Motor neuron diseases encompass a wide spectrum of neurological disorders, but common to all is a period of diagnostic uncertainty early in the disease, based on clinical grounds alone. That uncertainty can have important consequences for patients, including psychological stress, expenses incurred from multiple clinical tests and procedures, and delay in treatment. The delay in diagnosis also delays, and may even preclude, the ability to enroll in clinical trials of experimental therapies, the major hope for discovering new therapeutic strategies for those diseases that otherwise have no meaningful treatments.
Advances in genetic understanding of both amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) have made it possible to provide a definitive genetic diagnosis for many patients, in some cases allowing the physician to offer gene-specific information on prognosis.
ALS is characterized by loss of motor neurons, leading to progressive weakness and eventual death after an average of 3 to 5 years. About 10% of all ALS cases are familial; researchers believe that known ALS genes account for about 70% of these cases. Some of those same genes also account for a smaller but still significant proportion of sporadic ALS. The C9orf72 gene is the cause of between 24% and 46% of all familial cases, and between 4% and 20% of sporadic cases, depending on the population. The SOD1 gene accounts for about 20% of familial cases and 3% of sporadic cases.
C9orf72: FTD may be part of the picture
Up to half of ALS cases due to mutation in the C9orf72 gene will also develop some degree of frontotemporal dementia during their disease course. The most common form of FTD in the context of C9orf72 mutation is the behavioral variant, characterized by personality changes and inappropriate behavior. There is currently no way to predict the likelihood or extent of FTD symptoms based on the gene mutation, but knowing ahead of time that these changes may become part of the disease experience may allow families to plan for this eventuality.
SOD1: Some mutations affect prognosis
Dementia is rarely part of the clinical picture in ALS due to SOD1 mutation. The rate of motor symptom progression is, to some extent, mutation-specific. The A4V mutation is associated with a very rapid rate of progression, with survival of approximately one year, while the H46R mutation is associated with survival of more than a decade. There are over 170 known SOD1 mutations, most of which are quite rare, and information on progression is not available for most.
The newest and most promising news in experimental therapies for ALS is the development of gene-specific antisense technology. In this approach, modified RNA molecules that are complementary to the mutant gene are delivered intrathecally. These “antisense” molecules bind to the RNA transcript from the gene, triggering destruction of the transcript by cellular quality control machinery, releasing the antisense molecule for another round of binding and destruction. Antisense delivery was recently shown to be feasible and safe in ALS patients. Clinical trials testing the efficacy of this gene-specific approach against the C9orf72 gene are planned to begin in late 2015 or early 2016.
HSP is a group of disorders characterized by progressive weakness and spasticity. Onset of HSP can be at any age, making the diagnosis especially challenging. It may be mistaken for cerebral palsy, ALS, Friedreich ataxia, and other disorders.
There are over a dozen genes known to cause HSP. The clinical picture, and especially the family history, can help narrow the tests needed to obtain a molecular diagnosis. A clear pattern of autosomal dominant inheritance suggests one set of genes, autosomal recessive inheritance suggests another, and no family history or an unclear inheritance pattern suggests a third group. The details are outlined in the algorithm for HSP testing from the European Journal of Neurology, available here.
Reduction of spasticity is the mainstay of symptomatic therapy. There are a wide variety of treatments available, including physical therapy, occupational therapy, orthotics, oral medications, botulinum toxin injections, surgery, and intrathecal baclofen. Physical therapy is the foundation of treatment, focused on maintaining range of motion and preventing contracture.