective involvement of the motor cortex. There was complete absence of Betz cells from layer 5 of the precentral cortex and the remaining pyramidal cells were significantly smaller than those seen in normal controls. Magnetic resonance imaging (MRI) revealed atrophy of the precentral gyrus and positron emission tomography (PET) scans showed diminished glucose [18F]fluorodeoxyglucose uptake in the pericentral cortex. Magnetic motor cortex stimulation revealed markedly prolonged central motor conduction times. The literature is reviewed and diagnostic criteria for primary lateral sclerosis based on clinical, laboratory and imaging features are proposed.

The cause of several familial muscular diseases have recently been linked to mutations within skeletal muscle sodium and chloride channel genes. Thomsen's and Becker's diseases are autosomal dominant and recessive, respectively, and are caused by at least seven different mutations in the CLCN1 (ClC-1) skeletal muscle chloride channel gene on chromosome 7q35. Hyperkalaemic periodic paralysis, paramyotonia congenita and a small heterogeneous group of related 'pure' myotonias are autosomal dominant disorders and are due to at least 16 different mutations in the SCN4A (SkM1) adult skeletal muscle sodium channel gene on chromosome 17q23-25. There is generally little correlation between the position of a mutation in the channel and the phenotype. Indeed, identical sodium channel mutations in unrelated subjects and sometimes in different members of the same family can have different clinical expressions. It seems, however, that mutations of the inactivation gate (ID3-4 loop) of the sodium channel tend to produce paramyotonia or pure, sometimes severe, myotonia and respond most favourably to the same medications (tocainide and mexiletine). The structure and polarity of substituted amino acids at a mutation site, especially in highly evolutionally conserved regions of the gene, are undoubtedly important to the expression of a channel disease and may partly explain phenotypic variability. In addition, genetic polymorphisms elsewhere, either in the gene or other channel-related loci, and the net effect of other types of muscle ion channels on the electrical potential of the plasma membrane probably contribute to disease expression.

The hyperkalemic periodic paralyses are a clinically heterogeneous group of autosomal dominant syndromes characterized by episodic paralysis associated with an elevated serum potassium level. Affected individuals in the same family tend to have homogeneous symptom complexes, although phenotypic variation is present among different families. For example, myotonia is absent in some pedigrees, present in others, and, in a third variant, paramyotonia congenita, myotonia coexists with cold-induced paralysis. Electrophysiological studies have demonstrated variant-specific abnormalities in skeletal muscle membrane sodium conductance. We tested the hypothesis that hyperkalemic periodic paralysis (without myotonia) and paramyotonia congenita are tightly linked to the tetrodotoxin-sensitive adult skeletal muscle sodium channel gene on chromosome 17q23-25 in two large pedigrees. The DNA polymorphisms detected in the growth hormone skeletal muscle sodium channel complex (GH1-SCN4A) and by flanking polymorphic markers (D17S74 and D17S40) demonstrated no recombinants between the disease phenotypes and this complex. Phenotypic variation in the hereditary hyperkalemic periodic paralyses may result from allelic heterogeneity at the tetrodotoxin-sensitive adult skeletal muscle sodium channel locus.

We present clinical and pathologic data on four previously unreported familial ALS pedigrees and review and analyze by descriptive and exploratory statistical techniques all published cases of familial ALS (1850-1989). In contrast to the age-dependent incidence of sporadic ALS, the age of onset of familial ALS is normally distributed about a mean of 45.7 years (std. dev. 11.3 years). Survival curves for the familial ALS data also demonstrate a skewed distribution with a median survival time of 24 months with 74% surviving at 12 months, 48% at 24 months and 23% surviving at 60 months. The patient characteristics of age at onset of disease, sex and focus of disease onset are unrelated variables and age at onset of disease is the only predictor of survival (Cox's proportional hazard model, chi-square 14.74, p = 0.0001). By applying accelerated failure time models with a log-normal baseline distribution, estimated probabilities for survival adjusted by age at onset were calculated. It was found that the older the age at disease onset, the shorter the survival.