Jul 2026· American Journal of Medical Genetics. Part A· 1 citation· 17 references
Medicine
TL;DR
Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart.
Abstract
TOP3A-related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss-of-function of the mitochondrial-specific isoform of topoisomerase 3α, leading to multiple mitochondrial DNA deletions and mitochondrial DNA depletion. This condition has been associated with two different phenotypes. Very young patients present with severe growth faltering and early mortality, that is consistent with a Bloom syndrome-like disorder. Adult-onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS-like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of TOP3A-related mitochondrial disease with a mitochondrial childhood onset form and present four previously unreported patients, including the outcomes of heart transplantation for three patients. Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart. Heart transplantation was successful in patients with TOP3A-related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood, TOP3A-related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke-like episodes, and Leigh-like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom-like syndrome and the adult-onset form.
BACKGROUND
TTC19-related mitochondrial disease is a rare mitochondrial disorder of respiratory chain Complex III (CIII), typically associated with neurodegeneration and Leigh syndrome. However, its clinical presentation is variable, which complicates diagnosis and management.
OBJECTIVE
To characterize the clinical and neuroimaging features of pediatric patients with TTC19 variants, focusing on disease course and outcomes.
METHODS
We conducted a multicentric retrospective study of 11 patients diagnosed with TTC19 variants in France. Data were collected from patients'medical records from multiple mitochondrial disease reference centers, encompassing demographic, clinical, neuroimaging, and genetic information. Brain MRIs were reviewed by a sole neuroradiologist expert to standardize findings. All patients had genetic confirmation of TTC19-related mitochondrial disease.
RESULTS
The cohort consisted of 6 families, with a mean age at onset of 5.7 years (range: 0.8-15 years). Patients exhibited two distinct clinical patterns: progressive neurodegenerative disease (chronic Leigh syndrome) and acute/subacute Leigh syndrome. Neuroimaging consistently revealed striatal lesions in all patients and brainstem involvement in almost all of them. Additional findings included cerebellar atrophy and lactate peak on MR spectroscopy. Clinical manifestations were predominantly neurological, with motor involvement including, dystonia, cerebellar ataxia, and orofacial apraxia and frequently cognitive impairments. Acute Leigh episodes were observed in many patients, leading to sudden deterioration. The disease progression varied, with patients experiencing progressive decline, stepwise declines and others remaining stable between episodes.
CONCLUSION
TTC19-related mitochondrial disease leads to a severe neurodegenerative phenotype, characterized by early-onset motor and cognitive delays, with a consistent neuroimaging signature involving the striatum and brainstem. This study expands the understanding of TTC19-related mitochondrial disease and underscores the importance of neuroimaging in diagnosis and management.
Claire-Marine Bérat, G. Barcia, P. Gaignard et al.· Molecular Genetics and Metab...· 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
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
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
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
Multiple mitochondrial dysfunctions syndrome 6 (MMDS6), caused by biallelic likely pathogenic variants in PMPCB, is an extremely rare autosomal recessive childhood-onset neurodegenerative disorder, with only six reported cases to date, most resulting in early mortality. Pathogenic variants in VCP cause multisystem proteinopathy 1 (MSP1), an autosomal dominant adult-onset disorder encompassing inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically presenting in mid-adulthood. We describe a 23-year-old female with two likely pathogenic variants presumed to be in trans in PMPCB and a co-occurring pathogenic VCP variant. She was misdiagnosed for over 20 years with early-onset VCP-related neurodegeneration due to a maternal family history of ALS. Her disease began at birth with microcephaly and progressed throughout childhood, including developmental regression, cerebellar and cerebral atrophy, optic atrophy, seizures, spasticity, dysarthria, and loss of ambulation. Initial genetic testing identified only the familial VCP variant. Updated genomic sequencing at age 23 revealed two likely pathogenic PMPCB variants, strong supporting a diagnosis of MMDS6. Her clinical features closely align with previously reported MMDS6 cases and are inconsistent with the typical adult-onset phenotype of VCP-associated disorders. While she shares overlapping features with VCP-related disease (limb-girdle weakness, spasticity, FTD), the timing and severity of her neurodevelopmental findings support MMDS6 as the primary diagnosis. Early mitochondrial dysfunction may predispose her to an accelerated or more severe future VCP-associated phenotype. This is the first report of combined likely pathogenic and pathogenic variants in PMPCB and VCP respectively, expanding the phenotypic spectrum of both disorders. The case underscores the necessity of periodic re-evaluation with advanced genetic testing, highlights important ethical and familial implications, and informs future diagnosis and management of patients with overlapping rare genetic conditions.
Reme Unuakhalu, Alexandra Purcell, Ishaan Jindal et al.· Molecular Genetics and Metab...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
