Description of a Rare Compound Heterozygous Transthyretin Mutation Val30Met/Val122Ile Conferring Early Onset Hereditary Amyloidosis with Severe Features (P14-8.009)

Abstract

<h3>Objective:</h3> To describe a case of hereditary amyloidosis with a rare compound heterozygous mutation that is not described in the literature. <h3>Background:</h3> Hereditary amyloidosis is a rare disease characterized by accumulation of amyloid deposits in tissue, causing end-organ failure. Most common manifestations include cardiomyopathy, nephropathy, and neuropathy. The transthyretin (TTR) is encoded on chromosome 18 and functions to transport thyroxine and retinol through blood and CSF. Mutations in TTR increase the amyloidogenic potential of the protein. TTR is inherited in an autosomal dominant fashion, and thus mutagenic carriers often have a strong family history of the associated diseases. There are over 100 characterized mutations of this gene. The vast majority of genetically proven cases are associated with missense mutations in a single codon. Compound heterozygotes are rarely reported in the literature. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 40-year-old male with history of chronic diarrhea and anemia presents with two years of pedal edema, weight loss, dyspnea on exertion, and progressive limb weakness resulting in multiple falls. On cardiac evaluation he was found to have severe cardiomyopathy with increase LV thickness and evidence of amyloidosis on cardiac MRI. EMG demonstrated a severe sensorimotor polyneuropathy. Exam was notable for absent joint position sense resulting in gait dysfunction necessitating use of a cane. Subsequent endomyocardial biopsy revealed ATTR type amyloid deposition. Genetic evaluation demonstrated two separate pathogenic variants in TTR (Val30Met/Val122Ile). He was started on therapy with tafamidis and later transitioned to patisiran infusions with some symptomatic improvement. Genetic testing of family members was suggested however not yet completed. <h3>Conclusions:</h3> Compound heterozygous mutations in TTR are exceedingly rare, and this report presents a perhaps never before described case of an individual with both Val30Met and Val122Ile mutations resulting in early onset severe hereditary amyloidosis with multisystem involvement. <b>Disclosure:</b> Dr. Nardin has nothing to disclose. Dr. Traub has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Dr. Traub has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. The institution of Dr. Traub has received research support from Alnylam Pharmaceuticals. The institution of Dr. Traub has received research support from Alexion. The institution of Dr. Traub has received research support from Muscular Dystrophy Association (MDA). The institution of Dr. Traub has received research support from Ionis.