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. 2016 Nov;53(11):768-775.
doi: 10.1136/jmedgenet-2016-103910. Epub 2016 Jul 13.

The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

Yi Shiau Ng  1 , Charlotte L Alston  1 , Daria Diodato  2 , Andrew A Morris  3 , Nicole Ulrick  4 , Stanislav Kmoch  5 , Josef Houštěk  6 , Diego Martinelli  7 , Alireza Haghighi  8   9 , Mehnaz Atiq  10 , Montserrat Anton Gamero  11 , Elena Garcia-Martinez  11 , Hana Kratochvílová  12 , Saikat Santra  13 , Ruth M Brown  14 , Garry K Brown  14 , Nicola Ragge  15   16 , Ahmad Monavari  17 , Karen Pysden  18 , Kirstine Ravn  19 , Jillian P Casey  20 , Arif Khan  21 , Anupam Chakrapani  22 , Grace Vassallo  23 , Cas Simons  24 , Karl McKeever  25 , Siobhan O'Sullivan  25 , Anne-Marie Childs  18 , Elsebet Østergaard  19 , Adeline Vanderver  4 , Amy Goldstein  26 , Julie Vogt  27 , Robert W Taylor  1 , Robert McFarland  1
Affiliations

The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

Yi Shiau Ng et al. J Med Genet. 2016 Nov.

Abstract

Background: Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects.

Methods: We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype-phenotype correlates and performed survival analysis to identify prognostic factors.

Results: We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. Together with all previously published cases (n=32), we show that congenital sensorineural deafness, hypotonia, developmental delay and lactic acidaemia are common clinical manifestations with disease onset under 2 years. Renal involvement is more prevalent than seizures (66% vs 44%). In addition, median survival time was longer in patients with renal involvement compared with those without renal disease (6 years vs 8 months, p=0.009). The neurological phenotype also appears milder in patients with renal involvement.

Conclusions: The clinical phenotypes and prognosis associated with RMND1 mutations are more heterogeneous than that were initially described. Regular monitoring of kidney function is imperative in the clinical practice in light of nephropathy being present in over 60% of cases. Furthermore, renal replacement therapy should be considered particularly in those patients with mild neurological manifestation as shown in our study that four recipients of kidney transplant demonstrate good clinical outcome to date.

Keywords: congenital sensorineural deafness; lactic acidosis; mitochondrial respiratory chain deficiencies; prognosis; renal disease.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Radiological imaging. (A–D) Axial T2-weighted MRI head from P1. (A) There were prominent T2 hyperintensities in the white matter suggestive of delayed myelination and (B) basal ganglia appeared normal at 6 months. Repeat imaging (C) showed improvement of the white-matter abnormality but there were new, symmetrical changes in the basal ganglia (D) at 2 years old. (E) Renal ultrasound showed dysplastic kidney in P1. (F) Twelve-lead ECG of P10.2 showed atrioventricular (AV) dissociation and bradycardia (heart rate 39 bpm).
Figure 2
Figure 2
Histopathological and histochemical studies. (A–C) Skeletal muscle biopsy from P2; (D–F) postmortem cardiac tissue from P16; (G–I) postmortem kidney tissue from P16. Marked c oxidase (COX)-deficient muscle fibres (c) and renal tubules (i), lesser extent of COX deficiency in cardiomyocytes was identified through sequential COX/succinate dehydrogenase (SDH) histochemical reaction.
Figure 3
Figure 3
Pathogenic variants in RMND1 gene (n=13). Six novel variants are depicted in red font.
Figure 4
Figure 4
Kaplan-Meier curves comparing survival between patients with and without renal involvement. Censored data (represent the number of patients that are still alive at their most recent clinical review) are shown as crosses. The median survival time in patients with renal involvement (green) is significantly longer than those without renal involvement (blue), 6.0 years versus 8 months (log-rank test, p=0.009).
See this image and copyright information in PMC

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