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Kidney involvement in MELAS syndrome: Description of 2 cases
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Clinical report
Kidney involvement in MELAS syndrome: Description of 2 cases夽 Pau Alcubilla-Prats a , Manel Solé b , Albert Botey a , Josep Maria Grau c,d , Glòria Garrabou d,e , Esteban Poch a,∗ a
Servei de Nefrologia i Trasplantament Renal, Hospital Clínic, Universidad de Barcelona, Barcelona, Spain Servei de Anatomia Patològica, Hospital Clínic, Universidad de Barcelona, Barcelona, Spain Servei de Medicina Interna, Hospital Clínic, Universidad de Barcelona, Barcelona, Spain d Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Hospital Clínic, Universidad de Barcelona, Barcelona, Spain e Cellex, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universidad de Barcelona, Barcelona, Spain b
c
a r t i c l e
i n f o
Article history: Received 14 October 2016 Accepted 19 January 2017 Available online xxx Keywords: A3243G mutation Mitochondrial cythopathy Focal segmental glomerulosclerosis Chronic kidney disease
a b s t r a c t Introduction: MELAS syndrome – myopathy, encephalopathy, lactic acidosis and stroke-like episodes – is a maternally-inherited mitochondrial cytopathy related to several mitochondrial DNA mutations, with the A3243G mutation in tRNALeu gene being the most frequent of them. Patients and methods: Apart from its typical symptomatology, patients usually exhibit a maternallyinherited history of neurosensory deafness and insulin-dependent type 2 diabetes mellitus (T2DM). Recent studies have shown that few patients carrying a A3243G mutation also suffer from renal dysfunction, usually in form of focal segmental glomerulosclerosis (FSGS). Results: In this study we examine kidney involvement in 2 unrelated patients with a A3243G mutation by genetic testing. Both have a maternally-inherited neurosensory deafness and insulin-dependent T2DM. A renal biopsy was performed in both patients. One patient developed nephrotic proteinuria and renal insufficiency, with FSGS findings being observed in the kidney biopsy, whereas the other suffered from mild proteinuria and renal insufficiency, with non-specific glomerular changes. Conclusion: The presence of FSGS or other kidney involvement accompanied by hereditary neurosensory deafness and T2DM could be suggestive of a A3243G tRNALeu mutation and should prompt a genetic testing and an evaluation of potential extrarenal involvement. ˜ S.L.U. All rights reserved. © 2017 Elsevier Espana,
Afección renal en el síndrome de MELAS: descripción de 2 casos r e s u m e n Palabras clave: Mutación A3243G Citopatía mitocondrial Glomeruloesclerosis focal segmentaria Insuficiencia renal crónica
Introducción: El síndrome MELAS –miopatía, encefalopatía, acidosis láctica y episodios similares a ictus – es una citopatía mitocondrial relacionada con varias mutaciones del ADN mitocondrial, siendo la substitución A3243G en el gen tARNLeu la más frecuentemente asociada. Pacientes y métodos: Aparte de su sintomatología habitual, los pacientes presentan historia de sordera neurosensorial y diabetes tipo 2 (DM2). Además, estudios recientes muestran que algunos pacientes tienen también afección renal, normalmente en forma de glomeruloesclerosis focal y segmentaria (GFS). Resultados: En este artículo se discute la afección renal de 2 pacientes no emparentados portadores de la mutación A3243G. Los 2 presentan sordera neurosensorial y DM2. Se realizó estudio anatomopatológico en ambos. Uno de ellos desarrolló proteinuria en rango nefrótico e insuficiencia renal terminal, con cambios de GFS en la biopsia, mientras que el otro presentaba proteinuria leve e insuficiencia renal, sin ˜ cambios histológicos resenables en la microscopia óptica. ˜ Conclusión: La presencia de GFS u otra afección glomerular o tubular renal, acompanada de sordera neurosensorial y DM2, podría ser indicativa de la existencia de la mutación A3243G y estos hallazgos deberían propiciar un estudio genético y una evaluación de posible afección extrarrenal. ˜ S.L.U. Todos los derechos reservados. © 2017 Elsevier Espana,
夽 Please cite this article as: Alcubilla-Prats P, Solé M, Botey A, Grau JM, Garrabou G, Poch E. Afección renal en el síndrome de MELAS: descripción de 2 casos. Med Clin (Barc). 2017. http://dx.doi.org/10.1016/j.medcli.2017.01.029 ∗ Corresponding author. E-mail address: [email protected] (E. Poch). ˜ S.L.U. All rights reserved. 2387-0206/© 2017 Elsevier Espana,
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Introduction The myopathy, encephalopathy, lactic acidosis and stroke-like syndrome (MELAS) is one of the most frequent mitochondrial cytopathies. Although the structure and function of the mitochondrial DNA (mtDNA) were described over 40 years ago, the first pathogenic mutations were not identified until 1988. At least 30 of them have been associated with MELAS, with the A3243G tARNLeu mutation being the most common (80%).1 A wide variety of different mitochondrial cytopathies associated with point mutations that affect mtDNA genes encoding tRNA have been described.2 Although rare, kidney involvement has been described within the MELAS spectrum in various case series. It seems that the most common occurrence is focal segmental glomerulosclerosis (FSGS), although other injuries have been described. This article describes kidney involvement and complications of two unrelated patients, A3243G mutation carriers detected by genetic testing.
Case 1 60-year-old woman with no allergies or toxic habits, which was referred to the Nephrology Department due to the incidental finding of 1.49 mg/dl of serum creatinine during a systematic blood test. Worth noting as medical history, she was diagnosed at age 36 of diabetes mellitus type 2 (DM2), which was first treated with oral antidiabetics during 8 years, progressing to insulin treatment afterwards. Glycaemic control was correct, with HbA1c between 5.4 and 6.5%. Eye fundus revealed signs of diabetic retinopathy and no evidence of any microvascular disorder or target organs. Sensorineural deafness of unknown aetiology was also diagnosed before she was 25 years of age. Eight years earlier, she was diagnosed with melanoma located on his right knee, currently being free from disease. The patient denied a family history of DM2 or sensorineural deafness. On examination, her weight was 45 kg and height 152 cm, with a BMI of 19 kg/m2 . Blood pressure was 111/72 mmHg, heart rate 56 bpm and physical examination by systems showed no significant findings. Serum creatinine was 1.5 mg/dl, with an estimated glomerular filtration rate of 33 ml/min/m2 and BUN of 39 mg/dl; venous balance showed no metabolic acidosis and serum electrolytes were normal. Hemogram, liver function tests, serum lipids, creatinine kinase (CK) and serum uric acid were within normal limits. Urine tests showed no haematuria or proteinuria. Renal ultrasound showed a mild cortical reduction and several small cortical cysts. Although the patient had no family history of sensorineural deafness or DM2, and showed no obvious symptoms of mitochondrial cytopathy (i.e., lactic acidosis, exercise intolerance or myopathy or neurological symptoms), a mitochondrial disease was suspected. Genetic testing in urine confirmed a A3243G mutation with 29% of heteroplasmy. During follow-up, creatinine levels remained stable and urine sediment and proteinuria remained normal. Although a renal biopsy was proposed, the patient refused. Three years after the first visit, the patient reported increased fatigue and general weakness and exercise intolerance. Blood tests showed CK 2819 U/L, LDH 1571 U/l and aldolase 31.7 U/l (normal range between 0.3 and 6 U/l). Difficulty in speech and bilateral ptosis was observed on physical examination, along with a mild generalized loss of muscle strength (4/5). Her cognitive function was normal. The patient underwent a muscle biopsy, which showed unmistakable signs of mitochondrial myopathy (Fig. 1). In subsequent lab tests, CK, LDH and aldolase were normalized, despite the persistence of symptoms. No specific treatment was not considered, except physical therapy and aerobic exercise. Subsequently, a slight increase in serum creatinine was observed (1.6 mg/dl) and a kidney biopsy was performed in order to further study the incipient
Fig. 1. Muscle biopsy of patient 1 (modified Gomori trichrome staining for frozen tissue). Several typical “ragged red” fibres (black arrows) are observed, as well as nuclei inside some fibres and variability in the size of these. All this is consistent with mitochondrial myopathy.
renal failure in the context of a MELAS syndrome. Light microscopy showed nonspecific glomerular and interstitial changes. However, ultrastructural examination by electron microscopy revealed a focal effacement of the podocyte’s foot processes and abnormal mitochondria, many of them within the foot processes (Fig. 2). Five years after the first visit, the patient developed dysphagia and abnormal gait. Although a mild albuminuria of 300 mg/g of creatinine was detected at that time, renal function remained stable.
Case 2 30-year-old male patient with no allergies or toxic habits, is visited in the Nephrology Department due to a finding of proteinuria of 3.15 g in 24 h urine and serum creatinine of 1.5 mg/dl. Noteworthy within the family history is the death of his mother due to diabetic coma. No history of sensorineural deafness. An episode of rhabdomyolysis at the age of 12 accompanied by acute renal failure after spending 8 h walking is also part of the patient’s past medical history. He spent 30 days in hospital and received 20 sessions of haemodialysis. Renal function was completely recovered after the episode. His weight was 68 kg and its height was 170 cm; BMI of 23 kg/m2 . The physical examination was normal except for mild hypertension, properly controlled with ACE inhibitors, and mild unilateral sensorineural deafness diagnosed by audiometric tests, which remained stable. No haematuria was detected. The amount of proteinuria was reduced to levels between 1.5 and 2.5 g/24 h after treatment with ACE inhibitors without hypoalbuminemia, hyperlipidaemia or oedema. Because of the degree of proteinuria, the patient underwent renal biopsy which showed typical findings of FSGS with presence of C3 and IgM +++ (Fig. 3). At follow up, the patient progressively developed exercise intolerance, limb weakness and fatigue, along with abnormal muscle enzymes, which increased slightly at first (CK 3.47 U/l; LDH 506 U/l), and then progressively over time, at levels of 2308 U/l CK and 2324 U/l LDH, with worsening of symptoms. The electromyographic study found no abnormalities, but a muscle biopsy showed several “ragged red” type muscle cells, some with lipid depositions, very indicative of mitochondrial myopathy. A urine genetic analysis showed a A3243G mutation with 32% of heteroplasmy. In order to further study organ involvement, the patient underwent an echocardiogram, which showed no morphological abnormalities, with an
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Fig. 2. Electron microscope image taken from patient 1 biopsy. A. Focal foot-process effacement, with abnormal mitochondria, specific finding of the A3243G mutation. B. The black arrow points to abnormal mitochondria found in the podocyte cytoplasm, with some ridge distortion.
Fig. 3. Patient 2 biopsy images (haematoxylin/eosin). Several sclerotic glomeruli (A, black arrow) are observed. Typical FSGS changes can also be observed in these glomeruli. Segmental collapse with sclerosis is observed in the upper half (B, black arrow).
LVEF of 54%. A cranial MRI showed significant brain atrophy, with enlarged ventricles. At that time, the patient was diagnosed of DM2 with hyperinsulinemia, with a HbA1c of 8.8%, without retinopathy. Initially, the patient responded well to oral antidiabetic agents. However, glycaemic control was inadequate at follow-up, with HbA1c reaching 11.1%, at which time insulin treatment was introduced. During follow-up, proteinuria was barely controlled, with values between 2 and 5 g/24 h, despite optimal blood pressure control. Renal function was gradually reduced, reaching end stage renal disease 15 years later, when haemodialysis was started.
Discussion Kidney involvement is rare in the spectrum of the A3243G mutation. Common symptoms associated with this mutation include: exercise intolerance (93%),1 deafness (44–77%),1,2 myopathy and limb weakness (37–53%),2,3 DM2 (12–33%),1–3 symptoms onset in adulthood (40%)3 and family history of MELAS in less than 20%.3 The prevalence of this mutation in patients with renal disease has been reported on numerous occasions, although with controversial results.4,5 Further studies involving more patients from different ethnic groups would be required to establish an accurate incidence and prevalence of this mutation in patients with chronic kidney disease. In the general population, the presence of the A3243G mutation has been estimated between 16.3 and 236/100,000.6–9
Nowadays, it is widely accepted that mitochondrial cytopathies are the most common metabolic diseases in humans.1 The most common renal manifestation in mitochondrial cytopathies is the Toni-Debre-Fanconi syndrome (particularly in children), a proximal tubule dysfunction characterized by impaired reabsorption of glucose, amino acids, phosphate and bicarbonate, leading to a subsequent glycosuria, aminoaciduria, hyperphosphaturia and proximal tubular acidosis.10 None of the patients studied showed signs of Fanconi syndrome. In MELAS, the most common renal abnormalities found in adulthood is FSGS, a non-proliferative glomerulonephritis characterized by partial glomerular sclerosis, affecting only some glomeruli (focal), and among those affected, only some capillaries show pathologic changes (segmental).2 In our case series, both patients were biopsied. Patient 1 showed unspecific changes in light microscopy, and presence of abnormal mitochondria in podocytes in electron microscopy. The discovery of mitochondria within the foot processes of podocytes is proposed as pathognomonic of MELAS.11 Patient 2 showed typical FSGS changes in light microscopy. No electron microscopy techniques were performed in this patient. Both patients were diagnosed of DM2 at an early age. None of the patients were overweight. The presence of DM2 in atypical patients, especially with a family history, is very indicative of an underlying cause. This high prevalence of DM2 patients with renal disease in MELAS has already been reported,11 which points towards a possible pathophysiological relationship. Although Patient 1 was
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Table 1 Summary of the pathological findings in patients with mutations in mitochondrial DNA and renal involvement reported in the literature. StudyRef
Histological findings
FSGS
Jansen et al. (1997)12 (n = 581) Kurogouchi et al. (1998)14 (n = 1) Nakamura et al. (1999)15 (n = 1) Cheong et al. (1999)16 (n = 1) Doleris et al. (2000)17 (n = 581) Hotta et al. (2001)18 (n = 581) Yanagihara et al. (2001)19 (n = 1) Segawa-Takaeda et al. (2002)20 (n = 1) Yamagata (2002)21 (n = 2) Hirano et al. (2002)22 (n = 13) Maassen et al. (2002)23 (n = 1) Guery et al. (2003)11 (n = 5)
LM: lobular chronic glomerulonephritis (1). Focal glomerulosclerosis (1) EM: focal foot process effacement (1/4) LM: FSGS. Severe tubular atrophy. Interstitial fibrosis EM: abnormal mitochondria LM: FSGS EM: foot process effacement. Mesangial matrix expansion LM: FSGS EM: with no significant changes LM: glomerular hyalinosis. Thickening of perihilar capillaries. Interstitial fibrosis Afferent arteriole injury LM: FSGS, no arteriolar hyalinization EM: abnormal mitochondria in podocytes FSGS: sclerotic glomeruli and atrophic tubules EM: enlarged mitochondria with complex ridges LM: FSGS EM: abnormal mitochondria LM: FSGS and interstitial fibrosis EM: abnormal mitochondria in the glomerular epithelium cytoplasm LM: FSGS (10), chronic interstitial nephritis (1), mild glomerular abnormalities (2)
2/4
10/13
LM: chronic tubulointerstitial nephritis
0/1
LM: arteriolar hyaline thickening (4/5) and fibrous intimal thickening (5/5) EM: enlarged mitochondria with abnormal ridges (1/5). Dysmorphic mitochondria in proximal tubular cells LM: FSGS without mesangial proliferation. Focal tubulointerstitial infiltration and tubular atrophy EM: Diffuse foot process effacement LM: FSGS EM: slightly enlarged mitochondria LM: FSGS EM: foot process effacement. No abnormal mitochondria LM: FSGS EM: irregular and enlarged mitochondria in podocytes and dense depositions in paramesangial lesions LM: interstitial fibrosis. Renal carcinoma. Inflammatory infiltrate. Tubular atrophy
2/5
Löwik et al. (2005)24 (n = 1) Lau et al. (2007)25 (n = 1) Fujii et al. (2008)26 (n = 1) Yamaguchi et al. (2012)27 (n = 1) Piccoli et al. (2012)28 (n = 1) Seidowsky et al. (2013)2 (n = 3) Cavero-Escribano et al. (2014)29 (n = 2) This article (n = 2)
LM: FSGS and arteriolar hyalinization EM: abnormal mitochondria in pedicels (foot processes) (1/3) LM: tubular atrophy, arteriolar hyalinization (1/2). Normal biopsy (1/2) EM: abnormal mitochondria in podocytes (1/2) LM: nonspecific glomerular changes (1/2). FSGS (1/2) EM: abnormal mitochondria in podocytes with altered ridges (1/2)
1/1 1/1 1/1 4/4 4/4 1/1 1/1 2/2
1/1
1/1 1/1 1/1
1/1 3/3 1/2 1/2
FSGS: focal segmental glomerulosclerosis; EM: electron microscopy; LM: light microscopy.
diagnosed with DM2 years earlier, no signs of diabetic nephropathy were observed in the renal biopsy. In patient 2, DM2 was diagnosed after the renal biopsy, but the lack of metabolic control could have influenced the rapid deterioration of renal function. Both patients had some degree of sensorineural deafness. Hearing loss added to renal failure is highly indicative of Alport syndrome, and the differential diagnosis between this entity and mitochondrial cytopathy with kidney involvement should always be taken into account.2 Notably, none of the patients had any episodes resembling a stroke or other neurological symptoms other than deafness episodes, although a significant cerebral atrophy with diffuse increase in ventricular volume was observed in patient 2 by neuroimaging, which could be partly related to changes secondary to mitochondrial involvement in the CNS. Patient 1 only had DM2, deafness and myopathy plus nondiabetic renal disease. This subtype of clinical occurrence is mainly characterized by maternally inherited diabetes and deafness (MIDD) and the absence of other “classic” symptoms of MELAS syndrome, such as lactic acidosis or encephalopathy.12 Although patient 1 had no family history of diabetes and deafness, the clinical occurrence is more indicative of MIDD that of a classic MELAS syndrome. A prospective cohort study of 54 patients with MIDD, carriers of A3243G mutation, showed a significant dissociation between kidney disease and diabetic retinopathy (28 versus 8%), which shows
that a specifically renal involvement is secondary to mitochondrial disease.13 The pathophysiological differences between the classical MELAS syndrome and MIDD are unknown, but they are probably related to heteroplasmy and genetic drift phenomena. As we have seen, there is also variation in the occurrence of renal symptoms. Patient 1 only showed a mild elevation of creatinine levels with sporadic mild albuminuria and a moderate reduction in glomerular filtration rate, while case 2 had exercise-induced rhabdomyolysis during childhood, and, acute renal failure secondary to it. Renal biopsy of patient 1 showed only unspecific changes with light microscopy. Abnormal mitochondria were observed in podocytes with electron microscopy. One can speculate that these abnormal mitochondria found in podocytes could be a sign of possible future cell damage that could lead to the patient developing an established FSGS or a Fanconi syndrome. Table 1 shows the pathological findings in published cases of MELAS syndrome (A3243G mtDNA mutation) with kidney involvement. Of the 50 patients examined previously, 39 (78%) showed histological characteristics of FSGS. The occurrence of abnormal mitochondria in foot processes appears to be significant in electron microscopy findings. The mechanism by which selective damage occurs on foot processes of podocytes is not clear, but may be related to the presence of abnormal mitochondria, with altered apoptosis pathways and/or production of free radicals.
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In conclusion, kidney involvement is variable in patients with the A3243G mutation. The presence of FSGS or another chronic renal condition, accompanied by hereditary sensorineural deafness and DM2 may indicate the presence of the A3243G tARNLeu mutation and, therefore, these findings should lead to genetic testing and extensive evaluation of the potential extrarenal involvement of the same. Conflict of interests The authors declare no conflict of interest. References 1. Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci. 2008;1142:133–58, http://dx.doi.org/10.1196/annals.1444.011. 2. Seidowsky A, Hoffmann M, Glowacki F, Dhaenens CM, Devaux J, de Sainte Foy CL, et al. Renal involvement in MELAS syndrome – a series of 5 cases and review of the literature. Clin Nephrol. 2013;80:456–63, http://dx.doi.org/10.5414/CN107063. 3. Goodfellow JA, Dani K, Stewart W, Santosh C, McLean J, Mulhern S, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people. Postgrad Med J. 2012;88:326–34, http://dx.doi.org/10.1136/postgradmedj-2011-130326. 4. Iwasaki N, Babazono T, Tsuchiya K, Tomonaga O, Suzuki A, Togashi M, et al. Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA Leu (UUR) gene in Japanese patients with diabetes mellitus and end stage renal disease. J Hum Genet. 2001;46:330–4. 5. Koshiyama H, Inagaki N, Seino Y. Low prevalence of mitochondrial DNA 3243A > G point mutation in Caucasians with unexplained renal disease. Diabet Med. 2007;24:804. 6. Chinnery PF, Turnbull DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet. 2001;106:94–101, http://dx.doi.org/10.1002/ajmg.1426. 7. Majamaa K, Moilanen JS, Uimonen S, Remes AM, Salmela PI, Kärppä M, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet. 1998;63:447–54, http://dx.doi.org/10.1086/301959. 8. Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet. 2008;83:254–60, http://dx.doi.org/10.1016/j.ajhg.2008.07.004. 9. Manwaring N, Jones MM, Wang JJ, Rochtchina E, Howard C, Mitchell P, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion. 2007;7:230–3, http://dx.doi.org/10.1016/j.mito.2006.12.004. 10. Emma F, Bertini E, Salviati L, Montini G. Renal involvement in mitochondrial cytopathies. Pediatr Nephrol. 2012;27:539–50, http://dx.doi.org/10.1007/s00467-011-1926-6. 11. Guéry B, Choukroun G, Noël LH, Clavel P, Rötig A, Lebon S, et al. The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J Am Soc Nephrol. 2003;14:2099–108, http://dx.doi.org/10.1097/01.ASN.0000080180.51098.02. 12. Jansen JJ, Maassen JA, van der Woude FJ, Lemmink HA, van den Ouweland JM, t’Hart LM, et al. Mutation in mitochondrial tRNALeu(UUR) gene associated with progressive kidney disease. J Am Soc Nephrol. 1997;8:1118–24.
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13. Guillausseau PJ, Massin P, Dubois-LaForgue D, Timsit J, Virally M, Gin H, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med. 2001;134:721–8. 14. Kurogouchi F, Oguchi T, Mawatari E, Yamaura S, Hora K, Takei M, et al. A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with severe focal-segmental glomerulosclerosis as main clinical manifestation. Am J Nephrol. 1998;18:551–6, http://dx.doi.org/10.1159/000013406. 15. Nakamura S, Yoshinari M, Doi Y, Yoshizumi H, Katafuchi R, Yokomizo Y, et al. Renal complications in patients with diabetes mellitus associated with an A to G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Diabetes Res Clin Pract. 1999;44:183–9, http://dx.doi.org/10.1016/S0168-8227(99)00051-0. 16. Cheong HI, Chae JH, Kim JS, Park HW, Ha IS, Hwang YS, et al. Hereditary glomerulopathy associated with a mitochondrial tRNALeu gene mutation. Pediatr Nephrol. 1999;13:477–80. 17. Doleris LM, Hill GS, Chedin P, Nochy D, Bellanne-Chantelot C, Hanslik T, et al. Focal segmental glomerulosclerosis associated with mitochondrial cytopathy. Kidney Int. 2000;58:1851–8, http://dx.doi.org/10.1046/ j. 1523-1755.2000.00356.x. 18. Hotta O, Inoue CN, Miyabayashi S, Furuta T, Takeuchi A, Taguma Y. Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation. Kidney Int. 2001;59:1236–43. 19. Yanagihara C, Oyama A, Tanaka M, Nakaji K, Nishimura Y. An autopsy case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome with chronic renal failure. Intern Med. 2001;40:5–7. 20. Segawa-Takaeda C, Takeda S, Ieki Y, Takazakura E, Haratake J, Wada T, et al. Focal glomerulosclerosis expanding from the glomerular vascular pole in a Japanese male with mitochondrial-DNA mutation. Nephrol Dial Transplant. 2002;17:172–4. 21. Yamagata K. Mitochondrial DNA mutations in focal segmental glomerulosclerosis lesions. J Am Soc Nephrol. 2002;13:1816–23, http://dx.doi.org/10.1097/01.ASN.0000019772.17954.F8. 22. Hirano M, Konishi K, Arata N, Iyori M, Saruta T. Renal complications in a patient with A-to-G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Intern Med. 2002;41:113–8. 23. Maassen JA, Biberoglu S, t’Hart LM, Bakker E, de Knijff P. A case of a de novo A3243G mutation in mitochondrial DNA in a patient with diabetes and deafness. Arch Physiol Biochem. 2002;110:186–8. 24. Löwik MM, Hol FA, Steenbergen EJ, Wetzels JFM. Mitochondrial tRNA Leu (UUR) mutation in a patient with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2005;20:336–41, http://dx.doi.org/10.1093/ndt/gfh546. 25. Lau KK, Yang SP, Haddad MN, Butani L, Makker SP. Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes syndrome with hypothyroidism and focal segmental glomerulosclerosis in a paediatric patient. Int Urol Nephrol. 2007;39:941–6, http://dx.doi.org/10.1007/s11255-006-9172-8. 26. Fujii H, Mori Y, Kayamori K, Igari T, Ito E, Akashi T, et al. A familial case of mitochondrial disease resembling Alport syndrome. Clin Exp Nephrol. 2008;12:159–63, http://dx.doi.org/10.1007/s10157-007-0022-5. 27. Yamaguchi M, Yuya B, Yasumitsu Y, Yoshinari T. A case of mitochondrial kidney disease with insulin resistance and hypoadiponectinemia. Diabetol Int. 2012;3:54–60, http://dx.doi.org/10.1007/s13340-011-0050-y. 28. Piccoli GB, Bonino LD, Campisi P, Vigotti FN, Ferraresi M, Fassio F, et al. Chronic kidney disease, severe arterial and arteriolar sclerosis and kidney neoplasia: on the spectrum of kidney involvement in MELAS syndrome. BMC Nephrol. 2012;13:9, http://dx.doi.org/10.1186/1471-2369-13-9. 29. Cavero-Escribano T, Molero-Bermejo A, Ramos-Estévez E, Martínez-González MA, Bueno-Antúnez B, Conde-Olasagasti JL, et al. Nefropatía crónica, hipoacusia neurosensorial y diabetes mellitus. NefroPlus. 2014;6:66–9, http://dx.doi.org/10.3265/NefroPlus.pre2013.Sep.12035.
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Clinical report
Kidney involvement in MELAS syndrome: Description of 2 cases夽 Pau Alcubilla-Prats a , Manel Solé b , Albert Botey a , Josep Maria Grau c,d , Glòria Garrabou d,e , Esteban Poch a,∗ a
Servei de Nefrologia i Trasplantament Renal, Hospital Clínic, Universidad de Barcelona, Barcelona, Spain Servei de Anatomia Patològica, Hospital Clínic, Universidad de Barcelona, Barcelona, Spain Servei de Medicina Interna, Hospital Clínic, Universidad de Barcelona, Barcelona, Spain d Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Hospital Clínic, Universidad de Barcelona, Barcelona, Spain e Cellex, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universidad de Barcelona, Barcelona, Spain b
c
a r t i c l e
i n f o
Article history: Received 14 October 2016 Accepted 19 January 2017 Available online xxx Keywords: A3243G mutation Mitochondrial cythopathy Focal segmental glomerulosclerosis Chronic kidney disease
a b s t r a c t Introduction: MELAS syndrome – myopathy, encephalopathy, lactic acidosis and stroke-like episodes – is a maternally-inherited mitochondrial cytopathy related to several mitochondrial DNA mutations, with the A3243G mutation in tRNALeu gene being the most frequent of them. Patients and methods: Apart from its typical symptomatology, patients usually exhibit a maternallyinherited history of neurosensory deafness and insulin-dependent type 2 diabetes mellitus (T2DM). Recent studies have shown that few patients carrying a A3243G mutation also suffer from renal dysfunction, usually in form of focal segmental glomerulosclerosis (FSGS). Results: In this study we examine kidney involvement in 2 unrelated patients with a A3243G mutation by genetic testing. Both have a maternally-inherited neurosensory deafness and insulin-dependent T2DM. A renal biopsy was performed in both patients. One patient developed nephrotic proteinuria and renal insufficiency, with FSGS findings being observed in the kidney biopsy, whereas the other suffered from mild proteinuria and renal insufficiency, with non-specific glomerular changes. Conclusion: The presence of FSGS or other kidney involvement accompanied by hereditary neurosensory deafness and T2DM could be suggestive of a A3243G tRNALeu mutation and should prompt a genetic testing and an evaluation of potential extrarenal involvement. ˜ S.L.U. All rights reserved. © 2017 Elsevier Espana,
Afección renal en el síndrome de MELAS: descripción de 2 casos r e s u m e n Palabras clave: Mutación A3243G Citopatía mitocondrial Glomeruloesclerosis focal segmentaria Insuficiencia renal crónica
Introducción: El síndrome MELAS –miopatía, encefalopatía, acidosis láctica y episodios similares a ictus – es una citopatía mitocondrial relacionada con varias mutaciones del ADN mitocondrial, siendo la substitución A3243G en el gen tARNLeu la más frecuentemente asociada. Pacientes y métodos: Aparte de su sintomatología habitual, los pacientes presentan historia de sordera neurosensorial y diabetes tipo 2 (DM2). Además, estudios recientes muestran que algunos pacientes tienen también afección renal, normalmente en forma de glomeruloesclerosis focal y segmentaria (GFS). Resultados: En este artículo se discute la afección renal de 2 pacientes no emparentados portadores de la mutación A3243G. Los 2 presentan sordera neurosensorial y DM2. Se realizó estudio anatomopatológico en ambos. Uno de ellos desarrolló proteinuria en rango nefrótico e insuficiencia renal terminal, con cambios de GFS en la biopsia, mientras que el otro presentaba proteinuria leve e insuficiencia renal, sin ˜ cambios histológicos resenables en la microscopia óptica. ˜ Conclusión: La presencia de GFS u otra afección glomerular o tubular renal, acompanada de sordera neurosensorial y DM2, podría ser indicativa de la existencia de la mutación A3243G y estos hallazgos deberían propiciar un estudio genético y una evaluación de posible afección extrarrenal. ˜ S.L.U. Todos los derechos reservados. © 2017 Elsevier Espana,
夽 Please cite this article as: Alcubilla-Prats P, Solé M, Botey A, Grau JM, Garrabou G, Poch E. Afección renal en el síndrome de MELAS: descripción de 2 casos. Med Clin (Barc). 2017. http://dx.doi.org/10.1016/j.medcli.2017.01.029 ∗ Corresponding author. E-mail address: [email protected] (E. Poch). ˜ S.L.U. All rights reserved. 2387-0206/© 2017 Elsevier Espana,
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Introduction The myopathy, encephalopathy, lactic acidosis and stroke-like syndrome (MELAS) is one of the most frequent mitochondrial cytopathies. Although the structure and function of the mitochondrial DNA (mtDNA) were described over 40 years ago, the first pathogenic mutations were not identified until 1988. At least 30 of them have been associated with MELAS, with the A3243G tARNLeu mutation being the most common (80%).1 A wide variety of different mitochondrial cytopathies associated with point mutations that affect mtDNA genes encoding tRNA have been described.2 Although rare, kidney involvement has been described within the MELAS spectrum in various case series. It seems that the most common occurrence is focal segmental glomerulosclerosis (FSGS), although other injuries have been described. This article describes kidney involvement and complications of two unrelated patients, A3243G mutation carriers detected by genetic testing.
Case 1 60-year-old woman with no allergies or toxic habits, which was referred to the Nephrology Department due to the incidental finding of 1.49 mg/dl of serum creatinine during a systematic blood test. Worth noting as medical history, she was diagnosed at age 36 of diabetes mellitus type 2 (DM2), which was first treated with oral antidiabetics during 8 years, progressing to insulin treatment afterwards. Glycaemic control was correct, with HbA1c between 5.4 and 6.5%. Eye fundus revealed signs of diabetic retinopathy and no evidence of any microvascular disorder or target organs. Sensorineural deafness of unknown aetiology was also diagnosed before she was 25 years of age. Eight years earlier, she was diagnosed with melanoma located on his right knee, currently being free from disease. The patient denied a family history of DM2 or sensorineural deafness. On examination, her weight was 45 kg and height 152 cm, with a BMI of 19 kg/m2 . Blood pressure was 111/72 mmHg, heart rate 56 bpm and physical examination by systems showed no significant findings. Serum creatinine was 1.5 mg/dl, with an estimated glomerular filtration rate of 33 ml/min/m2 and BUN of 39 mg/dl; venous balance showed no metabolic acidosis and serum electrolytes were normal. Hemogram, liver function tests, serum lipids, creatinine kinase (CK) and serum uric acid were within normal limits. Urine tests showed no haematuria or proteinuria. Renal ultrasound showed a mild cortical reduction and several small cortical cysts. Although the patient had no family history of sensorineural deafness or DM2, and showed no obvious symptoms of mitochondrial cytopathy (i.e., lactic acidosis, exercise intolerance or myopathy or neurological symptoms), a mitochondrial disease was suspected. Genetic testing in urine confirmed a A3243G mutation with 29% of heteroplasmy. During follow-up, creatinine levels remained stable and urine sediment and proteinuria remained normal. Although a renal biopsy was proposed, the patient refused. Three years after the first visit, the patient reported increased fatigue and general weakness and exercise intolerance. Blood tests showed CK 2819 U/L, LDH 1571 U/l and aldolase 31.7 U/l (normal range between 0.3 and 6 U/l). Difficulty in speech and bilateral ptosis was observed on physical examination, along with a mild generalized loss of muscle strength (4/5). Her cognitive function was normal. The patient underwent a muscle biopsy, which showed unmistakable signs of mitochondrial myopathy (Fig. 1). In subsequent lab tests, CK, LDH and aldolase were normalized, despite the persistence of symptoms. No specific treatment was not considered, except physical therapy and aerobic exercise. Subsequently, a slight increase in serum creatinine was observed (1.6 mg/dl) and a kidney biopsy was performed in order to further study the incipient
Fig. 1. Muscle biopsy of patient 1 (modified Gomori trichrome staining for frozen tissue). Several typical “ragged red” fibres (black arrows) are observed, as well as nuclei inside some fibres and variability in the size of these. All this is consistent with mitochondrial myopathy.
renal failure in the context of a MELAS syndrome. Light microscopy showed nonspecific glomerular and interstitial changes. However, ultrastructural examination by electron microscopy revealed a focal effacement of the podocyte’s foot processes and abnormal mitochondria, many of them within the foot processes (Fig. 2). Five years after the first visit, the patient developed dysphagia and abnormal gait. Although a mild albuminuria of 300 mg/g of creatinine was detected at that time, renal function remained stable.
Case 2 30-year-old male patient with no allergies or toxic habits, is visited in the Nephrology Department due to a finding of proteinuria of 3.15 g in 24 h urine and serum creatinine of 1.5 mg/dl. Noteworthy within the family history is the death of his mother due to diabetic coma. No history of sensorineural deafness. An episode of rhabdomyolysis at the age of 12 accompanied by acute renal failure after spending 8 h walking is also part of the patient’s past medical history. He spent 30 days in hospital and received 20 sessions of haemodialysis. Renal function was completely recovered after the episode. His weight was 68 kg and its height was 170 cm; BMI of 23 kg/m2 . The physical examination was normal except for mild hypertension, properly controlled with ACE inhibitors, and mild unilateral sensorineural deafness diagnosed by audiometric tests, which remained stable. No haematuria was detected. The amount of proteinuria was reduced to levels between 1.5 and 2.5 g/24 h after treatment with ACE inhibitors without hypoalbuminemia, hyperlipidaemia or oedema. Because of the degree of proteinuria, the patient underwent renal biopsy which showed typical findings of FSGS with presence of C3 and IgM +++ (Fig. 3). At follow up, the patient progressively developed exercise intolerance, limb weakness and fatigue, along with abnormal muscle enzymes, which increased slightly at first (CK 3.47 U/l; LDH 506 U/l), and then progressively over time, at levels of 2308 U/l CK and 2324 U/l LDH, with worsening of symptoms. The electromyographic study found no abnormalities, but a muscle biopsy showed several “ragged red” type muscle cells, some with lipid depositions, very indicative of mitochondrial myopathy. A urine genetic analysis showed a A3243G mutation with 32% of heteroplasmy. In order to further study organ involvement, the patient underwent an echocardiogram, which showed no morphological abnormalities, with an
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Fig. 2. Electron microscope image taken from patient 1 biopsy. A. Focal foot-process effacement, with abnormal mitochondria, specific finding of the A3243G mutation. B. The black arrow points to abnormal mitochondria found in the podocyte cytoplasm, with some ridge distortion.
Fig. 3. Patient 2 biopsy images (haematoxylin/eosin). Several sclerotic glomeruli (A, black arrow) are observed. Typical FSGS changes can also be observed in these glomeruli. Segmental collapse with sclerosis is observed in the upper half (B, black arrow).
LVEF of 54%. A cranial MRI showed significant brain atrophy, with enlarged ventricles. At that time, the patient was diagnosed of DM2 with hyperinsulinemia, with a HbA1c of 8.8%, without retinopathy. Initially, the patient responded well to oral antidiabetic agents. However, glycaemic control was inadequate at follow-up, with HbA1c reaching 11.1%, at which time insulin treatment was introduced. During follow-up, proteinuria was barely controlled, with values between 2 and 5 g/24 h, despite optimal blood pressure control. Renal function was gradually reduced, reaching end stage renal disease 15 years later, when haemodialysis was started.
Discussion Kidney involvement is rare in the spectrum of the A3243G mutation. Common symptoms associated with this mutation include: exercise intolerance (93%),1 deafness (44–77%),1,2 myopathy and limb weakness (37–53%),2,3 DM2 (12–33%),1–3 symptoms onset in adulthood (40%)3 and family history of MELAS in less than 20%.3 The prevalence of this mutation in patients with renal disease has been reported on numerous occasions, although with controversial results.4,5 Further studies involving more patients from different ethnic groups would be required to establish an accurate incidence and prevalence of this mutation in patients with chronic kidney disease. In the general population, the presence of the A3243G mutation has been estimated between 16.3 and 236/100,000.6–9
Nowadays, it is widely accepted that mitochondrial cytopathies are the most common metabolic diseases in humans.1 The most common renal manifestation in mitochondrial cytopathies is the Toni-Debre-Fanconi syndrome (particularly in children), a proximal tubule dysfunction characterized by impaired reabsorption of glucose, amino acids, phosphate and bicarbonate, leading to a subsequent glycosuria, aminoaciduria, hyperphosphaturia and proximal tubular acidosis.10 None of the patients studied showed signs of Fanconi syndrome. In MELAS, the most common renal abnormalities found in adulthood is FSGS, a non-proliferative glomerulonephritis characterized by partial glomerular sclerosis, affecting only some glomeruli (focal), and among those affected, only some capillaries show pathologic changes (segmental).2 In our case series, both patients were biopsied. Patient 1 showed unspecific changes in light microscopy, and presence of abnormal mitochondria in podocytes in electron microscopy. The discovery of mitochondria within the foot processes of podocytes is proposed as pathognomonic of MELAS.11 Patient 2 showed typical FSGS changes in light microscopy. No electron microscopy techniques were performed in this patient. Both patients were diagnosed of DM2 at an early age. None of the patients were overweight. The presence of DM2 in atypical patients, especially with a family history, is very indicative of an underlying cause. This high prevalence of DM2 patients with renal disease in MELAS has already been reported,11 which points towards a possible pathophysiological relationship. Although Patient 1 was
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Table 1 Summary of the pathological findings in patients with mutations in mitochondrial DNA and renal involvement reported in the literature. StudyRef
Histological findings
FSGS
Jansen et al. (1997)12 (n = 581) Kurogouchi et al. (1998)14 (n = 1) Nakamura et al. (1999)15 (n = 1) Cheong et al. (1999)16 (n = 1) Doleris et al. (2000)17 (n = 581) Hotta et al. (2001)18 (n = 581) Yanagihara et al. (2001)19 (n = 1) Segawa-Takaeda et al. (2002)20 (n = 1) Yamagata (2002)21 (n = 2) Hirano et al. (2002)22 (n = 13) Maassen et al. (2002)23 (n = 1) Guery et al. (2003)11 (n = 5)
LM: lobular chronic glomerulonephritis (1). Focal glomerulosclerosis (1) EM: focal foot process effacement (1/4) LM: FSGS. Severe tubular atrophy. Interstitial fibrosis EM: abnormal mitochondria LM: FSGS EM: foot process effacement. Mesangial matrix expansion LM: FSGS EM: with no significant changes LM: glomerular hyalinosis. Thickening of perihilar capillaries. Interstitial fibrosis Afferent arteriole injury LM: FSGS, no arteriolar hyalinization EM: abnormal mitochondria in podocytes FSGS: sclerotic glomeruli and atrophic tubules EM: enlarged mitochondria with complex ridges LM: FSGS EM: abnormal mitochondria LM: FSGS and interstitial fibrosis EM: abnormal mitochondria in the glomerular epithelium cytoplasm LM: FSGS (10), chronic interstitial nephritis (1), mild glomerular abnormalities (2)
2/4
10/13
LM: chronic tubulointerstitial nephritis
0/1
LM: arteriolar hyaline thickening (4/5) and fibrous intimal thickening (5/5) EM: enlarged mitochondria with abnormal ridges (1/5). Dysmorphic mitochondria in proximal tubular cells LM: FSGS without mesangial proliferation. Focal tubulointerstitial infiltration and tubular atrophy EM: Diffuse foot process effacement LM: FSGS EM: slightly enlarged mitochondria LM: FSGS EM: foot process effacement. No abnormal mitochondria LM: FSGS EM: irregular and enlarged mitochondria in podocytes and dense depositions in paramesangial lesions LM: interstitial fibrosis. Renal carcinoma. Inflammatory infiltrate. Tubular atrophy
2/5
Löwik et al. (2005)24 (n = 1) Lau et al. (2007)25 (n = 1) Fujii et al. (2008)26 (n = 1) Yamaguchi et al. (2012)27 (n = 1) Piccoli et al. (2012)28 (n = 1) Seidowsky et al. (2013)2 (n = 3) Cavero-Escribano et al. (2014)29 (n = 2) This article (n = 2)
LM: FSGS and arteriolar hyalinization EM: abnormal mitochondria in pedicels (foot processes) (1/3) LM: tubular atrophy, arteriolar hyalinization (1/2). Normal biopsy (1/2) EM: abnormal mitochondria in podocytes (1/2) LM: nonspecific glomerular changes (1/2). FSGS (1/2) EM: abnormal mitochondria in podocytes with altered ridges (1/2)
1/1 1/1 1/1 4/4 4/4 1/1 1/1 2/2
1/1
1/1 1/1 1/1
1/1 3/3 1/2 1/2
FSGS: focal segmental glomerulosclerosis; EM: electron microscopy; LM: light microscopy.
diagnosed with DM2 years earlier, no signs of diabetic nephropathy were observed in the renal biopsy. In patient 2, DM2 was diagnosed after the renal biopsy, but the lack of metabolic control could have influenced the rapid deterioration of renal function. Both patients had some degree of sensorineural deafness. Hearing loss added to renal failure is highly indicative of Alport syndrome, and the differential diagnosis between this entity and mitochondrial cytopathy with kidney involvement should always be taken into account.2 Notably, none of the patients had any episodes resembling a stroke or other neurological symptoms other than deafness episodes, although a significant cerebral atrophy with diffuse increase in ventricular volume was observed in patient 2 by neuroimaging, which could be partly related to changes secondary to mitochondrial involvement in the CNS. Patient 1 only had DM2, deafness and myopathy plus nondiabetic renal disease. This subtype of clinical occurrence is mainly characterized by maternally inherited diabetes and deafness (MIDD) and the absence of other “classic” symptoms of MELAS syndrome, such as lactic acidosis or encephalopathy.12 Although patient 1 had no family history of diabetes and deafness, the clinical occurrence is more indicative of MIDD that of a classic MELAS syndrome. A prospective cohort study of 54 patients with MIDD, carriers of A3243G mutation, showed a significant dissociation between kidney disease and diabetic retinopathy (28 versus 8%), which shows
that a specifically renal involvement is secondary to mitochondrial disease.13 The pathophysiological differences between the classical MELAS syndrome and MIDD are unknown, but they are probably related to heteroplasmy and genetic drift phenomena. As we have seen, there is also variation in the occurrence of renal symptoms. Patient 1 only showed a mild elevation of creatinine levels with sporadic mild albuminuria and a moderate reduction in glomerular filtration rate, while case 2 had exercise-induced rhabdomyolysis during childhood, and, acute renal failure secondary to it. Renal biopsy of patient 1 showed only unspecific changes with light microscopy. Abnormal mitochondria were observed in podocytes with electron microscopy. One can speculate that these abnormal mitochondria found in podocytes could be a sign of possible future cell damage that could lead to the patient developing an established FSGS or a Fanconi syndrome. Table 1 shows the pathological findings in published cases of MELAS syndrome (A3243G mtDNA mutation) with kidney involvement. Of the 50 patients examined previously, 39 (78%) showed histological characteristics of FSGS. The occurrence of abnormal mitochondria in foot processes appears to be significant in electron microscopy findings. The mechanism by which selective damage occurs on foot processes of podocytes is not clear, but may be related to the presence of abnormal mitochondria, with altered apoptosis pathways and/or production of free radicals.
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In conclusion, kidney involvement is variable in patients with the A3243G mutation. The presence of FSGS or another chronic renal condition, accompanied by hereditary sensorineural deafness and DM2 may indicate the presence of the A3243G tARNLeu mutation and, therefore, these findings should lead to genetic testing and extensive evaluation of the potential extrarenal involvement of the same. Conflict of interests The authors declare no conflict of interest. References 1. Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci. 2008;1142:133–58, http://dx.doi.org/10.1196/annals.1444.011. 2. Seidowsky A, Hoffmann M, Glowacki F, Dhaenens CM, Devaux J, de Sainte Foy CL, et al. Renal involvement in MELAS syndrome – a series of 5 cases and review of the literature. Clin Nephrol. 2013;80:456–63, http://dx.doi.org/10.5414/CN107063. 3. Goodfellow JA, Dani K, Stewart W, Santosh C, McLean J, Mulhern S, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people. Postgrad Med J. 2012;88:326–34, http://dx.doi.org/10.1136/postgradmedj-2011-130326. 4. Iwasaki N, Babazono T, Tsuchiya K, Tomonaga O, Suzuki A, Togashi M, et al. Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA Leu (UUR) gene in Japanese patients with diabetes mellitus and end stage renal disease. J Hum Genet. 2001;46:330–4. 5. Koshiyama H, Inagaki N, Seino Y. Low prevalence of mitochondrial DNA 3243A > G point mutation in Caucasians with unexplained renal disease. Diabet Med. 2007;24:804. 6. Chinnery PF, Turnbull DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet. 2001;106:94–101, http://dx.doi.org/10.1002/ajmg.1426. 7. Majamaa K, Moilanen JS, Uimonen S, Remes AM, Salmela PI, Kärppä M, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet. 1998;63:447–54, http://dx.doi.org/10.1086/301959. 8. Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet. 2008;83:254–60, http://dx.doi.org/10.1016/j.ajhg.2008.07.004. 9. Manwaring N, Jones MM, Wang JJ, Rochtchina E, Howard C, Mitchell P, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion. 2007;7:230–3, http://dx.doi.org/10.1016/j.mito.2006.12.004. 10. Emma F, Bertini E, Salviati L, Montini G. Renal involvement in mitochondrial cytopathies. Pediatr Nephrol. 2012;27:539–50, http://dx.doi.org/10.1007/s00467-011-1926-6. 11. Guéry B, Choukroun G, Noël LH, Clavel P, Rötig A, Lebon S, et al. The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J Am Soc Nephrol. 2003;14:2099–108, http://dx.doi.org/10.1097/01.ASN.0000080180.51098.02. 12. Jansen JJ, Maassen JA, van der Woude FJ, Lemmink HA, van den Ouweland JM, t’Hart LM, et al. Mutation in mitochondrial tRNALeu(UUR) gene associated with progressive kidney disease. J Am Soc Nephrol. 1997;8:1118–24.
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