TY - JOUR
T1 - From genotype to outcome
T2 - Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease
AU - Heath, Oliver
AU - Del Cano-Ochoa, Francisco
AU - Baris, Safa
AU - Carrozzo, Rosalba
AU - Coman, David
AU - Distelmaier, Felix
AU - Ellaway, Carolyn
AU - Feichtinger, Rene G.
AU - Finocchi, Andrea
AU - Guerrero-Castillo, Sergio
AU - Halligan, Rebecca
AU - Hannibal, Iris
AU - Kritzer, Amy
AU - Lichter-Konecki, Uta
AU - Merkevicius, Kajus
AU - Panis, Bianca
AU - Pitceathly, Robert D. S.
AU - Pizzamiglio, Chiara
AU - Iwanicka-Pronicka, Katarzyna
AU - Rahman, Shamima
AU - Seltzer, Laurie
AU - Siepermann, Meinolf
AU - Tal, Galit
AU - Wevers, Ron A.
AU - Zietkiewicz, Szymon
AU - Ramon-Maiques, Santiago
AU - Mayr, Johannes A.
AU - Wortmann, Saskia B.
N1 - Heath, Feichtinger, Mayr, Wortmann: University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria
PY - 2026/4
Y1 - 2026/4
N2 - 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 Methods Sixty-three individuals (41 biallelic, 22 monoallelic; 6 unpublished) with disease-causing CLPB variants were identified via literature review and a multicenter survey.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.
AB - 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.
KW - 3-methylglutaconic aciduria
KW - Ankyrin repeat region
KW - Clpb
KW - Cataracts
KW - Congenital neutropenia
KW - Genotype-phenotype correlation
KW - Mitochondrial chaperonopathy
KW - Protein modeling
KW - Zygosity
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pmu_pure&SrcAuth=WosAPI&KeyUT=WOS:001699605000002&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1016/j.ymgme.2026.109752
DO - 10.1016/j.ymgme.2026.109752
M3 - Original Article
C2 - 41719910
SN - 1096-7192
VL - 147
JO - MOLECULAR GENETICS AND METABOLISM
JF - MOLECULAR GENETICS AND METABOLISM
IS - 4
M1 - 109752
ER -