Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, School of Medicine, 80 Vas Sofias Avenue, 11528, Athens, Greece.
Amyloidosis Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
BMC Med Genet. 2019 Jan 21;20(1):23. doi: 10.1186/s12881-019-0755-5.
Hereditary amyloidosis refers to a wide spectrum of rare diseases with different causative mutations in the genes of various proteins including transthyretin, apolipoprotein AI and AII, gelsolin, lysozyme, cystatin C, fibrinogen Aα-chain, β2-microglobulin, apolipoprotein CII and CIII.
Among hereditary amyloidosis subtypes, we describe here a specific case of Apolipoprotein AI amyloidosis (AApoAI), where the diagnosis began from an almost asymptomatic hepatomegaly followed by the development of primary hypogonadism. Baseline laboratory tests showed increased liver enzymes, while imaging tests revealed a suspected infiltrative liver disease. Patient underwent into liver biopsy and histological examination detected the presence of periodic acid-Schiff (-) and Congo-red (+) amorphous eosinophilic material within normal liver tissue. In the typing of amyloid by immunoelectron microscopy, the liver appeared heavily infiltrated by anti-apoAI (+) amyloid fibrils. Gene sequencing and mutational analysis revealed a single-base mutation at position c.251 T > C resulting in an amino acid substitution from leucine to proline in the mature ApoAI protein. This amino acid change led to lower cleavage and ApoAI deposition into the involved organs. Few years later, our patient remaining without treatment, came with symptoms consistent with primary hypogonadism but testicular involvement with ApoAI deposits could not be proven since the patient refused testicular biopsy. Based on this case, we recap the diagnostic challenges, the clinical manifestations, and the potential treatment options for this indolent hereditary amyloidosis subtype.
This case-report enlarges the clinical picture of ApoAI-driven disease and its complex genetic background and in parallel suggests for a more systematic approach in any case with strong suspicion of hereditary amyloidosis.
遗传性淀粉样变性是指一组广泛的罕见疾病，其不同的致病突变存在于各种蛋白质的基因中，包括转甲状腺素蛋白、载脂蛋白 AI 和 AII、胶凝蛋白、溶菌酶、半胱氨酸蛋白酶抑制剂 C、纤维蛋白原 Aα 链、β2-微球蛋白、载脂蛋白 CII 和 CIII。
在遗传性淀粉样变性亚型中，我们在这里描述了一个载脂蛋白 AI 淀粉样变性（AApoAI）的具体病例，该病例的诊断始于几乎无症状的肝肿大，随后发展为原发性性腺功能减退症。基线实验室检查显示肝酶升高，而影像学检查显示疑似浸润性肝病。患者行肝活检，组织学检查发现正常肝组织内有周期性酸-Schiff（-）和刚果红（+）无定形嗜酸性物质。免疫电子显微镜下的淀粉样蛋白分型显示，肝脏被抗 apoAI（+）淀粉样纤维严重浸润。基因测序和突变分析显示，c.251T>C 位置的单个碱基突变导致成熟 apoAI 蛋白中的亮氨酸突变为脯氨酸。这种氨基酸变化导致较低的切割和 apoAI 沉积到受累器官。几年后，我们的患者未经治疗，出现与原发性性腺功能减退症一致的症状，但由于患者拒绝睾丸活检，未能证实 apoAI 沉积的睾丸受累。基于该病例，我们总结了该隐匿遗传性淀粉样变性亚型的诊断挑战、临床表现和潜在治疗选择。
该病例报告扩大了 apoAI 驱动疾病及其复杂遗传背景的临床表现，并同时建议对任何有遗传性淀粉样变性强烈怀疑的病例采取更系统的方法。
