Review

Peripheral neuropathy in mitochondrial disorders

Davide Pareyson, Giuseppe Piscosquito, Isabella Moroni, Ettore Salsano, Massimo Zeviani

Why is peripheral neuropathy common but mild in many mitochondrial disorders, and why is it, in some cases, the Lancet Neurol 2013; 12: 1011–24 predominant or only manifestation? Although this question remains largely unanswered, recent advances in cellular Clinic of Central and Peripheral and molecular biology have begun to clarify the importance of mitochondrial functioning and distribution in the Degenerative Neuropathies peripheral nerve. Mutations in proteins involved in mitochondrial dynamics (ie, fusion and fi ssion) frequently result Unit, Department of Clinical Neurosciences (D Pareyson MD, in a Charcot-Marie-Tooth phenotype. Peripheral neuropathies with diff erent phenotypic presentations occur in G Piscosquito MD, mitochondrial diseases associated with abnormalities in mitochondrial DNA replication and maintenance, or E Salsano MD), Child Neurology associated with defects in mitochondrial respiratory chain complex V. Our knowledge of mitochondrial disorders is Unit, Department of Child rapidly growing as new nuclear genes are identifi ed and new phenotypes described. Early diagnosis of mitochondrial Neurology (I Moroni MD), and Molecular Neurogenetics Unit, disorders, essential to provide appropriate genetic counselling, has become crucial in a few treatable conditions. Department of Diagnostic and Recognising and diagnosing an underlying mitochondrial defect in patients presenting with peripheral neuropathy is Applied Technology therefore of paramount importance. (M Zeviani MD), IRCCS Foundation, C Besta Neurological Institute, Milan, Introduction complex V abnormalities are associated with a range of Italy; and MRC Mitochondrial Peripheral nerves are highly dependent on energy neuropathic phenotypes (panel). Peripheral neuropathy Biology Unit, Cambridge, UK metabolism, since they have long axons that are wrapped can occur in mitochondrial disorders other than those (M Zeviani) by myelin lamellae provided by Schwann cells. Thus, it due to disorders of mitochondrial dynamics or mtDNA Correspondence to: is not surprising that a third of patients with replication and maintenance, but it is usually mild or Dr Davide Pareyson, Clinic of Central and Peripheral mitochondrial disorders develop peripheral neuro- subclinical. Degenerative Neuropathies Unit, pathy.1–3 Although often mild or subclinical, peripheral Chronic sensorimotor axonal polyneuropathy is the Department of Clinical neuropathy can be severe and might be the main or only pattern most often seen in cases of peripheral neuropathy Neurosciences, IRCCS feature of a mitochondrial disorder. Identifi cation and associated with mitochondrial disorders.3,10,15–17 De- Foundation, C Besta Neurological Institute, via Celoria 11, 1–3,10,15,16 characterisation of peripheral neuropathy can be myelinating neuropathy is less common, but is 20133 Milan, Italy fundamental in diagnosing mitochondrial disorders. often associated with mitochondrial neurogastro- davide.pareyson@istituto- Peripheral neuropathy often occurs in mitochondrial intestinal encephalomyopathy (MNGIE; related to TYMP besta.it disorders associated with defects in mitochondrial DNA mutations)13 and occasionally with Leber hereditary optic (mtDNA) maintenance and replication or defects in neuropathy,18 Leigh syndrome,19 myoclonic epilepsy and respiratory chain complex V. The distribution of ragged-red fi bres (MERRF) syndrome,16 and mito- mitochondria along peripheral axons is regulated by a chondrial myopathy, encephalopathy, lactic acidosis, and continuous process of mitochondrial fusion and fi ssion stroke-like episodes (MELAS) syndrome.20 Sensory ataxic (this is termed mitochondrial dynamics and is neuropathy is another syndrome associated with fundamental for regulating number, shape, and mitochondrial disorders, particularly ataxia neuropathy transport of these organelles), and abnormalities in spectrum related to POLG1 mutations, and neuropathy, mitochondrial dynamics are increasingly understood to ataxia, and retinitis pigmentosa (NARP) syndrome be a cause of peripheral nerve dysfunction. Additionally, associated with MTATP6 mutations.1-3,10,11 nuclear genes associated with mitochondrial disorders In most mitochondrial disorders, peripheral neuropathy are continuously being identifi ed, and new phenotypes occurs in the setting of multisystem neurological are expanding the list of atypical presentations of known impairment as a minor manifestation that is useful for mitochondrial disorders. diagnosis but with little eff ect on patient disability. A small This Review addresses peripheral neuropathy in proportion of patients develop moderate-to-severe mitochondrial disorders, particularly when it is the key peripheral neuropathy in the context of multisystem or only feature. Peripheral neuropathy as a unique or diseases such as MELAS and MERRF syndromes, Leigh predominant manifestation of a mitochondrial disorder syndrome, and Kearns-Sayre syndrome.1–3,10 In these cases, is rare, and is restricted to disorders of mitochondrial peripheral neuropathy might be the fi rst manifestation, dynamics associated with MFN2 and GDAP1 subsequently complicated by involvement of other mutations;4–9 a few mitochondrial disorders related to neurological systems and extraneurological organs. defects in mtDNA replication and maintenance, caused It is important for neurologists to know when a by mutations in nuclear genes such as POLG1, C10ORF2, mitochondrial disorder might be the underlying cause of TYMP, and MPV17; or respiratory chain complex V peripheral neuropathy—ie, they should know the clinical defects associated with MTATP6 mutations leading to presentations, diagnostic clues, examinations to be decreased ATP synthesis.1–3,10–14 Whereas disorders of performed, diff erential diagnoses, and disorders mitochondrial dynamics usually present with a Charcot- amenable to treatment. This Review aims to provide an Marie-Tooth neuropathy (CMT), disorders of mtDNA update on peripheral neuropathy in mitochondrial replication and maintenance and respiratory chain disorders with a practical diagnostic approach. www.thelancet.com/neurology Vol 12 October 2013 1011 Review

(CMT6). More than 50 genes (eg, MFN2 and GDAP1) Panel: Mitochondrial disorders with peripheral neuropathy have been associated with CMT or distal hereditary Neuropathy as the only or predominant feature motor neuropathies and contribute to their further • MFN2-related disorders : autosomal dominant CMT2A, autosomal recessive CMT2, CMT5 subclassifi cation.21,22 (HMSN type V), CMT6 (HMSN type VI), complex phenotypes CMT might be the presenting phenotype of disorders • GDAP1-related disorders: autosomal recessive CMT2K, CMT4A, recessive intermediate of mitochondrial dynamics and other mitochondrial CMT, autosomal dominant CMT2K dysfunctions, including respiratory chain complex V • MTATP6-related disorders: CMT2 and dHMN defi cit. The main forms of mitochondrial CMT are listed • DHTKD1-related disorder: CMT2Q in table 1. Pure autosomal dominant CMT2 of varying • AIFM1-related disorder: CMTX4 (Cowchock syndrome) severity, sometimes complicated by pyramidal • PDK3-related disorder: CMTX6 involvement or optic atrophy, is associated with mutations in MFN2, whereas GDAP1 mutations usually Neuropathy as a key feature result in autosomal recessive CMT with normal or • MTATP6-related disorders: NARP, MILS decreased nerve conduction velocities. • POLG1-related disorders: ataxia neuropathy spectrum , SANDO, MNGIE-like syndrome MFN2 and GDAP1 are involved in the fusion and fi ssion • C10ORF2-related disorder: SANDO, IOSCA (MTDPS7), complex phenotypes of mitochondria (mitochondrial dynamics), processes that • TYMP-related disorder: MNGIE (MTDPS1) are fundamental in regulating mitochondrial shape, size, • RRM2B-related disorder: MNGIE-like syndrome (MTDPS8B) number, and transport along the cell (fi gure 1).4,5 Fusion is • MPV17-related disorder: Navajo neurohepatopathy (MTDPS6) governed by dynamin-like GTPases located in the outer • SLC25A19-related disorder: neuropathy and bilateral striatal necrosis membrane (MFN1 and MFN2) and inner membrane 4,5 Neuropathy as a minor feature (OPA1). MFN1 and MFN2 form homotypic and • OPA1-related disorder: DOA plus syndrome heterotypic oligomers, tethering mitochondria during • POLG1-related disorders: MIRAS, Alpers-Huttenlocher syndrome, MEMSA, complex fusion. OPA1 is important for inner membrane fusion and phenotypes cristae shaping. GDAP1, located in the outer membrane, 4,6 • ND1-related, ND4-related, and ND6-related disorders and other mtDNA mutations: has a role in mitochondrial fi ssion. At least three proteins LHON involved in mitochondrial dynamics are associated with • SURF1-related disorder and other gene mutations: Leigh syndrome peripheral neuropathy—ie, mutations aff ecting MFN2 7–9,21,22 • MTTL1 3243A→G and other mtDNA mutations: MELAS syndrome and GDAP1 can cause CMT, and OPA1 mutation 23–25 • MTTK 8344A→G and other mtDNA mutations: MERRF syndrome carriers can develop neuropathy. So far, no phenotype • Single mtDNA deletion-related disorder: Kearns-Sayre syndrome has been associated with MFN1 mutations. • ADCK3-related disorder: primary coenzyme Q10 defi ciency syndrome • Non-syndromic respiratory chain disorders MFN2-related CMT and more complex phenotypes MFN2 is a 19-exon gene on chromosome 1p36.22 that CMT=Charcot-Marie-Tooth neuropathy. HMSN=hereditary motor and sensory neuropathy. dHMN=distal hereditary motor encodes a 757-aminoacid protein containing a GTPase neuropathy. NARP=neuropathy, ataxia, and retinitis pigmentosa. MILS=maternally inherited Leigh syndrome. SANDO=sensory ataxia, neuropathy, dysarthria, and ophthalmoplegia. MNGIE=mitochondrial neurogastrointestinal encephalopathy. domain, two transmembrane domains, and two coiled-coil IOSCA=infantile-onset spinocerebellar ataxia. MTDPS=mitochondrial DNA depletion syndrome. DOA=autosomal dominant regions that mediate binding with other mitofusin optic atrophy. MIRAS=mitochondrial recessive ataxia syndrome. MEMSA=myoclonic epilepsy, myopathy, and sensory ataxia. molecules.7,26 MFN2 tethers mitochondria to the LHON=Leber hereditary optic neuropathy. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. MERRF=myoclonus epilepsy with ragged-red fi bres. mtDNA=mitochondrial DNA. endoplasmic reticulum and might have a role in calcium release and infl ux to mitochondria.26 MFN2 is also involved in increasing permeability of the outer membrane, Mitochondrial CMT oxidative phosphorylation and gradient coupling, and CMT is a heterogeneous group of hereditary neuropathies mitochondrial transport along neurons through the characterised by distal limb muscle wasting and microtubule system.5,26,27 This is a crucial process that weakness, with sensory loss, reduced or absent deep allows proper distribution of mitochondria in the cell, tendon refl exes, and foot deformities. Subdivision into including concentration in particular regions of peripheral demyelinating (CMT1 if autosomal dominant and CMT4 neurons (eg, Ranvier’s nodes and synaptic terminations).27 if autosomal recessive) and axonal forms (CMT2, which Although MFN2 is ubiquitously expressed, mutations in is typically dominant but can be recessive) is based on this protein have been associated only with neurological nerve conduction velocities (demyelinating if ≤38 m/s in dysfunction, particularly CMT. Low levels of MFN1 in upper limb motor nerves vs axonal if >38 m/s). neurons, which are not suffi cient to compensate the MFN2 Intermediate forms between CMT1 and CMT2 include defect, are postulated to contribute to the organ specifi city X-linked CMT (CMTX1), and dominant and recessive of the disease.4,26 intermediate CMT types. Pure motor forms are labelled as distal hereditary motor neuropathies. Rare subtypes Clinical characteristics and presentation include hereditary motor and sensory neuropathy type V, MFN2 mutations are usually associated with autosomal which indicates CMT plus corticospinal tract involvement dominant axonal CMT2 (CMT2A), and MFN2 is the most (CMT5), and type VI, which is CMT with optic atrophy frequently mutated gene in CMT2 (in up to about 20% of

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Gene Inheritance Nerve conduction velocity Neuropathology Frequency CMT2A MFN2 Autosomal dominant Normal to slightly reduced Axonal changes Around 10–20% of CMT2 Autosomal recessive CMT2A MFN2 Autosomal recessive Normal to slightly reduced Axonal changes A few families reported or semidominant CMT5 (HMSN type V) with MFN2* Autosomal dominant Preserved Axonal changes Rare pyramidal involvement CMT6 (HMSN type VI) with optic MFN2 Autosomal dominant Preserved Axonal changes 10–20% of CMT2A atrophy Autosomal dominant CMT2K GDAP1 Autosomal dominant Normal to slightly reduced Axonal changes Around 5% of CMT2 CMT4A GDAP1 Autosomal recessive Slowed nerve conduction Mainly axonal changes, Probably second most velocity, severely reduced with or without secondary common type of recessive CMAP myelin abnormalities CMT Recessive intermediate CMTA GDAP1 Autosomal recessive Intermediate Mainly axonal changes, Probably second most with or without secondary common type of recessive myelin abnormalities CMT Autosomal recessive CMT2K GDAP1 Autosomal recessive Preserved Mainly axonal changes, Probably second most with or without secondary common type of recessive myelin abnormalities CMT CMT2 and dHMN MTATP6 Matrilineal Normal to slightly reduced Onion bulbs in one biopsy Rare (<1% of CMT2) CMT2Q DHTKD1 Autosomal dominant Normal to slightly reduced Not determined One family CMTX4 (Cowchock syndrome) AIFM1 X-linked Preserved Not determined Deafness and cognitive impairment CMTX6 PDK3 X-linked Varying, slightly slowed Not determined One family

CMT=Charcot-Marie-Tooth neuropathy. HMSN=hereditary motor and sensory neuropathy. CMAP=compound muscle action potential. dHMN=distal hereditary motor neuropathy. *Other genes are also associated with CMT5.

Table 1: Main forms of mitochondrial CMT cases).7,28–33 Most patients with CMT2A have disabling hearing loss, which are non-specifi c features also neuropathy with early onset (during childhood or observed in other CMT types.7,21,30 About 10–20% of adolescence), a progressive course, and motor patients with MFN2-related neuropathy develop optic predominance, sometimes leading to loss of ambulation atrophy, showing that MFN2 mutations are a molecular and severe proximal weakness.7,28,29,31 Other cases show basis for hereditary motor and sensory neuropathy less severe phenotype and later onset.28 De-novo type VI (CMT6).28–30,36 Patients might develop subacute mutations occur with a high frequency in CMT2A.30,31 visual loss with subsequent good or incomplete Almost 100 sequence variants are known, mainly recovery—resembling Leber hereditary optic missense mutations in crucial MFN2 protein regions, neuropathy—or insidious and gradually worsening particularly the GTPase domain and coiled-coil motifs; a visual impair ment.28,29,36 Mutations in diff erent domains few small deletions as well as frameshift and nonsense have been associated with hereditary motor and sensory mutations have also been reported.26,31 Incomplete neuropathy type VI, although members of the same penetrance with no phenotype in mutation carriers has CMT2A family might or might not develop optic been reported; additionally, some sequence variations are atrophy.7,28–30 Pyramidal involvement can complicate probably benign polymorphisms.31 CMT2A, with increased deep tendon refl exes, Babinski In CMT2A, nerve conduction velocities are preserved sign, and, rarely, overt spastic paraplegia, suggesting or slightly slowed, with varying reduction in amplitudes another molecular basis for hereditary motor and sensory of compound muscle and sensory action potentials, neuropathy type V (CMT5).37,38 Discrete T2 hyperintense mainly in the lower limbs.29–31 Very rarely, nerve signals have been reported in brain MRIs of patients conduction velocity is slowed out of proportion with the with CMT2A;30,39,40 although unspecifi c, the occurrence of reduction in compound muscle action potential this fi nding in several young patients suggests an amplitude determined by axonal loss, suggesting association with the disease. secondary myelin abnormalities. Nerve biopsies usually A few families have been reported with early-onset show predominant chronic axonal degeneration axonal neuropathy and homozygous or compound sometimes with the presence of small onion bulbs heterozygous MFN2 mutations (some mutations were (fi gure 2).29,30,34 Some reports described mitochondrial intragenic deletions), which manifest as recessive or abnormalities with distal accumulation of abnormally semidominant traits with no or few signs in heterozygous shaped mitochondria with cristae alterations.29,34,35 carriers.34,41,42 The phenotype ranged from a severely More complex phenotypes that are sometimes seen disabling neuropathy with optic neuropathy, cranial with CMT2A include the presence of hand tremor and nerve, and respiratory involvement, to typical CMT2. www.thelancet.com/neurology Vol 12 October 2013 1013 Review

AB C

MFN2 GDAP1 OPA1 OPA1 OPA1 MFN2 MFN2 OPA1 MFN2 DRP1 GDAP1 MFN2 Miro Milton GDAP1

–+KHC GDAP1 Microtubules DE Thymine NDPs

TYMP RRM2B ↑Thymidine ↓dNDPs mRNA Intermembrane space * * * * * * * ↓dNTPs C10ORF2 Inner ↑Thymidine TK2 MPV17 mitochondrial III III IV V dCTD ↓dCMP → ↓dCTP POLG1mtDNA

membrane SURF1 ND6 Matrix α-KG SCA→↓ATP synthesis ND1 ND4 MTATP6 PDK3 α-KGD ↓ 7 1 3 2 ü PDH mRNA *Respiratory chain SLC25A19

TPP MTTL1 mtDNA MTTK

Figure 1: Overview of mechanisms underlying the main mitochondrial peripheral neuropathies (A) MFN2 is located in the outer mitochondrial membrane and interacts with Miro and Milton proteins, which belong to the molecular complex that links mitochondria to kinesin (KHC) motors. (B) MFN2 participates in bringing the outer membranes of two mitochondria into close proximity. Thus, MFN2 mutations can lead to defects in mitochondrial motility along the cytoskeletal microtubular tracks, and to dysfunction in fusion of the outer mitochondrial membranes of opposing mitochondria. Similarly, mutations in OPA1, which is located in the inner mitochondrial membrane, lead to dysfunction in the fusion process of the inner mitochondrial membrane. (C) Loss-of-function mutations in GDAP1, located in the outer mitochondrial membrane, can lead to dysfunction in the mitochondrial fi ssion process, since GDAP1 might be a positive eff ector of assembly of the fi ssion mediator DRP1. Dysfunction is shown by red oblique bars. (D) Dysfunctions in the respiratory chain can be due to the following: direct mutations in mitochondrial protein-coding genes (red segment of circular mtDNA) ND1, ND4, and ND6, which encode for subunits of complex I (NADH dehydrogenase), and MTATP6, which encodes for a subunit of complex V (ATP-synthase); mutations in mitochondrial tRNA-coding genes (light blue segment) MTTL1 and MTTK, which lead to dysfunction in transcription of mitochondrial protein-coding genes; or direct mutations in the nuclear gene SURF1 (in green), which encodes an ancillary protein involved in complex IV (cytochrome c oxidase) assembly. Dysfunction in the corresponding respiratory chain complexes are shown by red, light blue, and green asterisks, respectively. Encircled numbers show the number of subunits encoded by mtDNA. (E) Dysfunctions of the respiratory chain can also occur as a result of changes in mtDNA synthesis (red oblique bar), which lead to mtDNA depletion or multiple mtDNA deletions. mtDNA synthesis might be disturbed by the following: mutations in nuclear genes encoding components of the mitochondrial replisome—ie, polymerase gamma POLG and the helicase C10ORF2 genes; loss-of-function mutations (red oblique bar) in genes involved in the synthesis of nucleotides—ie, RRM2B and TYMP— which lead to nucleotide depletion (red lines show inhibition); or mutations in MPV17, a nuclear gene encoding an inner mitochondrial membrane protein of unknown function. Finally, mitochondrial peripheral neuropathies might result from changes in intermediary metabolism that eventually lead to decreased ATP synthesis. Mutations in SLC25A19 inhibit the passage of TPP from the cytosol to the mitochondrial matrix, thus leading to lactate accumulation and an increase in αKG (an intermediate of the Krebs cycle), since TPP is an essential cofactor of PDH and αKGD (green lines show stimulation); similarly, a gain-of-function mutation (green tick mark) in PDK3 might lock PDH in an inactive state, limiting glucose oxidation and favouring a switch toward anaerobic lactate production. nDNA=nuclear DNA. mtDNA=mitochondrial DNA. NDPs=nucleoside diphosphates. dNDPs=deoxynucleoside diphosphates. dCTD=deoxycytidine. dCMP=deoxycytosine monophosphate. dCTP=deoxycytosine triphosphate. α-KG=α-ketoglutarate. α-KGD=α-ketoglutarate dehydrogenase. SCA=succinyl-CoA. TPP=thiamine pyrophosphate. PDH=pyruvate dehydrogenase.

The spectrum of MFN2-related phenotypes is rapidly individuals; MRI and autopsy showed symmetric broadening, and complex clinical pictures have been vascular–necrotic lesions in the upper brainstem and reported. Macrocephaly and mild diff use signal periaqueductal grey matter. abnormalities in cerebral white matter occurred in two Recently, a large family harbouring a novel Asp210Val patients with CMT2A.40 Del Bo and colleagues38 reported substitution in the GTPase domain of MFN2 showed a a family with CMT2A with cognitive and visual very complex phenotype, with the following features impairment and, in one case, spastic paraparesis. present to a varying extent in aff ected individuals: optic Boaretto and colleagues43 studied a family carrying a atrophy, predominantly sensory axonal neuropathy, heterozygous intronic MFN2 mutation, where late- hearing loss, pyramidal involvement, cognitive impair- onset, rapidly progressive CMT2 was complicated by ment, proximal myopathy, cerebellar syndrome, cataracts, subacute, lethal, Wernicke-like encephalopathy in four supratentorial white matter changes, and muscle

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mitochondrial abnormalities (including ragged red fi bres A B and multiple mtDNA deletions).44 A de-novo Asp210Tyr substitution was also reported in a girl aff ected by a severe multisystem disorder with psychomotor retardation, microcephaly, chorea, neuropathy, optic atrophy, hearing loss, and mtDNA depletion.45

Diagnosis of CMT related to MFN2 mutations MFN2-related neuropathy should be suspected in all cases of axonal CMT, particularly if autosomal dominant, whatever the age of onset. Sporadic axonal CMT of early 100 µm 100 µm onset and severe course is a typical presentation related to the frequency of de-novo mutations. The co-occurrence of C D optic atrophy (CMT6) strongly points to MFN2 as a causative gene, and the presence of pyramidal involvement (CMT5) is another feature that warrants MFN2 mutation screening. The frequency with which mutated MFN2 causes very complex phenotypes is still unknown.

Pathological mechanisms How MFN2 mutations result in CMT2 or more complex phenotypes is unclear. In cellular studies, some MFN2 10 µm 10 µm mutations aff ect mitochondrial fusion, whereas others do 5,26,27 not. Abnormal mitochondrial transport leading to Figure 2: Nerve biopsy fi ndings in patients with CMT2A who carry MFN2 mutations distal axonal degeneration probably explains peripheral Light microscopy of transverse semithin sections stained with Toluidine blue, showing sural nerve biopsy in two neuropathy and pyramidal involvement in CMT2A and patients with CMT2A, a 6-year-old girl with heterozygous Arg94Gln mutation (A, C), and a 68-year-old-woman CMT5, with the longest axons preferentially aff ected.27 The with heterozygous Met376Ile mutation (B, D). (A, B) Nerve fascicles showing reduced myelinated fi bre density are more evident in the adult (B) case. (C, D) Higher magnifi cation of both cases showing myelin fi bre loss and occurrence of optic atrophy in patients with CMT6 links occasional regeneration clusters (asterisks). In the aff ected child (C), some fi bres with thin myelin sheaths with MFN2 dysfunction to OPA1, since mutations in this gene respect to the axonal calibre are present (arrows). Image courtesy of Tiziana Cavallaro and Gian Maria Fabrizi. are associated with dominant optic atrophy, a syndrome sometimes complicated by a multisystem neurological intermediate recessive (RI-CMT) forms have been disorder with multiple mtDNA deletions or even depletion. described, leading to uncertainty about whether the Dominant optic atrophy is probably due to impaired primary defect is in the myelin or axon.8,9,48,49 Neuropathy mitochondrial fusion and not to abnormal mitochondrial is characterised by a severe course, with onset in infancy transport.5,23–27 MFN2-related optic atrophy and more and rapid progression to loss of distal movements, complex phenotypes could be the result of changes in proximal weakness, and wheel-chair dependence MFN2 functions other than mitochondrial transport—eg, typically by age 20–30 years.46,49–51 Hoarseness of voice due mitochondrial fusion or oxidative phosphorylation to vocal cord palsy occurs in a high proportion of cases, coupling, as seen with OPA1 mutations. Such dysfunction and diaphragm involvement can also be observed.46,50 might lead to altered maintenance, instability, and Nerve conduction velocity is often preserved; however, secondary abnormalities of mtDNA, the ultimate patho- when reduced (sometimes substantially), it is physiological basis for complex phenotypes.44 accompanied by marked decrease in compound muscle action potential amplitude, suggesting concomitant GDAP1-related CMT severe axonal loss.46,49,51 Nerve biopsy shows constant and GDAP1 is encoded by a six-exon gene on chromosome predominant chronic axonal degeneration, with 8q21.11 and contains two glutathione S-transferase preferential loss of large myelinated fi bres; demyelination domains, one transmembrane domain, one hydrophobic features depend on the extent of axonal damage, in domain, and an alpha4–alpha5 loop important for protein keeping with a primary axonal neuropathy, with interaction.8,9,46 GDAP1 is involved in mitochondrial secondary myelin changes ensuing with disease fi ssion, although the mechanism is unknown. It is progression (fi gure 3).46,48,49 debated whether it is exclusively localised in axons or is More than 40 mutations associated with GDAP1-related also expressed in myelinating Schwann cells.4–6,9,47 CMT have been described, with either compound heterozygosity or homozygosity. Most of these are mis- Clinical characteristics and presentation sense mutations involving the glutathione S transferase GDAP1 mutations are usually associated with severe, domains or the alpha4–alpha5 loop, but several early-onset, autosomal recessive CMT. Axonal (auto- frameshift, nonsense, and splicing mutations have also somal recessive CMT2K), demyelinating (CMT4A), and been reported.46,51 Recessive truncating mutations might www.thelancet.com/neurology Vol 12 October 2013 1015 Review

be associated with more severe disease, suggesting that Pathological mechanisms the C-terminal portion is necessary for protein targeting A few GDAP1 mutations cause neuropathy in to mitochondria, and related mutations lead to a complete heterozygotes, whereas many others are associated with loss of function. Missense mutations might produce a disease only when both alleles are mutated. Niemann protein that is still targeted to the outer membrane but and colleagues6 showed that recessive mutations behave has reduced or altered function, resulting in less severe as loss-of-function mutations and are associated with consequences.46,49 Ten diff erent heterozygous GDAP1 decreased mitochondrial fi ssion, whereas dominant mutations have been reported to cause autosomal mutations can cause a gain of abnormal function dominant CMT2K, a form of CMT with later onset and resulting in impaired fusion (as with MFN2 mutations), less severe phenotype than recessive forms related to increased production of reactive oxygen species, and GDAP1, slowly progressive course, and only rarely enhanced apoptosis. In both cases, changes in leading to severe impairment; these patients show mitochondrial dynamics might lead to altered transport preserved or slightly slowed nerve conduction velocity, of mitochondria and the distal axonal degeneration without evidence of relevant myelin derangement.51–53 typical of CMT, albeit with diff erent degrees of severity. Decreased activity of respiratory chain complex I was Diagnosis of GDAP1-related CMT reported in muscle and fi broblasts from patients with Mutations in GDAP1 frequently cause recessive CMT and dominant GDAP1-associated CMT.51 Two families with should be screened for in all patients with early-onset and CMT had combined mutations in MFN2 and GDAP1.54,55 severe CMT, irrespective of nerve conduction velocities, These individuals had severe neuropathy and substantial and particularly if electrophysiology or nerve biopsy show mitochondrial functional abnormalities (ie, reduced prominent loss of axons. Vocal cord palsy is another respiratory chain complex I activity and energy feature suggesting GDAP1-related neuropathy. The uncoupling in fi broblasts, and enlarged mitochondria frequency of GDAP1 mutations in autosomal dominant with distorted cristae seen on nerve biopsy), because of CMT2 is undetermined, but might be high in regions the combined eff ect of the mutations on diff erent parts with founder mutations (ie, Spain).32,53 Diff erential of the same pathway in mitochondrial dynamics. diagnoses include acquired and inherited causes of severe neuropathy with onset in infancy and childhood (table 2). MTATP6-related CMT Maternally-inherited mutations in the mitochondrial A B C ATP-synthase subunit 6, encoded by MTATP6, usually present with NARP syndrome or Leigh syndrome; rarely, isolated peripheral neuropathy was reported in association with 9185T→C or 8993T→C mutations.56–60 Screening for the 8993T→C mutation in 96 clinically diagnosed (genetically undiagnosed) cases of CMT did not show any cases with the mutation;61 however, Pitceathly and colleagues62 recently found the 9185T→C mutation in 100 µm 10 µm 50 µm 1∙1% of 270 patients with genetically undiagnosed CMT2. Three families and one sporadic patient presented with a D E F phenotype that included pure motor or predominantly motor neuropathy (CMT2 and distal hereditary motor neuropathy); associated features were learning disabilities, pyramidal involvement, sensorineural hearing loss, retinitis pigmentosa, proximal neurogenic weakness, and illness with symptoms similar to those of Leigh syndrome. In another family, CMT2 was associated with the 9176T→C mutation.63 Therefore, diff erential

2 µm 1·5 µm 400 nm diagnosis of CMT2 now includes MTATP6 mutations, particularly when there are mild associated features and Figure 3: Nerve biopsy fi ndings in a patient with early-onset, severe, GDAP1-related neuropathy transmission is compatible with matrilineal inheritance. Sural nerve biopsy of a 3·5-year-old child with recessive CMT2K due to GDAP1 mutations (Arg125stop and Leu239Phe).49 (A, B) Light microscopy of transverse semithin sections stained with Toluidine blue. (A) A nerve fascicle showing reduced myelinated fi bre density. (B) Occasional Wallerian-like degenerations (arrow), cluster of Other CMT types regeneration (asterix), and Schwann cell hyperplasia (arrowheads) are seen. (C) Teased fi bres showing internodal Recently, a large Chinese family with autosomal and paranodal remyelination (arrows), short internodes as sign of regeneration (arrowheads), and fi bres with dominant CMT2 was shown to carry a nonsense rosary-like morphology, expression of Wallerian-like degeneration (asterisk). (D–F) Electron microscopy ultrathin mutation in DHTKD1, which is involved in mitochondrial section (treated with uranyl acetate and lead citrate). (D) Normally myelinated fi bre surrounded by Schwann cell 64 65 66 nuclei (asterisks) and cell processes containing amyelinated fi bres (arrows). (E) Several collagen pockets (arrows) energy production; additionally, CMTX4 and CMTX6 as sign of unmyelinated fi bre loss. (F) Higher magnifi cation shows that mitochondrial morphology is unaff ected have been associated with mutations in two genes (arrowheads). involved in mitochondrial metabolism (table 1).

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Peripheral neuropathy with visual impairment Gene Diff erential diagnoses Visual loss due to optic atrophy or pigmentary retinopathy in combination with polyneuropathy is a phenotype highly Disorders of mitochondrial dynamics suggestive of mitochondrial dysfunction, as in dominant CMT2 MFN2 Other axonal CMT, other inherited and acquired axonal neuropathies optic atrophy plus syndrome (OPA1 mutations), Leber CMT5 MFN2 Other causes of CMT5 (mutations in BSCL2, GJB1, HSPB1, SETX), hereditary optic neuropathy (ND1, ND4, ND6), CMT6 complicated hereditary spastic paraplegia, adrenomyeloneuropathy (MFN2), and NARP syndrome (MTATP6). In CMT6, CMT6 MFN2 LHON, DOA plus peripheral neuropathy precedes optic involvement and Recessive CMT GDAP1 Other CMT with early onset, CIDP both might be prominent. In dominant optic atrophy plus Dominant CMT GDAP1 Other mild-to-moderate axonal CMT, other inherited and acquired axonal neuropathies syndrome, visual loss is almost always a predominant DOA plus OPA1 LHON, CMT6, Wolfram syndrome feature and peripheral neuropathy is a possible subsequent Disorders of mtDNA replication and maintenance, and of complex V fi nding, often of minor importance. Leber hereditary optic NARP MTATP6 Acquired sensory ataxias, AVED, abetalipoproteinaemia, peroxisomal neuropathy is only rarely complicated by peripheral disorders (Refsum and Refsum-like diseases) neuropathy. Neuropathy and retinopathy are both typical CMT2 and dHMN MTATP6 Other axonal CMT and dHMN of NARP syndrome and can be severely disabling. SANDO POLG1 Inherited ataxias (Friedreich’s ataxia, AVED, SCA28, etc), CMT, abetalipoproteinaemia, acquired chronic progressive sensory ataxias Dominant optic atrophy plus syndrome and OPA1 (ie, Sjoegren syndrome) OPA1 is a 690-aminoacid protein encoded by a 30-exon SANDO, IOSCA C10ORF2 Inherited ataxias (Friedreich’s ataxia, AVED, SCA28, etc), CMT, gene on chromosome 3q29, and is involved in abetalipoproteinaemia, acquired chronic progressive sensory ataxias (ie, Sjoegren syndrome) mitochondrial fusion, cristae organisation, oxidative MNGIE TYMP Leukodystrophies, CIDP, demyelinating CMT phosphorylation, and maintenance of mitochondrial membrane potential. Heterozygous mutations lead to CMT=Charcot-Marie-Tooth neuropathy. LHON=Leber hereditary optic neuropathy. DOA plus=autosomal dominant early-onset and progressive dominant optic atrophy.5 optic atrophy plus syndrome. CIDP=chronic infl ammatory demyelinating polyradiculoneuropathy. mtDNA=mitochondrial DNA. NARP=neuropathy, ataxia, and retinitis pigmentosa. AVED=ataxia with vitamin E About 20% of patients develop subsequent hearing loss defi ciency. dHMN=distal hereditary motor neuropathy. SCA28=spinocerebellar ataxia type 28. SANDO=sensory ataxia, and further neurological abnormalities, such as neuropathy, dysarthria, and ophthalmoplegia. IOSCA=infantile-onset spinocerebellar ataxia. MNGIE=mitochondrial progressive external ophthalmoplegia, peripheral neurogastrointestinal encephalopathy. MILS=maternally inherited Leigh syndrome. neuropathy, proximal myopathy, and cerebellar ataxia Table 2: Diff erential diagnoses of the main mitochondrial disorders presenting with peripheral neuropathy (dominant optic atrophy plus syndrome); this multisystem disorder is associated with missense mutations in the GTPase domain.23–25 Muscle biopsy often shows multiple absent deep tendon refl exes, distal wasting and weakness, mtDNA deletions and sometimes depletion, ragged red distal sensory loss, and sensory ataxia.57–59 Electrophysiology fi bres, and COX-defi cient fi bres. Neuropathy is usually shows chronic axonal degeneration and reduced sensory mild, sensorimotor or mostly sensory, and axonal, action potential amplitudes.10,17,58,59 MTATP6 mutations can manifesting as reduced-to-absent deep tendon refl exes, manifest as a pure neuropathy. Mild-to-moderate sensory loss, varying ataxia (sensory and cerebellar), and neuropathy was the only manifestation in four individuals distal muscle wasting and weakness. Pes cavus can be from three unrelated families harbouring 9185T→C or seen. Nerve conduction studies show preserved nerve 8993T→C mutations;56,59,60 one individual had a previous conduction velocity but reduced compound muscle action diagnosis of CMT with ataxia.60 Another family carrying potential and sensory action potential amplitudes. Most the 8993T→C mutation showed adult-onset, slowly OPA1 sequence alterations are loss-of-function mutations, progressive ataxia and polyneuropathy.67 Diagnosis is but some can have a dominant-negative eff ect, since OPA1 diffi cult when the clinical picture is incomplete. forms homo-oligomers. As with other proteins that cause Furthermore, plasma lactic acid concentrations are not peripheral neuropathy, OPA1 and MFN2 seem to be increased and muscle biopsy usually does not show associated with mtDNA stability (table 3). mitochondrial histochemical abnormalities, since MTATP6 is involved in the fi nal step of ATP production in Defects of ATP synthesis energy coupling. NARP syndrome is usually characterised by neuropathy, neurogenic proximal weakness, cerebellar ataxia, and Leber hereditary optic neuropathy and Kearns-Sayre retinitis pigmentosa, with varying extent of supratentorial syndrome involvement. MTATP6 mutations, by causing defi cits in Leber hereditary optic neuropathy is associated with ATP produced by complex V of the respiratory chain, mutations in the mitochondrial genes ND1, ND4, and cause a range of phenotypes of diff erent severity, including ND6, which encode respiratory chain complex I subunits, maternally inherited Leigh syndrome.56–60 8993T→G is the and is only very rarely complicated by severe neuropathy most common mutation seen in MTATP6, but other that can be demyelinating.18 Peripheral neuropathy can missense changes have been reported, including occur in Kearns-Sayre syndrome, which is due to single 8993T→C and 9185T→C. Neuropathy is axonal, mainly mtDNA macrodeletions and is characterised by sensory, and can manifest as pes cavus, decreased or pigmentary retinopathy.10 www.thelancet.com/neurology Vol 12 October 2013 1017 Review

Inheritance Phenotype Pathophysiology Neuropathy Type Nerve conduction Severity range Relevance velocities MFN2 Autosomal CMT2A, HMSN type V, Mitochondrial Sensory-motor axonal Normal or slightly Mild to severe Usually the only feature dominant much HMSN type VI dynamics decreased more frequent than recessive GDAP1 Autosomal CMT4A, CMT2K, recessive Mitochondrial Sensory-motor axonal (with Normal or Autosomal Usually the only feature recessive more intermediate CMT dynamics or without secondary decreased recessive is severe; frequent than demyelinating changes) autosomal dominant dominant is mild to moderate OPA1 Autosomal DOA plus Mitochondrial Sensory-motor axonal Normal or slightly Subclinical to mild Occurs with other dominant dynamics decreased features MTATP6 Mitochondrial NARP and MILS, CMT2-like Oxidative Predominantly sensory Normal or slightly Moderate to severe Can be the sole or and dHMN-like phosphorylation axonal; predominantly motor decreased presenting feature coupling, ATP in CMT2-like synthesis POLG1 Autosomal Alpers-Huttenlocher mtDNA replication Sensory axonal; Normal or slightly Moderate to severe Can be the sole or recessive more syndrome, SANDO, MIRAS, and maintenance hypomyelinating when early decreased presenting feature frequent than MEMSA, MNGIE-like onset dominant C10ORF2 Autosomal SANDO, IOSCA, progressive mtDNA replication Usually sensory axonal Normal or slightly Mild or subclinical, Prominent dominant or external ophthalmoplegia and maintenance decreased rarely severe recessive TYMP Autosomal MNGIE mtDNA replication Sensory-motor demyelinating Decreased Subclinical to Can be the presenting recessive and maintenance severe feature RRM2B Autosomal MNGIE-like mtDNA replication Sensory-motor demyelinating Decreased Only one case Occurs with other recessive and maintenance reported features MPV17 Autosomal Navajo neurohepatopathy mtDNA Sensory-motor axonal or Normal or slightly Severe Substantial feature recessive maintenance demyelinating decreased MTTL1 3243A→G Mitochondrial MELAS Respiratory chain Sensory-motor predominantly Normal or Varies, usually mild Frequently occurs with (and other disorder axonal decreased other fi ndings, rarely mitochondrial severe mutations) MTTK 8344A→G Mitochondrial MERRF Respiratory chain Sensory-motor usually mixed Varies, often Varies, usually Frequent but mild and (and other disorder decreased mild, only rarely with other fi ndings mitochondrial severe mutations) mtDNA ND1, ND4, Mitochondrial LHON Respiratory chain Sensory-motor and Slightly decreased Varies, rarely Infrequent ND6 disorder predominantly demyelinating severe mtDNA large Mitochondrial Kearns-Sayre syndrome Respiratory chain Sensory-motor axonal Normal Varies, usually mild Infrequent deletion disorder SURF1, PDHA1 Autosomal Leigh syndrome Respiratory chain Sensory-motor demyelinating Decreased Varies, rarely Infrequent recessive disorder severe SLC25A19 Autosomal Bilateral striatal necrosis mtDNA replication Motor or sensory-motor Normal Moderate to severe One report recessive and maintenance axonal

CMT=Charcot-Marie-Tooth neuropathy. HMSN=hereditary motor and sensory neuropathy. DOA plus=autosomal dominant optic atrophy plus syndrome. NARP=neuropathy, ataxia, and retinitis pigmentosa. MILS=maternally inherited Leigh syndrome. dHMN=distal hereditary motor neuropathy. SANDO=sensory ataxia, neuropathy, dysarthria, and ophthalmoplegia. MIRAS=mitochondrial recessive ataxia syndrome. MEMSA=myoclonic epilepsy myopathy sensory ataxia. MNGIE=mitochondrial neurogastrointestinal encephalopathy. mtDNA=mitochondrial DNA. IOSCA=infantile-onset spinocerebellar ataxia. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. MERRF=myoclonus epilepsy with ragged-red fi bres. LHON=Leber hereditary optic neuropathy.

Table 3: Genetic causes and characteristics of mitochondrial neuropathies in mitochondrial disorders with peripheral nerve involvement

Sensory ataxic neuropathies POLG1 and C10ORF2 mutations Sensory ataxia as an isolated manifestation or, more Mutations in the nuclear gene POLG1, which encodes commonly, in the setting of a more widespread the catalytic subunit of mitochondrial gamma- neurological disorder is another possible presentation of polymerase involved in mtDNA replication, lead to a mitochondrial disorder caused by respiratory chain complex phenotypes that often include peripheral complex V defi cit, as in NARP syndrome, or by defects in neuropathy, particularly when onset occurs in mtDNA replication and maintenance, as with mutations adolescents or adults.1–3,11 Ataxia neuropathy spectrum in POLG1 and C10ORF2. encompasses a range of phenotypes associated with

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POLG1 mutations, including cerebellar and sensory MNGIE and TYMP mutations ataxia.11 Sensory ataxic neuropathy, dysarthria, and MNGIE is a rare autosomal recessive disease associated ophthalmoparesis (SANDO), by defi nition characterised with mutations in TYMP, which encodes thymidine by peripheral neuropathy, is usually inherited as an phosphorylase, a cytosolic transferase that catalyses the autosomal recessive trait with juvenile-to-adult onset.11,68,69 breakdown of thymidine into thymine and deoxyribose-1- The neuropathy is mainly sensory, with ataxia, loss of phosphate and is involved in mitochondrial nucleotide proprioception and vibration sense, touch and pinprick pool homoeostasis.78 MNGIE combines mtDNA depletion sensory changes (to a lesser extent), and a varying degree syndrome (MTDPS1) with accumulation of multiple of distal muscle wasting and weakness; pes cavus is deletions and point mutations. Clinical diagnosis is based sometimes reported. Nerve conduction studies show on the presence of severe gastrointestinal dysmotility decreased or absent sensory action potentials and (with pseudo-obstructions), cachexia, ptosis and varying motor involvement. Only a few pathology reports ophthalmoparesis, demyelinating peripheral neuropathy, are available, showing axonal and dorsal column and diff use (though generally asymptomatic) leuko- degeneration, suggesting involvement of dorsal root encephalopathy.13,79 Age at onset ranges between ganglia.69,70 Hypomyelinating or demyelinating 0·5–52 years, although the disease often starts during neuropathy are rarely reported and are usually associated childhood or adolescence.13,79,80 Progression varies, with early-onset phenotypes.11,71 Diagnosis can be sometimes with rapid course and often proving lethal challenging when onset occurs late, such as in an between ages 20 and 40 years;13 however, some patients 80-year-old man who presented with a 7-year history of live into their sixties.80 Diagnosis is based on demonstrating neurological dysfunction,72 or when neuropathy is the substantial decrease in thymidine phosphorylase activity only manifestation for a long period, mimicking CMT, in leucocytes or platelets, increase in thymidine and as reported in one family where individuals developed deoxyuridine urinary excretion and plasma concentrations, other SANDO features much later.73 Muscle biopsy can and defi nitively by TYMP mutations.13,78,81 Muscle biopsy show ragged red fi bres, COX-defi cient fi bres, and shows ragged red fi bres and COX-defi cient fi bres in most multiple mtDNA deletions or depletion in the most patients, together with multiple mtDNA deletions, severe cases; however, in some cases, no mitochondrial depletion, and point mutations.13,79,81 abnormalities are found. Peripheral neuropathy is almost always found in Neuropathy can also occur as the result of mutations MNGIE, and is typically demyelinating with slowed nerve in another gene involved in mtDNA replication—ie, conduction velocities presenting as weakness and wasting C10ORF2, which encodes twinkle helicase.12 Aff ected that preferentially aff ect distal muscles and as sensory individuals present with dominant or recessive loss. Neuropathy ranges in severity from asymptomatic phenotypes that can include progressive external involvement detected only on nerve conduction studies to ophthalmoplegia, myopathy, dysarthria, dysphagia, rapidly progressive and devastating course.13,79,81–84 Nerve parkinsonism, hearing loss, seizures, dementia, biopsy shows axonal degeneration together with diabetes, and liver damage.2,3,12 Neuropathy is often mild segmental demyelination and remyelination, thinly or subclinical. In a few patients it was prominent, with myelinated internodes, few onion bulbs, and tomacula- predominant motor involvement in one family,12 and like myelin irregularity.81–84 Dystrophic mitochondria, loss sensory ataxic presentation in other instances,74 of cristae, and occasional paracrystallin inclusions have including a family with SANDO associated with a been seen with electron microscopy.83 heterozygous mutation.75 Multiple mtDNA deletions, Peripheral neuropathy was the onset manifestation in ragged red fi bres, and COX-defi cient fi bres are often 12% of patients with MNGIE in a large series, and eight present and might help to guide diagnosis. of 102 patients were initially misdiagnosed as having Sensory ataxic neuropathy caused by degeneration of chronic infl ammatory demyelinating polyradiculo- dorsal root ganglia is a key feature of infantile onset neuropathy or CMT.13 Other investigators have also spinocerebellar ataxia with sensory neuropathy (IOSCA), reported a presentation similar to chronic infl ammatory a rare autosomal recessive spinocerebellar ataxia of the demye linating polyradiculoneuropathy in patients with Finnish population that is associated with C10ORF2 MNGIE.81,82 Conduction blocks and symptom fl uctuations mutations.76 IOSCA is an mtDNA depletion syndrome occur82 and, together with frequent CSF protein increase, (hepatocerebral form of MTDPS7), with mtDNA contribute to misdiagnosis. In another fi ve cases, the depletion aff ecting the brain and liver.77 clinical presentation mimicked CMT, with initial (predominantly) sensorimotor demyelinating neuropathy Peripheral neuropathy and gastrointestinal with pes cavus.83,84 manifestations The symptoms of MNGIE are an example of a Peripheral neuropathy has been associated with disrupted mitochondrial syndrome caused by an mtDNA replication gastrointestinal motility in MNGIE13 and with liver disease dysfunction that results from an imbalance in the in Navajo neurohepatopathy; 14 both disorders also show mitochondrial nucleotide pool. Indeed, there is an brain white matter abnormalities on MRI. overload of thymidine and deoxythymidine triphosphate www.thelancet.com/neurology Vol 12 October 2013 1019 Review

caused by loss-of-function mutations in TYMP. However, sensorimotor.16 Occasionally prominent neuropathy has mtDNA replication dysfunction is probably due to both been reported in Leber hereditary optic neuropathy,18 thymidine and deoxythymidine triphosphate overload Kearns-Sayre syndrome,10 and Leigh syndrome,19 and in and secondary depletion of deoxycytidine triphosphate. It primary coenzyme Q10 defi ciency due to ADCK3 has been proposed that thymidine and deoxythymidine mutations, which is usually characterised by cerebellar triphosphate overload might inhibit mitochondrial ataxia sometimes associated with mental retardation, thymidine kinase 2 thus leading to limited mitochondrial seizures, and peripheral neuropathy.93 deoxycytidine triphos phate availability—thymidine Moderate-to-severe progressive motor or sensorimotor kinase 2 is a deoxy ribonucleoside kinase that catalyses axonal neuropathy with foot deformities was reported in phosphorylation of intramitochondrial pyrimidine four siblings aff ected by bilateral striatal necrosis with nucleosides, including deoxycytidine, to monophosphate recurrent episodes of fl accid paralysis and encepha- nucleotides (fi gure 1).85 lopathy. CSF lactate concentration was elevated but respiratory chain complex activity was normal. MNGIE-like disorders Homozygosity mapping led to the identifi cation of a MNGIE-like phenotypes have occurred in association homozygous mutation in SLC25A19, encoding the with recessive POLG186,87 or RRM2B88 mutations; mitochondrial thiamine pyrophosphate transporter.94 leukoencephalopathy was either absent (POLG1) or patchy (RRM2B), unlike the diff use white matter changes Diagnosis of peripheral neuropathies associated of TYMP-related MNGIE. Neuropathy was demyelinating with respiratory chain dysfunction in a patient carrying RRM2B mutations, whereas patients Peripheral neuropathy in individuals with disrupted with POLG1 mutations had mainly sensorimotor axonal87 mitochondrial dynamics typically presents as CMT, and or sensory ataxic axonal86 neuropathy. MTATP6 mutations should be considered in patients with CMT2 or distal hereditary motor neuropathy, particularly Navajo neurohepatopathy and MPV17 when there are mild associated features and inheritance Peripheral neuropathy is a main feature of Navajo might be matrilineal. Not all patients presenting with pes neurohepatopathy, a rare mtDNA depletion syndrome cavus and sensorimotor neuropathy have CMT, thus (MTDPS6) associated with a homozygous recessive MNGIE (when peripheral neuropathy is demyelinating) mutation (Arg50Trp) in MPV17.14,89 The disease begins in or POLG1-related disorders (when peripheral neuropathy infancy or childhood, and is characterised by liver is axonal) should be considered. Similarly, MNGIE should disease, corneal ulcerations, leukoencephalopathy, and not be misdiagnosed as chronic infl ammatory recurrent metabolic acidosis. Aff ected patients develop demyelinating polyradiculoneuropathy. Sensory ataxia is a severe sensorimotor neuropathy with progressive muscle possible presentation in mitochondrial disorders and wasting and weakness, loss of deep tendon refl exes, might suggest POLG1-related neuropathy or NARP marked sensory defi cit leading to acromutilations, and syndrome. The diff erential diagnosis includes Friedreich’s corneal anaesthesia. Nerve conduction velocities are ataxia and vitamin E defi ciency (table 2). slowed. Nerve biopsy shows myelinated fi bre depletion In patients presenting with peripheral neuropathy, a and degenerative changes in unmyelinated fi bres.14 This mitochondrial disorder should be suspected when there unusual neuropathic phenotype seems to be limited to are other features, which are sometimes subtle, suggesting the Navajo population of the southwestern USA.14,90 A mitochondrial dysfunction—eg, ptosis, ophthalmoplegia, 21-year-old Pakistani man and a 65-year-old man of gastrointestinal dismotility, cerebellar ataxia, decreased European origin carrying other MPV17 recessive visual acuity, pigmentary retinopathy, hearing loss, and mutations developed axonal sensorimotor neuropathy in white matter changes on MRI. Lactic acid assay and the context of a multisystem disorder, with multiple muscle biopsy to detect ragged red fi bres, COX-defi cient mtDNA deletions seen in muscle biopsy.91,92 fi bres, respiratory chain complex defi ciency, and mtDNA depletion and deletions can aid diagnosis. Histochemical Peripheral neuropathy in other mitochondrial and biochemical evidence of a mitochondrial disorder are disorders sometimes absent; therefore, physicians must rely on Peripheral neuropathy occurs in many other syndromic clinical suspicion and look for mutations in common and non-syndromic mitochondrial disorders; however, it mtDNA hotspots, such as MTATP6, or in nuclear genes, only rarely manifests as a predominant feature. Peripheral such as POLG1 and OPA1 (table 4). nerve involvement is common but often subclinical in MELAS syndrome, where it is frequently axonal and Treatment predominantly sensory.1–3,10,15 A Guillain-Barrè-syndrome- Eff ective therapy for mitochondrial diseases is very like neuropathy was reported in one patient with MELAS limited, as noted in a recent Cochrane review.95 Current syndrome.15 Although common, neuropathy is rarely treatment for mitochondrial diseases is largely supportive relevant in MERRF syndrome, particularly in patients and mainly includes vitamins and cofactors with multiple lipomas, and is usually demyelinating and supplements—ie, antioxidants (coenzyme Q10,

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idebenone, vitamin C, vitamin E), respiratory chain decline in ankle dorsifl exion strength.95 There are no data cofactors (thiamine, ribofl avin, coenzyme Q10), and on possible treatments for mitochondrial diseases in compounds that correct secondary biochemical which neuropathy represents a major manifestation, defi ciencies (carnitine, creatine) or improve lactic such as NARP syndrome, SANDO, and dominant optic acidosis (dichloroacetate).3,95 atrophy; however, it is common practice to off er treatment Specifi c treatment is available for only a few diseases. with coenzyme Q10, often combined with thiamine, Supplementation can successfully treat primary coenzyme ribofl avin, and vitamin C, mostly to children with a Q10 defi ciency and often improve secondary defi ciencies.96 proven diagnosis of a mitochondrial disorder. Platelet infusion transiently restores circulating thymidine phosphorylase and reduces plasma thymidine and Conclusion and future directions deoxyuridine concentrations in patients with MNGIE.96 We reviewed mitochondrial disorders where peripheral Allogeneic haemopoietic stem-cell transplantation can neuropathy is a key feature. Peripheral neuropathy as a potentially halt MNGIE progression, although morbidity unique or predominant fi nding is frequent in disorders and mortality rates are high if general conditions are aff ecting mitochondrial dynamics, where abnormal compromised, thus timely diagnosis is necessary.97 mitochondrial transport along axons seems to be the main Enzyme replacement therapy (encapsulated in red cell pathological mechanism and neuropathy presents as ghosts) might be suitable for patients whose general CMT. Novel MFN2-related phenotypes are emerging and condition precludes allogenic haemopoietic stem cell resemble the complex clinical scenarios of dominant optic transplantation.98 Early and prolonged treatment with atrophy plus syndrome and other mitochondrial disorders. idebenone in patients with Leber hereditary optic Indeed, peripheral neuropathy might be the only or main neuropathy improved the frequency of visual recovery and presenting feature of some disorders of mtDNA possibly changed the natural history;99 a small pilot trial of replication and maintenance, and of specifi c disorders of idebenone for dominant optic atrophy reported some the respiratory chain, including ATP-synthase defects. improvement in visual function.100 Gene therapies (gene The number of genes and phenotypes associated with insertion or shifting, and nuclear transfer) are being tested mitochondrial disorders is rapidly expanding. The in cellular and animal models of hereditary optic availability of novel genetic techniques, including whole neuropathies and other mitochondrial disorders.101,102 An open-label trial with EPI-743 (a third-generation quinone molecule) recently showed possible halting of disease Associated genes and diagnoses progression in Leigh syndrome and Leber hereditary optic Axonal CMT MFN2 and CMT2A; GDAP1 and autosomal dominant or autosomal neuropathy.103 L-arginine seems to be a promising recessive CMT2K; MTATP6 and CMT2 or NARP; POLG1 and SANDO treatment for stroke-like episodes in MELAS syndrome.95 Demyelinating CMT and GDAP1 and autosomal recessive CMT4A, or recessive intermediate neuropathy CMT; TYMP (and RRM2B) and MNGIE; MPV17 and Navajo Some studies have reported increased muscle strength neurohepatopathy; MERRF with aerobic exercise and resistance training in adults with Neuropathy plus visual loss myopathies caused by single, large-scale mtDNA deletions; Optic atrophy MFN2 and CMT6; OPA1 and DOA plus; ND1, ND4, ND6 and LHON these results support the hypothesis of exercise-induced Retinopathy MTATP6 and NARP; Kearns-Sayre syndrome mitochondrial gene shifting in muscle-containing satellite Neuropathy plus pyramidal MFN2 and CMT5 cells that have low or absent levels of deleted mtDNA and involvement encourage further investigations in treating sporadic Pure motor neuropathy with or MTATP6 mtDNA diseases.95 without other neurological features Currently, there is no evidence of specifi c eff ects with Sensory ataxic neuropathy POLG1, C10ORF2 and SANDO, ataxia neuropathy spectrum; C10ORF2 any treatment for peripheral neuropathy related to a and IOSCA; MTATP6 and NARP mitochondrial disorder; conversely, peripheral nerve Predominantly sensory neuropathy MPV17 and Navajo neurohepatopathy with acromutilation toxicity occurred after dichloroacetate treatment in 95 Axonal neuropathy with CNS MELAS, MERRF, Kearns-Sayre syndrome, Leigh syndrome, MILS patients with the 3243A→G mutation in MTTL1. In a involvement series of patients with MNGIE, one patient given an Neuropathy with gastrointestinal TYMP (RRM2B, POLG1) and MNGIE; MPV17 and Navajo allogenic haemopoietic stem cell transplantation showed manifestations neurohepatopathy and related disorders clinically and electrophysiologically improved neuro- Neuropathy with TYMP (RRM2B, POLG1) and MNGIE; MPV17 and Navajo pathy.96 High-dose coenzyme Q10 was administered to leukoencephalopathy neurohepatopathy and related disorders; Kearns-Sayre syndrome, improve optic neuropathy in a patient with an MFN2 Leigh syndrome, MELAS mutation, but it did not change the course of peripheral CMT=Charcot-Marie-Tooth neuropathy. dHMN=distal hereditary motor neuropathy. NARP=neuropathy, ataxia, and neuropathy.104 There are no data on treatment effi cacy on retinitis pigmentosa. SANDO=sensory ataxia, neuropathy, dysarthria, and ophthalmoplegia. MNGIE=mitochondrial peripheral nerves in patients with coenzyme Q10 neurogastrointestinal encephalopathy. MERRF=myoclonus epilepsy with ragged-red fi bres. DOA plus=autosomal dominant optic atrophy plus syndrome. LHON=Leber hereditary optic neuropathy. IOSCA=infantile-onset 96 defi ciencies. Trials with treatment cocktails including spinocerebellar ataxia. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. coenzyme Q10, creatine, and lipoic acid in patients with MILS=maternally inherited Leigh syndrome. MELAS syndrome did not report on effi cacy in peripheral Table 4: Associated genes and diagnoses according to neuropathic presentation neuropathy, although such treatments attenuated the www.thelancet.com/neurology Vol 12 October 2013 1021 Review

7 Züchner S, Mersiyanova IV, Muglia M, et al. Mutations in the Search strategy and selection criteria mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 2004; 36: 449–51. References for this Review were identifi ed by searches of PubMed from Jan 1, 1989, until 8 Baxter RV, Ben Othmane K, Rochelle JM, et al. Ganglioside-induced May 31, 2013, with the terms “peripheral neuropathy and mitochondria/mitochondrial diff erentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease”, “Charcot-Marie-Tooth”, “DOA”, “HMSN”, “HMSN V”, “HMSN VI”, “IOSCA”, “Leber disease type 4A/8q21. Nat Genet 2002; 30: 21–22. 9 Cuesta A, Pedrola L, Sevilla T, et al. The gene encoding ganglioside- optic atrophy”, “Leigh syndrome”, “LHON”, “MILS”, “MNGIE”, “NARP”, “SANDO”, “C10ORF2”, induced diff erentiation-associated protein 1 is mutated in axonal “GDAP1”, “MFN2”, “MPV17”, “OPA1”, “PEO1”, “POLG1”, “SURF1”, “TYMP”, “Twinkle”, Charcot-Marie-Tooth type 4A disease. Nat Genet 2002; 30: 22–25. “mitochondrial disease and therapy”. Articles were also identifi ed through searches of the 10 Finsterer J. Inherited mitochondrial neuropathies. J Neurol Sci 2011; 304: 9–16. authors’ own fi les. Only reports published in English or French were reviewed. Selection 11 Milone M, Massie R. Polymerase gamma 1 mutations: clinical criteria were newness, ease of access, importance, originality, quality, relevance to the scope correlations. Neurologist 2010; 16: 84–91. of this Review, and opportunities for further references. 12 Martin-Negrier ML, Sole G, Jardel C, Vital C, Ferrer X, Vital A. TWINKLE gene mutation: report of a French family with an autosomal dominant progressive external ophthalmoplegia and literature review. Eur J Neurol 2011; 18: 436–41. exome sequencing, will allow detection of other diseases 13 Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum of characterised by mitochondrial dysfunction and mitochondrial neurogastrointestinal encephalomyopathy. Brain prominent or exclusive peripheral neuropathy. Growing 2011; 134: 3326–32. 14 Karadimas CL, Vu TH, Holve SA, et al. Navajo neurohepatopathy is knowledge of the pathological mechanisms is leading to caused by a mutation in the MPV17 gene. Am J Hum Genet 2006; development of treatment options for some mitochondrial 79: 544–48. disorders. Thus, the list of treatable disorders will increase, 15 Hanna MG, Cadia P. Pheripheral nerve diseases associated with mitochondrial respiratory chain dysfunction. In: Dyck PJ, as will the need for early diagnosis. Finally, preimplantation Thomas PK, eds. Peripheral neuropathy, 4th edn. Philadelphia: genetic testing raises hopes that prevention of human Elsevier Saunders, 2005: 1937–49. mtDNA disease transmission is feasible;105 however, 16 Bouillot S, Martin-Négrier ML, Vital A, et al. Peripheral neuropathy associated with mitochondrial disorders: 8 cases and review of the successful translation to clinical practice requires further literature. J Peripher Nerv Syst 2002; 7: 213–20. research to test safety and effi cacy, and remains 17 Menezes MP, Ouvrier RA. Peripheral neuropathy associated with controversial for ethical concerns.105 mitochondrial disease in children. Dev Med Child Neurol 2012; 54: 407–14. Contributors 18 Gilhuis HJ, Schelhaas HJ, Cruysberg JR, Zwarts MJ. Demyelinating DP designed and wrote the Review, did the literature search, and polyneuropathy in Leber hereditary optic neuropathy. designed the tables. GP helped to write the Review and do the literature Neuromuscul Disord 2006; 16: 394–95. search, and collaborated on designing and preparing the tables. IM 19 Santoro L, Carrozzo R, Malandrini A, et al. A novel SURF1 mutation wrote part of the Review, helped to do the literature search, and results in Leigh syndrome with peripheral neuropathy caused by collaborated on designing fi gures and tables. ES helped to write the cytochrome C oxidase defi ciency. Neuromuscul Disord 2000; Review and collaborated on designing and preparing fi gures and tables. 10: 450–53. MZ gave intellectual contribution and reviewed the manuscript. 20 Rusanen H, Majamaa K, Tolonen U, Remes AM, Myllylä R, Hassinen IE. Demyelinating polyneuropathy in a patient with the Confl icts of interest tRNA (Leu)(UUR) mutation at base pair 3243 of the mitochondrial DP received research funding from ACMT-Rete and Pfi zer Italia, and DNA. Neurology 1995; 45: 1188–92. travel expenses from Kedrion SpA and Pfi zer Italia. GP received travel 21 Pareyson D, Marchesi C. Diagnosis, natural history, and management expenses from Pfi zer Italia. ES received travel expenses from Actelion of Charcot-Marie-Tooth disease. Lancet Neurol 2009; 8: 654–67. Pharmaceuticals. All other authors reported no confl icts of interest. 22 Reilly MM, Murphy SM, Laurá M. Charcot-Marie-Tooth disease. Acknowledgments J Peripher Nerv Syst 2011; 16: 1–14. Our work was supported by Telethon Italy grants GPP10005 and 23 Yu-Wai-Man P, Griffi ths PG, Gorman GS, et al. Multi-system GGP11011 (to MZ). DP is a member of the Inherited Neuropathy neurological disease is common in patients with OPA1 mutations. Consortium Rare Disease Clinical Research Consortium funded by the Brain 2010; 133: 771–86. US National Institutes of Health (NINDS/ORD), Muscular Dystrophy 24 Amati-Bonneau P, Valentino ML, Reynier P, et al. OPA1 mutations Association, and Charcot-Marie-Tooth Association (CMTA).We thank induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain 2008; 131: 338–51. Tiziana Cavallaro and Gian Maria Fabrizi for nerve biopsy material and for preparing fi gure 2, and Michela Morbin for nerve biopsy material 25 Hudson G, Amati-Bonneau P, Blakely EL, et al. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, and for help preparing fi gures 2 and 3. ataxia, deafness and multiple mitochondrial DNA deletions: a novel References disorder of mtDNA maintenance. Brain 2008; 131: 329–37. 1 Finsterer J. Mitochondrial neuropathy. Clin Neurol Neurosurg 2005; 26 Cartoni R, Martinou JC. Role of mitofusin 2 mutations in the 107: 181–86. physiopathology of Charcot-Marie-Tooth disease type 2A. Exp Neurol 2 McFarland R, Taylor RW, Turnbull DM. A neurological perspective 2009; 218: 268–73. on mitochondrial disease. Lancet Neurol 2010; 9: 829–40. 27 Misko AL, Sasaki Y, Tuck E, Milbrandt J, Baloh RH. Mitofusin 2 3 Rahman S, Hanna MG. Diagnosis and therapy in neuromuscular mutations disrupt axonal mitochondrial positioning and promote disorders: diagnosis and new treatments in mitochondrial diseases. axon degeneration. J Neurosci 2012; 32: 4145–55. J Neurol Neurosurg Psychiatry 2009; 80: 943–53. 28 Züchner S, De Jonghe P, Jordanova A, et al. Axonal neuropathy 4 Detmer SA, Chan DC. Functions and dysfunctions of mitochondrial with optic atrophy is caused by mutations in mitofusin 2. dynamics. Nat Rev Mol Cell Biol 2007; 8: 870–79. Ann Neurol 2006; 59: 276–81. 5 Milone M, Benarroch EE. Mitochondrial dynamics: general 29 Verhoeven K, Claeys KG, Züchner S, et al. MFN2 mutation concepts and clinical implications. Neurology 2012; 78: 1612–29. distribution and genotype/phenotype correlation in Charcot-Marie- 6 Niemann A, Wagner KM, Ruegg M, Suter U. GDAP1 mutations Tooth type 2. Brain 2006; 129: 2093–102. diff er in their eff ects on mitochondrial dynamics and apoptosis 30 Chung KW, Kim SB, Park KD, et al. 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