Clinical Heterogeneity in a Family With Rare F33L Hereditary Transthyretin Amyloidosis: A Case Series of Three Siblings
Lamees Alhallaq1, J. David Avila2
1Neurology, Geisinger Medical Center, 2Geisinger Medical Center
Objective:
To describe the clinical characteristics and phenotypic variability in three male siblings with the extremely rare F33L variant of hereditary transthyretin amyloidosis (hATTR).
Background:
F33L is an exceptionally rare pathogenic transthyretin (TTR) variant. In the Transthyretin Amyloidosis Outcomes Survey analysis of over 6000 patients worldwide, F33L was not listed, indicating fewer than 10 patients enrolled globally. Unlike the common V30M variant which typically presents with early-onset length-dependent polyneuropathy, F33L demonstrates unpredictable phenotypic expression with minimal published data to guide clinical management.
Design/Methods:
We present three male siblings with genetically confirmed F33L hATTR. Evaluation included neurological examination, electromyography, skin biopsy for epidermal nerve fiber density, and cardiac assessment with technetium-99m pyrophosphate scanning. Disease severity was graded using Familial Amyloid Polyneuropathy (FAP) and Polyneuropathy Disability scores (PND).
Results:
All three siblings demonstrated cardiac amyloidosis. Neurological phenotypes varied dramatically despite identical genotype. The youngest sibling (age 57) presented with non-length-dependent pure sensory axonal polyneuropathy and lumbar radiculopathies (FAP stage I, PND stage II). One sibling (age 61) required heart transplant and exhibited bilateral carpal tunnel syndrome (CTS) with length-dependent sensorimotor polyneuropathy (FAP stage I, PND stage I). The third sibling (age 61) showed the most advanced neurological disease (FAP stage II, PND stage II) with clinical polyneuropathy, bilateral CTS, and multilevel spinal stenosis, yet no electrodiagnostic evidence of large fiber polyneuropathy and normal epidermal nerve fiber density, but amyloid deposition on skin biopsy. Treatment approaches included combinations of tafamidis, patisiran, and vutrisiran.
Conclusions:
This case series expands the limited literature on F33L hATTR, demonstrating a mixed phenotype with marked variability among siblings. Unlike more predictable presentations of common variants, F33L exhibits diverse manifestations including prominent early
cardiac involvement, atypical neuropathy patterns, and discordance between clinical and electrodiagnostic findings. These findings emphasize the importance of comprehensive multisystem evaluation and individualized treatment strategies for patients with rare TTR variants.
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