Characterization of the renal phenotype in RMND1‐related mitochondrial disease

Abstract

BackgroundThe nuclear encoded gene RMND1 (Required for Meiotic Nuclear Division 1 homolog) has recently been linked to RMND1‐related mitochondrial disease (RRMD). This autosomal recessive condition characteristically presents with an infantile‐onset multisystem disease characterized by severe hypotonia, global developmental delay, failure to thrive, sensorineural hearing loss, and lactic acidosis. Renal disease, however, appears to be one of the more prominent features of RRMD, affecting patients at significantly higher numbers compared to other mitochondrial diseases. We report the clinical, histological, and molecular findings of four RRMD patients across three academic institutions with a focus on the renal manifestations.MethodsFour patients were identified for the purpose of this study, all of whom had molecular confirmation at the time of inclusion, which included the common pathogenic variant c.713A>G (p.N238S) as well as the three rare variants: c.485delC (p.P162fs), c.533C>T (p.T178M), and c.1317 + 1G>C splice donor variant. Medical history and laboratory findings were collected from the medical records and medical providers.ResultsIn this study, all four patients developed renal disease characterized as tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end‐stage renal disease (4/4) necessitating renal transplantation (2/4). Histological evaluation of renal biopsy specimens revealed generalized tubular atrophy and on electron microscopy, abundant mitochondria with pleomorphism and abnormal cristae.ConclusionOur experience with RRMD demonstrates a specific pattern of renal disease manifestations and clinical course. Patients are unlikely to respond to traditional chronic kidney disease (CKD) treatments, making early diagnosis and consideration of renal transplantation paramount to the management of RRMD.

Two Novel Pathogenic Variants Confirm RMND1 Causative Role in Perrault Syndrome with Renal Involvement

“…Ovarian dysfunction (ovarian atrophy and hypergonadotropic hypogonadism) as a consequence of RMND1 pathogenic variants has been previously reported only once in a patient described by Demain et al [ 6 ] and in none of the approximately 40 patients with OXPHOS deficiency. This could be explained by the early, prepubertal age at which the majority of children were investigated [ 4 , 5 , 35 , 36 ]. In only two patients examined at the age of 14 and 17, no reference was made to their sexual development [ 36 ].…”

“…It could also be owed to some other yet unidentified modifying factors. It is still a conundrum why the single patient with a homozygous p.(Asn238Ser) variant, localizing within the DUF155 domain, presented a relatively mild phenotype resembling PRLTS [ 6 ], in contrast to the, currently, four other patients with the same causative variant and a more severe infantile-onset multisystem disorder [ 4 , 5 , 37 ].…”

“…It has been proposed that RMND1 tethers mitochondrial ribosomes close to the sites where the primary mRNAs are matured, spatially coupling mitochondrial transcription with translation [ 3 ]. In line with this, RMND1 pathogenic variants cause a generalized mitochondrial translation defect and are detected in patients with combined oxidative phosphorylation deficiency (COXPD11; MIM #614922), a severe recessive condition characterized by the presence of lactic acidosis, deafness, renal and liver dysfunction, central nervous system and muscle involvement with an onset at birth or early infancy [ 4 , 5 ].…”

Mitochondrial disease in children

“…Without aminoglycoside exposure, individuals with this variant may have normal hearing until well into adult life, implying a role for newborn screening for the variant followed by lifelong avoidance of aminoglycosides in at‐risk individuals [74]. Childhood‐onset mitochondrial syndromes in which hearing loss is a prominent feature include MERRF, MELAS, KSS and deficiencies of SUCLA2, BCS1L, RRM2B, SERAC1, RMND1 and TRNT1 [19,22,27,38,47,49,75‐78].…”

“…FSGS is relatively frequently observed in adults with m.3243A>G disease but rarely seen in children [92]. Some children with RMND1 mutations have a pseudohypoaldosteronism‐like picture with hyperkalaemia, hyponatraemia and progressive renal impairment [77].…”