Infertility and Hypergonadotropic Hypogonadism as First Evidence of Hereditary Apolipoprotein A-I Amyloidosis

Abstract

Purpose:We report that primary infertility and hypergonadotropic hypogonadism in young patients may be caused by testicular amyloidosis and it is associated with the presence of a mutation in the apoA-I gene, resulting in the replacement of proline for leucine at residue 75 of the protein. Materials and Methods:Ten patients presenting with infertility, gynecomastia, decreased libido, erectile dysfunction or a family history of amyloidosis underwent clinical evaluation, hormone assays, semen analysis, ultrasonographic investigation of the testicles, testicular biopsy and DNA sequencing of the apoA-I gene. Results: All patients showed azoospermia and 9 had increased testicular volume. Massive amyloid deposition was observed in all testicular biopsies and the apoA-I mutation of replacement of proline for leucine at residue 75 of the protein was noted. Five patients showed hypergonadotropic hypogonadism and 5 had normal testosterone values with high gonadotropin levels. Conclusions: Nonobstructive azoospermia and macro-orchidism with or without hypogonadism may be caused by hereditary apoA-I amyloidosis in young patients. Testicular amyloidosis can be the first manifestation of this systemic disease. Specific staining for amyloid deposits and genetic analysis of apoA-I mutations are recommended in young, infertile patients with macro-orchidism. Finally, surveillance in asymptomatic mutation carriers is suggested to evaluate the opportunity to implement sperm retrieval and start androgen replacement therapy when necessary.

Molecular basis for a novel systemic form of human hereditary apoA-I amyloidosis with vision loss

“…We also show that Glu34Lys variant causes early-onset male infertility due to massive amyloid deposition in testes. A similar clinical presentation was reported for many Leu75Pro carriers (Scalvini et al, 2007;Scalvini et al, 2008). Our study suggests that testicular involvement in AApoAI is more common than previously thought, leading to decreased male reproductive fitness.…”

Effects of the Known Pathogenic Mutations on the Aggregation Pathway of the Amyloidogenic Peptide of Apolipoprotein A-I

“…It is worth of note that amyloid fibrils in vivo are associated with prominent protein deposits of the ApoA-I peptide; such deposits are lacking the typical fibrillar features at the electron microscope and are then described as an amorphous aggregate. 15 Experimental data concerning the aggregation propensities of wild-type ApoA-I and its eight variants were compared with theoretical predictions obtained by the Zyggregator method, 6 which is based on the analysis of the physicochemical properties of the amino acid sequences, such as hydrophobicity and electrostatic charge, which are important in determining their aggregation behaviour (Table 1 and Fig. 5a).…”

Fertility Defects in Mice Expressing the L68Q Variant of Human Cystatin C

“…It is of interest, however, that ALS patients show reduced fecundity (48), and individuals with hereditary apolipoprotein A-I amyloidosis exhibit infertility and hypergonadotropic hypogonadism (50). Our studies examining the L68Q mouse model for the human disease HCCAA suggest that pathological amyloids can indeed play a role in male infertility by affecting sperm function.…”