Genetic factors in motor neuron disease

The term motor neuron disease is used by different authors to designate one or more of a wide variety of disorders whose principal common feature is dysfunction of the motor neuron (MN) or anterior horn cell (AHC). In one convention, the term motor neuron disease is used to denote all such disorders, including both infantile- and juvenile-onset forms of spinal muscular atrophy, and corticospinal degenerations in which the upper motor neuron is prominently affected. At other times the term motor neuron disease refers only to the relatively common and presumably more homogeneous condition which is idiopathic, has its onset in late adult life and is almost inevitably fatal. Often the distinction between these two uses is not clearly stated and must be inferred. In another more recent, but not yet universal convention, the term motor neuron disease designates all disorders of the anterior horn cell and associated motor system, and amyotrophic lateral sclerosis (ALS) is used to indicate the commonest disorder. This is also potentially confusing, as by definition the term ALS is the clinical presentation of a patient with combined upper and lower motor neuron signs in either or both of the bulbar and spinal regions. Therefore its use may implicitly exclude patients with the clinical features of progressive bulbar palsy (PBP) (exclusive lower motor neuron involvement in the bulbar region) or progressive muscular atrophy (PMA) (exclusive lower motor neuron involvement in the spinal region, (also called progressive spinal muscular atrophy (PSMA))). Some authors suggest that PMA has a sufficiently different clinical presentation and prognosis to define it is a different disease (Norris et al, 1978). However, there is poor correlation between the clinical and pathological features of clinically defined cases of ALS and PMA (Chou, 1978), the electrophysiological abnormalities are indistinguishable (Hansen and Ballantyne, 1978), and one clinical form may change into another (Friedman and Freedman, 1950). When patients with either pure PMA or pure PBP are examined repeatedly during the course of their illness, they are often found to develop upper motor neuron signs, so exclusive lower motor neuron syndromes confirmed at autopsy are probably quite rare (cf the Mayo Clinic patients in Juergens et al, 1980). Therefore, a reasonable inference is that ALS, PBP and PMA are clinical variants of one disease. By contrast, most authors are cautious to discuss pure upper motor neuron degeneration, or primary lateral sclerosis (PLS), as a separate entity (Stark and Moersch, 1945; Younger et al, 1988). In this thesis, the uncapitalised phrase 'motor neuron diseases' will refer to all disorders where loss or degeneration of the AHC is the principal salient feature. The abbreviation MND/ALS will be this author's term for the idiopathic, adult-onset disease which may have the variety of clinical presentations (ALS, PBP, PMA) described above. The terms MND or ALS will be used alone when they refer to a patient or group of patients described by a specific author, so that then the reference will be to the definition utilised by that author. Clinical presentations will be called the ALS, PMA or PBP 'form' of MND/ALS