Motor Neuron Disorders

Motor neuron diseases are neurological disorders that compromise motor neurons that control voluntary muscle movement. Two sets of motor neurons can be affected: the upper motor neurons (UMNs), which originate from the cerebral cortex, and send signals for voluntary movement to the lower motor neurons (LMNs); and the lower motor neurons, which originate in the brainstem and spinal cord, and directly innervate skeletal muscles.^17,24 Motor neuron diseases cause damage to these neurons, preventing neurotransmission to muscles that depend on these nerve cells for normal function. Symptoms in patients with motor neuron disease vary depending on which set of motor neurons is affected: UMN damage results in muscle weakness, spasticity, hyperreflexia, and pseudobulbar palsy; LMN damage results in muscle weakness, atrophy, cramps, hyporeflexia, and fasciculations.^17,24

• Hereditary Spastic Paraplegia⁴⁰ (HSP) is a group of inherited disorders characterized clinically by progressive, often severe, lower extremity spastic weakness and pathologically by axonal degeneration at the distal ends of the corticospinal tracts.^41,42 Patients with genetically diverse types of uncomplicated HSP have similar clinical presentations. Different genetic types of uncomplicated HSP cannot be distinguished reliably by clinical parameters alone. Age of onset and severity of symptoms, however, may vary - even among family members. The majority (60-70%) of uncomplicated HSP is the result of autosomal dominant inheritance. Clinical testing for HSP is available for the SPG4 (spastin) gene and the SPG3A (atlastin) gene, accounting for more than 50% of dominantly inherited HSP.^41,42
  
  
• Spinal Muscular Atrophy (SMA) is a group of predominantly autosomal recessive disorders characterized by severe hypotonia and muscle weakness due to lower motor neuron dysfunction.¹⁶ The four types of SMA affect different age groups, ranging from infancy to young adulthood, with various survival rates.²⁴ Infants may have arthrogryposis congenita multiplex or delayed gross motor milestones.²⁴ The juvenile form usually presents with slowly progressive limb-girdle weakness.²⁴ EMG may demonstrate reduced compound muscle action potential amplitudes with acute denervation, while sensory nerve conduction studies may be normal.²⁴ Elevated CK levels are common in some types of SMA.²⁴ A homozygous deletion of the survival motor neuron (SMN) gene on chromosome 5 is diagnostic of SMA.¹⁵ SMA may also present similar to ALS and congenital hypomyelinating neuropathy (CHN).⁹
  
• Kennedy's Disease (also known as Spinal-Bulbar Muscular Atrophy, SBMA) is an X-linked recessive disorder characterized by slowly progressive skeletal muscle weakness, especially in the muscles of mouth and throat.^16,24 Swallowing problems, slurred speech, facial weakness, and hand tremors are also common clinical features.²⁴ Androgen associated abnormalities such as breast development and testicular wasting may be present in patients with SBMA.^16,24 Motor nerve conduction studies may appear similar to chronic lower motor neuron disorders, while sensory nerve conduction studies may point to a sensory polyneuropathy.²⁴ Sural nerve biopsy shows loss of myelinated fibers.²⁴ CK levels are commonly elevated in this disorder.²⁴ CAG repeats of the androgen receptor gene on the X chromosome are diagnostic of SBMA.²⁴ SBMA may be confused clinically with ALS.²⁴
  
• Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) can present as an autosomal dominant disorder, although most cases are sporadic. It is characterized by progressive muscle weakness, atrophy, stiffness, spasticity and fasciculations as a result of lower/upper motor neuron degeneration.¹⁷ As the voluntary/skeletal muscles deteriorate, the disorder eventually leads to respiratory paralysis and death. MRI and CT scans, as well as electrophysiological examinations, are helpful in diagnosing ALS.²⁴ Standard blood tests such as blood chemistry panels and serum CK levels are usually ordered in the clinical workup of a patient. A mutation of the superoxide dismutase (SOD-1) gene on chromosome 21 is diagnostic of 15-20% of familial ALS cases.²⁴ Multifocal motor neuropathy, SBMA, a combination of cervical myelopathy and spondylotic polyradiculopathy, and numerous other disorders may present similar to ALS.²⁴

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