Testicular Involvement is a Hallmark of Apo A-I Leu75Pro Mutation Amyloidosis

J Clin Endocrinol Metab. 2020 Dec 1;105(12):dgaa587. doi: 10.1210/clinem/dgaa587.


Context: Apo A-I Leu75Pro is a rare hereditary form of amyloidosis that mainly involves the kidney, the liver, and the testis.

Objective: To define the characteristics of organ damage and testis impairment in the largest cohort collected to date of men with Apo A-I Leu75Pro amyloidosis.

Design, setting, and patients: Retrospective study from a prospectively collected database of 129 male subjects >18 years with Apo A-I Leu75Pro amyloidosis from a reference center at the University Hospital of Brescia, Italy.

Main outcome measures: We evaluated liver and renal function, scrotal ultrasound, reproductive hormone levels, testis biopsy, hypogonadal symptoms, and fertility.

Results: Progressive involvement of testis, kidney, and liver was observed in 96/129 (74.4%) cases. Testis impairment was found in 88/129 patients (68.2%), liver in 59 (45.7%) and renal in 50 (38.8%). Testis damage was often the first manifestation of the disease and the only dysfunction in 30% of younger patients (<38 years). Testicular involvement was characterized mainly by primary (73/88 patients, 83.0%) and subclinical (8/88, 9.1%) hypogonadism. Almost all (85/88, 96.6%) also had high follicle-stimulating hormone, suggesting a primary global damage of endocrine and spermatogenic functions, and 30% of them did not conceive. Macroorchidism was found in 53/88 (60.2%) patients, especially in men <54 years (30/33, 90.9%). Apo A-I amyloid deposits were found in Sertoli cells, germinal epithelium, and vessel walls.

Conclusion: In men with Apo A-I Leu75Pro amyloidosis, testicular involvement is the hallmark of the disease, characterized by global primary testicular dysfunction and macroorchidism due to amyloid deposits.

Keywords: amyloidosis; apolipoprotein A-I; fertility; hypogonadism; testis; testosterone.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Substitution
  • Amyloidosis / epidemiology
  • Amyloidosis / genetics*
  • Amyloidosis / pathology
  • Apolipoprotein A-I / genetics*
  • Cohort Studies
  • Databases, Factual
  • Genetic Predisposition to Disease
  • Humans
  • Italy / epidemiology
  • Leucine / genetics
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Proline / genetics
  • Retrospective Studies
  • Testicular Diseases / epidemiology
  • Testicular Diseases / genetics*
  • Testicular Diseases / pathology
  • Testis / pathology
  • Young Adult


  • APOA1 protein, human
  • Apolipoprotein A-I
  • Proline
  • Leucine