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

Yi Shiau Ng; Charlotte L Alston; Daria Diodato; Andrew D Morris; Nicole Ulrick; Stanislav Kmoch; Josef Houštěk; Diego Martinelli; Alireza Haghighi; Mehnaz Atiq; Montserrat Anton Gamero; Elena Garcia-Martinez; Hana Kratochvílová; Saikat Santra; Ruth M Brown; Garry K Brown; Nicola Ragge; Ahmad Monavari; Karen Pysden; Kirstine Ravn; Jillian P Casey; Arif Khan; Anupam Chakrapani; Grace Vassallo; Cas Simons; Karl McKeever; Siobhan O'Sullivan; Anne-Marie Childs; Elsebet Østergaard; Adeline Vanderver; Amy Goldstein; Julie Vogt; Robert W Taylor; Robert McFarland

doi:10.1136/jmedgenet-2016-103910

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

Yi Shiau Ng, Charlotte L Alston, Daria Diodato, Andrew D Morris, Nicole Ulrick, Stanislav Kmoch, Josef Houštěk, Diego Martinelli, Alireza Haghighi, Mehnaz Atiq, Montserrat Anton Gamero, Elena Garcia-Martinez, Hana Kratochvílová, Saikat Santra, Ruth M Brown, Garry K Brown, Nicola Ragge, Ahmad Monavari, Karen Pysden, Kirstine RavnJillian P Casey, Arif Khan, Anupam Chakrapani, Grace Vassallo, Cas Simons, Karl McKeever, Siobhan O'Sullivan, Anne-Marie Childs, Elsebet Østergaard, Adeline Vanderver, Amy Goldstein, Julie Vogt, Robert W Taylor, Robert McFarland

Department of Clinical Medicine

18 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medical Genetics
Volume	53
Issue number	11
Pages (from-to)	768-775
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2016-103910
Publication status	Published - 1 Nov 2016

Keywords

Journal Article

Access to Document

10.1136/jmedgenet-2016-103910Licence: CC BY

Cite this

Ng, Y. S., Alston, C. L., Diodato, D., Morris, A. D., Ulrick, N., Kmoch, S., Houštěk, J., Martinelli, D., Haghighi, A., Atiq, M., Gamero, M. A., Garcia-Martinez, E., Kratochvílová, H., Santra, S., Brown, R. M., Brown, G. K., Ragge, N., Monavari, A., Pysden, K., ... McFarland, R. (2016). The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease. Journal of Medical Genetics, 53(11), 768-775. https://doi.org/10.1136/jmedgenet-2016-103910

Ng, YS, Alston, CL, Diodato, D, Morris, AD, Ulrick, N, Kmoch, S, Houštěk, J, Martinelli, D, Haghighi, A, Atiq, M, Gamero, MA, Garcia-Martinez, E, Kratochvílová, H, Santra, S, Brown, RM, Brown, GK, Ragge, N, Monavari, A, Pysden, K, Ravn, K, Casey, JP, Khan, A, Chakrapani, A, Vassallo, G, Simons, C, McKeever, K, O'Sullivan, S, Childs, A-M, Østergaard, E, Vanderver, A, Goldstein, A, Vogt, J, Taylor, RW & McFarland, R 2016, 'The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease', Journal of Medical Genetics, vol. 53, no. 11, pp. 768-775. https://doi.org/10.1136/jmedgenet-2016-103910

@article{f9e9de0a2deb4f11afb7dc94d8af3855,

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

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 = "Journal Article",

author = "Ng, {Yi Shiau} and Alston, {Charlotte L} and Daria Diodato and Morris, {Andrew D} and Nicole Ulrick and Stanislav Kmoch and Josef Hou{\v s}t{\v e}k and Diego Martinelli and Alireza Haghighi and Mehnaz Atiq and Gamero, {Montserrat Anton} and Elena Garcia-Martinez and Hana Kratochv{\'i}lov{\'a} and Saikat Santra and Brown, {Ruth M} and Brown, {Garry K} and Nicola Ragge and Ahmad Monavari and Karen Pysden and Kirstine Ravn and Casey, {Jillian P} and Arif Khan and Anupam Chakrapani and Grace Vassallo and Cas Simons and Karl McKeever and Siobhan O'Sullivan and Anne-Marie Childs and Elsebet {\O}stergaard and Adeline Vanderver and Amy Goldstein and Julie Vogt and Taylor, {Robert W} and Robert McFarland",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2016",

month = nov,

day = "1",

doi = "10.1136/jmedgenet-2016-103910",

language = "English",

volume = "53",

pages = "768--775",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "B M J Group",

number = "11",

}

TY - JOUR

T1 - The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

AU - Ng, Yi Shiau

AU - Alston, Charlotte L

AU - Diodato, Daria

AU - Morris, Andrew D

AU - Ulrick, Nicole

AU - Kmoch, Stanislav

AU - Houštěk, Josef

AU - Martinelli, Diego

AU - Haghighi, Alireza

AU - Atiq, Mehnaz

AU - Gamero, Montserrat Anton

AU - Garcia-Martinez, Elena

AU - Kratochvílová, Hana

AU - Santra, Saikat

AU - Brown, Ruth M

AU - Brown, Garry K

AU - Ragge, Nicola

AU - Monavari, Ahmad

AU - Pysden, Karen

AU - Ravn, Kirstine

AU - Casey, Jillian P

AU - Khan, Arif

AU - Chakrapani, Anupam

AU - Vassallo, Grace

AU - Simons, Cas

AU - McKeever, Karl

AU - O'Sullivan, Siobhan

AU - Childs, Anne-Marie

AU - Østergaard, Elsebet

AU - Vanderver, Adeline

AU - Goldstein, Amy

AU - Vogt, Julie

AU - Taylor, Robert W

AU - McFarland, Robert

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1136/jmedgenet-2016-103910

DO - 10.1136/jmedgenet-2016-103910

M3 - Journal article

C2 - 27412952

SN - 0022-2593

VL - 53

SP - 768

EP - 775

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 11

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this