Abstract Mitochondrial respiratory chain dysfunction and impaired oxidative phosphorylation are rare but significant causes of mitochondrial diseases in children, presenting with diverse clinical features. Combined oxidative phosphorylation deficiency type 23 (COXPD23), an autosomal recessive disorder due to GTPBP3 gene mutations, typically manifests as lactic acidosis, hypertrophic cardiomyopathy, and encephalopathy. This case report describes a male infant born at 35 weeks gestation, who exhibited severe lactic aciduria and hypotonia but no cardiomyopathy, which is atypical for COXPD23. Genetic analysis revealed a novel homozygous missense variant in the GTPBP3 gene. Despite intensive metabolic and supportive treatments, the patientʼs condition worsened, leading to death on the 23rd day. This case emphasizes the need to consider mitochondrial cytopathies in neonates with persistent metabolic acidosis and hyperlactatemia and highlights the importance of early genetic screening for accurate diagnosis and management. 

The rare reason for massive lactic aciduria and mitochondrial disorders: combined oxidative phosphorylation deficiency type 23 (COXPD23)

Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) is a rare mitochondrial disease caused by mutations in the GTPBP3 gene. The rare incidence of the disease and the high clinical heterogeneity pose challenges in making a precise diagnosis. Investigations into the rare COXPD23 patients are of pathophysiological and etiological value. In this study, we investigated the genotype-phenotype relationship in a COXPD23 patient from a Manchu family, with GTPBP3 mutations.Routine physical examinations, laboratory assays and imaging analyses were performed. The metabolic profiles of amino acids in blood, acylcarnitine in blood and organic acids in urine were used to determine the presence of inherited metabolic diseases. Genetic variations in the family were investigated using whole-exome sequencing and Sanger sequencing. Splicing disruption by a mutation was predicted and verified using a minigene assay.The patient presented with severe lactic acidosis, neurological symptoms, multiple symmetrical lesions in the brain and serious mitochondrial energy metabolism disturbances. The c.689A > C (p.Q230P) and c.809-1_809delinsA compound heterozygous mutations were detected in GTPBP3. The novel c.809-1_809delinsA mutation was located at the splicing site of exon 7 and intron 6 and multiple tools predicted that it would disrupt the normal splicing. The minigene assay proved that the novel mutation resulted in two aberrant transcripts that created premature termination codons.The clinical manifestations, brain imaging change, mitochondrial metabolism disturbances and the detection and validation of the GTPBP3 mutations expand the profile of COXPD23 and the pathogenic mutation spectrum. Our study improves the understanding of the pathophysiology and etiology of COXPD23. 

A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing

Background: Wilson’s disease (WD) is an autosomal recessive disease that is caused by mutations in the ATP7B (a copper-transporting P-type ATPase) gene. The disease has a low prevalence and is characterized by a copper metabolism disorder. However, various characteristics of the disease are determined by race and geographic region. We aimed to discover novel ATP7B mutations in pediatric patients with WD from Yunnan province, where there is a high proportion of ethnic minorities. We also performed a comprehensive analysis of ATP7B mutations in the different ethnic groups found in Southwest China. Methods: We recruited 45 patients who had been clinically diagnosed with WD, from 44 unrelated families. Routine clinical examinations and laboratory evaluations were performed and details of age, gender, ethnic group and symptoms at onset were collected. Direct sequencing of the ATP7B gene was performed in 39 of the 45 patients and their families. Results: In this study, participants came from seven different ethnic groups in China: Han, Bai, Dai, Zhuang, Yi, Hui and Jingpo. Three out of ten patients from ethnic minorities presented with elevated transaminases, when compared to the majority of the Han patients. Forty distinct mutations (28 missense, six splicing, three non-sense, two frameshift and one mutation of uncertain significance) were identified in the 39 patients with WD. Four of the mutations were novel and the most frequent mutation was c.2333G > T (p.R778L, allelic frequency: 15.38%). Using the phenotype-genotype correlation analysis, patients from ethnic minorities were shown to be more likely to have homozygous mutations (p = 0.035) than Han patients. The patients who carried the c.2310C > G mutation had lower serum ceruloplasmin levels (p = 0.012). In patients with heterozygous mutations, c.3809A > G was significantly associated with ethnic minorities (p = 0.042). The frequency of a protein-truncating variant (PTV) in Han patients was 34.38% (11/32), while we did not find PTV in patients from ethnic minorities. Conclusion: This study revealed genetic defects in 39 pediatric patients with WD from Yunnan province. Four novel mutations were identified and have enriched the WD database. We characterized the genotypes and phenotypes in different minorities, which will enhance the current knowledge on the population genetics of WD in China.

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Clinical and genetic characterization of pediatric patients with Wilson’s disease from Yunnan province where ethnic minorities gather

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A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre-mRNA splicing

Clinical and genetic characterization of pediatric patients with Wilson’s disease from Yunnan province where ethnic minorities gather

The clinical and genetic profiles of spinal muscular atrophy with respiratory distress type 1 and identification of a novel mutation in IGHMBP2 in China