The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey

Abstract

Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS.

Keywords: CLINICAL NEUROLOGY; GENETICS; MOLECULAR BIOLOGY; MOTOR NEURON DISEASE; PRION.

Figure 1

Developments in cellular and clinical probes for amyotrophic lateral sclerosis (ALS) over 130 years. Lockhart Clarke's hand-drawn atrophied anterior horn cells (top left) are contrasted with RNA foci (below, red dots) visualised within cortical neurons (nuclei, ∼5–10 µ diameter, stained blue with DAPI) differentiated from induced pluripotent stem cells derived from patient with ALS fibroblasts. Gowers’ textbook contained detailed illustrations of a classical ‘flail arm’ variant of ALS with a head drop (top middle and right), contrasted with the white matter tractography of diffusion tensor MRI (bottom right, temporal lobe projection tracts shown in a cutaway coronal plane from the front). Cortical neuron image provided courtesy of Professor Kevin Talbot, University of Oxford.

Figure 2

The cell versus the system in amyotrophic lateral sclerosis (after Talbot40). From the top: Genetic, environmental and stochastic events influence events at the cellular and also the motor system level. These interact with each other to result in the core ALS syndrome of mixed upper and lower motor neuron signs associated in the majority with relatively minor cognitive impairment. However, rarer pure upper motor neuron (primary lateral sclerosis, PLS), lower motor neuron (progressive muscular atrophy, PMA) and frontotemporal dementia (FTD) variants are recognised. Moreover, these are all characteristically slower in progression, possibly reflecting the relative containment of pathology due to as yet unidentified ‘firewalls’ between neuronal networks.