MOTOR NEURON DISEASES

Amyotrophic Lateral Sclerosis (ALS) is a fatal degenerative disorder of upper and lower motor neurons. Lower motor neuron loss causes muscle weakness, atrophy, and fasciculations; upper motor neuron involvement causes spasticity, clonus, hyperactive tendon reflexes, and Babinski signs. Dementia appears at the onset or develops later in a significant proportion of ALS patients. Primary lateral sclerosis is an ALS variant which affects upper motor neurons only. In about 25% of cases, ALS begins with brainstem symptoms (dysarthria, difficulty swallowing) followed by extremity weakness. This variant is called progressive bulbar palsy and has a worse prognosis. Some ALS patients have only lower motor neuron involvement (progressive muscular atrophy). ALS is relentlessly progressive. The majority of patients die, usually from respiratory paralysis, within 2-3 years from the onset of symptoms. There is no specific diagnostic test for ALS. The diagnosis is based on a combination of clinical and electrodiagnostic findings and muscle biopsy results.

About 5-10% of ALS cases are familial, mostly autosomal dominant. Several gene mutations have been discovered in this group. These mutations affect protein stability, RNA biology, cytoskeletal maintenance, and other functions. Mutations of the same genes are also found in a significant proportion of sporadic ALS cases. The most common cause of FALS is mutation of a gene on chromosome 21q that encodes Cu/Zn superoxide dismutase (SOD1). This enzyme protects cells from toxic oxygen radicals. However, the disease in these cases is not due to loss of antioxidant properties of SOD1 but to a toxic action of the mutated enzyme. This toxicity may have to do with decreased Zn binding by the mutant SOD1. Glutamate toxicity and oxidative stress have been implicated in the pathogenesis of sporadic ALS, and anti-glutamate therapy with Riluzole prolongs survival in some patients.

About 4% of FALS cases are caused by mutations of the RNA processing gene TARDBP. Degenerating motor neurons in FALS due to TARDBP mutations contain ubiquitin-positive neuronal and glial inclusions, which are immunoreactive for TDP-43. TDP-43 is normally a nuclear protein. In FALS due to TARDBP mutations, it is translocated into the cytoplasm, cleaved, ubiquitinated, and phosphorylated. In this form, TDP-43 is presumably toxic. TDP-43 inclusions in TARDBP related ALS are also present in the cerebral cortex, striatum, substantia nigra, and other locations. Identical inclusions are also seen in most cases of TDP-43 fronto-temporal lobar degeneration. Taken together with the presence of dementia in some ALS cases, these observations suggest that this form of ALS is not just a motor neuron disease but a multisystem neurodegenerative disorder and is part of the spectrum of TDP-43 proteinopathy, which includes ALS and FTD. TDP-43 deposits are not seen in SOD1 mutations. About 4% of FALS cases are caused by mutations of FUS, which also encodes an RNA processing protein. Another recently identified gene which accounts for a significant proportion of FALS cases is C9ORF72 on 9p21. This mutation causes hexanucleotide repeat expansion in a noncoding region of the gene and is associated with FTD and TDP-43 inclusions.

Loss of motor neurons in the hypoglossal nuclei ALS, medulla. Loss of neurons in the hypoglossal nuclei. The open space at the top is the floor of the 4th ventricle.

Denervation atrophy ALS. Denervation atrophy (see also chapter 13-Myopathology).

Degeneration of the corticospinal tracts ALS. Degeneration of the corticospinal tracts. Myelin stain.

The pathology of ALS is degeneration and loss of motor neurons in the anterior horns and motor nuclei of brain stem. Because of loss of lower motor neurons, muscles undergo denervation atrophy. There is also degeneration of upper motor neurons . As the name of the disease indicates, this is most evident in the lateral corticospinal tracts, which lose axons and myelin and become gliotic. Involvement of the internal capsule and motor cortex is usually mild or inapparent, but in severe cases there is loss of upper motor neurons (Betz cells). Degeneration may also infrequently involve sensory tracts.

Spinal Muscular atrophy (SMA) is a group of genetic disorders that cause degeneration and loss of spinal and brain stem motor neurons. The group includes several distinct clinical and genetic syndromes. Most are autosomal recessive, but there are X-linked and autosomal dominant forms also. Autosomal recessive SMA is the most common fatal recessive disorder in children after cystic fibrosis. It is caused by mutations involving both copies of the spinal motor neuron gene (SMN) on chromosome 5q11-q13. Normal persons have two copies of this gene, the telomeric (SMN1) and centromeric copy (SMN2), arranged in tandem. SMN2 encodes a partially functional protein. Most SMA patients have homozygous deletions of exons 7 and 8 of SMN1. This causes motor neuron loss by an unkown mechanism.

Spinal muscular atrophy. Myofiber atrophy and excessive variation in size. Toluidin blue stain.

Autosomal recessive SMA covers a wide clinical spectrum. At one end of this spectrum are cases that have a prenatal onset, paralysis of facial and extraocular muscles, and a very short survival. Arthrogryposis (joint contractures) is seen in some cases. At the other end, there are cases that begin in young adult life and have a slow progression. The most important entity in this group is SMA1 (Infantile Spinal Muscular Atrophy; Werdning-Hoffmann Disease) which begins in infancy and is usualy fatal within two years. Loss of lower motor neurons causes denervation atrophy of muscle, manifested by severe hypotonia, weakness, and inability to breathe. Brain stem and spinal motor neurons shrink, become pyknotic, and die. Activated microglial cells often surround and ingest degenerated neurons (neuronophagia). In advanced cases, there is gliosis. In some cases, other neuronal groups besides motor neurons are affected. SMA1 must be distinguished from other causes of neonatal hypotonia which include CNS malformations, metabolic diseases, infections, and congenital myopathies. Fasciculations of the tongue, which are a prominent feature of SMA, are helpful in making this distinction.

SMA3 (Juvenile Spinal Muscular Atrophy; Kugelberg-Welander Disease) begins in adolescence and has a slow progression, compatible with long survival (in a wheelchair). It tends to cause proximal weakness and may be confused with myopathy.

There are also rare progressive, autosomal recessive upper motor neuron degenerations (Infantile –Onset Ascending Hereditary Spastic Paralysis, Juvenile Primary Lateral Sclerosis, and Juvenile ALS) which begin during childhood and present with spasticity and weakness.

The changes of denervation are obvious in the muscle biopsy. Today, the diagnosis of SMA is usually made by DNA analysis. Ninety five percent of cases of SMA can be diagnosed with a DNA test that detects deletion of exons 7 and 8 from the telomeric copy of the SMN gene. There is no correlation between the type of mutation and the phenotype. An adult onset, X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is associated with CAG trinucleotide repeats.