CHCHD10 mutations and motor neuron disease: the distribution in Finnish patients

Motor neuron disorders (MNDs) are a heterogeneous group of diseases that result from degeneration of motor neurons. If both upper and lower motor neurons (UMNs and LMNs) are affected, the disease is classified as amyotrophic lateral sclerosis (ALS). Primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) selectively affect the UMNs or LMNs, respectively, but are sometimes considered to be incomplete ALS variants because their phenotype may evolve into typical ALS over time. Bulbar affection in a UMN disease would favour a diagnosis of PLS over hereditary spastic paraplegia (HSP), whereas rapid progression may separate PMA from adult-onset spinal muscular atrophy (SMA).Some SMA-like or even ALS-like phenotypes have been incorporated into the large category of sensorimotor axonal neuropathies (Charcot-Marie-Tooth disease type 2, CMT2),1 although sensory abnormalities may be subtle in some forms.2 On the other hand, spinal and bulbar muscular atrophy (Kennedy disease) is classified as a form of adult-onset SMA despite prominent sensory abnormalities. It has recently been argued that the current classification system of MNDs is unsatisfactory and should be revised to include genetically and prognostically important categories.3We have recently identified a new form of motor neuron disease in 55 patients from 17 Finnish families, where distinctive phenotype did not match any pre-existing neuromuscular disease category.4–6 Spinal muscular atrophy Jokela type (SMAJ, OMIM #615048) is characterised by painful cramps, fasciculations, decreased or absent tendon reflexes, elevated creatine kinase and hand tremor. The first symptoms appear commonly after age 30–40. Electromyography (EMG) and muscle biopsy display widespread neurogenic findings and a proportion of patients show sensory abnormalities. Muscle weakness and atrophy appear much later in the disease course, and patients have remained ambulant for several decades and their life expectancy is within normal range.4 ,5 SMAJ is caused by a dominant …