Clinical and biochemical characterization of asymptomatic carriers and symptomatic patients with hereditary transthyretin amyloidosis caused by TTR V30L mutation
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View abstract on PubMed
Summary
This summary is machine-generated.Hereditary transthyretin amyloidosis (ATTR) with the rare V30L mutation affects multiple systems, causing neuropathy and cardiac issues. The mutation destabilizes TTR protein, and current stabilizers are ineffective, necessitating new treatments.
Area Of Science
- Genetics and Molecular Biology
- Neurology
- Cardiology
Background
- Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disorder.
- Amyloid fibril deposition characterizes ATTR.
- The TTR c.148G>T (V30L) mutation is rare, with unknown biochemical properties.
Purpose Of The Study
- To investigate the clinical, biochemical, and pathological characteristics of the rare V30L mutation in hereditary transthyretin amyloidosis.
- To evaluate the efficacy of small molecule stabilizers on V30L-mutant TTR fibril formation.
Main Methods
- Analysis of clinical data, electrophysiology, corneal confocal microscopy (CCM), and pathology in patients and carriers with the V30L variant.
- Biochemical experiments to assess the thermodynamic and kinetic stability of the V30L mutant TTR protein.
- In vitro assessment of small molecule stabilizers' inhibition on V30L fibril formation.
Main Results
- ATTR V30L patients exhibit multisystem involvement, including peripheral neuropathy, autonomic dysfunction, and cardiac issues.
- CCM and nerve biopsies reveal nerve fiber abnormalities in both patients and asymptomatic carriers.
- The V30L mutation destabilizes TTR protein, lowers plasma TTR tetramer levels, and is resistant to current small molecule stabilizers.
Conclusions
- The V30L mutation causes significant multisystemic disease in ATTR.
- Early detection of nerve and corneal abnormalities is possible in carriers.
- The ineffectiveness of current stabilizers highlights the need for novel therapeutic strategies for ATTR V30L.
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