Hearing Impairment in Alpha-Mannosidosis: Case Series

Background. Alpha-mannosidosis is a rare hereditary disorder belonging to the group of lysosomal storage diseases, characterized by a wide spectrum of clinical manifestations, including hearing impairment, which is often one of the first symptoms. The mixed nature of hearing loss, along with the polymorphism of the clinical presentation, contributes to diagnostic difficulties. The aim of this study is to analyze case series to raise awareness among physicians about alpha-mannosidosis.

Case series: Two case reports of type 2 alpha-mannosidosis in children are presented. In the first case report, a 3-year-5-month-old girl with psychomotor developmental delay and a specific phenotype was diagnosed with bilateral severe hearing loss. An interdisciplinary approach and the vigilance of an audiologist allowed for timely biochemical and genetic diagnostics (a homozygous pathogenic variant c.2248C>T in the MAN2B1 gene was identified) and the initiation of enzyme replacement therapy at the age of 3 years 10 months. In the second case report, diagnosis was delayed in two sisters born from a consanguineous marriage: hearing impairment and speech development delay were identified late, hearing aids were provided with a delay, and low compliance was noted. Large deletions in the MAN2B1 gene were genetically confirmed. The late initiation of treatment and the age of primary hearing aid fitting resulted in a lack of significant positive dynamics in auditory-verbal development.

Conclusion. The presented case series highlight the critical importance of early diagnosis of alpha-mannosidosis. “Unexplained” mixed or sensorineural hearing loss, especially when combined with psychomotor developmental delay, dysmorphic facial features, and recurrent otitis media, requires the exclusion of lysosomal storage disorders. Timely interdisciplinary examination, including assessment of lysosomal enzyme activity, enables diagnosis verification and initiation of pathogenetic therapy, thereby improving the disease prognosis.

1. Beck M, Olsen KJ, Wraith JE, et al. Natural history of alpha mannosidosis a longitudinal study. Orphanet J Rare Dis. 2013;8(1):88. doi: https://doi.org/10.1186/1750-1172-8-88

2. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis. 2008;3:21. doi: https://doi.org/10.1186/1750-1172-3-21

3. Riise Stensland HMF, Frantzen G, Kuokkanen E, et al. amamutdb.no: A Relational Database for MAN2B1 Allelic Variants that Compiles Genotypes, Clinical Phenotypes, and Biochemical and Structural Data of Mutant MAN2B1 in α-Mannosidosis. Hum Mutat. 2015;36(6):581–586. doi: https://doi.org/10.1002/humu.22787

4. Saftig P. Lysosomal storage disorders. Lysosomes. Georgetown: Landes Bioscience; 2003. pp. 60–73.

5. Paciotti S, Codini M, Tasegian A, et al. Lysosomal alpha-manno-sidase and alpha-mannosidosis. Front Biosci. 2017;22:157–167. doi: https://doi.org/10.2741/4478

6. Riise Stensland HM, Klenow HB, Van NL, et al. Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. Hum Mutat. 2012;33(3):511–520. doi: https://doi.org/10.1002/humu.22005

7. Borgwardt L, Lund A, Dali C. Alpha-mannosidosis — a review of genetic, clinical findings and options of treatment. Pediatr Endocrinol Rev. 2014;12(Suppl 1):185–191.

8. Malm D, Riise Stensland HM, Edvardsen O, Nilssen O. The natural course and complications of alpha-mannosidosis — a retrospective and descriptive study. J Inherit Metab Dis. 2014;37(1):79–82. doi: https://doi.org/10.1007/s10545-013-9622-2

9. Lehalle D, Colombo R, O’Grady M, et al. Hearing impairment as an early sign of alpha-mannosidosis in children with a mild phenotype: report of seven new cases. Am J Med Genet A. 2019;179(9): 1756–1763. doi: https://doi.org/10.1002/ajmg.a.61273

10. Wiesinger T, Schwarz M, Mechtler TP, et al. α-Mannosidosis — an underdiagnosed lysosomal storage disease in individuals with an ‘MPS-like’ phenotype. Mol Genet Metab. 2020;130(2):149–152. doi: https://doi.org/10.1016/j.ymgme.2020.04.001

11. Vashakmadze ND, Zhurkova NV, Mikhaylova LK, et al. Alfa-mannosidosis: Frequent Symptoms in Rare Patient. Voprosy sovremennoi pediatrii — Current Pediatrics. 2022;21(6S):577–582. (In Russ). doi: https://doi.org/10.15690/vsp.v21i6S.2498

12. Patent No. 2839219 C1 Russian Federation, IPC A61B 5/12 (2006.01), H04R 25/00 (2006.01), H04R 29/00 (2006.01). Possibility of modifying the acoustic stimulus for recording short-latency auditory evoked potentials: No. 2024125449: declare 30.08.2024: publ. 28.04.2025. Tufatulin GSh, Soganov MI, Goleva MA, et al. 8 p. (In Russ).