Neuromuscular and Genetic Neurological Disorders

Friedreich Ataxia and Pierre-Marie Disease

Friedreich Ataxia (AR)

Friedreich ataxia is an autosomal recessive (AR) disorder characterized by childhood onset, mutations in the FRDA gene, and GAA triplet repeats. It involves the degeneration of posterior columns (decreased vibration and position sense), corticospinal tracts (positive Babinski sign), and peripheral nerves (areflexia), with mild cerebellar involvement.

• Clinical Features: Progressive gait ataxia, dysarthria, dysphagia, and preserved cognition.
• Associated Conditions: Pes cavus, scoliosis, diabetes mellitus, and hypertrophic cardiomyopathy.
• Prognosis: Wheelchair dependence typically occurs around 10 years after onset, with death occurring around age 35, usually due to cardiac complications.
• Treatment: There is no cure; however, idebenone may reduce cardiac hypertrophy.

Pierre-Marie Disease (SCA3, AD)

Pierre-Marie disease (Spinocerebellar Ataxia Type 3) is an autosomal dominant (AD) condition with adult onset involving cerebellar and brainstem degeneration. 46

• Clinical Features: Gait and limb ataxia, dysarthria.
• Associated Signs: Hyperreflexia, dystonia, ophthalmoplegia, ptosis, and dysphagia.

Wilson Disease and Copper Metabolism

Wilson disease is an autosomal recessive disorder (ATP7B gene, chromosome 13) leading to impaired copper metabolism. This results in decreased ceruloplasmin, increased free serum copper, and increased urinary copper. Free copper accumulates in the liver, cornea (Kayser-Fleischer rings), and basal ganglia. 47

• Hepatic Features: Childhood onset, hepatopathy, acute or chronic hepatitis, cirrhosis, and hemolytic anemia.
• Neurologic Features: Postural or intention tremor (wing-beating), dysarthria, dystonia, rigidity, and psychiatric changes (depression, personality changes, psychosis).
• Other Features: Renal tubular damage, osteopenia, and hemolytic anemia.
• Diagnosis:
  • Kayser-Fleischer rings (Descemet membrane).
  • MRI: Basal ganglia signal changes and cortical atrophy.
  • Labs: Decreased serum ceruloplasmin, increased 24-hour urinary copper.
  • Gold Standard: Increased hepatic copper on liver biopsy or genetic testing (ATP7B).
• Treatment:
  • Copper chelation with D-penicillamine or trientine.
  • Zinc sulfate to decrease intestinal copper absorption.
  • Low-copper diet: Avoid organ meat, chocolate, nuts, and mushrooms.

Muscular Dystrophies: DMD, BMD, and FSHD

Duchenne Muscular Dystrophy (DMD)

X-linked (Xp21.2) condition caused by a complete absence of dystrophin. Onset is typically between 2–5 years of age. 48

• Features: Proximal weakness, Gowers sign, calf pseudohypertrophy (fat and connective tissue), dilated cardiomyopathy, and progressive respiratory failure.
• Diagnosis: Markedly elevated CK levels early on; muscle biopsy shows absent dystrophin.
• Prognosis: Death typically occurs between 18–25 years due to respiratory failure.

Becker Muscular Dystrophy (BMD)

X-linked condition with reduced or partially functional dystrophin. Onset occurs in adolescence.

• Features: Similar to DMD but milder with slower progression, calf pseudohypertrophy, and proximal weakness.
• Prognosis: Loss of ambulation around age 30; life expectancy is 40–50 years.

Facioscapulohumeral Dystrophy (FSHD)

Autosomal dominant condition where abnormal DUX4 expression leads to muscle apoptosis. Onset is in adolescence.

• Features: Facial weakness (inability to whistle) and scapular winging. Life expectancy is usually normal.

Limb-Girdle Muscular Dystrophy (LGMD)

A heterogeneous group (AR/AD) of mutations in sarcomere stability or membrane repair proteins. Onset can be in childhood or adulthood, featuring slowly progressive weakness of the pelvic and shoulder girdle muscles.

Syringomyelia: Spinal Cord Cavitation

Syringomyelia involves a fluid-filled cavity (syrinx) within the central spinal cord. 48

• Pathogenesis: CSF flow obstruction creates a pressure gradient, causing CSF to enter the cord. The expanding syrinx damages decussating fibers.
• Clinical Features: Bilateral segmental loss of pain and temperature with preserved vibration and proprioception (dissociated sensory loss). Lower motor neuron (LMN) signs at the level of the lesion (atrophy, hyporeflexia) and upper motor neuron (UMN) signs below the level (spasticity, hyperreflexia). May include autonomic involvement (Horner syndrome) and scoliosis.
• Diagnosis: Clinical evaluation and MRI (gold standard).
• Treatment: Address the underlying cause; for example, Chiari I malformation requires foramen magnum decompression.

Myasthenia Gravis and NMJ Disorders

Myasthenia gravis is an autoimmune neuromuscular junction (NMJ) disorder resulting in decreased functional postsynaptic acetylcholine (ACh) receptors, leading to fatigable skeletal muscle weakness. 49

• Etiology and Pathogenesis: IgG antibodies against AChR (~80%), MuSK (5–10%), or rarely LRP4/agrin. The thymus is often involved (hyperplasia in ~65%, thymoma in 10–15%), becoming an active autoimmune organ.
• Clinical Features: Fluctuating weakness that worsens with activity or in the evening and improves with rest.
  • Ocular: Ptosis and diplopia.
  • Bulbar/Facial: Dysarthria, dysphagia, and chewing fatigue.
  • Limb: Proximal weakness (greater than distal). Reflexes remain normal; no sensory or autonomic signs.
• Diagnosis:
  • Anticholinesterase response (pyridostigmine; edrophonium is historical).
  • Antibody testing: AChR and MuSK.
  • Neurophysiology: Repetitive nerve stimulation (>10% decrement in CMAP) and single-fiber EMG (increased jitter, the most sensitive test).
  • Imaging: Chest CT/MRI to exclude thymoma.
• Treatment:
  • Symptomatic: Pyridostigmine (first-line).
  • Immunomodulation: Corticosteroids, azathioprine, mycophenolate, cyclosporine, or cyclophosphamide for severe cases.
  • Thymectomy: Recommended for all thymomas and generalized AChR-positive MG in patients under 55 years.