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Severe impairment of an artery with marked intimal fibrosis leading to narrowing of the lumen. (1). Small arteries (2) have hyaline deposits (PAS stain)
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MELAS syndrome (MIM ID#540000), an acronym for Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with protean manifestations and occasional kidney involvement. Interest in the latter is rising due to the identification of cases with predominant kidney involvement and to the...
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MELAS syndrome, which is known with the acronym of myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, is a progressive neurodegenerative disorder characterized by acute neurological episodes resembling strokes associated with lactic acidosis and mitochondrial myopathy. Before the acronym was given, similar patients have been descr...
Mitochondrial disease was a clinically and genetically heterogeneous group of diseases, thus the diagnosis was very difficult to clinicians. Our objective was to analyze clinical and genetic characteristics of children with mitochondrial disease in China. We tested 141 candidate patients who have been suspected of mitochondrial disorders by using t...
Citations
... In addition to hypertrophic cardiomyopathy, cardiac manifestations can encompass preexcitation pattern with short PR intervals and delta waves (Wolff-Parkinson-White), sick sinus syndrome and atrioventricular block [53]. Kidney involvement with nephrotic proteinuria, renal insufficiency, renal tubular acidosis/dysfunction, focal segmental glomerulosclerosis and mitochondrial abnormalities in podocytes/tubular cells is also possible [54]. Gastrointestinal manifestations like intestinal pseudo-obstruction, diarrhea, constipation, failure to thrive and gastric dysmotility have also observed [55]. ...
Mitochondrial diseases are the most common inheritable metabolic diseases, due to defects in oxidative phosphorylation. They are caused by mutations of nuclear or mitochondrial DNA in genes involved in mitochondrial function. The peculiarity of “mitochondrial DNA genetics rules” in part explains the marked phenotypic variability, the complexity of genotype-phenotype correlations and the challenge of genetic counseling. The new massive genetic sequencing technologies have changed the diagnostic approach, enhancing mitochondrial DNA-related syndromes diagnosis and often avoiding the need of a tissue biopsy.
Here we present the most common phenotypes associated with a mitochondrial DNA mutation with the recent advances in diagnosis and in therapeutic perspectives.
... Renal involvement in MELAS is frequent and renal disease has been clinically evident prior to mitochondrial disorder diagnosis [40,41,43e45]. Chronic renal failure with FSGS has been suggested to be a typical manifestation of MELAS [46e53] and likely tied to kidney cancer [54,55]. RMND1-related mitochondrial disease, a nuclear-encoded gene involved in translation of mtDNAencoded peptides, has clinically significant renal disease in 66% of patients [56], with mutations identified as a biallelic pathogenic variant [57e59] in which many patients progressed to end-stage renal disease [56]. ...
The kidney is one of the most metabolically active organs and contains several different cell types that work in varied and dynamic macro- and microenvironments. This high compartmentalization reflects the organ's structural characteristics, which are dictated by the important functions of blood filtration, electrolyte regulation, and fluid balance. As a result, energy demands within different renal cells are extremely tailored to the specific cellular functions. Cellular energy demands are largely met by mitochondria and, as such, the mitochondrion is uniquely intertwined with kidney function. This organelle is the powerhouse of the cell, and it provides for the high demand of adenosine triphosphate in the kidney, but it has become increasingly apparent that energy production is only one of the many important functions that the mitochondria play within different renal cells. Placement of mitochondria as the central hub of a multitude of cellular processes underlies why there has been so much current interest in this organelle's role in health and disease. Indeed, mitochondrial dysfunction is associated with almost all types of kidney diseases and is a growing area of current research. In this chapter, we attempt to cover this very broad topic by highlighting the most recent findings describing the role of mitochondria in kidney homeostasis and disease condition. In particular, we describe how mitochondria are distributed in the kidney and influence cellular specification, as well as the different functions within specific renal cell types. Additionally, we describe the main process regulating mitochondrial homeostasis, including mitochondrial biogenesis, dynamics, trafficking, and disposal, and how these processes may be involved in the initiation and progression of kidney diseases. Lastly, we have mentioned how noncoding RNA molecules and one-carbon metabolism may impact mitochondria.
... Genetic workup revealed the variant m.617G>A in tRNA(Phe) [19]. In a 41-year-old male with MELAS due to the variant m.3243A>G, diabetes, and kidney cancer, histological workup of the resected kidney revealed widespread interstitial fibrosis and prominent vascular lesions, with the vessel displaying marked intimal fibrosis, and arterioles with hyaline deposits typical of hyaline arteriolosclerosis [20]. In an autopsy study of two brothers with hypoacusis, diabetes, progressive photomyoclonic epilepsy, and progressive renal insufficiency, after death in their thirties, biochemical investigations of the muscle revealed a combined complex-III and complex-IV defect [21]. ...
One of the systems that are potentially affected in mitochondrial disorders, but hardly get systematically investigated, are the arteries. One of the phenotypic manifestations in arteries is atherosclerosis. This review focuses on the current knowledge and recent advances of mitochondrial atherosclerosis. We conducted a systematic literature review via PubMed using appropriate search terms.
Atherosclerosis in mitochondrial disorders may result from a primary pathomechanism or a secondary one due to mitochondrial diabetes, arterial hypertension, or hyperlipidemia. Anecdotal reports show that primary atherosclerosis can be a phenotypic feature of mitochondrial disorders. Predominantly, patients carrying mutations in mtDNA-located genes may develop primary mitochondrial atherosclerosis. Though not systematically investigated, it is conceivable that primary mitochondrial atherosclerosis results from increased oxidative stress, mitophagy, metabolic breakdown, or lactic acidosis. Mitochondrial disorder patients with primary mitochondrial atherosclerosis should receive not only antithrombotic medication but also antioxidants and cofactors.
Atherosclerosis in mitochondrial disorders may occur even in the absence of classical atherosclerosis risk factors, suggesting that atherosclerosis can be a primary manifestation of the metabolic defect. Though primary atherosclerosis in mitochondrial disorders has not been systematically investigated, anecdotal data indicate that mitochondrial dysfunction can be a mechanism for the development of primary, mitochondrial atherosclerosis. These patients require antioxidants and cofactors in addition to antithrombotic medication.
... Despite the mitochondrial genome being widely ignored in relation to CKD, a number of studies have identified mitochondrial genomic loci associated with specific forms of renal disease (Table 1). SNPs within MT-HV2, MT-CO1, and MT-CO2c have been associated with IgAN (Douglas et al., 2014); the A3243G point mutation in the leucine UUR tRNA gene (MT-TL1) was identified in patients with FSGS (Jansen et al., 1997;Kurogouchi et al., 1998;Nakamura et al., 1999;Doleris et al., 2000;Hotta et al., 2001;Hirano et al., 2002;Guéry et al., 2003), other forms of renal disease (Guéry et al., 2003) and in a male with a history of MELAS syndrome including kidney cancer, who rapidly developed renal failure after removal of the cancerous kidney (Piccoli et al., 2012). In general, mtDNA biomarkers have not been considered as potential biomarkers in association studies, therefore most findings concerning the mitochondrial genome in relation to CKD come from case reports. ...
Chronic kidney disease (CKD) is a major global health problem with an increasing prevalence partly driven by aging population structure. Both genomic and environmental factors contribute to this complex heterogeneous disease. CKD heritability is estimated to be high (30–75%). Genome-wide association studies (GWAS) and GWAS meta-analyses have identified several genetic loci associated with CKD, including variants in UMOD, SHROOM3, solute carriers, and E3 ubiquitin ligases. However, these genetic markers do not account for all the susceptibility to CKD, and the causal pathways remain incompletely understood; other factors must be contributing to the missing heritability. Less investigated biological factors such as telomere length; mitochondrial proteins, encoded by nuclear genes or specific mitochondrial DNA (mtDNA) encoded genes; structural variants, such as copy number variants (CNVs), insertions, deletions, inversions and translocations are poorly covered and may explain some of the missing heritability. The sex chromosomes, often excluded from GWAS studies, may also help explain gender imbalances in CKD. In this review, we outline recent findings on molecular biomarkers for CKD (telomeres, CNVs, mtDNA variants, sex chromosomes) that typically have received less attention than gene polymorphisms. Shorter telomere length has been associated with renal dysfunction and CKD progression, however, most publications report small numbers of subjects with conflicting findings. CNVs have been linked to congenital anomalies of the kidney and urinary tract, posterior urethral valves, nephronophthisis and immunoglobulin A nephropathy. Information on mtDNA biomarkers for CKD comes primarily from case reports, therefore the data are scarce and diverse. The most consistent finding is the A3243G mutation in the MT-TL1 gene, mainly associated with focal segmental glomerulosclerosis. Only one GWAS has found associations between X-chromosome and renal function (rs12845465 and rs5987107). No loci in the Y-chromosome have reached genome-wide significance. In conclusion, despite the efforts to find the genetic basis of CKD, it remains challenging to explain all of the heritability with currently available methods and datasets. Although additional biomarkers have been investigated in less common suspects such as telomeres, CNVs, mtDNA and sex chromosomes, hidden heritability in CKD remains elusive, and more comprehensive approaches, particularly through the integration of multiple –“omics” data, are needed.
... In previous literature, patients were misdiagnosed with Alport syndrome although they did not have haematuria [21]. In patients with the m.3243A>G mutation, steroid treatment for proteinuria or nephrotic syndrome is ineffective and may induce or progress the development of myopathy and diabetes [9,17,22]. This may be due to the fact that symptoms are caused by mitochondrial alterations and nephron loss of vascular origin. ...
... Hirano et al. [29] detected FSGS in 9 of 16 (56%) patients. But the spectrum of possible lesions is more variable, including tubulointerstitial nephropathy, bilateral enlarged cystic kidneys [17], chronic interstitial nephritis [29], IgA nephropathy [30], neoplasm [22], cystic renal disease [31] and chronic ischaemia in one patient from our own case series. ...
Background:
Renal involvement in patients with the m.3243A>G mutation may result in end-stage renal disease (ESRD) requiring renal replacement therapy. Although kidney transplantations have been performed in a small number of patients, short- and long-term follow-up data are lacking.
Methods:
We describe five patients with the m.3243A<G mutation who received a kidney transplant, including follow-up data up to 13 years. We also summarize all cases (n = 13) of kidney transplantation in m.3243A>G carriers described in the literature.
Results:
Proteinuria with or without renal failure was the first clinical presentation of renal involvement in 13 of 18 (72%) patients. Focal segmental glomerulosclerosis (FSGS) was found in 9 of 13 (69%) biopsies. Sixteen of 18 (84%) patients developed hearing loss. All patients were diagnosed with diabetes mellitus, of whom eight (44%) developed the disease after transplantation. All patients with reported follow-up data (13/18) had stable kidney function from 6 months to 13 years of follow-up after transplantation.
Conclusions:
Renal involvement in carriers of the m.3243A>G mutation most commonly leads to proteinuria and FSGS and may lead to ESRD. Proper recognition of the mitochondrial origin of the renal disease in these patients is important for adequate treatment selection and suitable supportive care. This case series and review of the available literature on long-term follow-up after kidney transplantation shows it is feasible for non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype carriers of the m.3243A>G mutation to be considered for kidney transplantation in case of ESRD. These patients should not be excluded from transplant solely for their mitochondrial diagnosis.
... The kidney disease associated with MELAS syndrome is protean and may involve at a different degree all structures: vascular (infarction, nephroangiosclerosis), interstitial (Fancony syndrome, complex tubular disorders), and glomerular, where the appearance of focal segmental lesions is frequently associated with progressive kidney failure [17][18][19][20]. Different kidney neoplastic diseases may also occur [18]. ...
... The kidney disease associated with MELAS syndrome is protean and may involve at a different degree all structures: vascular (infarction, nephroangiosclerosis), interstitial (Fancony syndrome, complex tubular disorders), and glomerular, where the appearance of focal segmental lesions is frequently associated with progressive kidney failure [17][18][19][20]. Different kidney neoplastic diseases may also occur [18]. ...
Pregnancy is a challenge in the life of a woman with chronic kidney disease (CKD), but also represents an occasion for physicians to make or reconsider diagnosis of kidney disease. Counselling is particularly challenging in cases in which a genetic disease with a heterogeneous and unpredictable phenotype is discovered in pregnancy. The case reported regards a young woman with Stage-4 CKD, in which “Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes” (MELAS syndrome), was diagnosed during an unplanned pregnancy. A 31-year-old Caucasian woman, being followed for Stage-4 CKD, sought her nephrologist’s advice at the start of an unplanned pregnancy. Her most recent data included serum creatinine 2–2.2 mg/dL, Blood urea nitrogen (BUN) 50 mg/dL, creatinine clearance 20–25 mL/min, proteinuria at about 2 g/day, and mild hypertension which was well controlled by angiotensin-converting enzyme inhibitors (ACEi); her body mass index (BMI) was 21 kg/m2 (height 152 cm, weight 47.5 kg). Her medical history was characterized by non-insulin-dependent diabetes mellitus (at the age of 25), Hashimoto’s thyroiditis, and focal segmental glomerulosclerosis. The patient’s mother was diabetic and had mild CKD. Mild hearing impairment and cardiac hypertrophy were also detected, thus leading to suspect a mitochondrial disease (i.e., MELAS syndrome), subsequently confirmed by genetic analysis. The presence of advanced CKD, hypertension, and proteinuria is associated with a high, but difficult to quantify, risk of preterm delivery and progression of kidney damage in the mother; MELAS syndrome is per se associated with an increased risk of preeclampsia. Preterm delivery, associated with neurological impairment and low nephron number can worsen the prognosis of MELAS in an unpredictable way. This case underlines the importance of pregnancy as an occasion to detect CKD and reconsider diagnosis. It also suggests that mitochondrial disorders should be considered in the differential diagnosis of kidney impairment in patients who display an array of other signs and symptoms, mainly type-2 diabetes, kidney disease, and vascular problems, and highlights the difficulties encountered in counselling and the need for further studies on CKD in pregnancy.
... Also overlooked sometimes are mitochondrial DNA mutations reported in cases of FSGS [e.g. [35][36][37][38][39], and glycogen storage diseases said to cause FSGS [40,41]. ...
... Another reason why this is important is related to understanding of the pathogenesis of segmental lesions. A few papers reporting mitochondrial DNA mutations have shown that the lesions in affected glomeruli are at the vascular pole or hilum and are associated with abnormalities of arterioles [35][36][37]39]. Although this does not explain how the lesions develop, it suggests where research could concentrate to find out the pathogenesis. ...
Many genetic causes of focal segmental glomerulosclerosis (FSGS) have been described. A paradox is that the science in the molecular biology, which generally appears of high quality, is not mirrored by a similarly critical analysis of the renal pathology. FSGS has been applied to such a wide range of conditions that it can reasonably be said to have no useful meaning. Attempts to refine the term have been largely ignored. Study of 252 papers on genetic causes of FSGS found various clinical features. Many papers took the reported diagnosis without question. Few papers reported a pathological review, almost half reported FSGS and up to six other conditions caused by any particular gene, some reported FSGS with recognisable glomerular disorders, over 80% did not apply the Columbia classification, and in nearly all with photomicrographs, the images were not useful for refinement of FSGS. Some workers commented on a lack of genotype-phenotype correlation. One reason is a disregard of the principle that scientific investigation requires an unambiguous definition of the condition studied, to allow others to replicate or refute the findings. Genetic studies of FSGS should use a similarly rigorous approach to renal pathology to that used in molecular biology.
... Chronic renal failure appears to be a typical manifestation of MELAS (22) and FSGS may be the dominant feature in these patients (23). Kidney cancer was reported in a 41-year-old male who was exhibiting MELAS syndrome (24). A histological work-up additionally revealed arteriolonephrosclerosis (24) and renal cell carcinoma was reported in a 2-year-old male with MELAS syndrome (25). ...
... Kidney cancer was reported in a 41-year-old male who was exhibiting MELAS syndrome (24). A histological work-up additionally revealed arteriolonephrosclerosis (24) and renal cell carcinoma was reported in a 2-year-old male with MELAS syndrome (25). ...
... Today, his symptoms have been widely thought to be secondary to a form of mitochondrial disease (MD) called MELAS syndrome that includes mitochondrial encephalopathy, lactic acidosis, and strokelike episodes. MELAS syndrome is associated in ~ 80% of cases with a mitochondrial gene mutation at position m.3243A>G [2]. Primary MDs are complex, heterogeneous inherited diseases and they can be caused by mutations in either the mitochondrial or nuclear DNA. ...
Primary mitochondrial diseases (MD) are complex, heterogeneous inherited diseases caused by mutations in either the mitochondrial or nuclear DNA. Glomerular diseases in MD have been reported with tRNA mutation m.3243A>G causing a syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). We describe here a case of focal segmental glomerulosclerosis (FSGS) associated with a new tRNA mutation site. A 34-year-old man with a history of living related kidney transplantation, diabetes, hearing loss, and developmental delay presented to the outpatient clinic with complaints of new behavioral difficulties, worsening symptoms, and brain involvement on imaging. Physical examination was remarkable for difficulty hearing, a pattern of dysarthric speech, and cerebellar gait. Laboratory investigations including lactate levels were unremarkable. Based on this set of clinical circumstances, concern for an underlying genetic abnormality was raised. Multiple metabolic tests were unremarkable. Whole exome sequencing revealed a mitochondrial MT-TW tRNA change at position m.5538G>A. Genotype-phenotype correlations are consistent with this tRNA mutation as a cause of his symptoms. To the best of our knowledge, this is the first case describing FSGS-associated MD caused by an m.5538 G>A mutation. Consideration of an underlying MD should be made in patients presenting with deafness, neurologic changes, diabetes, and renal failure.
... In some reports by our group, we described kidney disease in diabetic patients not characterized by proteinuria. These cases encompassed various conditions including metabolic derangements, genetic syndromes, and "primary" nephroangiosclerosis [182][183][184][185]. In a recent series of pregnant patients with "severe" kidney disease and type 1 diabetes, median proteinuria was 1.6 g/day at the start of pregnancy or at referral. ...
Low-protein diets (LPDs) are often considered as contraindicated in diabetic patients, and are seldom studied. The aim of this observational study was to provide new data on this issue. It involved 149 diabetic and 300 non-diabetic patients who followed a LPD, with a personalized approach aimed at moderate protein restriction (0.6 g/day). Survival analysis was performed according to Kaplan–Meier, and multivariate analysis with Cox model. Diabetic versus non-diabetic patients were of similar age (median 70 years) and creatinine levels at the start of the diet (2.78 mg/dL vs. 2.80 mg/dL). There was higher prevalence of nephrotic proteinuria in diabetic patients (27.52% vs. 13.67%, p = 0.002) as well as comorbidity (median Charlson index 8 vs. 6 p = 0.002). Patient survival was lower in diabetic patients, but differences levelled off considering only cases with Charlson index > 7, the only relevant covariate in Cox analysis. Dialysis-free survival was superimposable in the setting of good compliance (Mitch formula: 0.47 g/kg/day in both groups): about 50% of the cases remained dialysis-free 2 years after the first finding of e-GFR (estimated glomerular filtration rate) < 15 mL/min, and 1 year after reaching e-GFR < 10 mL/min. In patients with type 2 diabetes, higher proteinuria was associated with mortality and initiation of dialysis. In conclusion, moderately restricted LPDs allow similar results in diabetic and non non-diabetic patients with similar comorbidity.
