Neurology · MU Sofia

75. Familial amyloid polyneuropathy

Explains familial amyloid polyneuropathy as a hereditary systemic amyloidosis, mostly caused by transthyretin gene mutations, and how misfolded protein deposits damage nerves and organs. It walks through genetics, pathogenesis, sensory, motor, autonomic and systemic features, examination findings, and the disease pattern. It then covers diagnosis with a Congo red and genetic testing approach, differential diagnoses, and treatment options including TTR stabilisers, gene-silencing drugs and liver transplantation.

Inside: 1 section · 16 flashcards · 2 min

Topic 75 of 88 in the MU Sofia syllabus for Neurology (Medicine, Year 4). The free AceMed note covers it in 1 section, about 325 words (2 min of reading), with 16 flashcards.

In this note

  1. Familial amyloid polyneuropathy

Familial amyloid polyneuropathy

Definition: Familial amyloid polyneuropathy (FAP) is a hereditary systemic disorder characterized by deposition of amyloid fibrils in peripheral nerves and multiple organs, leading to a progressive sensory-motor and autonomic neuropathy.

It is a form of hereditary amyloidosis, most commonly due to transthyretin (TTR) mutations.

Etiology & Genetics

  • Most common: autosomal dominant mutation in transthyretin (TTR) gene
  • Abnormal TTR protein → misfolding → amyloid deposition

Pathogenesis

  • Mutant TTR → amyloid fibril formation
  • Deposition in: Peripheral nerves. Autonomic nervous system. Heart, kidneys, GI tract

→ Leads to progressive axonal degeneration + autonomic failure

Clinical Features

A. Peripheral Neuropathy

  • Sensory Symptoms: Early pain and burning in feetP aresthesia (tingling). Loss of temperature and pain sensation (small fiber neuropathy first)
  • Motor Symptoms: Progressive distal weakness. Muscle wasting (later stage)

B. Autonomic Dysfunction: Orthostatic hypotension.Diarrhea or constipation. Erectile dysfunction. Urinary retention/incontinence. Sweating abnormalities

C. Systemic Features:

  • Cardiac: Restrictive cardiomyopathy. Arrhythmias. Heart failure.
  • Gastrointestinal: Weight loss. Malabsorption. Early satiety
  • Ocular: Vitreous opacities

Examination Findings: Distal sensory loss (glove and stocking). Reduced pain/temperature sensation early. Hyporeflexia. Muscle wasting (late). Signs of autonomic failure (postural drop in BP)

Disease Pattern

  • Progressive length-dependent neuropathy
  • Small fibers affected early → pain + autonomic symptoms precede motor weakness

Diagnosis

  1. A. Clinical Suspicion: Family history of neuropathy + autonomic dysfunction
  2. B. Nerve Biopsy (Gold standard in many settings): Amyloid deposits (Congo red stain → apple-green birefringence)
  3. C. Genetic Testing: TTR gene mutation confirmation
  4. D. Electrophysiology: Axonal polyneuropathy pattern
  5. E. Additional Tests: Cardiac evaluation (echocardiography → restrictive pattern)

Differential Diagnosis

  1. 1. Diabetic Polyneuropathy: Similar distal neuropathy but no amyloid deposition
  2. 2. Charcot–Marie–Tooth Disease: No autonomic involvement
  3. 3. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): Demyelinating pattern, treatable
  4. 4. Alcoholic Neuropathy: Nutritional + toxic cause

Treatment

Disease-Modifying Therapy

  • TTR stabilizers: Tafamidis
  • Gene-silencing therapies: Patisiran. Inotersen

Definitive Treatment: Liver transplantation (reduces mutant TTR production)

Supportive Treatment: Pain management (neuropathic pain drugs). Cardiac management.

  • Autonomic symptom control: Fludrocortisone / midodrine for hypotension

Prognosis: Progressive and life-limiting if untreated. Cardiac involvement worsens prognosis significantly

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