Elsevier

Revue Neurologique

Volume 170, Issue 5, May 2014, Pages 323-338
Revue Neurologique

Mitochondrial diseases
An overview of neurological and neuromuscular signs in mitochondrial diseasesDiversité des atteintes neurologiques et neuromusculaires dans les maladies mitochondriales héréditaires

https://doi.org/10.1016/j.neurol.2014.03.007Get rights and content

Abstract

Mitochondrial disorders have a broad clinical spectrum and are genetically heterogeneous, involving two genomes. These disorders may be develop at any age, with isolated or multiple system involvement, and any pattern of inheritance. Neurological involvement is the most frequent, and concerns muscular, peripheral and central nervous system. Among these diverse signs, some are suggestive of mitochondrial disease, such as progressive external ophthalmoplegia, exercise intolerance, psychomotor regression, stroke-like episodes, refractory epilepsy and Epilepsia Partialis Continua. Others are less specific and mitochondrial hypothesis may be evocated because of either association of different neuromuscular signs or a multisystemic involvement. This review describes the wealth of this neurological and neuromuscular symptomatology through different syndromes reported in the literature, according to preponderant signs and to modes of inheritance, as key elements to guide genetics testing.

Résumé

Les maladies mitochondriales présentent un large spectre clinique et une grande hétérogénéité génétique liée au double contrôle génétique, rendant ainsi leur diagnostic difficile. Elles peuvent se manifester à tout âge, sous la forme d’une atteinte isolée ou le plus souvent d’atteintes associées de tissus ou organes, et tous les modes de transmissions sont possibles. L’atteinte neurologique est la plus fréquente. Elle concerne le système musculaire, nerveux périphérique et nerveux central, engendrant ainsi une grande diversité de signes. Certains sont très évocateurs de maladie mitochondriale, comme l’ophtalmoplégie progressive externe, l’intolérance à l’effort, la régression psychomotrice, les « pseudo-stroke », l’épilepsie réfractaire ou l’épilepsie partielle continue. D’autres sont moins spécifiques et c’est l’association de différents signes neurologiques, musculaires ou systémiques qui vont faire suggérer une hypothèse mitochondriale. Dans cette revue, nous présentons un aperçu de la richesse de cette symptomatologie à travers les différents syndromes décrits dans la littérature, en fonction du signe prépondérant et du mode de transmission, ainsi que des éléments clefs permettant d’orienter les analyses génétiques.

Section snippets

Muscular manifestations of MiDs

The most evocative signs of MiDs remain the muscular signs, particularly ocular myopathy and exercise intolerance. Progressive external ophthalmoplegia (PEO) is characterized by progressive weakness or paresis of the extraocular eye muscles leading to bilateral gaze limited in all directions, usually without diplopia, and associated with ptosis. Ptosis may be also isolated. Myopathy begins usually in the teens or during adulthood and can occasionally be congenital. The weakness is slowly

Cerebellar ataxia

Ataxia is one of the most prevalent clinical CNS manifestations of MiDs, but is not specific. Ataxia is usually either cerebellar, due to cerebellum involvement, or sensory due to a spinal or peripheral lesion, but both are most frequently associated in MiDs. In this section, we present only phenotypes including at least a predominant cerebellar ataxia, but not an isolated sensory ataxia.

Polyneuropathy

Polyneuropathy is frequently reported in MiDs, but rarely as an isolated or dominant feature, except in some phenotypes including particularly NARP syndrome, CMT2A due to MFN2 mutations, CMT2K and CMT4A due to GDAP1 mutations, isolated sensory or sensorimotor axonal neuropathy due to POLG mutations [38], [42], [43], [74] or SANDO due to POLG [40].

MPV17 recessive mutations were reported in patients with adult-onset progressive peripheral neuropathy and liver cirrhosis associated with

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

References (140)

  • I. Holt et al.

    Deletion of muscle mitochondrial DNA in patients with mitochondrial myopathies

    Nature

    (1988)
  • D. Wallace et al.

    Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy

    Science

    (1988)
  • A.H. Schapira

    Mitochondrial disease

    Lancet

    (2006)
  • S. DiMauro et al.

    Mitochondrial disorders in the nervous system

    Annu Rev Neurosci

    (2008)
  • T.P. Kearns et al.

    Retinitis pigmentosa, external ophthalmophegia, and complete heart block: unusual syndrome with histologic study in one of two cases

    AMA Arch Ophthalmol

    (1958)
  • L.P. Rowland et al.

    Diverse clinical disorders associated with morphological abnormalities in mitochondria

  • S. Bannwarth et al.

    Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders

    J Med Genet

    (2013)
  • A.L. Andreu et al.

    Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA

    New Eng J Med

    (1999)
  • R. Horvath et al.

    Childhood-onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene

    J Med Genet

    (2002)
  • K. Maniura-Weber et al.

    A novel point mutation in the mitochondrial tRNA(Trp) gene produces a neurogastrointestinal syndrome

    Eur J Hum Genet

    (2004)
  • R. Horváth et al.

    Heteroplasmic mutation in the anticodon-stem of mitochondrial tRNA(Val) causing MNGIE-like gastrointestinal dysmotility and cachexia

    Neurol

    (2009)
  • R. Horvath et al.

    Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy

    Brain

    (2009)
  • A. Saada et al.

    Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy

    Nat Genet

    (2001)
  • M. Mancuso et al.

    Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene

    Arch Neurol

    (2003)
  • M. Oskoui et al.

    Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene

    Arch Neurol

    (2006)
  • A. Götz et al.

    Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome

    Brain

    (2008)
  • O. Elpeleg et al.

    Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion

    Am J Hum Genet

    (2005)
  • E. Ostergaard et al.

    Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion

    Am J Hum Genet

    (2007)
  • A. Bourdon et al.

    Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion

    Nat Genet

    (2007)
  • B. Bornstein et al.

    Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene

    Neuromuscul Disord

    (2008)
  • B. Acham-Roschitz et al.

    A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy

    Mol Genet Metab

    (2009)
  • G. Kollberg et al.

    A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion

    Neuromuscul Disord

    (2009)
  • A. Spinazzola et al.

    Clinical and molecular features of mitochondrial DNA depletion syndromes

    J Inherit Metab Dis

    (2009)
  • A. Behin et al.

    Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum

    Neurology

    (2012)
  • A.H. Buchaklian et al.

    Recessive deoxyguanosine kinase deficiency causes juvenile-onset mitochondrial myopathy

    Mol Genet Metab

    (2012)
  • D. Ronchi et al.

    Next generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions

    Brain

    (2012)
  • A. Di Fonzo et al.

    The mitochondrial disulfide relay system protein GFER is mutated in autosomal recessive myopathy with cataract and combined respiratory chain deficiency

    Am J Hum Genet

    (2009)
  • K. Auré et al.

    Progression despite replacement of a myopathic form of coenzyme Q10 defect

    Neurology

    (2004)
  • C.M. Quinzii et al.

    Human CoQ10 deficiencies

    Biofactors.

    (2008)
  • L.G. Riley et al.

    Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia: MLASA syndrome

    Am J Hum Genet

    (2010)
  • K. Casas et al.

    Mitochondrial myopathy and sideroblastic anemia

    Am J Med Genet

    (2004)
  • L.G. Riley et al.

    Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia

    Orphanet J Rare Dis

    (2013)
  • M. Gerards et al.

    Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene

    Brain

    (2011)
  • F. Mochel et al.

    Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance

    Am J Hum Genet

    (2008)
  • R. Spiegel et al.

    Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy

    Eur J Hum Genet

    (2013)
  • C.V. Logan et al.

    UK10K Consortium. Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling

    Nat Genet

    (2014)
  • A. Di Fonzo et al.

    POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions

    Hum Mutat

    (2003)
  • R. Horvath et al.

    Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene

    Brain

    (2006)
  • P.T. Luoma et al.

    Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome

    Hum Mol Genet

    (2005)
  • G. Van Goethem et al.

    Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia

    Neuromuscul Disord

    (2003)
  • P. Luoma et al.

    Parkinsonism, premature menopause, and mitochondrial DNA polymerase-gamma mutations: clinical and molecular genetic study

    Lancet

    (2004)
  • G. Davidzon et al.

    Early-onset familial parkinsonism due to POLG mutations

    Ann Neurol

    (2006)
  • C. Rouzier et al.

    Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort

    Eur J Hum Genet

    (2014)
  • C. Fratter et al.

    RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions

    Neurology

    (2011)
  • R.D. Pitceathly et al.

    Kearns-Sayre syndrome caused by defective R1/p53R2 assembly

    J Med Genet

    (2011)
  • R.D. Pitceathly et al.

    Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics

    Brain

    (2012)
  • C. Garone et al.

    MPV17 mutations causing adult-onset multisystemic disorder with multiple mitochondrial DNA deletions

    Arch Neurol

    (2012)
  • H. Tyynismaa et al.

    Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions

    Hum Mol Genet

    (2012)
  • C. Kornblum et al.

    Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease

    Nat Genet

    (2013)
  • M. Hirano et al.

    MNGIE: a disease of two genomes

    Neurologist

    (2004)

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