Abstract

Background. The mitochondrial DNA (mtDNA) m.3243A>G mutation is one of the most common pathogenic mtDNA variants. The phenotypes associated with this mutation range from asymptomatic induviduals to well-defined clinical syndromes, or non-syndromic mitochondrial disorders. Variable clinical features in pediatric cases may cause difficulty in diagnosis. Kidney involvement in this mutation is uncommon and reported on a case-by-case basis. Here, we report on a patient with m.3243A>G mutation, who presented with short stature and proteinuria, and his family, who share the same genotype but exhibit different heteroplasmy levels in different tissues and variable phenotypes.

Case presentation. A 15-year-old male patient was admitted to the pediatric endocrinology department with short stature. His examinations revealed nephrotic range proteinuria, hearing loss, impaired glucose tolerance, and Wolf-Parkinson-White syndrome. From family history, it was learned that diabetes mellitus (DM) and progressive sensorineural hearing loss were common in this family. The patient’s mother, who had chronic kidney disease, DM, and hearing loss, had died suddenly for an unknown reason. Considering the family history, a genetic analysis was performed for mitochondrial disease. Mitochondrial DNA analysis revealed a m.3243A>G mutation with 47% heteroplasmy in blood, 62% heteroplasmy in buccal cells, and 96% heteroplasmy in urothelial cells in our patient.

Conclusions. Short stature without any other complaint and renal involvement are rare findings in m.3243A>G mutation. In patients presenting with proteinuria, in the presence of conditions affecting many systems such as endocrine system pathologies, hearing loss, and cardiac pathologies, and in the presence of individuals with a similar family history of multiple organ involvement, mitochondrial diseases should be considered, and examined from this perspective. Our case illustrates the value of a detailed medical and family history. 

Keywords: maternally inherited diabetes and deafness, mitochondrial disease, m.3243A>G, proteinuria, short stature

Copyright and license

Copyright © 2024 The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.

How to cite

1.
Büyükyılmaz G, İnözü M, Çavdarlı B. A case with short stature and proteinuria: atypical presentation of a family with m.3243A>G mutation. Turk J Pediatr 2024; 66: 490-498. https://doi.org/10.24953/turkjpediatr.2024.4702

References

  1. Baron J, Sävendahl L, De Luca F, et al. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol 2015; 11: 735-746. https://doi.org/10.1038/nrendo.2015.165
  2. Braun LR, Marino R. Disorders of growth and stature. Pediatr Rev 2017; 38: 293-304. https://doi.org/10.1542/pir.2016-0178
  3. Viteri B, Reid-Adam J. Hematuria and proteinuria in children. Pediatr Rev 2018; 39: 573-587. https://doi.org/10.1542/pir.2017-0300
  4. El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 2015; 116: 4-12. https://doi.org/10.1016/j.ymgme.2015.06.004
  5. Gorman GS, Chinnery PF, DiMauro S, et al. Mitochondrial diseases. Nat Rev Dis Primers 2016; 2: 16080. https://doi.org/10.1038/nrdp.2016.80
  6. Schon KR, Ratnaike T, van den Ameele J, Horvath R, Chinnery PF. Mitochondrial diseases: a diagnostic revolution. Trends Genet 2020; 36: 702-717. https://doi.org/10.1016/j.tig.2020.06.009
  7. Grady JP, Pickett SJ, Ng YS, et al. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol Med 2018; 10: e8262. https://doi.org/10.15252/emmm.201708262
  8. Shanske S, Pancrudo J, Kaufmann P, et al. Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis. Am J Med Genet A 2004; 130A: 134-137. https://doi.org/10.1002/ajmg.a.30220
  9. Li D, Liang C, Zhang T, et al. Pathogenic mitochondrial DNA 3243A>G mutation: from genetics to phenotype. Front Genet 2022; 13: 951185. https://doi.org/10.3389/fgene.2022.951185
  10. Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990; 348: 651-653. https://doi.org/10.1038/348651a0
  11. van den Ouweland JM, Lemkes HH, Ruitenbeek W, et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet 1992; 1: 368-371. https://doi.org/10.1038/ng0892-368
  12. Sotiriou E, Coku J, Tanji K, Huang HB, Hirano M, DiMauro S. The m.3244G>A mutation in mtDNA is another cause of progressive external ophthalmoplegia. Neuromuscul Disord 2009; 19: 297-299. https://doi.org/10.1016/j.nmd.2009.01.014
  13. Shen X, Du A. The non-syndromic clinical spectrums of mtDNA 3243A>G mutation. Neurosciences (Riyadh) 2021; 26: 128-133. https://doi.org/10.17712/nsj.2021.2.20200145
  14. Yang M, Xu L, Xu C, et al. The mutations and clinical variability in maternally inherited diabetes and deafness: an analysis of 161 patients. Front Endocrinol (Lausanne) 2021; 12: 728043. https://doi.org/10.3389/fendo.2021.728043
  15. Fabrizi GM, Cardaioli E, Grieco GS, et al. The A to G transition at nt 3243 of the mitochondrial tRNALeu(UUR) may cause an MERRF syndrome. J Neurol Neurosurg Psychiatry 1996; 61: 47-51. https://doi.org/10.1136/jnnp.61.1.47
  16. El-Hattab AW, Almannai M, Scaglia F. MELAS. In: Adam MP, Feldman J, Mirzaa GM, et al, editors. GeneReviews(®). Seattle, WA: University of Washington, Seattle; 1993.
  17. Xia CY, Liu Y, Liu H, Zhang YC, Ma YN, Qi Y. Clinical and molecular characteristics in 100 chinese pediatric patients with m.3243A>G mutation in mitochondrial DNA. Chin Med J (Engl) 2016; 129: 1945-1949. https://doi.org/10.4103/0366-6999.187845
  18. Chin J, Marotta R, Chiotis M, Allan EH, Collins SJ. Detection rates and phenotypic spectrum of m.3243A>G in the MT-TL1 gene: a molecular diagnostic laboratory perspective. Mitochondrion 2014; 17: 34-41. https://doi.org/10.1016/j.mito.2014.05.005
  19. Wolny S, McFarland R, Chinnery P, Cheetham T. Abnormal growth in mitochondrial disease. Acta Paediatr 2009; 98: 553-554. https://doi.org/10.1111/j.1651-2227.2008.01148.x
  20. Al-Gadi IS, Haas RH, Falk MJ, Goldstein A, McCormack SE. Endocrine disorders in primary mitochondrial disease. J Endocr Soc 2018; 2: 361-373. https://doi.org/10.1210/js.2017-00434
  21. Robinson KN, Terrazas S, Giordano-Mooga S, Xavier NA. The role of heteroplasmy in the diagnosis and management of maternally inherited diabetes and deafness. Endocr Pract 2020; 26: 241-246. https://doi.org/10.4158/EP-2019-0270
  22. Suzuki S, Oka Y, Kadowaki T, et al. Clinical features of diabetes mellitus with the mitochondrial DNA 3243 (A-G) mutation in Japanese: maternal inheritance and mitochondria-related complications. Diabetes Res Clin Pract 2003; 59: 207-217. https://doi.org/10.1016/s0168-8227(02)00246-2
  23. Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med 2001; 134: 721-728. https://doi.org/10.7326/0003-4819-134-9_part_1-200105010-00008
  24. Iwasaki N, Babazono T, Tsuchiya K, 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: 330-334. https://doi.org/10.1007/s100380170068
  25. 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: 133-158. https://doi.org/10.1196/annals.1444.011
  26. Seidowsky A, Hoffmann M, Glowacki F, et al. Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature. Clin Nephrol 2013; 80: 456-463. https://doi.org/10.5414/CN107063
  27. Alcubilla-Prats P, Solé M, Botey A, Grau JM, Garrabou G, Poch E. Kidney involvement in MELAS syndrome: description of 2 cases. Med Clin (Barc) 2017; 148: 357-361. https://doi.org/10.1016/j.medcli.2017.01.029
  28. Güçer S, Talim B, Aşan E, et al. Focal segmental glomerulosclerosis associated with mitochondrial cytopathy: report of two cases with special emphasis on podocytes. Pediatr Dev Pathol 2005; 8: 710-717. https://doi.org/10.1007/s10024-005-0058-z
  29. Manwaring N, Jones MM, Wang JJ, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion 2007; 7: 230-233. https://doi.org/10.1016/j.mito.2006.12.004
  30. Pickett SJ, Grady JP, Ng YS, et al. Phenotypic heterogeneity in m.3243A>G mitochondrial disease: the role of nuclear factors. Ann Clin Transl Neurol 2018; 5: 333-345. https://doi.org/10.1002/acn3.532
  31. Niedermayr K, Pölzl G, Scholl-Bürgi S, et al. Mitochondrial DNA mutation "m.3243A>G"-Heterogeneous clinical picture for cardiologists ("m.3243A>G": A phenotypic chameleon). Congenit Heart Dis 2018; 13: 671-677. https://doi.org/10.1111/chd.12634
  32. Ng YS, Grady JP, Lax NZ, et al. Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults. Eur Heart J 2016; 37: 2552-2559. https://doi.org/10.1093/eurheartj/ehv306