From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: CLPB-related mitochondrial disease causes congenital neutropenia, developmental delay/intellectual disability, progressive brain atrophy, movement disorders, cataracts, and 3-methylglutaconic aciduria. Both monoallelic and biallelic forms exist. This retrospective cohort study compared clinical outcomes and genotype-structure-phenotype correlations across zygosity groups. METHODS: Sixty-three individuals (41 biallelic, 22 monoallelic; 6 unpublished) with disease-causing CLPB variants were identified via literature review and a multicenter survey. In silico modeling assessed structural impact. A modified CLPB Disease Burden Index (DBI) quantified severity. RESULTS: Median age at last follow-up was 4.0 years (IQR: 0.25-12.6) in biallelic and 12.0 years (IQR: 5.3-21.0) in monoallelic cases. Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years). Biallelic cases had significantly higher DBI scores and poorer survival (4-year survival: 50% vs 82%). Stop/stop genotypes were associated with greater disease burden than missense combinations. Structural predictions-particularly variants causing nonsense-mediated decay or ankyrin domain disruption-were stronger survival predictors than zygosity or age of onset. Early-onset disease (<12 months) correlated with more severe progression. Later onset often resulted in milder phenotypes. Hematologic and neurologic features overlapped across zygosity; cataracts and dystonia were more common in biallelic cases. Milestone attainment was poor, with <50% walking or speaking, and only 10-20% doing so on time. Four monoallelic patients received hematopoietic stem cell transplants with mixed outcomes. Granulocyte colony-stimulating factor was associated with improved survival. CONCLUSIONS: This is the largest cohort study to date comparing biallelic and monoallelic CLPB deficiency. Structural variant impact-particularly ankyrin domain disruption-emerged as a key prognostic factor.
Authors: Oliver Heath, Francisco Del Caño-Ochoa, Safa Baris, Rosalba Carrozzo, David Coman, Felix Distelmaier, Carolyn Ellaway, Rene G. Feichtinger, Andrea Finocchi, Sergio Guerrero-Castillo, Rebecca Halligan, Iris Hannibal, Amy Kritzer, Uta Lichter-Konecki, Kajus Merkevicius, Bianca Panis, Robert D.S. Pitceathly, Chiara Pizzamiglio, Katarzyna Iwanicka-Pronicka, Shamima Rahman, Laurie Seltzer, Meinolf Siepermann, Galit Tal, Ron A. Wevers, Szymon Ziętkiewicz, Santiago Ramón-Maiques, Johannes A. Mayr, Saskia B. Wortmann
Institutions: Paracelsus Medical University, Consejo Superior de Investigaciones Científicas, Instituto de Biomedicina de Valencia, Centro de Investigacion Principe Felipe, Marmara University, Bambino Gesù Children's Hospital, Children's Health Queensland Hospital and Health Service, Heinrich Heine University Düsseldorf, Sydney Children's Hospital, Sydney Children’s Hospitals Network, Istituti di Ricovero e Cura a Carattere Scientifico, University Medical Center Hamburg-Eppendorf, Evelina London Children's Healthcare, Ludwig-Maximilians-Universität München, Boston Children's Hospital, Children's Hospital of Pittsburgh, Vilnius University, Maastricht University Medical Centre, National Health Service, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, Children's Memorial Health Institute, Great Ormond Street Hospital for Children NHS Foundation Trust, University of Rochester Medicine, University of Rochester, Rambam Health Care Campus, Radboud University Nijmegen, Radboud University Medical Center, University of Gdańsk, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,680
Funders: Muscular Dystrophy UK, LifeArc, Ministerio de Ciencia, Innovación y Universidades, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, National Institute for Health and Care Research, Department of Health and Social Care, University College London, Rosetrees Trust, Great Ormond Street Hospital Charity, Austrian Science Fund, Ministerio de Ciencia e Innovación, Universita degli Studi di Bari Aldo Moro, University College London Hospitals NHS Foundation Trust, Lily Foundation, Medical Research Council, Agencia Estatal de Investigación, NIHR Great Ormond Street Hospital Biomedical Research Centre
Awards: G1018302662, G2262748287, MitoCluster: an integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction, G3480869486, G425668148, MRC TS Award: Investigating the role of cardiolipin metabolism in mitochondrial DNA replication and mitochondrial division, G7084143925, G7896879033
OpenAlex ID: W7128680030