Autosomal Dominant Inheritance: Familial amyloidosis is most often inherited in this pattern.
🫀 Associated with cardiac disease, autonomic dysfunction, and peripheral neuropathy.
🌍 Endemic clusters described in Portugal, Japan, and Northern Sweden.

🧬 Aetiology

Hereditary amyloidosis: Caused by mutations leading to abnormal amyloidogenic proteins.
🔑 Transthyretin (TTR) gene mutations: The most common cause; TTR is a 127 amino acid, 55 kDa transport protein for thyroxine and retinol-binding protein, synthesised in the liver.
Over 100 TTR mutations have been identified → destabilised protein misfolds and deposits in tissues.

🧾 Types

Transthyretin (ATTR) amyloidosis: Most common; TTR mutations → systemic neuropathy & cardiomyopathy.
Apolipoprotein A-I amyloidosis: Mutations in APOA1.
Fibrinogen A alpha-chain amyloidosis: Mutations in FGA.
Lysozyme amyloidosis: Mutations in LYZ.

🩺 Clinical Features

ATTR amyloidosis:
- 🧠 Neurological: Peripheral neuropathy, autonomic dysfunction (orthostatic hypotension, bladder/bowel disturbance), bilateral carpal tunnel syndrome.
- 🫀 Cardiac: Restrictive cardiomyopathy, heart failure, arrhythmias, conduction block.
- 🍽️ Gastrointestinal: Diarrhoea, constipation, weight loss, malabsorption.
- 👁️ Ocular: Vitreous opacities, glaucoma.
Other hereditary amyloidoses: May also present with renal dysfunction (proteinuria, nephrotic syndrome), hepatomegaly, and GI involvement.

🔎 Investigations

🧬 Genetic testing: Identify mutations (e.g. TTR, APOA1, FGA, LYZ).
📖 Family history: Key to identifying hereditary patterns.
🔬 Biopsy: Congo red staining (apple-green birefringence under polarised light), with immunohistochemistry to type the amyloid.
🫀 Imaging: Echocardiography (increased wall thickness, diastolic dysfunction), cardiac MRI (late gadolinium enhancement typical of amyloidosis).
⚡ Electromyography (EMG) and nerve conduction studies: Detect neuropathy and autonomic dysfunction.

⚕️ Management

💊 Tafamidis: TTR stabiliser – prevents dissociation and amyloid fibril formation (esp. in cardiac ATTR).
💉 Patisiran and Inotersen: RNA interference / antisense therapies → reduce hepatic TTR production; effective in hereditary ATTR with neuropathy.
🫁 Liver transplantation: Removes the main source of mutant TTR (historically mainstay; now less used due to newer drugs).
🫀 Heart ± liver transplantation: Consider in advanced cardiomyopathy.
Supportive: heart failure therapy, autonomic dysfunction management, mobility and nutrition support.
⚠️ Prognosis: Cardiac disease in ~⅓ of patients; responsible for ~50% of deaths.

📚 References

Adams D, et al. Hereditary transthyretin amyloidosis: recent advances in therapy. J Neurol. 2019.
NICE Guidance: Tafamidis for treating transthyretin amyloidosis (TA861).

The content on this website is provided for educational and informational purposes only to support exam preparation (e.g., MLA, MRCP, USMLE) and learning. This is NOT medical advice, diagnosis, treatment, or professional guidance. It does not replace consultation with a qualified healthcare professional, official guidelines (e.g., NICE, GMC, BNF), or supervised clinical practice. Always verify information with current, authoritative sources. Makindo and its contributors accept no liability for any reliance on this content, including errors, omissions, or any resulting harm, loss, or consequences. By using this site, you agree to these terms.

Familial/Hereditary Amyloidosis

📖 About