Combined oxidative phosphorylation deficiency-1 (COXPD1) resulting from a mutation in the G elongation factor mitochondrial 1 (GFM1) gene is an autosomal recessive multisystem disorder arising from a defect in the mitochondrial oxidative phosphorylation system. Death usually appears in the first weeks or years of lifespan.
We report a male patient with ventriculomegaly diagnosed in the 8th month of pregnancy. The delivery was done by caesarean section and respiratory failure occurred immediately after birth. Hypoglycemia, lactic acidosis, elevated gamma-glutamyl transferase and hepatomegaly were confirmed. The brain MRI detected hypoplasia of the cerebellar hemispheres, dilated lateral ventricles, and markedly immature brain parenchyma. Epilepsy had been present since the third month. At 5 months of age, neurological follow-up showed his head circumference to be 37 cm, with plagiocephaly, a low hairline, a short neck, axial hypotonia and he did not adopt any developmental milestones. A genetic mutation, a missense variant in the GFM1 gene, was confirmed: c.748C > T (p.Arg250Trp) was homozygous in the GFM1 gene.
To the best of our knowledge, 28 cases of COXPD1 disease caused by mutations in the GFM1 gene have been described in the literature. COXPD1 should be considered due to symptoms and signs which begin during intrauterine life or at birth. Signs of impaired energy metabolism should indicate that the disease is in the group of metabolic encephalopathies.

Iron‑sulfur clusters (FeS) are one of the most primitive and ubiquitous cofactors used by various enzymes in multiple pathways. Biosynthesis of FeS is a complex multi-step process that is tightly regulated and requires multiple machineries. IBA57, along with ISCA1 and ISCA2, play a role in maturation of [4Fe-4S] clusters which are required for multiple mitochondrial enzymes including mitochondrial Complex I, Complex II, lipoic acid synthase, and aconitase. Pathogenic variants in IBA57 have been associated with multiple mitochondrial dysfunctions syndrome 3 (MMDS3) characterized by infantile to early childhood-onset psychomotor regression, optic atrophy and nonspecific dysmorphism. Here we report a female proband who had prenatal involvement including IUGR and microcephaly and developed subacute psychomotor regression at the age of 5 weeks in the setting of preceding viral infection. Brain imaging revealed cortical malformation with polymicrogyria and abnormal signal alteration in brainstem and spinal cord. Biochemical analysis revealed increased plasma glycine and hyperexcretion of multiple organic acids in urine, raising the concern for lipoic acid biosynthesis defects and mitochondrial FeS assembly defects. Molecular analysis subsequently detected compound heterozygous variants in IBA57, confirming the diagnosis of MMDS3. Although the number of MMDS3 patients are limited, certain degree of genotype-phenotype correlation has been observed. Unusual brain imaging in the proband highlights the need to include mitochondrial disorders as differential diagnoses of structural brain abnormalities. Lastly, in addition to previously known biomarkers including high blood lactate and plasma glycine levels, the increase of 2-hydroxyadipic and 2-ketoadipic acids in urine organic acid analysis, in the appropriate clinical context, should prompt an evaluation for the lipoic acid biosynthesis defects and mitochondrial FeS assembly defects.

Dominant genetic variants in the mitofusin 2 (MFN2) gene lead to Charcot-Marie-Tooth type 2A (CMT2A), a neurodegenerative disease caused by genetic defects that directly damage axons. In this study, we reported a proband with a pathogenic variant in the GTPase domain of MFN2, c.494A > G (p.His165Arg). To date, at least 184 distinct MFN2 variants identified in 944 independent probands have been reported in 131 references. However, the field of medical genetics has long been challenged by how genetic variation in the MFN2 gene is associated with disease phenotypes. Here, by collating the MFN2 variant data and patient clinical information from Leiden Open Variant Database 3.0, NCBI clinvar database, and available related references in PubMed, we determined the mutation frequency, age of onset, sex ratio, and geographical distribution. Furthermore, the results of an analysis examining the relationship between variants and phenotypes from multiple genetic perspectives indicated that insertion and deletions (indels), copy number variants (CNVs), duplication variants, and nonsense mutations in single nucleotide variants (SNVs) tend to be pathogenic, and the results emphasized the importance of the GTPase domain to the structure and function of MFN2. Overall, three reliable classification methods of MFN2 genotype-phenotype associations provide insights into the prediction of CMT2A disease severity. Of course, there are still many MFN2 variants that have not been given clear clinical significance, which requires clinicians to make more accurate clinical diagnoses.

We report the long way to the correct diagnosis in two teenage sisters who developed a cardiac arrest after consuming minimal amounts of alcohol. The older girl dramatically survived two cardiac arrests at the age of 14 and 15 years. She underwent an extensive examination that revealed isolated cardiac abnormalities including fibrosis, dilated cardiomyopathy and inflammation. The younger girl also had a cardiac arrest at the age of 15 and died suddenly after consuming 1-2 beers, 3 years after her sister´s first incident. Autopsy of the heart revealed acute myocarditis without structural alterations. Multigene panel analysis (not including PPA2) showed SCN5A and CACNA1D variants in both sisters and their healthy mother. Six years later duo exome allowed the diagnosis of an autosomal recessive PPA2-related mitochondriopathy. We discuss the molecular results and clinical picture of our patients compared to other PPA2-related cases. We highlight the diagnostic contribution of multigene panels and exome analysis. The genetic diagnosis is important for medical care and for everyday life, specifically because alcohol intake can result in cardiac arrest and should be strictly avoided.   Conclusion: Duo exome sequencing clarified the diagnosis of PPA2-related mitochondriopathy in two sisters with isolated cardiac features and sudden cardiac arrest triggered by minimal amounts of alcohol. What is Known: • Multigene-Panel or exome analysis is a valuable tool to identify genetic causes of hereditary cardiac arrhythmias. • Variants of unknown significance can lead to misinterpretation. PPA2-related mitochondriopathy is a very rare autosomal recessive condition that is normally fatal in infancy. What is New: • Duo exome analysis in two teeenage sisters with cardiac arrest revealed a homozygous mild PPA2 mutation as the underlying pathology restricted to the heart muscle.

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Harel-Yoon syndrome is a disease caused by variants in the ATAD3A gene, which manifest as global developmental delay, hypotonia, intellectual disability, and axonal neuropathy. The aim of this study is to summarize the clinical and gene mutation characteristics of a child with refractory epilepsy caused by ATAD3A gene mutation.
The whole-exome sequencing combined with copy number variation analysis could help to understand the genetic diversity and underlying disease mechanisms in ATAD3A gene mutation.
We report a Chinese boy with Harel-Yoon syndrome presenting with refractory epilepsy, hypotonia, global developmental delay, and congenital cataract through whole-exome sequencing. Genetic analysis showed a missense mutation, c.251T>C(p.Thr84Met) in the ATAD3A gene (NM_001170535.1). Further copy number variation analysis identified a novel heterozygous deletion on chromosome1p36.33, which spans ATAD3A exon 1 and 2 regions. Multiple antiepileptic drugs failed to control his seizures. Eventually, seizure was controlled through ketogenic diet (KD).
Our case shows the potential diagnostic role of whole-exome sequencing in Harel-Yoon syndrome and expands the ATAD3A gene mutation spectrum. Multiple antiepileptic drugs failed to control refractory epilepsy in Harel-Yoon syndrome. The KD therapy may be effective for patients with refractory epilepsy who carry the ATAD3A variants.

Ethylmalonic encephalopathy (EE) is a rare, severe, autosomal recessive condition caused by pathogenic variants in ETHE1 leading to progressive encephalopathy, hypotonia evolving to dystonia, petechiae, orthostatic acrocyanosis, diarrhea, and elevated ethylmalonic acid in urine. In this case report, we describe a patient with only mild speech and gross motor delays, subtle biochemical abnormalities, and normal brain imaging found to be homozygous for a pathogenic ETHE1 variant (c.586G>A) via whole exome sequencing. This case highlights the clinical heterogeneity of ETHE1 mutations and the utility of whole-exome sequencing in diagnosing mild cases of EE.

Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term encompassing various inherited neurological disorders characterised by abnormal iron accumulation in basal ganglia. We aimed to study the clinical, radiological and molecular spectrum of disorders with NBIA. All molecular-proven cases of NBIA presented in the last 5 years at 2 tertiary care genetic centres were compiled. Demographic details and clinical and neuroimaging findings were collated. We describe 27 individuals from 20 unrelated Indian families with causative variants in 5 NBIA-associated genes. PLA2G6-associated neurodegeneration (PLAN) was the most common, observed in 13 individuals from 9 families. They mainly presented in infancy with neuroregression and hypotonia. A recurrent pathogenic variant in COASY was observed in two neonates with prenatal-onset severe neurodegeneration. Pathogenic bi-allelic variants in PANK2, FA2H and C19ORF12 genes were observed in the rest, and these individuals presented in late childhood and adolescence with gait abnormalities and extrapyramidal symptoms. No intrafamilial and interfamilial variability were observed. Iron deposition on neuroimaging was seen in only 6/17 (35.3%) patients. A total of 22 causative variants across 5 genes were detected including a multiexonic duplication in PLA2G6. The variants c.1799G > A and c.2370 T > G in PLA2G6 were observed in three unrelated families. In silico assessments of 8 amongst 9 novel variants were also performed. We present a comprehensive compilation of the phenotypic and genotypic spectrum of various subtypes of NBIA from the Indian subcontinent. Clinical presentation of NBIAs is varied and not restricted to extrapyramidal symptoms or iron accumulation on neuroimaging.

MPV17 is a mitochondrial inner membrane protein, involved in transporting deoxynucleotides into the mitochondria. Pathogenic MPV17 mutations can cause mitochondrial deoxyribonucleic acid (DNA) depletion syndrome, which has a varied presentation with neurological, muscular and hepatic involvement. Presentation as liver failure is relatively uncommon. Here, we report four infants from four separate families with pathogenic, homozygous MPV17 mutations. All had predominant hepatic involvement with cholestasis, lactic acidosis and hypoketotic hypoglycemia. Three of them had presented with liver failure. Interestingly, one of them showed fluctuating liver functions, which worsened with infection and improved after aggressive treatment with antibiotics and supplements. Two of the four cases died in infancy, while the other two improved on conservative management with medium-chain triglyceride-based diet, vitamin supplements, co-enzyme Q and carnitine. The two surviving children are alive at 12 and 25 months of age with native liver with normal to mildly deranged liver function and no neurological dysfunction. Next-generation sequencing confirmed the diagnosis in all of our cases. One of the detected mutations, c.55delC (p.Gln19ArgfsTer3) is a novel pathogenic frameshift mutation, while another mutation c.388G>C (p.Ala130Pro), which was previously reported in Single Nucleotide Polymorphism Database in heterozygous form, is being predicted as likely pathogenic in our case series. We, therefore, propose mutation testing for MPV17 gene during evaluation of indeterminate infantile liver failure, especially those with hypoglycemia and raised plasma lactate.

Human NEET proteins contain two [2Fe-2S] iron-sulfur clusters, bound to three Cys residues and one His residue. They exist in two redox states. Recently, these proteins have revealed themselves as attractive drug targets for mitochondrial dysfunction-related diseases, such as type 2 diabetes, Wolfram syndrome 2, and cancers. Unfortunately, the lack of information and mechanistic understanding of ligands binding to the whole functional, cytoplasmatic domain has limited rational drug design approaches. Here, we use an enhanced sampling technique, volume-based metadynamics, recently developed by a team involving some of us, to predict the poses and affinity of the 2-benzamido-4-(1,2,3,4-tetrahydronaphthalen-2-yl)-thiophene-3-carboxylate ligand to the entire surface of the cytoplasmatic domain of the human NEET protein mitoNEET (mNT) in an aqueous solution. The calculations, based on the recently published X-ray structure of the complex, are consistent with the measured affinity. The calculated free energy landscape revealed that the ligand can bind in multiple sites and with poses other than the one found in the X-ray. This difference is likely to be caused by crystal packing effects that allow the ligand to interact with multiple adjacent NEET protein copies. Such extra contacts are of course absent in the solution; therefore, the X-ray pose is only transient in our calculations, where the binding free energy correlates with the number of contacts. We further evaluated how the reduction and protonation of the Fe-bound histidine, as well as temperature, can affect ligand binding. Both such modifications introduce the possibility for the ligand to bind in an area of the protein other than the one observed in the X-ray, with no or little impact on affinity. Overall, our study can provide insights on the molecular recognition mechanisms of ligand binding to mNT in different oxidative conditions, possibly helping rational drug design of NEET ligands.