Extremely Early Onset Transthyretin Familial Amyloid Polyneuropathy with a Leu55Pro Mutation: A Pediatric Case Report and Literature Review

Abstract

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a life-threatening autosomal dominant disease caused by the deposition of amyloid fibrils composed of TTR proteins. Symptoms of this disease include progressive sensorimotor neuropathy, cardiomyopathy, and involvement of other organs. We described a pediatric case of extremely early onset TTR-FAP with a TTR Leu55Pro mutation. A 17-year-old boy began to suffer from lower limb weakness, gait disturbance, and decreased sensation from 14 years of age onward. He presented with hypertrophic cardiomyopathy, periorbital and scleral ecchymosis, anhidrosis, orthostatic intolerance, and gastrointestinal autonomic dysfunction including nausea, vomiting, and diarrhea alternating with constipation. The patient's older sister had developed similar gastrointestinal symptoms from 20 years of age onward and was diagnosed as having hypertrophic cardiomyopathy. The boy's biopsy results showed infiltrated amyloid deposition on subcutaneous fat tissue and endocardium. Genetic analysis of the TTR gene demonstrated that both the patient and his sister had a pathogenic mutation, c.224T > C (Leu55Pro). Both patients were prescribed tafamidis, a TTR stabilizing agent. Although a majority of TTR-FAPs occur during adulthood, it should be suspected, even in pediatric populations, when symmetric length dependent neuropathy occurs in conjunction with a family history of neuropathy, autonomic neuropathy, and/or cardiomyopathy.

Keywords

amyloid neuropathy - transthyretin - Leu55Pro - early onset

• References

• 1 Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis 2018; 13 (01) 6
• 2 Jacobson DR, McFarlin DE, Kane I, Buxbaum JN. Transthyretin Pro55, a variant associated with early-onset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement. Hum Genet 1992; 89 (03) 353-356
• 3 Yamamoto K, Hsu SP, Yoshida K. , et al. Familial amyloid polyneuropathy in Taiwan: identification of transthyretin variant (Leu55-->Pro). Muscle Nerve 1994; 17 (06) 637-641
• 4 Kon T, Misumi Y, Nishijima H. , et al. Effects of liver transplantation and tafamidis in hereditary transthyretin amyloidosis caused by transthyretin Leu55Pro mutation: a case report. Amyloid 2015; 22 (03) 203-204
• 5 Xu J, Yang M, Pan X. , et al. Transthyretin-related hereditary amyloidosis with recurrent vomiting and renal insufficiency as the initial presentation: a case report. Medicine (Baltimore) 2017; 96 (10) e5737
• 6 Choi K, Seok JM, Kim BJ. , et al. Characteristics of South Korean patients with hereditary transthyretin amyloidosis. J Clin Neurol 2018; 14 (04) 537-541
• 7 Parman Y, Adams D, Obici L. , et al; European Network for TTR-FAP (ATTReuNET). Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Curr Opin Neurol 2016; 29 (Suppl. 01) S3-S13
• 8 Sousa A, Andersson R, Drugge U, Holmgren G, Sandgren O. Familial amyloidotic polyneuropathy in Sweden: geographical distribution, age of onset, and prevalence. Hum Hered 1993; 43 (05) 288-294
• 9 Quintas A, Vaz DC, Cardoso I, Saraiva MJ, Brito RM. Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants. J Biol Chem 2001; 276 (29) 27207-27213
• 10 Castro-Rodrigues AF, Gales L, Saraiva MJ, Damas AM. Structural insights into a zinc-dependent pathway leading to Leu55Pro transthyretin amyloid fibrils. Acta Crystallogr D Biol Crystallogr 2011; 67 (Pt 12): 1035-1044
• 11 Kobayashi Y, Sekijima Y, Ogawa Y, Kondo Y, Miyazaki D, Ikeda SI. Extremely early onset hereditary ATTR amyloidosis with G47R (p.G67R) mutation. Amyloid 2016; 23 (03) 205-206
• 12 Tojo K, Sekijima Y, Machida K, Tsuchiya A, Yazaki M, Ikeda S. Amyloidogenic transthyretin Val30Met homozygote showing unusually early-onset familial amyloid polyneuropathy. Muscle Nerve 2008; 37 (06) 796-803
• 13 Hamann S, Jensen PK, Fledelius HC. Bilateral optic neuropathy in a patient with familial amyloidotic polyneuropathy. BMJ Case Rep 2013;2013;
• 14 Rossetti A, Spedicato L, Fassina A, Doro D. Bilateral optic neuropathy and intraretinal deposits after pars plana vitrectomy in amyloidosis. Indian J Ophthalmol 2015; 63 (01) 72-74
• 15 Conceição I, González-Duarte A, Obici L. , et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst 2016; 21 (01) 5-9