[Clinical and genetic analysis of a patient with HUPRA syndrome due to missense variants of SARS2 gene and literature review].

Objective: To explore the clinical manifestations and genotype of an infant with hyperuricemia, pulmonary hypertension, renal failure in infancy, and alkalosis syndrome (HUPRAS). Methods: Clinical data of the patient were collected. Peripheral blood samples from the patient and his parents were acquainted for whole exome sequencing. The filtrated variants were verified by Sanger sequencing. The pathogenicity of the variants was predicted by bioinformatic tools. Results: The patient is a male infant of 6 months old, carrying two missense variants in the SARS2 allele: a paternal inherited c.1205G>A (p. Arg402His) and a maternal inherited c.680G>A (p. Arg227Gln). The two variants were in extremely low population frequencies. The pathogenetic prediction tools categorized them as deleterious. Arg402 and Arg227 were highly conserved in evolution. The variants led to changes in the hydrogen bonds and hydrophobicity of seryl-tRNA synthetase encoded by SARS2. Conclusions: c.1205G>A (p. Arg402His) and c.680G>A (p. Arg227Gln) are the possible causative variants of the HUPRA syndrome.

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions.

BACKGROUND: Progressive external ophthalmoplegia (PEO) is a common subtype of mitochondrial encephalomyopathy. OBJECTIVE: The study aimed to investigate the relationship between mitochondrial DNA (mtDNA) abnormalities, muscle pathology, and clinical manifestations in Chinese patients with single large-scale mtDNA deletion presenting with PEO. METHODS: This is a retrospective single-center study. Patients with PEO who had a single large deletion in mitochondrial DNA were included in this study. The associations were analyzed between mtDNA deletion patterns, myopathological changes, and clinical characteristics. RESULTS: In total, 155 patients with mitochondrial PEO carrying single large-scale mtDNA mutations were enrolled, including 137 chronic progressive external ophthalmoplegia (CPEO) and 18 Kearns-Sayre syndrome (KSS) patients. The onset ages were 9.61 ± 4.12 in KSS and 20.15 ± 9.06 in CPEO. The mtDNA deletions ranged from 2225 bp to 9131 bp, with m.8470_13446del being the most common. The KSS group showed longer deletions than the CPEO group (p = 0.004). Additionally, a higher number of deleted genes encoding respiratory chain complex subunits (p = 0.001) and tRNA genes (p = 0.009) were also observed in the KSS group. A weak negative correlation between the mtDNA deletion size and ages of onset (p < 0.001, r = -0.369) was observed. The proportion of ragged red fibers, ragged blue fibers, and cytochrome c negative fibers did not correlate significantly with onset ages (p > 0.05). However, a higher percentage of abnormal muscle fibers corresponds to an increased prevalence of exercise intolerance, limb muscle weakness, dysphagia, and cerebellar ataxia. CONCLUSION: We reported a large Chinese cohort consisting of mitochondrial PEO patients with single large-scale mtDNA deletions. Our results demonstrated that the length and locations of mtDNA deletions may influence onset ages and clinical phenotypes. The severity of muscle pathology could not only indicate diagnosis but also may be associated with clinical manifestations beyond the extraocular muscles.

Mitochondrial Dysfunction in Kidney Tubulopathies.

Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.

Electrolyte Disorders in Mitochondrial Cytopathies: A Systematic Review.

SIGNIFICANCE STATEMENT: Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the diagnostic workup of patients with electrolyte disorders. In this systematic review, we investigated the presence of electrolyte disorders in patients with mitochondrial cytopathies to determine the relevance of mitochondrial mutation screening in this population. Our analysis demonstrates that electrolyte disorders are commonly reported in mitochondrial cytopathies, often as presenting symptoms. Consequently, more clinical attention should be raised for mitochondrial disease as cause for disturbances in electrolyte homeostasis. Further prospective cohort studies are required to determine the exact prevalence of electrolyte disorders in mitochondrial cytopathies. BACKGROUND: Electrolyte reabsorption in the kidney has a high energy demand. Proximal and distal tubular epithelial cells have a high mitochondrial density for energy release. Recently, electrolyte disorders have been reported as the primary presentation of some mitochondrial cytopathies. However, the prevalence and the pathophysiology of electrolyte disturbances in mitochondrial disease are unknown. Therefore, we systematically investigated electrolyte disorders in patients with mitochondrial cytopathies. METHODS: We searched PubMed, Embase, and Google Scholar for articles on genetically confirmed mitochondrial disease in patients for whom at least one electrolyte is reported. Patients with a known second genetic anomaly were excluded. We evaluated 214 case series and reports (362 patients) as well as nine observational studies. Joanna Briggs Institute criteria were used to evaluate the quality of included studies. RESULTS: Of 362 reported patients, 289 had an electrolyte disorder, with it being the presenting or main symptom in 38 patients. The average number of different electrolyte abnormalities per patient ranged from 2.4 to 1.0, depending on genotype. Patients with mitochondrial DNA structural variants seemed most affected. Reported pathophysiologic mechanisms included renal tubulopathies and hormonal, gastrointestinal, and iatrogenic causes. CONCLUSIONS: Mitochondrial diseases should be considered in the evaluation of unexplained electrolyte disorders. Furthermore, clinicians should be aware of electrolyte abnormalities in patients with mitochondrial disease.

Increased Sphingomyelin and Free Sialic Acid in Cerebrospinal Fluid of Kearns-Sayre Syndrome: New Findings Using Untargeted Metabolomics.

BACKGROUND: Kearns-Sayre syndrome (KSS) is caused by duplications and/or deletions of mitochondrial DNA (mtDNA) and is typically diagnosed based on a classic triad of symptoms with chronic progressive external ophthalmoplegia (CPEO), retinitis pigmentosa, and onset before age 20 years. The present study aimed to diagnose two patients, on suspicion of KSS. METHODS: One of the patients went through a diagnostic odyssey, with normal results from several mtDNA analyses, both in blood and muscle, before the diagnosis was confirmed genetically. RESULTS: Two patients presented increased tau protein and low 5-methyltetrahydrofolate (5-MTHF) levels in the cerebrospinal fluid (CSF). Untargeted metabolomics on CSF samples also showed an increase in the levels of free sialic acid and sphingomyelin C16:0 (d18:1/C16:0), compared with four control groups (patients with mitochondrial disorders, nonmitochondrial disorders, low 5-MTHF, or increased tau proteins). CONCLUSIONS: It is the first time that elevated sphingomyelin C16:0 (d18:1/C16:0) and tau protein in KSS are reported. Using an untargeted metabolomics approach and standard laboratory methods, the study could shed new light on metabolism in KSS to better understand its complexity. In addition, the findings may suggest the combination of elevated free sialic acid, sphingomyelin C16:0 (d18:1/C16:0), and tau protein as well as low 5-MTHF as new biomarkers in the diagnostics of KSS.

Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study.

BACKGROUND: Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset. METHODS: A retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres. RESULTS: A total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%). CONCLUSION: Our study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.

Kearns-Sayre syndrome case. Novel 5,9 kb mtDNA deletion.

BACKGROUND: Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder characterized by onset before 20 years of age and a typical clinical triad: progressive external ophthalmoplegia, pigmentary retinopathy and cardiac conduction anomalies. In most cases KSS is caused by spontaneous heteroplasmic single large-scale mitochondrial DNA (mtDNA) deletions. Long-range polymerase chain reaction (LR-PCR), next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) are the most widely applied methods for the identification of mtDNA deletions. Here, we report the case of 20-year-old male who presented with classic Kearns-Sayre syndrome, confirmed by novel 5,9 kb mtDNA deletion. METHODS AND RESULTS: LR-PCR and MLPA methods were applied to identify the mitochondrial DNA deletion for the patient, but the results were conflicting. Molecular analysis using primer walking and Sanger sequencing identified a novel 5888 base pairs mtDNA deletion (NC_012920.1:m.6069_11956del) with CAAC nucleotides repeat sequence at the breakpoints. CONCLUSION: Our study enriched the mtDNA variation spectrum associated with KSS and demonstrated the importance of choosing relevant molecular genetic methods.

Propofol and Kearns-Sayre Syndrome: An idiographic approach.

With the focus on an idiographic approach whereby the observations incorporated the various dimensions of individual functioning 'top-down' to 'bottom-up', this case report describes the successful management of a 14-year-old girl with Kearns-Sayre syndrome and Dyggve-Melchior-Clausen disease requiring a transvenous permanent pacemaker implantation for complete heart block. The patient presented to a tertiary care centre in Muscat, Oman, in 2023 seeking consultation. The current idiographic approach appears to have a heuristic value for 2 interrelated reasons. Firstly, it is unlikely that even tertiary care units can accrue such rare presentations and scrutinise them under nomothetic approach. Secondly, by employing the idiographic approach that is capable of examining each case in-depth, the aspiration for good health and well-being may come to the forefront. To the best of the authors' knowledge this is the first published idiographic report in anaesthesia care.

Clinical Spectrum of Biopsy Proven Mitochondrial Myopathy.

Objectives: Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking. Materials and Methods: Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies. Results: Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness. Conclusion: We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.

Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes.

Patients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34+ hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders.

Mitochondrial disorders: Understanding mitochondrial DNA point mutations and deletion syndromes.

ABSTRACT: Mitochondrial disorders arise from DNA mutations in either the mitochondrial DNA (mtDNA) or nuclear DNA genomes. This article focuses on a mtDNA base-pair mutation associated with neuropathy, ataxia, and retinitis pigmentosa and Leigh syndrome and the large-scale mtDNA deletion associated with Kearns-Sayre syndrome. Disease sequelae and management strategies are reviewed, along with implications for the nurse practitioner in primary or specialty care.

Ventricular arrhythmias in Kearns-Sayre syndrome: A cohort study using the National Inpatient Sample database 2016-2019.

BACKGROUND: Degeneration of the cardiac conduction system resulting in complete heart block (CHB), ventricular arrhythmias (VA), and sudden cardiac death (SCD) is recognized in patients with Kearns-Sayre syndrome (KSS) and is potentially preventable with permanent pacemaker (PPM) implantation. However, other mechanisms for SCD have been proposed, and the efficacy of implanting a defibrillator instead of PPM remains to be investigated. METHODS: We utilized the National Inpatient Sample (NIS) database 2016-2019 to investigate the risk of VA or dysrhythmic cardiac arrest (dCA) in KSS patients. We compared the outcomes of KSS to myotonic dystrophy (MD), a more common genetic disorder with similar clinical cardiac features and course. RESULTS: We identified 640 admissions for KSS. VA or dCA were lower in admissions for KSS than MD patients (2.3% vs. 4.5%, p = .009). Device implantation differed between study groups. Approximately, 70% of cases with KSS and conduction abnormalities had pacemaker (± defibrillator) on hospital discharge, compared to 35% in MD. Conduction abnormalities were associated with higher rates of VA or dCA in both study groups. None of the admissions for KSS patients who developed VA or dCA had a pacemaker, and all of them had conduction abnormalities. One-third of admissions for MD patients who developed VA or dCA had a device already implanted prior to the event. CONCLUSION: Despite its effectiveness in preventing VA, PPM remains underutilized in patients with KSS or MD who have conduction abnormalities. PPM alone do not fully prevent VA in MD patients; therefore, addition of defibrillator capacity might be necessary.

Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure.

Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in infancy. Bone marrow cytology with vacuolization in erythroid and myeloid precursors and ring-sideroblasts guides to the correct diagnosis, which is established by detection of SLSMDs. Non hematological symptoms suggesting a mitochondrial disease are often lacking at initial presentation, thus PS is an important differential diagnosis in isolated hypogenerative anemia in infancy. Spontaneous resolution of anemia occurs in two-third of patients at the age of 1-3 years, while multisystem non-hematological complications such as failure to thrive, muscle hypotonia, exocrine pancreas insufficiency, renal tubulopathy and cardiac dysfunction develop during the clinical course. Some patients with PS experience a phenotypical change to Kearns-Sayre syndrome. In the absence of curative therapy, the prognosis of patients with PS is dismal. Most patients die of acute lactic acidosis and multi-organ failure in early childhood. There is a great need for the development of novel therapies to alter the natural history of patients with PS.

Kidney manifestations of mitochondrial disorders.

Mitochondria are intracellular organelles involved in a number of key biologic processes in the cell, including energy production, redox signaling, calcium homeostasis, inflammation, senescence, innate immune response, and mitophagy. Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation, leading to multi-organ involvement and progressive clinical deterioration. Mitochondrial cytopathies can result from mitochondrial or nuclear DNA mutations. Mitochondrial defects play an important role in the pathogenesis of nephropathies as tubular syndromes, interstitial nephritis, focal and segmental glomerulosclerosis and diabetic nephropathy. The role of mitochondria in a pathogenesis of nephrotoxicity and kidney carcinogenesis is also discussed (Tab. 2, Fig. 7, Ref. 100). Keywords: mitochondrial nephropathy, interstitial nephritis, glomerulosclerosis, diabetic nephropathy, nephrotoxicity, mitochondrial cytopathies.

Potpourri of retinopathies in rare eye disease - A case series.

This case series describes the ocular and retinal manifestations of rare eye diseases in systemic syndromes. This observational case series consists of five patients with varied ophthalmic manifestations and documentation of imaging in rare pediatric and adult retinopathies. Two patients had Kearns Sayre syndrome (KSS) based on the classical triad of external ophthalmoplegia, pigmentary retinopathy, and onset before 20 years of age. In one patient of KSS, the mitochondrial retinopathy was seen in an asymmetric pattern, and the second patient presented with KSS after being mis-diagnosed as myasthenia gravis elsewhere. A case of Senior Loken syndrome in pediatric age is described in this series with varied ophthalmic manifestations ranging from retinitis pigmentosa to orbital abscess. This series also enlightens features of Hallervorden Spatz syndrome presenting with bull's eye maculopathy and a case of spino-cerebellar ataxia type 7 presenting with pigmentary retinopathy.