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.

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Thomsen's disease (autosomal dominant myotonia congenita) has recently been linked to chromosome 7q35 in the region of the human skeletal muscle chloride channel gene (HUMCLC). Single strand conformation polymorphism analysis (SSCP) was used to screen DNA from members of four unrelated pedigrees with this disorder for mutations in HUMCLC. Abnormal bands were detected in all affected, but no unaffected individuals in three of the families. Direct sequencing revealed a G to A transition that results in the substitution of a glutamic acid for a glycine residue located between the third and fourth predicted membrane spanning segments. This glycine residue is conserved in all known members of this class of chloride channel proteins. These findings establish HUMCLC as the Thomsen's disease gene.

It has been suggested that the degeneration of lower motor neurons in amyotrophic lateral sclerosis (ALS) is a transneuronal event, secondary to the loss of corticospinal and corticobulbar neurons. In an attempt to test this hypothesis, the cross-sectional areas of pyramidal cells in layer 5 of the foot and tongue areas of the precentral gyri were measured in 12 cases of the classical sporadic form of ALS, and in 10 control subjects. The areas of motor neurons in the hypoglossal nuclei and in the ventral horns of segment L4 of the spinal cord were also measured. The number of neurons per 20 microns section of ventral horn or hypoglossal nucleus provided a more reliable index of severity of lower motor neuron loss at the time of death than did a semiquantitative score derived from clinical observations. Cortical neurons and lower motor neurons were significantly smaller in the cases of ALS than in the controls. In the cortex this change included, but was not confined to, the largest neurons. These observations indicate that shrinkage precedes neuronal death. There was no correlation, positive or negative, between the numbers of surviving lower motor neurons and the mean sizes of pyramidal cells in layer 5 of the corresponding areas of the precentral gyri. The absence of such a correlation indicates that functionally related cortical and lower motor neurons probably degenerate independently, and not from a transsynaptic effect. Neuronal shrinkage has been observed in other diseases in which interconnected systems of neurons degenerate. The possible association of shrinkage with cytoskeletal degradation is discussed.

Neuronal degeneration in the precentral gyrus alone cannot account for the occurrence of spastic paresis in motor neuron diseases. To look for more extensive cortical atrophy we measured MRIs of the upper parts of the frontal and parietal lobes in 11 sporadic cases of classical amyotrophic lateral sclerosis (ALS), eight patients with primary lateral sclerosis (PLS) and an age- and sex-matched group of 49 neurologically normal people. None of the patients had overt dementia or other mental diseases. In PLS there is progressive spastic paresis but in contrast to ALS there is no lower motor neuron degeneration. The surface area of the precentral gyri and the amount of underlying white matter in PLS were consistently approximately 75% of the normal size. By contrast, there was some shrinkage of the precentral gyri in some of the ALS patients but the mean measurements for the group did not differ significantly from the controls. Anterior to the precentral sulci, the cortical surface area in PLS was approximately 85% of that of the controls, with correspondingly reduced white matter. In ALS the cortical surface areas of the anterior frontal lobes did not differ from those of the controls, but the amount of underlying white matter was reduced almost as much in ALS as it was in PLS. The measured changes in the frontal lobes suggest that in PLS there is simultaneous atrophy of the primary, premotor and supplementary motor areas of the cortex, with consequent degeneration of corticospinal and corticoreticular axons descending through the underlying white matter. These changes could account for the progressive upper motor neuron syndrome. In ALS, with no significant frontal cortical atrophy, the shrinkage of the white matter may be due to degeneration of axons projecting to the frontal cortex from elsewhere. Deprivation of afferents could explain the diminution of motor functions of the frontal lobes in ALS and also the changes in word fluency, judgement and attention that can be detected by appropriate testing in some patients with the disease. Incidental observations include slightly larger parietal lobes but no difference in the frontal lobes in men as compared with women. There was also a small but significant decrease in size of the normal frontal lobes with age. The latter change was much smaller than the atrophy seen in patients with ALS and PLS.