Motor neuron disease (MND) is a degenerative disease with primary damage to the central (upper) and peripheral (lower) motor neurons. The disease proceeds gradually and results in fatal outcome. MND is a rare disease and encounters 2–5 cases per 100,000 people per year. The average age of its onset is 50–70 years; it is less common in people younger than 40 years.
Etiology and pathogenesis
In 10% of cases, MND may be a family disease with monogenic inheritance (often associated with SOD1, FUS, TARDBP, UBQLN2, PFN1, С9orf72 genes). With a mutation in the SOD1 gene encoding the antioxidant enzyme copper-zinc-containing superoxide dismutase, neurons can degrade due to antioxidant deficiency. The remaining 90% of cases are a sporadic form with polygenic inheritance. To date, about 100 genes associated with MND have been identified. Most mutations are inherited by an autosomal dominant type. In patients with sporadic forms of the disease, mutations related to the systems of the motor neuron cytoskeleton and DNA repair, regulation of survival and programmed cell death, etc., have been identified. The phenotype of sporadic MND can develop with structural or functional defects in various genes that trigger the mechanism of motor neuron degeneration. This mechanism is thought to interact with provoking environmental factors, where gender and age are considered reliable. The possible relation of the MND with the exogenous toxins (heavy metals, etc.), mechanical trauma, viral infections has not been confirmed.
The role of the following links in the pathogenesis of the disease has been experimentally confirmed:
- glutamate excitotoxicity;
- abnormal accumulation of neurofilaments in the bodies of motor neurons;
- deficiency of neurotrophic factors and signaling systems;
- violation of axonal transport;
- mitochondrial dysfunction;
- violation of micro-DNA expression, mechanisms of apoptosis;
- activation of free radical oxidation.
Currently, the pathogenetic theory of proteinopathy is prevailing; based on this theory, in MND, abnormal conformation of proteins and pathological aggregation of protein deposits occur in the bodies of motor neurons.
Motor neurone degeneration is clinically detected after the death of at least 80% of cells. This largely limits the timely treatment of MND as the disease should be diagnosed at the preclinical stage.
Pathomorphology
Pathomorphological examination demonstrates degeneration of motor neurons in the layers III and V of the anterior central gyrus, adjacent frontal lobes, motor nuclei of the CNs V, VII, X, XII, as well as significant degeneration of motor neurons of the anterior horns of the spinal cord and corticospinal tracts throughout their entire length. At different stages of motor neuron degeneration, pathological inclusions may occur — basophilic, eosinophilic and protein including Bunina’s bodies, which include abnormally phosphorylated structures of the cytoskeleton and proteins of the proteolytic degradation system. Axonal spheroids are detected in the proximal axons of motor neurons (these findings were the basis of the theory of proteinopathy). In the muscles of patients with MND, signs of denervated muscle atrophy are noted.
Clinical presentation
According to international diagnostic criteria, a reliable diagnosis of MND is based on the following findings:
- combinations of signs and symptoms of damage to central and peripheral motor neurons at three levels of the CNS out of four possible ones (brainstem, cervical, thoracic and lumbar spinal cord);
- progressive nature of the disease (positive diagnostic criteria);
- no evident disorders of higher mental functions, oculomotor and sensory disorders and pelvic organ dysfunction (negative diagnostic criteria).
There are the following forms of MND (classification of F. Norris):
- amyotrophic lateral sclerosis (ALS) in 80% of cases;
- progressive bulbar palsy (PBP) in 10% of cases;
- progressive muscular atrophy in 8% of cases;
- primary lateral sclerosis in 2% of cases.
In the first two most common forms, the symptoms related to involvement of the central and peripheral motor neurons are combined, while the last two forms present only with signs of damage to the peripheral or central motor neurons, respectively. In ALS and PBP, either a combination of evenly pronounced signs and/or symptoms of peripheral and central palsy (classic variant) is observed, or the signs and/or symptoms of peripheral motor neuron damage prevail over the symptoms of central motor neuron damage (segmental-nuclear variant), or central motor disorders prevail (pyramidal variant).
ALS refers to cases when the disease manifests with an involvement of the motor neurons of the anterior horns of the spinal cord; PBP presents with a primary lesion of the neurons of the cranial motor nuclei. As the disease progresses, bulbar disorders occur in ALS, and spinal disorders in PBP. However, ALS and PBP are thought to be separate forms of the disease due to differences in age- and gender-related morbidity; thus, men are twice as likely to be affected by ALS, and women are more likely to suffer from PBP. In average, PBP manifests later than BAS.
Classic version of PBP manifests with bulbar disorders, i.e., dysarthria and nasal twang (nasolalia). Subsequently, dysarthria and dysphonia increase, dysphagia (swallowing disorder) joins, as well as weakness of the facial and masticatory muscles. At the same time, pseudobulbar symptoms are noted in the form of involuntary laughter and crying. The examination reveals a combination of bulbar and pseudobulbar symptoms: atrophy and fasciculation of the tongue muscles, palatal palsy, brisk pharyngeal reflex and reflexes of oral automatism. Later, weakness of the cervical extensors, weakness with hypotrophy and fasciculations of the muscles of the upper shoulder girdle in combination with brisk tendon reflexes, spastic muscle tone in the extremities and the appearance of pathological reflexes develop.