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The Clinical, Biochemical and Genetic Features Associated with RMND1

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The Clinical, Biochemical and Genetic Features Associated with RMND1 Genotype-phenotype correlations J Med Genet: first published as 10.1136/jmedgenet-2016-103910 on 13 July 2016. Downloaded from ORIGINAL ARTICLE 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,15,27 Ahmad Monavari,16 Karen Pysden,17 Kirstine Ravn,18 Jillian P Casey,19 Arif Khan,20 Anupam Chakrapani,21 Grace Vassallo,22 Cas Simons,23 Karl McKeever,24 Siobhan O’Sullivan,24 Anne-Marie Childs,17 Elsebet Østergaard,18 Adeline Vanderver,4 Amy Goldstein,25 Julie Vogt,26 Robert W Taylor,1 Robert McFarland1 ▸ Additional material is ABSTRACT synthesis secondary to mutations in mitochondrial published online only. To view Background Mutations in the RMND1 (Required for tRNA synthetases, mitochondrial ribosomal pro- please visit the journal online (http://dx.doi.org/10.1136/ Meiotic Nuclear Division protein 1) gene have recently teins and mitochondrial elongation factors are jmedgenet-2016-103910). been linked to infantile onset mitochondrial disease increasingly recognised and identified through 1 fi characterised by multiple mitochondrial respiratory chain next-generation sequencing. Mutations in the For numbered af liations see RMND1 end of article. defects. (Required for Meiotic Nuclear Division Methods We summarised the clinical, biochemical and protein 1) gene cause multiple mitochondrial Correspondence to molecular genetic investigation of an international cohort respiratory chain deficiencies and were first linked Dr Robert McFarland, of affected individuals with RMND1 mutations. In to human disease in 2012.23Recent findings Wellcome Trust Centre for RMND1 Mitochondrial Research, addition, we reviewed all the previously published cases suggest that plays an important role in Institute of Neuroscience, to determine the genotype–phenotype correlates and mitochondrial translation by anchoring or stabilis- Newcastle University, performed survival analysis to identify prognostic factors. ing the mitochondrial ribosome near the site of Framlington Place, Newcastle Results We identified 14 new cases from 11 pedigrees mRNA maturation.34 upon Tyne NE2 4HH, UK; that harbour recessive RMND1 mutations, including 6 The clinical phenotypes associated with RMND1 robert.mcfarland@newcastle. ac.uk novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, mutations are expanding, ranging from a fatal, infant- p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, ile encephalomyopathy with lactic acidosis25to a less http://jmg.bmj.com/ Received 18 March 2016 p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. severe phenotype characterised by developmental Revised 11 May 2016 Together with all previously published cases (n=32), we delay, congenital sensorineural deafness, hypotonia Accepted 26 May 2016 46 fi Published Online First show that congenital sensorineural deafness, hypotonia, and renal disease. In this study, we identi ed new 13 July 2016 developmental delay and lactic acidaemia are common patients harbouring recessive mutations in RMND1 clinical manifestations with disease onset under 2 years. from several metabolic clinics and research centres Renal involvement is more prevalent than seizures (66% across Europe (UK, Ireland, Italy, Denmark, Spain vs 44%). In addition, median survival time was longer in and Czech Republic) and the USA. We aimed to on September 24, 2021 by guest. Protected copyright. patients with renal involvement compared with those describe the phenotype–genotype correlate and without renal disease (6 years vs 8 months, p=0.009). determine the prognostic factors in survival by com- The neurological phenotype also appears milder in bining all other previously reported cases. patients with renal involvement. Conclusions The clinical phenotypes and prognosis SUBJECTS AND METHODS associated with RMND1 mutations are more Subjects heterogeneous than that were initially described. Regular Clinical and laboratory data were collated using a monitoring of kidney function is imperative in the clinical standardised data collection form. We also con- practice in light of nephropathy being present in over ducted a literature review to ascertain previously 60% of cases. Furthermore, renal replacement therapy published cases, approaching respective authors for should be considered particularly in those patients with additional data wherever required. This study was mild neurological manifestation as shown in our study performed in accordance with the World Medical that four recipients of kidney transplant demonstrate Association’s Declaration of Helsinki, research and good clinical outcome to date. ethical guidelines issued by each of our institutions. Mitochondrial histochemistry INTRODUCTION For patients who underwent muscle biopsy, To cite: Ng YS, Alston CL, Mitochondrial disease is clinically and genetically oriented muscle blocks were subjected to cyto- Diodato D, et al. J Med heterogeneous and often causes multisystem mani- chrome c oxidase (COX), succinate dehydrogenase – Genet 2016;53:768 775. festations. Defects in mitochondrial protein (SDH) and sequential COX/SDH histochemical 768 Ng YS, et al. J Med Genet 2016;53:768–775. doi:10.1136/jmedgenet-2016-103910 Genotype-phenotype correlations J Med Genet: first published as 10.1136/jmedgenet-2016-103910 on 13 July 2016. Downloaded from reaction to evaluate the numbers of COX-deficient fibres as a additional cystic changes in the cerebral lobe(s) (figure 1A–D). marker of mitochondrial respiratory chain deficiency.7 The SDH Basal ganglia calcification was identified on CT head in three reaction was also used to determine the number of ‘ragged-blue’ patients. Acute ischaemic infarct involving the unilateral par- fibres, whereby such muscle fibres exhibit increased levels of this ietal–temporal area was identified in one patient (P12). No enzyme activity in the subsarcolemmal region. The same histo- brainstem abnormalities were observed and five patients had a chemical studies were applied to study the cardiac and kidney normal cranial MRI. tissues. EEG was available for review in 10 patients. The EEG changes were non-specific with a variable degree of background Identification of pathogenic RMND1 mutations slowing and low amplitude being the most common findings The selection criteria of patients with suspected mitochondrial (n=6) and epileptic discharge was captured in four patients. disease for whole exome sequencing (WES) and the interpret- Three patients had febrile seizures (P4.1, P4.2 and P18.2) of ation of results have been described elsewhere.689Sanger whom only one developed on-going epilepsy (generalised sequencing was applied to verify the RMND1 mutations and seizure and myoclonus, P18.2). Infantile spasm was reported in study segregation within the pedigree. Where the RMND1 two patients (P1 and P8) though typical pattern of hypsarrhyth- mutation(s) were identified by candidate gene sequencing, the mia was not present in one of them (P8). coding region (11 coding exons) and intron–exon boundaries of the RMND1 gene were amplified using M13-tagged primers, Metabolic derangement and renal involvement and the resultant Sanger sequencing chromatograms were com- Lactic acidaemia (2.2–29 mmol/L, normal range <2.2 mmol/L) pared with the RMND1 reference sequence (GenBank Accession was documented in 20 patients (63%). CSF lactate level was Number NM_017909.2). Ensembl was used to investigate measured in seven patients and was generally lower (1.5– amino acid conservation of novel RMND1 variants. 5.9 mmol/L) than the serum lactate level except in one patient. Renal involvement was evident in 21 patients (66%). The mani- Statistical analysis festations of kidney disease included different stages of chronic Kaplan-Meier analysis and Cox-regression analysis were applied kidney disease (CKD, n=17), arterial hypertension (n=15), per- to determine the survival and associated prognostic factors. All sistent hyponatraemia and hyperkalaemia (which were suggest- analyses were performed using SPSS software (V.22.0) and sig- ive of renal tubular acidosis type 4, n=13), dysplastic or nificance level (p value) was determined at ≤0.05 level. hypoplastic kidneys (n=8, figure 1E) and normocytic anaemia (n=9). Hypouricosuric hyperuricaemia was identified in three RESULTS patients (P1, P7.1 and P7.2). Two patients had metabolic acid- Clinical phenotypes osis without evidence of lactic acidaemia (P7.1 and P7.2). The clinical features of 32 patients (male:female=12:20) from Urinary electrolyte levels were available in three cases, which 21 pedigrees are summarised in table 1. Fourteen patients from showed high urinary sodium and low potassium levels. Results 11 families (P1–P9, P10.1, P10.2, P11.1) are new cases; their of short-synacthen test were available in two patients and were clinical details are provided in online supplementary normal. Tubulointerstitial changes were identified in three renal data 1. Authors from the previously published cases568(P11.2, biopsies. P12–P18.2) also completed the case report form and provided Twelve patients developed end-stage renal failure (ESRF), additional data for this study (P11.2, P12–P16, online supple- which was fatal for seven of them. Four patients (P5, P6, P18.1 http://jmg.bmj.com/ mentary data 1). Clinical data were extracted from the literature
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