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