Hereditary ATTR Amyloidosis (hATTR): Multisystem Disease and Modern Management

hATTR is a systemic amyloidosis from mutant transthyretin deposition. Phenotype varies by mutation and modifier genes—neuropathic, cardiac, mixed, or leptomeningeal.

Clinical Presentation

• Early: Fatigue, paresthesias, orthostatic dizziness, carpal tunnel (often bilateral, precede diagnosis by years).
• Neuropathic (V30M, others): Progressive sensorimotor + autonomic neuropathy.
• Cardiac (V122I, others): HFpEF, arrhythmias, thickened walls on echo, elevated NT-proBNP/troponin.
• Mixed: Both systems significantly involved.
• Leptomeningeal: Cognitive, cerebellar, hemorrhage risk (rare mutations).

Diagnosis

1. Clinical suspicion + family history
2. Genetic testing (TTR sequencing) — confirms mutation
3. Tissue biopsy (abdominal fat pad: 80% sensitivity; endomyocardial: gold standard cardiac)
4. PYP scan (Grade 1–3 cardiac uptake; specific for ATTR vs. AL)
5. Exclude AL amyloidosis (free light chains, SPEP/UPEP)

Treatment Algorithm

Phenotype	First-Line Disease-Modifying
Polyneuropathy	Patisiran / Vutrisiran / Inotersen (TTR silencers)
Cardiomyopathy	Tafamidis (stabilizer) — only FDA-approved for cardiac ATTR
Mixed	Silencer (covers both) or Tafamidis + silencer (trial data emerging)

• Liver transplant: historical; now rare.
• Symptomatic care: multidisciplinary (neurology, cardiology, genetics, PT/OT, palliative).

Monitoring

• Every 6–12 months: NIS, mNIS+7, Norfolk QOL-DN, NT-proBNP, echo, PYP, renal/hepatic labs.
• Family cascade testing + genetic counseling.

Emerging

• CRISPR-based gene editing (NTLA-2001) — Phase 1 promising.
• Antisense oligonucleotides (next-gen); small molecule stabilizers (acoramidis — Phase 3 positive).