Selected Lower Motor Neuron Disorders
In these motor neuron diseases, the peripheral motor neurons are affected without evidence of involvement of the corticospinal motor system (Tables 374-1, 374-2, and 374-3).
X-Linked Spinobulbar Muscular Atrophy (Kennedy's Disease)
This is an X-linked lower motor neuron disorder in which progressive weakness and wasting of limb and bulbar muscles begins in males in mid-adult life and is conjoined with androgen insensitivity manifested by gynecomastia and reduced fertility (Chap. 346). In addition to gynecomastia, which may be subtle, two findings distinguishing this disorder from ALS are the absence of signs of pyramidal tract disease (spasticity) and the presence of a subtle sensory neuropathy in some patients. The underlying molecular defect is an expanded trinucleotide repeat (-CAG-) in the first exon of the androgen receptor gene on the X chromosome. DNA testing is available. An inverse correlation appears to exist between the number of -CAG- repeats and the age of onset of the disease.
Several reports have described adult-onset, predominantly lower motor neuropathies arising from deficiency of the enzyme β-hexosaminidase (hex A). These tend to be distinguishable from ALS because they are very slowly progressive; dysarthria and radiographically evident cerebellar atrophy may be prominent. In rare cases, spasticity may also be present, although it is generally absent (Chap. 361).
The SMAs are a family of selective lower motor neuron diseases of early onset. Despite some phenotypic variability (largely in age of onset), the defect in the majority of families with SMA maps to a locus on chromosome 5 encoding a putative motor neuron survival protein (SMN, for survival motor neuron) that is important in the formation and trafficking of RNA complexes across the nuclear membrane. Neuropathologically these disorders are characterized by extensive loss of large motor neurons; muscle biopsy reveals evidence of denervation atrophy. Several clinical forms exist.
Infantile SMA (SMA I, Werdnig-Hoffmann disease) has the earliest onset and most rapidly fatal course. In some instances it is apparent even before birth, as indicated by decreased fetal movements late in the third trimester. Though alert, afflicted infants are weak and floppy (hypotonic) and lack muscle stretch reflexes. Death generally ensues within the first year of life. Chronic childhood SMA (SMA II) begins later in childhood and evolves with a more slowly progressive course. Juvenile SMA (SMA III, Kugelberg-Welander disease) manifests during late childhood and runs a slow, indolent course. Unlike most denervating diseases, in this chronic disorder weakness is greatest in the proximal muscles; indeed, the pattern of clinical weakness can suggest a primary myopathy such as limb-girdle dystrophy. Electrophysiologic and muscle biopsy evidence of denervation distinguish SMA III from the myopathic syndromes. There is no primary therapy for SMA, although remarkable recent experimental data indicate that it may be possible to deliver the missing SMN gene to motor neurons using intravenously delivered adeno-associated viruses (e.g., AAV9) immediately after birth.
Multifocal Motor Neuropathy with Conduction Block
In this disorder lower motor neuron function is regionally and chronically disrupted by remarkably focal blocks in conduction. Many cases have elevated serum titers of mono- and polyclonal antibodies to ganglioside GM1; it is hypothesized that the antibodies produce selective, focal, paranodal demyelination of motor neurons. MMCB is not typically associated with corticospinal signs. In contrast with ALS, MMCB may respond dramatically to therapy such as IV immunoglobulin or chemotherapy; it is thus imperative that MMCB be excluded when considering a diagnosis of ALS.
Other Forms of Lower Motor Neuron Disease
In individual families, other syndromes characterized by selective lower motor neuron dysfunction in an SMA-like pattern have been described. There are rare X-linked and autosomal dominant forms of apparent SMA. There is an ALS variant of juvenile onset, the Fazio-Londe syndrome, that involves mainly the musculature innervated by the brainstem. A component of lower motor neuron dysfunction is also found in degenerative disorders such as Machado-Joseph disease and the related olivopontocerebellar degenerations (Chap. 373).
Selected Disorders of the Upper Motor Neuron
Primary Lateral Sclerosis
This exceedingly rare disorder arises sporadically in adults in mid- to late life. Clinically PLS is characterized by progressive spastic weakness of the limbs, preceded or followed by spastic dysarthria and dysphagia, indicating combined involvement of the corticospinal and corticobulbar tracts. Fasciculations, amyotrophy, and sensory changes are absent; neither electromyography nor muscle biopsy shows denervation. On neuropathologic examination there is selective loss of the large pyramidal cells in the precentral gyrus and degeneration of the corticospinal and corticobulbar projections. The peripheral motor neurons and other neuronal systems are spared. The course of PLS is variable; while long-term survival is documented, the course may be as aggressive as in ALS, with ˜3-year survival from onset to death. Early in its course, PLS raises the question of multiple sclerosis or other demyelinating diseases such as adrenoleukodystrophy as diagnostic considerations (Chap. 380). A myelopathy suggestive of PLS is infrequently seen with infection with the retrovirus human T cell lymphotropic virus (HTLV-I) (Chap. 377). The clinical course and laboratory testing will distinguish these possibilities.
Familial Spastic Paraplegia
In its pure form, FSP is usually transmitted as an autosomal trait; most adult-onset cases are dominantly inherited. Symptoms usually begin in the third or fourth decade, presenting as progressive spastic weakness beginning in the distal lower extremities; however, there are variants with onset so early that the differential diagnosis includes cerebral palsy. FSP typically has a long survival, presumably because respiratory function is spared. Late in the illness there may be urinary urgency and incontinence and sometimes fecal incontinence; sexual function tends to be preserved.
In pure forms of FSP, the spastic leg weakness is often accompanied by posterior column (vibration and position) abnormalities and disturbance of bowel and bladder function. Some family members may have spasticity without clinical symptoms.
By contrast, particularly when recessively inherited, FSP may have complex or complicated forms in which altered corticospinal and dorsal column function is accompanied by significant involvement of other regions of the nervous system, including amyotrophy, mental retardation, optic atrophy, and sensory neuropathy.
Neuropathologically, in FSP there is degeneration of the corticospinal tracts, which appear nearly normal in the brainstem but show increasing atrophy at more caudal levels in the spinal cord; in effect, the pathologic picture is of a dying-back or distal axonopathy of long neuronal fibers within the CNS.
Defects at numerous loci underlie both dominantly and recessively inherited forms of FSP (Table 374-3). More than 20 FSP genes have now been identified. The gene most commonly implicated in dominantly inherited FSP is spastin, which encodes a microtubule interacting protein. The most common childhood-onset dominant form arises from mutations in the atlastin gene. A kinesin heavy-chain protein implicated in microtubule motor function was found to be defective in a family with dominantly inherited FSP of variable onset age.
An infantile-onset form of X-linked, recessive FSP arises from mutations in the gene for myelin proteolipid protein (Chap. 365). This is an example of rather striking allelic variation, as most other mutations in the same gene cause not FSP but Pelizaeus-Merzbacher disease, a widespread disorder of CNS myelin. Another recessive variant is caused by defects in the paraplegin gene. Paraplegin has homology to metalloproteases that are important in mitochondrial function in yeast.
Several websites provide valuable information on ALS including those offered by the Muscular Dystrophy Association (www.mdausa.org), the Amyotrophic Lateral Sclerosis Association (www.alsa.org), and the World Federation of Neurology and the Neuromuscular Unit at Washington University in St. Louis (www.neuro.wustl.edu/neuromuscular).