How to Spot Mitochondrial Disease in Adults

CME Neurology Clinical Medicine 2013, Vol 13, No 1: 87–92

Clinical feature(s) suggestive Family history of How to spot of mitochondrial disease neurological disease mitochondrial disease in adults Are there any features of a Full multisystem enquiry Yes Michael J Keogh, ST3 at James Cook and assessment mitochondrial disease? Hospital, Middlesbrough and academic clinical fellow, Northern Region; Patrick F Chinnery, professor of neurogenetics and director of the Institute of Genetic Medicine, Newcastle University; Wellcome Trust Senior Is it a classical syndrome? No Fellow in Clinical Science; honorary consultant neurologist, Newcastle upon Tyne Hospitals NHS Foundation Trust

Mitochondrial Yes Oligosymptomatic Numerous mitochondria are present in disease less likely every nucleated cell in the body. They have a diverse role in cellular metabolism and are the principal source of adenosine tri- phosphate (ATP). ATP is produced through Testing (see Fig 2) oxidative phosphorylation (OXPHOS) by the mitochondrial respiratory chain. Fig 1. Mechanisms of alerting the clinician to the presence of a mitochondrial disorder. Impairment of OXPHOS leads to cellular dysfunction and, eventually, cell death. As a result, mitochondrial disorders primarily features that suggest the possibility of such Specific clinical features in affect tissues that have a high metabolic disease (Fig 1; Table 1). Occasionally, these ‘suspected mitochondrial disease’ demand, such as the neural, muscular, car- features form a ‘classic mitochondrial syn- diac, ocular and endocrine systems. drome’ (Table 2). Although some patients Key neurological features of mitochondrial Mitochondrial function is dependent on fall neatly into a defined syndrome, many disease are outlined in Table 1. Chronic pro- the interplay of mitochondrial DNA and patients will be so-called ‘oligosymptomatic’, gressive external ophthalmoplegia (CPEO) the nuclear genome.2 Mitochondria con- having one or two components of a syn- is the most common specific manifestation tain their own DNA (mtDNA), which com- drome (such as a young individual with an of mitochondrial disease, and is considered prises 16,569 base pairs (bp) and encodes occipital stroke-like lesion, or mild nonfati- to be present in approximately 20% of 4,5 only 37 genes (compared with the 3.3 bil- gable ptosis without ophthalmoplegia), and patients presenting in adult life. It typically lion bp in, and thousands of genes encoded are more problematic to reach a diagnosis causes symmetrical limitation of all extraoc- by, the nuclear genome). However, most of for. These patients often also have several ular muscles and usually occurs in conjunc- 6 the approximately 1,500 mitochondrial other features that, if present, further sup- tion with ptosis. Other patients present proteins are coded by nuclear DNA and port evidence of a mitochondrial disease. A with refractory seizure disorders, particu- synthesised on cytoplasmic ribosomes.3 clinician should look and test for these addi- larly associated with underlying stroke-like 7 Therefore, abnormalities of mitochondrial tional feature if suspecting the diagnosis lesions (especially occipital) or fluctuating proteins can result from defects in both (Table 3). Non-neurological involvement in or progressive encephalopathy. Ataxia, mtDNA and nuclear DNA, and so cause a patient with unexplained multisystem peripheral neuropathy and proximal myop- maternally inherited, Mendelian (auto- neurological disease is a ‘red flag’ for mito- athy are common, and can lead to fatigue somal dominant, recessive or X-linked), or chondrial disease. Finally, and perhaps most and myalgia in middle age as the presenting 8 sporadic diseases (owing to de novo muta- challenging, are patients presenting with feature. Myoclonic jerks, optic atrophy tions, or recessive inheritance). ‘non-specific presentations’ (such as epi- and pigmentary retinopathy also suggest a lepsy, diabetes or sensorineural deafness), mitochondrial aetiology. Neurological who often have a multisystem disease that features, such as extrapyramidal How to spot mitochondrial symptoms (Parkinsonism and dystonia) and disease does not fit neatly into any particular category. In these circumstances, the diagnosis spasticity, are recognised but uncommon Although mitochondrial disease can present of a mitochondrial disorder is often only features of mitochondrial disease. with a heterogeneous array of symptoms, made in a tertiary referral centre with direct Key extra-neurological features include there are certain key neurological clinical access to specialist laboratory investigations. sensorineural hearing loss developing in

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young adulthood, short stature, cardiomy- is easy to diagnose with a simple blood test, Heteroplasmy refers to the presence of opathy, diabetes and other endocrine disor- because three mutations (m.3460G>A, more than one type of mtDNA genome ders, often associated with gastrointestinal m.11778G>A or m.14484T>C) are respon- within a cell. Given that each cell has dysmotility (Table 3). sible for 90% of cases.11 Clear diagnostic between 100 and 10,000 mitochondria, criteria also exist for Kearns–Sayre syn- each with 2–10 copies of the mtDNA, a Classic ‘mitochondrial drome, myoclonic epilepsy with ragged red mixture of mutated and ‘wild-type’ DNA syndromes’ fibres (MERRF) and mitochondrial neuro- can exist within cells. Differences in the gastrointestinal encephalopathy (MNGIE) ratio of mutant and wild-type mtDNA (the Several classic clinical syndromes of mito- (Table 2). ‘mutation load’) between individual family chondrial disease are detailed in Table 2, members, and between organs within the 9 and have been reviewed elsewhere. Some Family history and heteroplasmy same individual, lead to a high degree of mitochondrial syndromes, such as mito- clinical heterogeneity. This also poses diag- chondrial encephalomyopathy with lactic Mitochondrial disorders can present with nostic challenges, because low levels of acidosis and stroke-like episodes (MELAS), any form of inheritance pattern, and one- mutant mtDNA in sampled tissues (eg are readily recognised when ‘full blown’, third of patients have a sporadic dis- blood) can lead to false negative tests and and suggest specific genetic causes; how- order.12 Therefore, the importance of must always be interpreted with caution. ever, milder forms can be difficult to recog- taking a family history is to direct genetic This is particularly the case for the nise, particularly in the early stages. Patients tests and to determine potential disease in m.3243A>G mutation (see above, in the usually present after normal childhood other family members. If a diagnosis of context of MELAS). development, before sensorineural deaf- mitochondrial DNA disease is suspected ness, diabetes and stroke-like episodes (and especially if it might be a primary 10 Defining the extent of the clinical begin during their late teens. Genetic mtDNA disorder; ie there is no male–male phenotype blood tests can be misleadingly negative transmission in the pedigree), then it is (explained below). Leber’s hereditary optic important to ask about subtle clinical fea- Several investigations can help to build neuropathy (LHON) has a highly stereo- tures in additional family members.2 This the ‘mitochondrial phenotype’. Mandatory typic presentation, with progressive pain- is because different family members often investigations are an electrocardiogram less visual loss that affects men more than have different phenotypes, owing in part (ECG), echocardiogram, fasting blood women. Once suspected clinically, LHON to ‘mtDNA heteroplasmy’. sugar and formal retinal assessment,

Table 1. Neurological features that should specifically prompt the clinician to consider a potential mitochondrial disorder.

Neurological feature Additional information Syndrome Ataxia Highly variable severity and temporal relation with disease KSS, NARP, POLG, MELAS, MERRF CPEO Can be isolated or on a spectrum with other symptoms CPEO, CPEO+, KSS, MELAS, MNGIE, OPA1 Dementia Variable age of presentation KSS, Leigh, MELAS, MERRF Encephalopathy Can be highly variable and intermittent KSS, MELAS, Leigh, MNGIE, MERRF MRI features Heterogeneous and include basal ganglia necrosis, stroke- KSS, Leigh, MELAS like lesions, calcification and leukodystrophy (unexplained) Myoclonus Subtle to frank myoclonus and generalised seizures MERRF Myopathy Can be ocular, proximal, distal or generalised CPEO+, KSS, MERRF, NARP, MNGIE Optic atrophy Can be clinically mild LHON, OPA1, MERRF, HMSN VI Peripheral neuropathy Sensory, motor or both; usually axonal MNGIE, NARP, MERRF, KSS, OPA1 Pigmentary retinopathy From retinitis pigmentosa to ‘salt and pepper’ fundi KSS, MELAS, NARP Seizures Often progressive, generalised and difficult to control MERRF, Leigh, MELAS SNHL Often in younger patients MELAS, MERRF, KSS Stroke-like episodes Predominantly occipital MELAS

CPEO ϭ chronic progressive external ophthalmoplegia; CPEOϩ ϭ chronic progressive external ophthalmoplegia plus; HMSN ϭ hereditary motor and sensory neuropathy; KSS ϭ Kearns–Sayre syndrome; LHON ϭ Leber’s hereditary optic neuropathy; MERRF ϭ mitochondrial encephalopathy with ragged red fibres; MELAS ϭ mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MNGIE ϭ mitochondrial neurogastrointestinal encephalopathy; NARP ϭ neuropathy ataxia and retinitis pigmentosa; OPA ϭ optic atrophy; POLG ϭ polymerase gamma; SNHL ϭ sensorineural hearing loss.

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because manifestations in these systems Specific mitochondrial Fig 2 provides an overview of the basic are often subclinical. Subsequent investi- investigations investigative approach. gations might be necessary, depending on For a specific clinical syndrome, a non- the phenotype and symptoms (Table 4). The diagnosis of mitochondrial disorders invasive genetic test might be possible on Blood lactate levels can be abnormal, can range from the simple to awkwardly blood, urine or buccal mucosa. However, especially during an acute metabolic crisis, complex. In the first instance, the decision if these tests return negative, or the clin- although lactate levels are often normal in of whether to embark on this process ical features in the first instance necessi- adults presenting with mitochondrial dis- depends on how strongly the phenotype is tate a muscle biopsy (eg CPEO), then this ease subacutely. felt to represent a mitochondrial disorder. is most commonly undertaken. Other

Table 2. Classic mitochondrial phenotypes.

Syndrome Primary features Secondary features Inheritance Common mutations CPEO Progressive external ophthalmoplegia and Mild facial or proximal myopathy S/M 95% sporadic; bilateral ptosis generally mtDNA deletions; more than 150 described Kearns–Sayre CPEO onset before the age of 20 with Dementia, diabetes mellitus, S/M Generally sporadic pigmentary retinopathy plus one of the sensorineural deafness (50%) mtDNA deletions; following: CSF protein Ͼ1 g/l, cerebellar ataxia myopathy, hypoparathyroidism and over 100 described and/or heart block dysphagia

MELAS Stroke-like episodes (typically before the age of Recurrent headaches, recurrent M 3243AϾG, 40); encephalopathy with seizures and or vomiting, sensorineural deafness, 3271TϾC, dementia; mitochondrial myopathy on muscle short stature, diabetes mellitus, 3251AϾG biopsy ataxia, pigmentary retinopathy and cardiomyopathy

MERRF Myoclonus, seizures, encephalopathy and ataxia Dementia, peripheral neuropathy, M 8344AϾG, cervical lipomatosis, sensorineural 8356TϾC deafness and optic atrophy

NARP Pigmentary retinopathy, ataxia and peripheral Dementia, SNHL, short stature, M 8993TϾG/C neuropathy seizures, basal ganglia MRI changes and clinical overlap with Leigh’s syndrome

MNGIE Gastrointestinal dysmotility, cachexia, peripheral GORD, vomiting, distal weakness AR Mutation in TYMP neuropathy, ptosis and SNHL and leukoencephalopathy on MRI gene OPA1 Painless visual loss or asymptomatic SNHL, peripheral neuropathy and AD Over 200 mutations ataxia in OPA1 gene described

LHON Subacute painless bilateral visual failure; more Dystonia and cardiac arrhythmias M 11778GϾA, common in males (4:1) 14484TϾC, 3460GϾA

Leigh’s Subacute relapsing encephalopathy with Overlap with NARP and basal M 8993TϾG/C syndrome cerebellar and brainstem signs presenting during ganglia changes on MRI infancy

POLG Sensory or cerebellar ataxia Highly variable: ptosis, PEO, AR/AD Numerous myopathy, myoclonus, epilepsy mutations in DNA (continuum of conditions previously Polymerase γ felt to be discrete diagnostic entities (POLG) eg Alpers’ syndrome, MEMSA and arPEO or adPEO)

AD ϭ autosomal dominant; AR = autosomal recessive; CPEO ϭ chronic progressive eternal ophthalmoplegia; CSF ϭ cerebrospinal fluid; GORD ϭ gastrooesophageal reflux disease; LHON ϭ Leber’s hereditary optic neuropathy; MERRF ϭ maternal inheritance; MEERF ϭ mitochondrial encephalopathy with ragged red fibres; MELAS ϭ mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MEMSA ϭ myoclonic epilepsy myopathy sensory ataxia; MNGIE ϭ mitochondrial neurogastrointestinal encephalopathy; MRI ϭ magnetic resonance imaging; NARP ϭ neuropathy ataxia retinitis pigmentosa; OPA1 ϭ optic atrophy type 1; PEO ϭ progressive external ophthalmoplegia; POLG ϭ polymerase gamma; S ϭ sporadic; SNHL ϭ sensorineural hearing loss; TYMP ϭ thymidine phosphorylase.

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organs are sometimes biopsied (eg liver or Table 3. Non-neurological symptoms that clinicians should assess for and, if present, add to the suspicion of a mitochondrial disease. myocardium) if they dominate the clinical picture. Histochemical analysis might Category Symptom support a mitochondrial abnormality and guide subsequent biochemical and genetic Cardiovascular Hypertrophic cardiomyopathy with conduction deficit testing. Thereafter, appropriate testing for Cardiac conduction defect mtDNA deletions, depletion, point muta- Cardiomyopathy with lactic acidosis tions or nuclear gene screening will lead Wolff–Parkinson–White syndrome to a genetic diagnosis in most cases.13,14 Endocrine Diabetes However, in a substantial proportion of Hypothyroidism patients, a genetic diagnosis is not pos- Hypoparathyroidism sible using National Health Service (NHS) Gonadal failure services. Under these circumstances, it is helpful to engage an active research labo- Gastrointestinal Severe dysmotility ratory with an interest in the patient’s Pseudo-obstruction phenotype or biochemical abnormality. Unexplained cyclical vomiting At present, three laboratories in the UK Dysphagia (in Newcastle, Oxford and London) have Hepatic failure been awarded National Specialist General Short stature Commissioning (NSC) funding to pro- Hypersensitivity to general anaesthesia vide the Rare Mitochondrial Disorders Sudden death in family Service for Adults and Children, which is a diagnostic and clinical service for Recurrent miscarriages in patient or family patients with mitochondrial disease in Exercise intolerance England and Scotland.15 With the devel- Ophthalmologic (in addition to Ptosis (nonfatigable) opment of sequencing techniques, such as those already listed) Colour vision deficits whole-exome sequencing, this process Renal Renal tubular disease (renal tubular acidosis and/or might change because investigation is aminoaciduria) likely to become much simpler, less inva- De Toni–Debré–Fanconi syndrome sive and, ultimately, available across the Nephrotic syndrome NHS.

Clinical management

Genetic counselling for mitochondrial disorders is complex. For some mtDNA Key points diseases, such as mtDNA deletions (which Mitochondrial DNA disorders are a common cause of inherited disease, affecting 1 in often occur as sporadic mutations in 5,000 of the UK population1 patients), the recurrence rate in offspring They should be considered in any complex multisystem disorder, especially those is low. Other mtDNA disorders are mater- disorders in which neurological, ocular or endocrine features predominate nally inherited, such as LHON, and have Many patients will fit neatly into defined classic syndromes, but significant numbers empirical gender-specific recurrence risks are oligosymptomatic, or have an overlapping, poorly defined, phenotype that can be given to families. Heteroplasmic If a mitochondrial disorder is suspected, it is vital to assess fully the clinical mutations are complex and the inherit- phenotype in the patient and their relatives with symptoms, paying particular ance pattern can be difficult to predict. attention to the non-neurological manifestations, because these can often be Nuclear DNA disorders causing mtDNA effectively managed disorders are counselled according to their Counselling depends on the underlying molecular basis of disease and might inheritance pattern (dominant, recessive necessitate discussion with specialist centres or X-linked), and known clinical There are currently no treatments known to modify the underlying disease process penetrance. Investigation of mitochondrial disorders can be complex and might necessitate Treatment options are also limited for referral to one of the three commissioned groups forming the Rare Mitochondrial patients, and management remains largely Disorders Service for Adults and Children (in Newcastle, Oxford and London) supportive.16 Prevention of secondary KEY WORDS: mitochondria, genetic, neurology, familial, metabolic, mitochondrial complications is best achieved by specialist disease teams with multidisciplinary resources.

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Table 4. Clinical investigations most commonly undertaken to investigate a potential mitochondrial disorder.

Investigation Potential abnormalities CK Raised in several mitochondrial myopathies, but often normal Clinical examination All systems with a particular focus on a neurological examination, including fundoscopy, cognitive assessment, features of ataxia, myopathy and neuropathy CSF Generally normal with exception of a potentially raised lactate; often used to exclude alternative diagnoses Echocardiography Assessment of ventricular wall thickness and function for a possible cardiomyopathy Electrocardiography Assessment of cardiac conduction defects and for features of left or right ventricular or hypertrophy Electroencephalography For ictal activity or features of an underlying encephalopathy Electromyography and nerve For evidence of myopathy or peripheral neuropathy (sensory or motor) conduction studies Endocrine investigations Fasting glucose, haemoglobin A1c, thyroid function tests and parathyroid hormone as an initial screen Neuroimaging MRI most useful to assess for cortical and subcortical abnormalities; CT occasionally more valuable to assess for basal ganglia calcification (present in approximately one in six patients) Ophthalmological assessment Optic atrophy, pigmentary retinopathy (retinitis pigmentosa, salt and pepper fundi), ptosis and extraocular movement disorder Personal and family history Full personal multisystem history with special focus on neurological, ocular, cardiac, endocrine and gastrointestinal symptoms; family history assessing for miscarriages, sudden death, death in infancy and neurological abnormalities Plasma lactate Generally raised but non specific and, if normal, does not exclude a mitochondrial disease Urine dipstick and renal Dipstick for blood and protein to suggest renal disease; blood tests for renal function function blood test

CK ϭ creatine kinase; CSF ϭ cerebrospinal fluid; CT ϭ computerised tomography; MRI ϭ magnetic resonance imaging.

High suspicion of mitochondrial disease Common facets, such as epilepsy, heart failure and gastrointestinal dysmotility, are usually managed according to standard Defined and/or classic syndrome? clinical practice, but these features can be challenging to manage in the context of multisystem complications, and long-term No Yes Positive: diagnosis follow-up might be required, with ongoing surveillance.

Non-invasive test available? Yes References

1 Schaefer AM, Taylor RW, Turnbull DM, No Negative Chinnery PF. The epidemiology of mitochondrial disorders: past, present and future. Biochim Biophys Acta 2004;1659:115–20. Muscle biopsy for histochemistry +/- respiratory chain complex 2 Cree LM, Samuels DC, Chinnery PF. The inheritance of pathogenic mitochondrial DNA mutations. Biochim Biophys Acta Nuclear DNA 2009;1792:1097–102. PCR-RFLP sequencing Real-time PCR Long-range PCR mtDNA sequencing 3 Smeitink J, van den Heuvel L, DiMauro S. (common mtDNA (Sanger or next- (for mtDNA depletion) (mtDNA deletions) (novel mutations) The genetics and pathology of oxidative point mutations) generation) for known or novel mutations phosphorylation. Nat Rev Genet 2001;2:342–52. Fig 2. A broad schematic of the investigatory process of suspected mitochondrial 4 Petty RK, Harding AE, Morgan-Hughes JA. disease. mtDNA ϭ mitochondrial DNA; PCR ϭ polymerase chain reaction; RFLP = restriction The clinical features of mitochondrial fragment length polymorphism. myopathy. Brain 1986;109:915–38.

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5 Kirkman MA, Yu-Wai-Man P, Chinnery PF. 10 Sproule DM, Kaufmann P. Mitochondrial 15 Rare Mitochondrial Disease Service for The clinical spectrum of mitochondrial encephalopathy, lactic acidosis, and stroke- Adults and Children, 2012. www.mito- genetic disorders. Clin Med 2008;8:601–6. like episodes: basic concepts, clinical phe- chondrialncg.nhs.uk [Accessed 3 January 6 Richardson C, Smith T, Schaefer A, Turnbull notype, and therapeutic management of 2013]. D, Griffiths P. Ocular motility findings in MELAS syndrome. Ann N Y Acad Sci 16 Pfeffer G, Majamaa K, Turnbull DM et al. chronic progressive external ophthalmo- 2008;1142:133–58. Treatment for mitochondrial disorders. plegia. Eye (Lond) 2005;19:258–63. 11 Yu-Wai-Man P, Griffiths PG, Chinnery PF. Cochrane Database Syst Rev. 7 Goodfellow JA, Dani K, Stewart W et al. Mitochondrial optic neuropathies – disease 2012;4:CD004426. Mitochondrial myopathy, encephalopathy, mechanisms and therapeutic strategies. lactic acidosis and stroke-like episodes: an Prog Retin Eye Res 2011;30:81–114. important cause of stroke in young people. 12 Chinnery PF. Inheritance of mitochondrial Postgrad Med J 2012;88:326–34. disorders. Mitochondrion 2002;2:149–55. Address for correspondence: Prof PF 8 Pfeffer G, Chinnery PF. Diagnosis and 13 Chinnery PF. Could it be mitochondrial? Chinnery, Institute of Genetic treatment of mitochondrial myopathies. When and how to investigate. Pract Neurol Medicine, Newcastle University, Ann Med 2011;early online:1–13. 2006;6:90–101. Central Parkway, Newcastle-upon- 9 Taylor RW, Turnbull DM. Mitochondrial 14 Taylor RW, Schaefer AM, Barron MJet al. DNA mutations in human disease. Nat Rev The diagnosis of mitochondrial muscle dis- Tyne, NE1 3BZ. Genet 2005;6:389–402. ease. Neuromuscular Disord 2004;14:237–45. Email: [email protected]

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