The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses.

PURPOSE: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples. METHODS: 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mtDNA sequencing (ES+mtDNAseq) or genome sequencing (GS). RESULTS: Diagnostic yield was 55% (n=77) with variants in nuclear (n=37) and mtDNA (n=18) MD genes, as well as phenocopy genes (n=22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases, and comparable in children with non-European (78%) versus European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, three adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood. CONCLUSION: Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.

Using a Previsit Questionnaire for Initial Visits in a Pediatric Mitochondrial Clinic: Perspectives of Parents, a Specialty Physician, and a Clinical Coordinator.

Objective: In this study, we assessed the usefulness of a previsit questionnaire for children who were referred for an initial evaluation in a mitochondrial subspecialty clinic. We explored the themes regarding parent's questions, concerns, and goals. We aimed to add to existing knowledge about the usefulness of previsit questionnaires in a pediatric specialty setting from the perspective of parents, the specialist, and the clinical coordinator. Method: We enrolled 25 patients and their parent(s) over 25 months. Questionnaires were completed by the parent(s), the clinical coordinator, and the mitochondrial specialist. Descriptive statistics and thematic analysis were used to summarize results. Results: Parental responses suggested that they are most concerned about their child's clinical problems, communication, language and developmental delays, disease progression and prognosis, understanding mitochondrial disease, quality of life, and physical challenges including muscle and energy problems. Parents felt the previsit questionnaire was very helpful for both the doctor and for themselves to be prepared for their visit. The specialist and the clinical coordinator also found it to be helpful. Parental comments suggested that they felt that writing down the story of their child's life was helpful for the provider, allowed time for reflection, and improved the appointment experience. Some felt it was a difficult or redundant activity. Conclusion: Parents were often pleased to complete the previsit questionnaire. This allowed them to highlight concerns and share information that they wanted the care team to know about their child. We revised the tool based on feedback from parents and the specialist and will continue to use it in our clinic.

Unilateral Hearing Loss and Auditory Asymmetry in Mitochondrial Disease: A Scoping Review.

Background/Objectives: Mitochondrial transfer RNA mutations are one of the most important causes of hereditary hearing loss in humans. In most cases, its presentation is bilateral and symmetrical; however, there are numerous cases of single-sided presentation or asymmetrical onset described in the literature that may represent a diagnostic challenge. The aim of this review is to present the evidence of auditory asymmetry in mitochondrial diseases, highlighting the possible presence of cases with atypical presentation. Methods: A review of the English literature to date on hearing loss and mitochondrial diseases was performed using PubMed, Scopus, and Google Scholar databases. The literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines for scoping review. Results: A total of 10 full-text articles were included in this review, comprising 25 patients with single-sided or asymmetrical hearing loss associated with mitochondrial disease. Conclusions: Sensorineural hearing loss due to mitochondrial disease can represent a complex diagnostic challenge in cases of asymmetric or unilateral presentation. It is critical to recognize this clinical variant and to diagnose it in daily clinical practice.

Inclusion body myositis: Correcting mitochondfrial and lysosomal autophagy impairment as a potential therapeutic strategy.

Inclusion body myositis (IBM) is a late onset sporadic myopathy with a characteristic clinical presentation, but as yet unknown aetiology or effective treatment. Typical clinical features are early predominant asymmetric weakness of finger flexor and knee extensor muscles. Muscle biopsy shows endomysial inflammatory infiltrate, mitochondrial changes, and protein aggregation. Proteostasis (protein turnover) appears to be impaired, linked to potentially dysregulated chaperone-mediated autophagy and mitophagy (mitochondrial quality control). In this review, we bring together the most recent clinical and biological data describing IBM. We then address the question of diagnosing this pathology and the relevance of the current biological markers that characterize IBM. In these descriptions, we put a particular emphasis on data related to the deregulation of autophagic processes and to the mitochondria-lysosome crosstalk. Finally, after a short description of current treatments, an overview is provided pointing towards novel therapeutic targets and upcoming regulating molecules tested for treating IBM. Special attention is paid to autophagy inhibitors that may offer innovative breakthrough therapies for patients with IBM.

Diagnostic dilemma: Leber's hereditary optic neuropathy in a 70-year-Old woman.

Purpose: Reports of atypical cases have increased awareness that Leber's hereditary optic neuropathy (LHON) is not solely a disease of young men. Here, we present a case of a 70-year-old woman who presented with bilateral sequential loss of vision, and, after several diagnostic dilemmas, was ultimately found to have LHON. Observations: Our patient presented with a one-month history of progressive central vision loss in the right eye. Her visual acuities were 20/200-1 and 20/25-2. She had no afferent pupillary defect and intraocular pressures were normal. Fundus examination revealed cup-to-disc ratios of 0.9 and 0.7 with an inferior notch on the right. Visual fields showed superior arcuate and cecocentral depressions on the right and an inferior nasal step on the left. Ocular coherence tomography showed bilateral, superior and inferior retinal nerve fiber layer thinning. She was diagnosed with normal-tension glaucoma. Laboratory studies and neuroimaging were unremarkable. One month later, she presented with new central vision loss in the left eye. Ocular coherence tomography revealed new, mild optic nerve swelling in the left eye. Due to concern for an acute-on-chronic process, she was hospitalized and treated with intravenous steroids and later plasmapheresis with modest improvement. An extensive laboratory evaluation, lumbar puncture, temporal artery biopsy, and PET CT were normal. Mitochondrial genetic testing was ordered. After a six-week delay, the results revealed a pathogenic variant at mitochondrial position 11778, consistent with a diagnosis of LHON. She began treatment with idebenone. At the most recent visit, her vision had improved to 20/40 and 20/30. Conclusions and importance: LHON is typically not part of the initial differential diagnosis of an optic neuropathy in patients outside the typical demographic. As genetic testing has become more widely available, clinicians should consider including LHON in their differential diagnosis of any optic neuropathy, especially if other, more common causes have been ruled out.

Emerging Multi-omic Approaches to the Molecular Diagnosis of Mitochondrial Disease and Available Strategies for Treatment and Prevention.

Mitochondria are semi-autonomous organelles present in several copies within most cells in the human body that are controlled by the precise collaboration of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) encoding mitochondrial proteins. They play important roles in numerous metabolic pathways, such as the synthesis of adenosine triphosphate (ATP), the predominant energy substrate of the cell generated through oxidative phosphorylation (OXPHOS), intracellular calcium homeostasis, metabolite biosynthesis, aging, cell cycles, and so forth. Previous studies revealed that dysfunction of these multi-functional organelles, which may arise due to mutations in either the nuclear or mitochondrial genome, leads to a diverse group of clinically and genetically heterogeneous disorders. These diseases include neurodegenerative and metabolic disorders as well as cardiac and skeletal myopathies in both adults and newborns. The plethora of phenotypes and defects displayed leads to challenges in the diagnosis and treatment of mitochondrial diseases. In this regard, the related literature proposed several diagnostic options, such as high throughput mitochondrial genomics and omics technologies, as well as numerous therapeutic options, such as pharmacological approaches, manipulating the mitochondrial genome, increasing the mitochondria content of the affected cells, and recently mitochondrial diseases transmission prevention. Therefore, the present article attempted to review the latest advances and challenges in diagnostic and therapeutic options for mitochondrial diseases.

Cochlear Implantation for Isoleucyl-tRNA Synthetase Mutation-Associated Mitochondrial Disease: A Case Report.

Biallelic missense mutations in the nuclear-encoded, cytosolic isoleucyl-tRNA synthetase (IARS) gene are associated with a rare and complex multisystemic phenotype, including growth retardation, intellectual disability, muscular hypotonia, diabetes mellitus, and deafness. These mutations impact the cytosolic isoform of IARS, which plays a crucial role in protein synthesis. The pathogenesis involves mitochondrial dysfunction, despite IARS being primarily a cytosolic enzyme, potentially linking it to the observed clinical manifestations. The efficacy of cochlear implantation for deafness due to IARS mutations and the safety of general anesthesia in such patients remain unclear. This report describes a rare case of progressive sensorineural hearing loss caused by IARS mutation-associated mitochondrial disease, which was successfully treated with cochlear implantation. Additionally, we discuss the safety of general anesthesia in this patient. A Japanese woman with IARS mutation-associated mitochondrial disease was diagnosed with severe bilateral sensorineural hearing loss at five years of age and immediately received hearing aids. Her hearing progressively deteriorated to profound impairment, necessitating cochlear implantation at 26 years of age, which resulted in satisfactory hearing. Furthermore, no perioperative general anesthesia-related adverse events were reported. Our case demonstrates that cochlear implantation can effectively restore hearing. This suggests that sensorineural hearing loss caused by IARS deficiency is primarily due to cochlear dysfunction. This case demonstrated that hearing loss is a crucial feature of IARS mutation-associated mitochondrial disease, which can be mitigated by cochlear implantation. While general anesthesia can be safely administered, careful consideration of anesthetic choices, such as avoiding depolarizing muscle relaxants and prolonged use of propofol, is essential to prevent complications. In this case, general anesthesia was well tolerated without perioperative events, providing valuable insight into the potential safety of such procedures in similar patients. Nevertheless, further studies are needed to confirm these findings across a broader population.

Myoclonic Epilepsy With Ragged Red Fiber Cardiomyopathy: A Case Report and Brief Review of Literature.

Myoclonic epilepsy with ragged red fibers (MERRF) is a rare mitochondrial disease that can affect various organs, including the heart. We present a case report and brief review of the literature with the aim of exploring the progression of cardiac involvement in patients with MERRF. A 65-year-old male with a history of MERRF, first diagnosed at age 55 with interventricular septum hypertrophy, presented with acute heart failure. The patient's clinical course over 10 years demonstrated a transition from a hypertrophic to a dilated cardiomyopathy phenotype, contrasting earlier findings suggesting rapid progression in younger patients. Despite optimized heart failure therapy, the patient experienced a progressive decline in ventricular function with frequent ventricular arrhythmias, ultimately requiring implantable cardioverter-defibrillator (ICD) placement. This case supports the hypothesis that MERRF-related cardiac involvement may progress more slowly when onset occurs later in life, leading to a gradual transition from hypertrophic to dilated cardiomyopathy. An accurate cardiac diagnostic workup is essential for early detection and timely intervention in such patients. The natural history of cardiac involvement in MERRF can vary significantly based on the age of onset, highlighting the importance of personalized diagnostic and therapeutic approaches in managing this rare mitochondrial disorder.

Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.

Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid (PL) metabolism. Cardiolipin (CL), the signature PL of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesised and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to CL biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human CL-related PMDs are not fully characterised. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo CL biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy, and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy, and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterise the molecular defects associated with mutant PTPMT1 and confirm the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterise the functional role of PTPMT1 in CL homeostasis, we established a zebrafish ptpmt1 knockout model associated with abnormalities in body size, developmental alterations, decreased total CL levels, and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired CL metabolism, highlight the contribution of aberrant CL metabolism towards human disease, and emphasise the importance of normal CL homeostasis during neurodevelopment.

Pregnancy in women with mitochondrial disease-A literature review and suggested guidance for preconception and pregnancy care.

Mitochondrial donation to reduce the risk of primary mitochondrial disease transmission from mother to child is now permitted under Australian law as part of a clinical trial. The energy demands of pregnancy have the potential to worsen mitochondrial disease symptoms and severity in affected women. We conducted a systematic literature review on mitochondrial disease in pregnancy; five cohort studies and 19 case reports were included. For many women with mitochondrial disease, pregnancy does not have a negative effect on health status. However, serious adverse outcomes may occur. We provide suggested guidelines for preconception counselling and antenatal care.

Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy.

Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.

Queuine ameliorates impaired mitochondrial function caused by mt-tRNAAsn variants.

BACKGROUND: Mitochondrial tRNA (mt-tRNA) variants have been found to cause disease. Post-transcriptional queuosine (Q) modifications of mt-tRNA can promote efficient mitochondrial mRNA translation. Q modifications of mt-tRNAAsn have recently been identified. Here, the therapeutic effectiveness of queuine was investigated in cells from patients with mt-tRNAAsn variants. METHODS: Six patients (from four families) carrying mt-tRNAAsn variants were included in the study. Queuine levels were quantified by mass spectrometry. Clinical, genetic, histochemical, biochemical, and molecular analysis was performed on muscle tissues and lymphoblastoid cell lines (LCLs) from patients to investigate the pathogenicity of the novel m.5708 C > T variant. The use of queuine in mitigating mitochondrial dysfunction resulting from the mt-tRNAAsn variants was evaluated. RESULTS: The variants included the m.5701 delA, m.5708 C > T, m.5709 C > T, and m.5698 G > A variants in mt-tRNAAsn. The pathogenicity of the novel m.5708 C > T variant was confirmed, as demonstrated by a decreased steady-state level of mt-tRNAAsn, mtDNA-encoded protein levels, oxygen consumption rate (OCR), and the respiratory complex activity. Notably, the serum queuine level was significantly reduced in these patients and in vitro queuine supplementation was found to restore the reductions in mitochondrial protein activities, mitochondrial membrane potential, OCR, and increases in reactive oxygen species. CONCLUSIONS: The study not only confirmed the pathogenicity of the m.5708 C > T variant but also explored the therapeutic potential of queuine in individuals with mt-tRNAAsn variants. The recognition of the novel m.5708 C > T variant's pathogenic nature contributes to our comprehension of mitochondrial disorders. Furthermore, the results emphasize queuine supplementation as a promising approach to enhance the stability of mt-tRNAAsn and rescue mitochondrial dysfunction caused by mt-tRNAAsn variants, indicating potential implications for the development of targeted therapies for patients with mt-tRNAAsn variants.

IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency.

BACKGROUND: Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear. METHODS: Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants. RESULTS: We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells. CONCLUSION: Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.

The interplay between mitochondria, the gut microbiome and metabolites and their therapeutic potential in primary mitochondrial disease.

The various roles of the mitochondria and the microbiome in health and disease have been thoroughly investigated, though they are often examined independently and in the context of chronic disease. However, the mitochondria and microbiome are closely connected, namely, through their evolution, maternal inheritance patterns, overlapping role in many diseases and their importance in the maintenance of human health. The concept known as the "mitochondria-microbiome crosstalk" is the ongoing bidirectional crosstalk between these two entities and warrants further exploration and consideration, especially in the context of primary mitochondrial disease, where mitochondrial dysfunction can be detrimental for clinical manifestation of disease, and the role and composition of the microbiome is rarely investigated. A potential mechanism underlying this crosstalk is the role of metabolites from both the mitochondria and the microbiome. During digestion, gut microbes modulate compounds found in food, which can produce metabolites with various bioactive effects. Similarly, mitochondrial metabolites are produced from substrates that undergo biochemical processes during cellular respiration. This review aims to provide an overview of current literature examining the mitochondria-microbiome crosstalk, the role of commonly studied metabolites serve in signaling and mediating these biochemical pathways, and the impact diet has on both the mitochondria and the microbiome. As a final point, this review highlights the up-to-date implications of the mitochondria-microbiome crosstalk in mitochondrial disease and its potential as a therapeutic tool or target.

Demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases: a retrospective cross-sectional study.

BACKGROUND: This study aimed to explore the demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases. METHODS: This retrospective cross-sectional study enrolled patients diagnosed with mitochondrial diseases from the Department of Neurology at Peking University First Hospital between January 2010 and December 2021. A questionnaire covering demographic characteristics, diagnostic dilemma, treatment, economic aspects, and caregiver stress was administered, and disability was assessed using the modified Rankin Scale (mRS). RESULTS: A total of 183 patients (mean age: 16 (IQR: 12-25), 49.72% males) were enrolled, including 124 pediatric patients and 59 adult patients. MELAS (106. 57.92%) and Leigh syndrome (37, 20.22%) were predominant among the mitochondrial disease subtypes. Among them, 132 (72.13%) patients were initially misdiagnosed with other diseases, 58 (31.69%) patients visited 2 hospitals before confirmed as mitochondrial disease, and 39 (21.31%) patients visited 3 hospitals before confirmed as mitochondrial disease. Metabolic modifiers were the most common type of drugs used, including several dietary supplements such as L-carnitine (117, 63.93%), Coenzyme Q10 (102, 55.74%), idebenone (82, 44.81%), and vitamins (99, 54.10%) for proper mitochondrial function. Mothers are the primary caregivers for both children (36.29%) and adults (38.98%). The mRS score ranged from 0 to 5, 92.35% of the patients had different degrees of disability due to mitochondrial disease. The average monthly treatment cost was 3000 RMB for children and 3100 RMB for adults. CONCLUSIONS: This study provided valuable insights into the characteristics and challenges of mitochondrial diseases, which underscores the need for improved awareness, diagnostic efficiency, and comprehensive support for patients and caregivers.

Endocrine Disorders in Children with Primary Mitochondrial Diseases: Single-Center Experience.

Objective: Endocrine abnormalities may represent the only clinical manifestation of primary mitochondrial disorders. This study aimed to evaluate the endocrinological characteristics of mitochondrial disease in our cohort. Methods: A total of twenty-six pediatric patients diagnosed with mitochondrial disease were categorized on the basis of their specific genetic abnormalities. The auxologic data, pubertal development, and, based on their clinical symptoms, hormonal profiles were obtained. Results: Twelve of the cohort of 26 patients (46%) were female. In 15 of the patients (57.6%), their mitochondrial disease (MD) was caused by nuclear DNA mutations (nDNA group). Four patients had Leigh syndrome, 2 patients had LHON syndrome, 2 patients had MELAS, and 1 patient had KSS clinical phenotype. The median age at diagnosis was 2.91 (0.59-16.8) years, and the median age at first endocrinologic evaluation was 4.62 (1.26-18) years. The mean height SDS was -1.34 ± 2.12, and the mean BMI SDS was -0.82 ± 1.96 for all patients. Of the 26 patients, 6 (23%) had a range of hormonal deficits. Ovarian insufficiency, central adrenal insufficiency, central hypothyroidism, diabetes mellitus, and critical illness-related adrenal insufficiency were all observed. Three of the patients were initially monitored in the endocrine clinic for hormone deficiencies but it was later determined that the hormonal abnormalities were caused by underlying mitochondrial disease. Conclusion: Individuals diagnosed with mitochondrial disease, particularly those with specific genetic abnormalities, are considered a high-risk group for developing hormonal deficits. Endocrine diseases could be one of the primary mitochondrial disorders' early warning symptoms.

Homozygosity for a Rare FASTKD2 Variant Resulting in an Adult Onset Autosomal Recessive Mitochondrial Podocytopathy.

Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction, and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with subnephrotic proteinuria who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 variants. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy-which might be, instead, pathogenically related to adenosine triphosphate deficiency.

Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update.

Mitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.

Prenatal molecular diagnosis of pyruvate dehydrogenase complex deficiency enables rapid initiation of ketogenic diet.

Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder of carbohydrate oxidation characterized by lactic acidosis and central nervous system involvement. Knowledge of the affected metabolic pathways and clinical observations suggest that early initiation of the ketogenic diet may ameliorate the metabolic and neurologic course of the disease. We present a case in which first trimester ultrasound identified structural brain abnormalities prompting a prenatal molecular diagnosis of PDCD. Ketogenic diet, thiamine, and N-acetylcysteine were initiated in the perinatal period with good response, including sustained developmental progress. This case highlights the importance of a robust neurometabolic differential diagnosis for prenatally diagnosed structural anomalies and the use of prenatal molecular testing to facilitate rapid, genetically tailored intervention.