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Boesch, S.* ; Zech, M.

AOPEP-related autosomal recessive dystonia: Update on Zech-Boesch syndrome.

J. Med. Genet., DOI: 10.1136/jmg-2025-110656 (2025)
DOI PMC
Gene discovery efforts have contributed to a better understanding of the molecular causes of dystonia, but knowledge of the individual monogenic forms remains limited. This review seeks to summarise all available data on the recently identified autosomal recessive subtype of dystonia caused by variants in AOPEP, focusing on the geographical origins of affected families, mutational spectrum, phenotypic expressions and pathophysiology. AOPEP-related dystonia, documented as Zech-Boesch syndrome in the Online Mendelian Inheritance in Man database, has been diagnosed in cohorts around the globe including under-represented populations with increased rates of consanguinity. Predictably leading to loss of protein function, the majority (74%) of disease-associated AOPEP alleles are protein-truncating variants comprising homozygous and compound heterozygous stop-gain, frameshift and splice-site changes. The dystonic disorder shows onset from childhood to the fourth decade and generalises in a significant proportion of cases (60%). Variable expressivity and age-related penetrance are likely to play a role in manifestation of the condition, consistent with occasional occurrence of AOPEP homozygous pathogenic variants in subjects without a diagnosis of dystonia. AOPEP encodes aminopeptidase O, a proteolytic processing enzyme that is preferentially expressed in glia and potentially linked to endosomal-lysosomal pathways. AOPEP-related autosomal recessive Zech-Boesch syndrome is of worldwide relevance for the diagnosis of genetic dystonia. Future research focusing on AOPEP`s role in cellular protein metabolism may provide new insights into dystonia pathogenesis and yet-unidentified therapeutic targets.
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Publication type Article: Journal article
Document type Review
Corresponding Author
Keywords Diagnosis ; Genetic Diseases, Inborn; M1 Family; Aminopeptidases; Mutations; Onset; Phenotype; Genomics; Brain
ISSN (print) / ISBN 0022-2593
e-ISSN 1468-6244
Journal Journal of Medical Genetics
Publisher BMJ Publishing Group
Publishing Place British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants
EJP RD (EJP RD Joint Transnational Call 2022)
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)
Federal Ministry of Education and Research (BMBF)
Free State of Bavaria under the Excellence Strategy of the Federal Government
Lander
Technical University of Munich-Institute for Advanced Study
Else Kroner- Fresenius- Stiftung
German Research Foundation
EJP RD
Laender
Else Kroener-Fresenius-Stiftung
German Research Foundation (DFG)