68 Other Motor Neuron Diseases and Motor Neuropathies

Clinical Vignette

A 63-year-old man was evaluated for 3 years of slowly progressive symptoms of proximal lower extremity weakness. He first noted difficulty negotiating the high step up from the dock to the deck of his boat. Eleven years prior to his neurologic evaluation for weakness, he had been evaluated for painful enlarged breasts, attributed to alcoholic liver disease. More recently, he had noticed difficulty swallowing and had received the Heimlich maneuver on one occasion. Increasingly, muscle cramping had become an annoyance. His mother was troubled by dysphagia and questionable weakness in later life; a brother, two sons, and a daughter had no symptoms. Examination was remarkable for mild facial, tongue, neck flexor and proximal weakness of upper and lower extremities. Tongue and chin fasciculations were seen. There was a mild postural tremor of the hands. Muscle stretch reflexes were traced at the patellar and biceps tendons but otherwise absent. Sensory examination was normal. There were no upper motor neuron signs. Serum creatine kinase level was modestly elevated to 500 IU/L. On nerve conduction studies (NCS), the amplitudes of sensory nerve action potentials were reduced. Needle electromyography (EMG) demonstrated reduced recruitment of high-amplitude and long-duration motor unit potentials consistent with chronic partial denervation and reinnervation in a generalized distribution. Fasciculation potentials were abundant. No evidence of active denervation was demonstrable. Genetic testing revealed expansion of the CAG trinucleotide repeat (>35 CAGs) in the androgen receptor (AR) gene.

Motor neuron diseases (MNDs) are disorders that produce painless weakness, atrophy, cramps, and fasciculations and are consequent to degeneration of anterior horn cells and selective cranial nerve nuclei. This chapter will address notable MNDs other than ALS.

Many of the disorders discussed in this chapter have known or suspected genetic mechanisms. The spinal muscular atrophies (SMAs) are conceptualized as largely inherited disorders in which there is predominant degeneration of anterior horn cells and selective cranial nerve nuclei. In the childhood SMAs, mutations of a single gene and derangement of a single gene product are responsible for the majority of cases, and the resultant phenotype is fairly homogeneous. In other disorders, for example, hereditary spastic paraplegia (HSP), there are a plethora of recognized genotypes correlating with an almost equally heterogeneous array of phenotypic variations.

Because of the relative rarity of these disorders, societal impact is usually limited. However, as with most hereditary disorders, the impact on individuals and families is substantial. This is particularly true for spinal muscular atrophy type I where parents have to cope with the consequences of a newborn with a lethal illness as well as with the specter that subsequent children are at risk. SMA I, also known as Werdnig–Hoffman disease, is the most common of the SMAs. Its incidence is estimated to be between 4 and 10 in 100,000 live births depending on the geographic cohort studied. After cystic fibrosis, it is the second most common, lethal, recessively inherited disorder of Caucasians.

Clinical Presentation

Spinal Muscular Atrophy Types I–IV

Spinal muscular atrophy types I–IV are allelic disorders of the survival motor neuron (SMN) gene 1 located on chromosome 5q12.2-q13.3. When there is more than one affected individual in a given family, the phenotype is typically homogeneous but may be disparate in some cases. In normal individuals, there are two copies each of the SMN1 and SMN2 genes. Both genes produce similar but not identical proteins; the SMN2 gene appears to produce an unstable and rapidly degrading protein that can partially compensate for the lack of the SMN1 protein. There are no known clinical consequences from mutations of the SMN2 gene alone.

It is estimated that 95% of SMA I–III patients are homozygous for deletion of exons 7 and 8 of the SMN1 gene. The remainder are thought to be compound heterozygotes with absence of exons 7 and 8 on one allele and a point mutation of the other SMN1 allele. The severity of the SMA phenotype appears to be related to the number of SMN2 copies available to compensate for deleted SMN1 gene. Homozygotes devoid of SMN1 who harbor two copies of SMN2 tend to manifest as an SMA I phenotype. An increasing number of SMN2 copies correlates with proportionately milder (SMA II-IV) forms of the disease. Individuals homozygous for the SMN1 mutation with five copies of the SMN2 gene have been reported to be asymptomatic. Why motor neurons remain selectively vulnerable to SMN deficiency remains unknown.

Of the multiple SMA phenotypes, the infantile and childhood forms are the most prevalent. SMA type I or Werdnig–Hoffman disease is the most severe form (Fig. 68-1). Clinical manifestations become evident within the first 6 months of life. In contrast to the latter three categories, afflicted children with SMA I never develop the capability of sitting independently. In some cases, recognition of reduced movement occurs in utero or within the first few days of life. Affected infants are hypotonic with a symmetric, generalized, or proximally predominant pattern of weakness. Like ALS, facial weakness is typically mild and extraocular muscles are spared. Fasciculations are seen in the tongue but rarely in limb muscles, presumably because of the ample subcutaneous tissue of neonates. Manual tremor, so characteristic of SMA types II and III, is rarely present. Deep tendon reflexes are typically absent. Abdominal breathing, a weak cry, and a poor suck are commonplace. Ventilation difficulties stem primarily from intercostal rather than diaphragmatic weakness. Pectus excavatum and a diminished anteroposterior diameter of the chest are seen. Mild contractures may occur but arthrogryposis is not part of the classic phenotype. Intellectual development is normal. Without mechanical ventilation, death is inevitable, almost always within a year or two. An earlier age of onset correlates with a shorter life expectancy.