The ever wider clinical spectrum of RMND1-related disorders and limitedness of phenotype-based classifications

Abstract

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.

Keywords: Mitochondriopathy; Myelodysplasia; Myopathy; Perrault syndrome; RMND1.

Fig. 1

Cumulative survival of individuals with mutations in RMND1. A Kaplan–Meier survival curves with and without renal failure. Reproduced from Ng et al. [4]. B RMND1. Top row, RMND1 gene with exon–intron organization. Middle and bottom rows, encoded protein showing domain–exon relationships. Abbreviations and signs: CC, coiled coil domain; DUF, domain of unknown function; MLS, mitochondrial localization signal; TM, transmembrane domain; *, stop codon. Variant identified in the current case is just past the middle of exon 5 as pointed by the arrow. Length of exons, introns, and domains are drawn to scale. Genes tested in the Renome are listed in Footnote

Fig. 2

Audiograms taken at age of 5 and 54. Top panel, right ear. Bottom panel, left ear. Signs: cross, bone conduction; circle, air conduction

Fig. 3

Laboratory results prior to consultation. As a function of age are shown: A serum creatinine, B estimated GFR, and C serum CK levels. Arrows point to slightly increased azotemia (33 mg/dL) or capillary lactate levels (2.6 mmol/L) at the ages shown

Fig. 4

Pedigree of the proband’s first-degree relatives. Refer to bottom note in the figure for signification of colors and signs. Abbreviations: DD, developmental delay

Fig. 5

Histological analysis of muscle and bone marrow sections. Abnormalities are shown through arrows. Stain used in this legend are between parentheses. A Muscle biopsy. Subpanel 1 (MHCF): atrophied muscle fibers. Subpanel 2 (COX): subsarcolemmal aggregates representing apoptotic mitochondria. Subpanel 3 (SDH): fibers devoid of enzyme activity. B Bone marrow aspirate. Subpanel 1 (Giemsa): binucleated erythroblast. Subpanel 2 (Giemsa): erythroblast with scant cytoplasm (left) and hemosiderophage (right). Subpanel 3 (Prussian blue): islet of ring sideroblasts. Subpanel 4 (Giemsa): abnormally small megakaryocyte. C Bone marrow biopsy. Subpanel 1 (H&E): area of hypocellularity (left) and hypercellularity (right). Subpanel 2 (H&E): areas densely populated with erythroblasts. Subpanel 3 (Giemsa): megaloblastoid cell. Subpanel 4 (Prussian blue): diffuse iron deposition. Subpanel 5 (H&E): erythrophagocyte (left) and hemosiderophage (right). Note that a cytogenetic analysis carried out on 26 mitoses revealed normal. D Electron microscopy of a sideroblast. Iron deposition is seen in several of the mitochondria captured