The ever wider clinical spectrum of RMND1-related disorders and limitedness of phenotype-based classifications.
Mitochondriopathy
Myelodysplasia
Myopathy
Perrault syndrome
RMND1
Journal
Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
received:
19
04
2023
accepted:
02
08
2023
revised:
10
07
2023
pubmed:
16
8
2023
medline:
16
8
2023
entrez:
16
8
2023
Statut:
ppublish
Résumé
RMND1 has been identified as a mitochondriopathy-associated gene less than 12 years ago. The most common phenotype related to this gene is an early onset, severe form of encephalomyopathy that leads to death in a medium time of three years after birth. However, milder and later onset presentations have been reported in some individuals, including two in whom the mitochondriopathy was identified at ~ 40 years of age, and the early onset presentations have been the object of no reports in those who survived beyond age 10. It is thus unclear how lethal RMND1-related conditions really are. We herein describe the oldest case to have been identified hitherto with this condition, i.e., that of a white female who was 61 at the time of diagnosis but was still active in her everyday life. The gene defect identified was nonetheless associated with many manifestations including ovarian insufficiency and sensorineural hearing loss (two features of what is currently designated as Perrault syndrome) as well as chronic renal failure, asymptomatic myopathy, leukopenia, and a few others. In our opinion, this case is of great translational interest for at least three reasons. First, it hints towards the possibility of near-normal life expectancies in some if not many individuals with RMND1 insufficiency. Second, it underlines the wide clinical spectrum associated with this gene. Third, it brings us to question the use of eponyms and syndromic features to identify the true etiology of multisystemic phenotypes. KEY MESSAGES: RMND1-related conditions typically manifest at an early age with a progressive and lethal form of encephalomyopathy. More benign presentations have been described with some being categorized as Perrault syndrome but none have been diagnosed after the age of 45. The clinical spectrum and presenting age of RMND1-related mitochondriopathies are probably much more varied than implied in the current literature. The case reported in this manuscript illustrates the limitedness of phenotype-based classifications of genetic disorders to identify the defect at cause.
Identifiants
pubmed: 37584739
doi: 10.1007/s00109-023-02356-x
pii: 10.1007/s00109-023-02356-x
pmc: PMC10560146
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1229-1236Informations de copyright
© 2023. The Author(s).
Références
Janer A, Antonicka H, Lalonde E, Nishimura T, Sasarman F, Brown GK, Brown RM, Majewski J, Shoubridge EA (2012) An RMND1 Mutation causes encephalopathy associated with multiple oxidative phosphorylation complex deficiencies and a mitochondrial translation defect. Am J Hum Genet 91:737–743. https://doi.org/10.1016/j.ajhg.2012.08.020
doi: 10.1016/j.ajhg.2012.08.020
pubmed: 23022098
pmcid: 3484649
Garcia-Diaz B, Barros MH, Sanna-Cherchi S, Emmanuele V, Akman HO, Ferreiro-Barros CC, Horvath R, Tadesse S, El Gharaby N, DiMauro S et al (2012) Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation. Am J Hum Genet 91:729–736. https://doi.org/10.1016/j.ajhg.2012.08.019
doi: 10.1016/j.ajhg.2012.08.019
pubmed: 23022099
pmcid: 3484479
Vinu N, Puri RD, Anand K, Verma IC (2018) Expanding the phenotype of the founder South Asian mutation in the nuclear encoding mitochondrial RMND1 gene. Indian J Pediatr 85:87–92. https://doi.org/10.1007/s12098-017-2515-x
doi: 10.1007/s12098-017-2515-x
pubmed: 29071585
Ng YS, Alston CL, Diodato D, Morris AA, Ulrick N, Kmoch S, Houstek J, Martinelli D, Haghighi A, Atiq M et al (2016) The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease. J Med Genet 53:768–775. https://doi.org/10.1136/jmedgenet-2016-103910
doi: 10.1136/jmedgenet-2016-103910
pubmed: 27412952
Ozieblo D, Pazik J, Stepniak I, Skarzynski H, Oldak M (2020) Two novel pathogenic variants confirm RMND1 causative role in Perrault Syndrome with renal involvement. Genes (Basel) 11. https://doi.org/10.3390/genes11091060
Fong CT (1993) Clinical diagnosis of genetic diseases. Pediatr Ann 22:277–281. https://doi.org/10.3928/0090-4481-19930501-07
doi: 10.3928/0090-4481-19930501-07
pubmed: 8510994
Faridi R, Rea A, Fenollar-Ferrer C, O’Keefe RT, Gu S, Munir Z, Khan AA, Riazuddin S, Hoa M, Naz S et al (2022) New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder. Hum Genet 141:805–819. https://doi.org/10.1007/s00439-021-02319-7
doi: 10.1007/s00439-021-02319-7
pubmed: 34338890
Lee CY, Yen HY, Zhong AW, Gao H (2021) Resolving misalignment interference for NGS-based clinical diagnostics. Hum Genet 140:477–492. https://doi.org/10.1007/s00439-020-02216-5
doi: 10.1007/s00439-020-02216-5
pubmed: 32915251
Haydock L, Garneau AP, Tremblay L, Yen HY, Gao H, Harrisson R, Isenring P (2022) Genetic abnormalities in biopsy-proven, adult-onset hemolytic uremic syndrome and C3 glomerulopathy. J Mol Med (Berl) 100:269–284. https://doi.org/10.1007/s00109-021-02102-1
doi: 10.1007/s00109-021-02102-1
pubmed: 34714369
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30
doi: 10.1038/gim.2015.30
pubmed: 25741868
pmcid: 4544753
Newman WG, Friedman TB, Conway GS, Demain LAM (1993) Perrault syndrome. 2014 Sep 25 [updated 2018 Sep 6]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A (eds) GeneReviews
Demain LAM, Antunes D, O’Sullivan J, Bhaskhar SS, O’Keefe RT, Newman WG (2018) A known pathogenic variant in the essential mitochondrial translation gene RMND1 causes a Perrault-like syndrome with renal defects. Clin Genet 94:276–277. https://doi.org/10.1111/cge.13255
doi: 10.1111/cge.13255
pubmed: 29671881
Jorde LB, Carey JC, Bamshad MJ (2019) Medical genetics (6th ed.). Elsevier Health Science. ISBN: 9780323597371. Publication Date: 2019-12-16
Stefano GB, Kream RM (2016) Mitochondrial DNA heteroplasmy in human health and disease. Biomed Rep 4:259–262. https://doi.org/10.3892/br.2016.590
doi: 10.3892/br.2016.590
pubmed: 26998260
pmcid: 4774312
Boros E, Elilie Mawa Ongoth F, Heinrichs C, Mansbach AL, Seneca S, Aeby A, Ismaili K, Brachet C (2022) Primary ovarian insufficiency in RMND1 mitochondrial disease. Mitochondrion 66:51–53. https://doi.org/10.1016/j.mito.2022.07.004
doi: 10.1016/j.mito.2022.07.004
pubmed: 35901949
Tesarova M, Vondrackova A, Stufkova H, Veprekova L, Stranecky V, Berankova K, Hansikova H, Magner M, Galoova N, Honzik T et al (2019) Sideroblastic anemia associated with multisystem mitochondrial disorders. Pediatr Blood Cancer 66:e27591. https://doi.org/10.1002/pbc.27591
Sreedhar A, Aguilera-Aguirre L, Singh KK (2020) Mitochondria in skin health, aging, and disease. Cell Death Dis 11:444. https://doi.org/10.1038/s41419-020-2649-z
doi: 10.1038/s41419-020-2649-z
pubmed: 32518230
pmcid: 7283348
Gao X, Jiang Z, Yan X, Liu J, Li F, Liu P, Li J, Wei Y, Sun YE, Zhang Y et al (2021) ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease. Cell Death Dis 12:701. https://doi.org/10.1038/s41419-021-03993-1
doi: 10.1038/s41419-021-03993-1
pubmed: 34262025
pmcid: 8280182
O’Rourke K, Buddles MR, Farrell M, Howley R, Sukuraman S, Connolly S, Turnbull DM, Hutchinson M, Taylor RW (2009) Phenotypic diversity associated with the mitochondrial m.8313G>A point mutation. Muscle Nerve 40:648–651. https://doi.org/10.1002/mus.21342
doi: 10.1002/mus.21342
pubmed: 19618438
Finsterer J, Mahjoub SZ (2012) Primary mitochondrial arteriopathy. Nutr Metab Cardiovasc Dis 22:393–399. https://doi.org/10.1016/j.numecd.2012.01.002
doi: 10.1016/j.numecd.2012.01.002
pubmed: 22520486
Brunetti-Pierri N, Pignatelli R, Fouladi N, Towbin JA, Belmont JW, Craigen WJ, Wong LJ, Jefferies JL, Scaglia F (2011) Dilation of the aortic root in mitochondrial disease patients. Mol Genet Metab 103:167–170. https://doi.org/10.1016/j.ymgme.2011.02.007
doi: 10.1016/j.ymgme.2011.02.007
pubmed: 21406331