Single-port versus multiport robotic-assisted radical prostatectomy: A systematic review and meta-analysis on the da Vinci SP platform.

CONTEXT: Prostate cancer is the most common cancer in men; robotic prostatectomy has cemented itself as part of the standard of care. Since its approval by the Food and Drug Administration in 2018, the SP console's application has been increasingly studied and compared with the multiport (MP) robotic approach. METHODS: Following PRISMA guidelines and PROSPERO registration CRD42021228744, a systematic review was performed in April 2021 on single-port robotic-assisted radical prostatectomies (SP-RARPs) compared to MP. Outcomes of interest were operative time, bleeding, complications, analgesic use, and postoperative continence, and erectile function. Data were analyzed with Review Manager 5.3. RESULTS: Seven studies were included, of which six studies met the inclusion criteria for quantitative synthesis, totalling 1068 patients, out of which 324 underwent SP-RARP and 744 underwent MP-RARP. No differences were found in baseline characteristics such as age, body mass index, prostatic-specific antigen, or stage. No differences in blood loss-15.77 mL [-42.44, 10.89], p = 0.25, operative time 3.93 min [-4.12, 11.98], p = 0.34, or positive surgical margins, with an odds ratio (OR) of 0.78 [0.55, 1.10], p = 0.15-were found. Length of stay was significantly shorter in SP -0.94 days [-1.56, -0.33], p = 0.003, with no differences in complication rates, with an OR of 1.29 [0.78, 2.14], p = 0.32, continence rates, with an OR of 1.29 [0.90, 1.83], p = 0.16, erectile function, with an OR of 0.86 [0.52, 1.40], p = 0.54, or biochemical recurrence. Qualitative evidence suggests decreased opioid consumption. CONCLUSION: SP-RARPs are feasible alternatives to the traditional MP with possible benefits in pain management and length of stay. Future high-quality studies are needed to confirm these findings.

Recurrent brachial plexopathy as initial presentation of systemic lupus erythematosus: A case report and review of the literature.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects many organs of the body including the peripheral nervous system (PNS) which has potential significant impact. Plexopathy is rare but one of the serious PNS manifestations of lupus. CASE: A 41-year-old female presented with recurrent attacks of painful brachial plexopathy and right hemi-diaphragmatic paralysis. After extensive workup, she was diagnosed with SLE and started on hydroxychloroquine and mycophenolate mofetil. The frequency and severity of the attacks of plexopathy has significantly improved after starting the immune suppressive therapy for SLE. Whole exome sequencing unveiled previously unreported mutations encoding non-synonymous amino acids in titin and minichromosome maintenance 3-associated protein. CONCLUSION: Recurrent attacks of painful brachial plexopathy may warrant careful evaluation for underlying SLE with a premise of therapeutic benefit.

Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus.

Liver disease (LD), defined as ≥ 2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment.

Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene.

In 2001, we reported linkage of an autosomal dominant form of limb-girdle muscular dystrophy, limb-girdle muscular dystrophy 1F, to chromosome 7q32.1-32.2, but the identity of the mutant gene was elusive. Here, using a whole genome sequencing strategy, we identified the causative mutation of limb-girdle muscular dystrophy 1F, a heterozygous single nucleotide deletion (c.2771del) in the termination codon of transportin 3 (TNPO3). This gene is situated within the chromosomal region linked to the disease and encodes a nuclear membrane protein belonging to the importin beta family. TNPO3 transports serine/arginine-rich proteins into the nucleus, and has been identified as a key factor in the HIV-import process into the nucleus. The mutation is predicted to generate a 15-amino acid extension of the C-terminus of the protein, segregates with the clinical phenotype, and is absent in genomic sequence databases and a set of >200 control alleles. In skeletal muscle of affected individuals, expression of the mutant messenger RNA and histological abnormalities of nuclei and TNPO3 indicate altered TNPO3 function. Our results demonstrate that the TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expand our knowledge of the molecular basis of muscular dystrophies and bolster the importance of defects of nuclear envelope proteins as causes of inherited myopathies.

N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double-blind, placebo-controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N-acetylcysteine (NAC). METHODS: A total of 36 SLE patients received either daily placebo or 1.2 gm, 2.4 gm, or 4.8 gm of NAC. Disease activity was evaluated monthly by the British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index (SLEDAI), and the Fatigue Assessment Scale (FAS) before, during, and after a 3-month treatment period. Mitochondrial transmembrane potential and mTOR were assessed by flow cytometry. Forty-two healthy subjects matched to patients for age, sex, and ethnicity were studied as controls. RESULTS: NAC up to 2.4 gm/day was tolerated by all patients, while 33% of those receiving 4.8 gm/day had reversible nausea. Placebo or NAC 1.2 gm/day did not influence disease activity. Considered together, 2.4 gm and 4.8 gm NAC reduced the SLEDAI score after 1 month (P = 0.0007), 2 months (P = 0.0009), 3 months (P = 0.0030), and 4 months (P = 0.0046); the BILAG score after 1 month (P = 0.029) and 3 months (P = 0.009); and the FAS score after 2 months (P = 0.0006) and 3 months (P = 0.005). NAC increased Δψm (P = 0.0001) in all T cells, profoundly reduced mTOR activity (P = 0.0009), enhanced apoptosis (P = 0.0004), reversed expansion of CD4-CD8- T cells (mean ± SEM 1.35 ± 0.12-fold change; P = 0.008), stimulated FoxP3 expression in CD4+CD25+ T cells (P = 0.045), and reduced anti-DNA production (P = 0.049). CONCLUSION: This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.

Pielonefritis xantogranulomatosa: un reto actual para la laparoscopia.

OBJECTIVE: To present the results of our case series on laparoscopic nephrectomy in xanthogranulomatous pyelonephritis (XGP). METHODS: A retrospective study was conducted that included 143 patients treated with laparoscopic nephrectomy for non-functioning kidney, of whom 15 had XGP, within the time frame of 2011 to 2019. The demographic and clinical data were collected, along with the intraoperative results, complications, and days of hospital stay. RESULTS: Transperitoneal laparoscopic nephrectomy was successfully performed on 15 patients with XGP, with no need for conversion. Mean intraoperative time was 124.4 minutes (range 70-240) and intraoperative blood loss was 148.5 ml (range 30-550), with no blood transfusion required. No intraoperative complications occurred but there was one postoperative complication (6.6%), classified as Clavien-Dindo I (surgical wound infection). Mean hospital stay was 2.85 days (range 2-7). CONCLUSIONS: Nephrectomy is the definitive management for XGP, and the laparoscopic approach should be considered a treatment modality, despite the fact that the pathology involves a severe chronic inflammatory process. Its benefits are reduced surgery duration, less blood loss, a lower complication rate, and fewer days of hospital stay, when performed by a skilled and experienced surgeon.

OBJETIVO: Presentar los resultados de nuestra serie de nefrectomía laparoscópica en pielonefritis xantogranulomatosa (PXG). MÉTODO: Se realizó un estudio retrospectivo que incluyó 143 pacientes tratados con nefrectomía laparoscópica por exclusión renal, de los cuales 15 fueron por PXG, en el periodo comprendido de 2011 a 2019. Se recolectaron datos demográficos y clínicos, resultados transoperatorios, complicaciones y días de estancia hospitalaria. RESULTADOS: Se realizó nefrectomía laparoscópica transperitoneal de forma exitosa en 15 pacientes con PXG, sin necesidad de conversión. El tiempo transoperatorio promedio fue de 124.4 minutos (rango: 70-240). El sangrado transoperatorio fue de 148.5 ml (rango: 30-550), sin requerimiento de transfusión sanguínea. No se reportaron complicaciones transoperatorias; se presentó una complicación en el posoperatorio (6.6%) clasificada como Clavien-Dindo I (infección de la herida quirúrgica). La estancia hospitalaria promedio fue de 2.85 días (rango: 2-7). CONCLUSIONES: El manejo definitivo de la PXG es la nefrectomía, y el abordaje laparoscópico debe ser considerado como una modalidad de tratamiento a pesar de ser una patología que presenta un proceso inflamatorio grave y crónico, obteniéndose beneficios como disminución en el tiempo quirúrgico, menor sangrado, menor tasa de complicaciones y menos días de estancia hospitalaria cuando es realizado por un cirujano experimentado.

Advantages and Short-Term Outcomes of Laparoscopic-Assisted Renal Surgery in Elderly Patients.

OBJECTIVE: To compare the perioperative results of adult and elderly patients undergoing laparoscopic renal surgery. METHODOLOGY: Retrospective, analytical study. 448 who underwent kidney surgery for benign or malignant pathologies between 2011-2019 were included in the General Hospital of Mexico "Dr. Eduardo Liceaga". They were categorized into two groups: Group 1 <60 years and Group 2 >60 years. Descriptive statistics and bivariate analysis were performed, the calculations were performed with 95% reliability and a value of p (<0.05). RESULTS: In the group over 60 years of age, the following was found: Age: 67.1 years (60-83). IMC 28.3 kg/m2 (19-48.7). Intra and postsurgical outcomes: intraoperative bleeding = 184.4cc (5-1700). Surgical Time = 112.6min (30-240). Days of hospital stay = 2 (1-7). Complications in 2.6% (Clavien-Dindo: I = 2; II = 1), no conversion was required in any patient. There were no statistically significant differences with group 1, an exception for intraoperative bleeding. CONCLUSIONS: Our study is a pioneer in Latin America in the evaluation of the geriatric population and outcomes with laparoscopic surgery and we recommend that renal procedures with a laparoscopic approach should be considered as the best strategy in the management of benign or malignant renal pathology in geriatric patients.

Oncological and functional results after robot-assisted radical prostatectomy in high-risk prostate cancer patients.

BACKGROUND: Pentafecta is currently the standard in the comprehensive evaluation of patients undergoing radical prostatectomy, the objective of this study is the evaluation of oncological and functional outcomes in patients with prostate cancer of high risk undergoing robot-assisted radical prostatectomy. METHOD: Descriptive, retrospective study of 20 cases with a diagnosis of high-risk prostate cancer. The high-risk group is composed of a prostate-specific antigen equal or greater than 20 ng/mL, Gleason score equal or greater than 8, or clinical stages T2/T3 treated with robotic approach. RESULTS: Biochemical control was achieved from the first six weeks after the surgical event. 75% (n = 15) had negative surgical margins. 100% of the patients (n = 20) presented urinary continence immediately after removal of the urinary catheter. Erectile function was preserved at 3, 6 and 12 months in 100% of the patients who underwent neuropreservation but with use of an PDE inhibitor. (n = 5). Complications were reported in 10% (Clavien-Dindo I-II). CONCLUSIONS: Robot-assisted radical prostatectomy in patients with high-risk prostate cancer is considered an appropriate treatment option in selected patients. A different experimental design is needed to define the advantages or disadvantages of this approach, as well as to determine its role and application in clinical practice.

ANTECEDENTES: Pentafecta es el estándar en la evaluación integral de los pacientes sometidos a prostatectomía radical. El objetivo de este estudio es evaluar y describir los desenlaces oncológicos y funcionales en pacientes con cáncer de próstata de alto riesgo sometidos a prostatectomía radical asistida por robot. MÉTODO: Estudio descriptivo, retrospectivo, de 20 pacientes con diagnóstico de cáncer de próstata de alto riesgo. El grupo de alto riesgo se compone por pacientes con antígeno prostático específico mayo o igual a 20 ng/ml, reporte histopatológico con Gleason mayor o igual a 8 y/o estadios clínicos T2/T3 tratados con abordaje robótico. RESULTADOS: El control bioquímico se alcanzó a partir de las primeras 6 semanas posterior al evento quirúrgico. El 75% (n = 15) presentaron márgenes quirúrgicos negativos. El 100% de los pacientes (n = 20) presentaron continencia urinaria inmediatamente después del retiro de la sonda vesical. La función eréctil se conservó a 3, 6 y 12 meses en el 100% de los pacientes a los que se realizó neuropreservación, pero con uso de inhibidor de la fosfodiesterasa (n = 5). Se reportaron complicaciones en el 10% de los casos (Clavien-Dindo I-II). CONCLUSIONES: La prostatectomía radical asistida por robot en pacientes con cáncer de próstata de alto riesgo se considera una opción de tratamiento adecuada en casos seleccionados. Se necesita un diseño experimental distinto para definir las ventajas o desventajas de este abordaje, así como determinar su papel y aplicación en la práctica clínica.

Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice.

Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. This concept has been proven by in vitro studies over many years, but in vivo models are required to demonstrate its relevance to multicellular organisms and to human diseases. Accordingly, we have generated thymidine phosphorylase (TP) and uridine phosphorylase (UP) double knockout (TP(-/-)UP(-/-)) mice, which show severe TP deficiency, increased thymidine and deoxyuridine in tissues and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes and encephalopathy. These findings largely account for the pathogenesis of mitochondrial neurogastrointestinal encephalopathy (MNGIE), the first inherited human disorder of nucleoside metabolism associated with somatic DNA instability.

X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1.

Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G-->C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.

Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues: implications for human mitochondrial disease.

Mammalian SCO1 and SCO2 are evolutionarily-related copper-binding proteins that are required for the assembly of cytochrome c oxidase (COX), a mitochondrial respiratory chain complex, but the exact roles that they play in the assembly process are unclear. Mutations in both SCO1 and SCO2 are associated with distinct clinical phenotypes as well as tissue-specific COX deficiency, but the reason for such tissue specificity is unknown. We show in this study that although both genes are expressed ubiquitously in all mouse and human tissues examined, surprisingly, SCO1 localizes predominantly to blood vessels, whereas SCO2 is barely detectable in this tissue. To our knowledge, SCO1 is the first known example of a mitochondrial protein that is strongly expressed in the vasculature. We also show that the expression of SCO1, but not of SCO2, is very high in liver (the tissue most affected in SCO1-mutant patients), whereas the reverse holds true in muscle (the tissue most affected in SCO2-mutant patients). Our findings may help explain the differences in clinical presentations due to mutations in SCO1 and SCO2 and provide clues regarding the partially nonoverlapping functions of these two proteins.

Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation.

Persistent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T cell activation and death pathway selection in systemic lupus erythematosus. Treatment with rapamycin, which effectively controls disease activity, normalizes CD3/CD28-induced calcium fluxing but fails to influence MHP, suggesting that altered calcium fluxing is downstream or independent of mitochondrial dysfunction. In this article, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in lupus T cells. Activation of mTOR was inducible by NO, a key trigger of MHP, which in turn enhanced the expression of HRES-1/Rab4, a small GTPase that regulates recycling of surface receptors through early endosomes. Expression of HRES-1/Rab4 was increased in CD4(+) lupus T cells, and in accordance with its dominant impact on the endocytic recycling of CD4, it was inversely correlated with diminished CD4 expression. HRES-1/Rab4 overexpression was also inversely correlated with diminished TCRzeta protein levels. Pull-down studies revealed a direct interaction of HRES-1/Rab4 with CD4 and TCRzeta. Importantly, the deficiency of the TCRzeta chain and of Lck and the compensatory up-regulation of FcepsilonRIgamma and Syk, which mediate enhanced calcium fluxing in lupus T cells, were reversed in patients treated with rapamcyin in vivo. Knockdown of HRES-1/Rab4 by small interfering RNA and inhibitors of lysosomal function augmented TCRzeta protein levels in vitro. The results suggest that activation of mTOR causes the loss of TCRzeta in lupus T cells through HRES-1/Rab4-dependent lysosomal degradation.

Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.

Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including thymidine kinase (TK2), which encodes a ubiquitous mitochondrial protein. To study the pathogenesis of TK2-deficiency, we generated mice harboring an H126N Tk2 mutation. Homozygous Tk2 mutant (Tk2(-/-)) mice developed rapidly progressive weakness after age 10 days and died between ages 2 and 3 weeks. Tk2(-/-) animals showed Tk2 deficiency, unbalanced dNTP pools, mtDNA depletion and defects of respiratory chain enzymes containing mtDNA-encoded subunits that were most prominent in the central nervous system. Histopathology revealed an encephalomyelopathy with prominent vacuolar changes in the anterior horn of the spinal cord. The H126N TK2 mouse is the first knock-in animal model of human MDS and demonstrates that the severity of TK2 deficiency in tissues may determine the organ-specific phenotype.

A functionally dominant mitochondrial DNA mutation.

Mutations in mitochondrial DNA (mtDNA) tRNA genes can be considered functionally recessive because they result in a clinical or biochemical phenotype only when the percentage of mutant molecules exceeds a critical threshold value, in the range of 70-90%. We report a novel mtDNA mutation that contradicts this rule, since it caused a severe multisystem disorder and respiratory chain (RC) deficiency even at low levels of heteroplasmy. We studied a 13-year-old boy with clinical, radiological and biochemical evidence of a mitochondrial disorder. We detected a novel heteroplasmic C>T mutation at nucleotide 5545 of mtDNA, which was present at unusually low levels (<25%) in affected tissues. The pathogenic threshold for the mutation in cybrids was between 4 and 8%, implying a dominant mechanism of action. The mutation affects the central base of the anticodon triplet of tRNA(Trp) and it may alter the codon specificity of the affected tRNA. These findings introduce the concept of dominance in mitochondrial genetics and pose new diagnostic challenges, because such mutations may easily escape detection. Moreover, similar mutations arising stochastically and accumulating in a minority of mtDNA molecules during the aging process may severely impair RC function in cells.

Successful treatment of secondary macrophage activation syndrome with emapalumab in a patient with newly diagnosed adult-onset Still's disease: case report and review of the literature.

Here, we present a 22-year-old female patient with adult-onset Still's disease (AOSD) who was newly diagnosed in the setting of secondary macrophage activation syndrome (MAS), a rare, life-threatening inflammatory disease with 50% mortality due to multi-organ failure. She met the diagnostic criteria of AOSD and MAS, while genetic testing excluded primary causes of MAS. She had high fevers, anemia, thrombocytopenia, splenomegaly, hematophagocytosis, and elevated serum ferritin (37,950 ng/mL) and CD25 levels (11,870 pg/mL), which remained unresponsive to corticosteroids and anakinra. Her serum interferon gamma (IFN-γ) levels were elevated (7 pg/mL). She was markedly responsive to IFN-γ blockade with emapalumab that eliminated her fevers and all MAS-associated laboratory abnormalities. This report provides initial evidence for therapeutic efficacy for IFN-γ blockade in AOSD and secondary MAS.

Light microscopic methods to visualize mitochondria on tissue sections.

Mitochondria are cytoplasmic, double-membrane organelles, a main role of which is to synthesize ATP, the universal energy 'supply' of cells. In the last three decades, molecular genetic, biochemical, immunological and cell biological techniques have been applied in a coordinated fashion to unveil the pathogenesis of known mitochondrial disorders, as well as to explore the role of mitochondria in aging and neurodegenerative diseases. Once to be thought to be rare, it is now clear that mitochondrial dysfunction is an important cause of neurological and cardiac diseases, and age-related disorders such as cancer. Here, we review, illustrate, and provide updated protocols of two histochemical, and three immunohistochemical methods that in our opinion are the most reliable tools to visualize mitochondria on tissue sections from normal and disease specimens.

Fever as the Sole Presentation of Giant Cell Arteritis: A Near Miss.

Giant cell arteritis (GCA) presenting solely as fever is very rare. Usually, it manifests with typical features such as visual problems, headache, jaw claudication, or it can be associated with polymyalgia rheumatica. We present a case of a patient with GCA who presented only with prolonged fever. The cause of fever could not be initially identified in spite of a comprehensive workup. The patient was started on steroids for presumed GCA resulting in the resolution of fever. It is of paramount importance to consider GCA in the differential diagnosis of fever of unknown origin. Early diagnosis with effective treatment is crucial since the mortality rate remains high for untreated cases.

Ureteroscopic Excision of Distal Ureteral Endometriosis.

Background: Endometriosis is the presence of endometrial tissue outside the uterus. Involvement of the urinary tract is uncommon; however, ureteral endometriosis (UE) is even more unusual. Most patients are clinically asymptomatic, which may lead to silent renal loss secondary to obstructive urinary tract endometriosis. Only a few cases of intrinsic UE treated by endoscopic excision have been reported. Case Presentation: We report a case of a 40-year-old woman with chronic right flank pain, with a right distal ureteral obstructive lesion. Ureteroscopy identified a lesion and ureteroscopic resection was performed. Histologic analysis revealed intrinsic UE. Conclusion: Ureteroscopic excision of intrinsic UE is a feasible option for treatment as we have shown in this case.

Association of common mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus.

Mitochondrial dysfunction has been implicated in the pathogenesis of multiple sclerosis (MS) and systemic lupus erythematosus (SLE). This study re-investigates the roles of previously suggested candidate genes of energy metabolism (Complex I genes located in the nucleus and in the mitochondria) in patients with MS relative to ethnically matched SLE patients and healthy controls. After stringent correction for multiple testing, we reproduce the association of the mitochondrial (mt)DNA haplotype K* with MS, but reject the importance of previously suggested borderline associations with nuclear genes of Complex I. In addition, we detect the association of common variants of the mitochondrial ND2 and ATP6 genes with both MS and SLE, which raises the possibility of a shared mitochondrial genetic background of these two autoimmune diseases.

The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases.

BACKGROUND: The number of molecular causes of MELAS (a syndrome consisting of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) and Leigh syndrome (LS) has steadily increased. Among these, mutations in the ND5 gene (OMIM 516005) of mitochondrial DNA are important, and the A13513A change has emerged as a hotspot. OBJECTIVE: To describe the clinical features, muscle pathological and biochemical characteristics, and molecular study findings of 12 patients harboring the G13513A mutation in the ND5 gene of mitochondrial DNA compared with 14 previously described patients with the same mutation. DESIGN: Clinical examinations and morphological, biochemical, and molecular analyses. SETTING: Tertiary care university hospital and molecular diagnostic laboratory. PATIENTS: Three patients had the typical syndrome features of MELAS; the other 9 had typical clinical and radiological features of LS. RESULTS: Family history suggested maternal inheritance in a few cases; morphological studies of muscle samples rarely showed typical ragged-red fibers and more often exhibited strongly succinate dehydrogenase-reactive blood vessels. Biochemically, complex I deficiency was inconsistent and generally mild. The mutation load was relatively high in the muscle and blood specimens. CONCLUSION: The G13513A mutation is a common cause of MELAS and LS, even in the absence of obvious maternal inheritance, pathological findings in muscle, or severe complex I deficiency.