Jul 2026· Journal of the peripheral nervous system· Vol 31· 0 citations· 6 references
Medicine
TL;DR
It is demonstrated that SCO2‐related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported.
Abstract
ABSTRACT Background and Aims SCO2 encodes a mitochondrial copper chaperone required for cytochrome c oxidase (COX) assembly and is classically associated with severe multisystem mitochondrial disease. We characterize a motor‐predominant axonal neuropathy presentation associated with biallelic SCO2 variants. Methods Clinical, genetic, and functional studies were performed in a 15‐year‐old female presenting with axonal neuropathy. Functional studies were conducted in patient‐derived fibroblasts, including Western blot analysis and spectrophotometric cytochrome c oxidation assay. Structural modeling was performed using ChimeraX. Results The patient presented with a motor‐predominant axonal neuropathy consistent with Charcot‐Marie‐Tooth (CMT) disease. Clinical genetic testing identified compound heterozygous SCO2 variants of uncertain significance: a missense variant (p.Arg120Trp) and a frameshift variant (p.Asp252ValfsTer24). Structural modeling predicted disruption of protein stability for both variants. Functional studies in patient‐derived fibroblasts demonstrated complete absence of SCO2 protein and reduced mitochondrial complex IV activity, supporting a loss‐of‐function mechanism. Interpretation These findings demonstrate that SCO2‐related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported. Our study also highlights the value of integrating in silico prediction tools with functional assays to establish pathogenicity in rare sporadic cases of inherited neuropathy.
Background Multiple mitochondrial dysfunction syndrome type 3 (MMDS3; OMIM #615330) is a rare autosomal recessive disorder caused by mutations in IBA57. Its complex clinical presentation and molecular pathogenesis remain incompletely understood. Methods The study included comprehensive clinical evaluation, IBA57 genetic testing, Western Blotting for protein expression, and transcriptomic and metabolomic analyses of amniotic fluid cells. Results The proband presented with typical MMDS3 features, and both affected siblings carried compound heterozygous IBA57 missense mutations (c.310G>T and c.826C>T) leading to reduced IBA57 protein expression. RNA-seq revealed transcriptional dysregulation of the PI3K-Akt signaling pathway, and metabolomics demonstrated TCA cycle disturbances in amniocytes. Respiratory chain enzyme assays showed a selective deficiency of complex II activity in fetal liver. Conclusion The compound heterozygous IBA57 mutations c.310G>T and c.826C>T lead to reduced IBA57 protein expression, selective impairment of respiratory chain complex II, and transcriptional dysregulation of the PI3K-Akt pathway, together contributing to the MMDS3 phenotype in the proband and the affected fetus.
Yijuan Huang, C. Gou, Yuanqiu Chen et al.· Frontiers in Genetics· 0 citations
There is moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype, suggesting that the allelic and clinical heterogeneity of HARS1‐related disease is expanded.
Christina Del Greco, Allison R. Cale, Karl Haeberlein et al.· Journal of the peripheral ne...· 0 citations
COX16 is a nuclear-encoded assembly factor essential for mitochondrial cytochrome c oxidase (complex IV) biogenesis. Only two patients with COX16-related disease have previously been reported.
We describe two siblings born to consanguineous parents who presented with neonatal hypotonia, respiratory failure, lactic acidosis and early death. Neuroimaging revealed diffuse white matter abnormalities; neither had cardiac involvement. Muscle and fibroblast studies demonstrated isolated complex IV deficiency. Whole-exome sequencing identified a novel homozygous intronic COX16 variant (c.70-11_70-8del), extremely rare in population databases and observed only in the heterozygous state and predicted to have minimal splicing impact.
Reverse transcription-PCR and long-read complementary DNA sequencing confirmed complete exon 2 skipping in patient fibroblasts. Blue native polyacrylamide gel electrophoresis showed defective complex IV assembly.
These findings establish the pathogenicity of a splice-altering
COX16
variant and expand the genetic and phenotypic spectrum of
COX16
-related mitochondrial disease. Our report underscores the importance of transcript-level assays when in silico predictions are inconclusive and highlights the usefulness of integrated genomic and functional approaches.
Nicolas Geoffre, N. Gueguen, Anne-Sophie Guémann et al.· BMJ Connections Clinical Gen...· 0 citations
The molecular and functional spectrum of SLC25A4-associated disease is expanded and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.
Mazhor Aldosary, Hanan Alqudairy, Nourah Alshalan et al.· International Journal of Mol...· 0 citations
COX14 encodes a transmembrane protein essential for cytochrome c oxidase (COX) complex assembly. A homozygous missense variant in COX14 was reported in three siblings from a single consanguineous family with severe, fatal infantile mitochondrial complex IV deficiency nuclear type 10 (MC4DN10; MIM# 619053). No additional cases have been identified since, and the ClinGen Mitochondrial Disease Gene Curation Expert Panel classified the COX14-MC4DN10 gene-disease association as having limited evidence. We report a 9-year-old male with biallelic COX14 variants (c.82delT, p.Tyr28Thrfs*83, and c.3G>A, p.Met1?) representing the second unrelated family with MC4DN10. In contrast to the fatal neonatal course previously described, this individual demonstrates an attenuated encephalomyopathic phenotype with prolonged survival. Initial presentation at 6 months included hypotonia, feeding difficulties, and developmental delay. Previously unreported features included growth hormone deficiency, ascending aortic dilation, and distinct neuroradiological findings. At age 8 years, he developed neurological regression and ataxia with brain MRI findings consistent with Leigh syndrome. Muscle biopsy confirmed reduced COX enzymatic activity (33% of mean). Identification of a second unrelated family with biallelic COX14 variants and biochemically confirmed complex IV deficiency strengthens the gene-disease association for MC4DN10. This individual presents an attenuated encephalomyopathic phenotype with novel endocrine and cardiovascular manifestations, underscoring the importance of genomic evaluation in suspected mitochondrial disorders even in the absence of classic biochemical markers such as lactic acidosis.
Elias K. Awad, Emily Waskow, Hari P. Tunuguntla et al.· American Journal of Medical...· 0 citations
BACKGROUND
Mitochondrial Contact Site and Cristae Organizing System (MICOS13)- related combined oxidative phosphorylation deficiency 37 is a rare autosomal recessive disorder caused by disruption of mitochondrial structure and function, leading to early-onset multisystem disease. Case report: A genetically confirmed case is described in a 5-month-old female infant born to consanguineous Iraqi parents, presenting with hypotonia, developmental delay, feeding difficulties, laryngomalacia, and recurrent cyanotic episodes. Clinical findings included diminished reflexes and a small atrial septal defect, while laboratory tests revealed hypoalbuminaemia and mild coagulopathy. Whole-exome sequencing identified a homozygous MICOS13 splice-site variant (c.260-2A >G). Despite supportive care, progressive respiratory failure developed, resulting in death at 5months. Review of 13 reported cases demonstrates consistent early onset, universal hepatic and neurological involvement, frequent respiratory compromise, and, among reported cases, uniformly fatal outcomes. Most identified variants are loss-of-function, predominantly frameshift, with no missense variants reported to date.
CONCLUSION
The present report adds a genetically confirmed case and reinforces the value of considering MICOS13 deficiency in consanguineous infants with early encephalopathy and hepatic dysfunction.
K. Hamad, Sadraldin-Ali Braim, Dyari Q. Hamad et al.· Fetal and Pediatric Patholog...· 0 citations
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