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JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 88 April 1995 The investigation of mitochondrial respiratory chain disease A A M Morris MRCP M J Jackson MRCP L A Bindoff MD MRCP D M Turnbull MD FRCP J R Soc Med 1995;88:217P-222P BASED ON A PAPER READ TO SEC77ON OF PAEDIATRICS, 25 JANUARY 1994 Keywords: mitochondria; respiratory chain; biochemistry; histochemistry INTRODUCTION Table 1 Presentations of respiratory chain disease The mitochondrial respiratory chain couples the oxidation of Reference fuels to the generation of cellular energy. It consists of five Disease protein complexes embedded in the inner mitochondrial Neurological 4 membrane. Each respiratory chain complex has multiple MELAS syndrome subunits; most are encoded by nuclear genes, induding all the MERRF syndrome 18 subunits of complex II, but the other complexes also have NARP syndrome 19 mitochondrial DNA The Leigh disease 3,12 subunits encoded by (mtDNA). Alpers-Huttenlocher disease 20 mitochondrial genome is inherited exclusively from the KSS 2 mother and many copies are present in each mitochondrion. CPEO 2 Normal and mutant mtDNA can be found in the same Sensorineural deafness 5 mitochondrion (heteroplasmy) and the proportions vary in Muscle 21 different tissues1. Benign infantile myopathy Fatal infantile myopathy 21 Diseases ofthe mitochondrial respiratory chain are a major Myopathy in children and adults 22 diagnostic challenge. They can present in an enormous variety Rhabdomyolysis of ways, making clinical recognition difficult. There are no Ophthalmological reliable screening tests and the diagnostic tests are generally LHON 23 Pigmentary retinopathy, optic atrophy (in KSS, invasive, expensive and not widely available. In this paper we Leigh disease, etc.) describe an approach to the investigation of these disorders. Heart First, we outline the clinical and biochemical features helpful Cardiomyopathy: hypertrophic, dilated or 24 in selecting which patients to investigate. Next, we consider histiocytoid whether the initial investigation should be to look for a Barth syndrome 25 biochemical defect in the respiratory chain or a genetic defect in Renal mtDNA. Respiratory chain defects cannot be detected reliably Fanconi syndrome 26 Liver in all tissues. In our third section we discuss which tissues mtDNA depletion syndrome 27 should be examined and how they should be obtained. Finally, Pearson syndrome 28 we compare the advantages of histochemistry and Alpers-Huttenlocher disease 20 conventional biochemical tests. Haematological Sideroblastic anaemia, pancytopenia 28 (Pearson syndrome) SELECTION OF APPROPRIATE PATIENTS Neutropenia (Barth syndrome) 25 TO INVESTIGATE Gastro-intestinal Pancreatic exocrine dysfunction (Pearson syndrome) 28 Clinical clues Partial villous atrophy 29 The first step in investigating suspected disorders of the Motility disorders 30 respiratory chain is patient selection. Despite the diversity of Endocrine Diabetes mellitus 31 Parathyroid, thyroid dysfunction (KSS) 32 Metabolic decompensation Lactic acidaemia (in many of the above, see text) Division of Clinical Neuroscience, University of Newcastle upon Tyne, Newcastle MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like upon Tyne, UK episodes; MERRF=myoclonic epilepsy and ragged-red fibres; NARP=neurogenic to: Professor D M Tumbull, Division of Clinical Neuroscience, weakness, ataxia and retinitis pigmentosa; KSS=Kearns-Sayre Syndrome; Correspondence CPEO=chronic progressive external ophthalmoplegia; LHON=Leber's hereditary The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK optic neuropathy 217P JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 88 April 1995 respiratory chain disease, patient selection is still based on Table 2 Non-respiratory chain causes of hyperlactateemia recognizing the common clinical presentations. Table 1 summarizes these with references that give details of the Metabolic diseases Pyruvate dehydrogenase deficiency various conditions. Four main dues in the clinical Gluconeogenic defects: Fructose 1,6-bisphosphatase deficiency presentation may suggest respiratory chain disease. Pyruvate carboxylase, multiple carboxylase or biotinidase (1) Diagnosis is easiest when the presentation conforms to deficiency one of the characteristic syndromes that have been reported. Phosphoenolpyruvate carboxykinase deficiency Glycogen storage disease type 1 It is important, however, to be aware that these syndromes Hereditary fructose intolerance show considerable variability: they may be incomplete, Long-chain hydroxyacyl-CoA dehydrogenase deficiency present in atypical ways or overlap with other syndromes. For Organic acidaemias: propionic, methyl malonic and isovaleric example, the cardinal features of Kearns-Sayre syndrome acidaemias, maple syrup urine disease (KSS) are progressive external ophthalmo-plegia and Secondary causes present with Tissue hypoxia: hypoxia (including crying) pigmentary retinopathy, but it can lschaemia hypocalcaemia or short stature; other patients progress Venous stasis from Pearson syndrome in infancy to KSS in childhood. There Shock is also overlap with adult onset chronic progressive external Exercise, seizures ophthalmoplegia (CPEO)2. Hepatic failure (2) The described syndromes often include features in several apparently unrelated systems. This should suggest respiratory chain disease even if the particular combination does not form part of a previously described syndrome. The hardest cases of respiratory chain disease to identify Myopathy combined with an unrelated symptom is are those in whom a single system is affected, without a particularly characteristic. In infancy, respiratory chain characteristic finding such as ophthalmoplegia. Isolated myopathy is usually associated with lactic acidosis and often skeletal myopathy is one such presentation: the aetiology is with de Toni-Fanconi-Debre syndrome or liver failure; later, usually apparent ifhistochemistry is performed on the muscle it is often found with cardiomyopathy or CNS disease such as biopsy. Deafness can also be an isolated finding in respiratory dementia, MERRF syndrome (myoclonic epilepsy with chain disease5, but the aetiology would seldom be suspected ragged-red fibres) or MELAS syndrome (mitochondrial unless there are affected relatives. myopathy, encephalopathy, lactic acidosis and stroke-like episodes). (3) Within each system respiratory chain disorders cause Biochemical clues certain patterns of disease and not others. Thus, de Toni- A raised lactate concentration in blood or CSF is an important Fanconi-Debre syndrome is the only renal disease commonly pointer to respiratory chain disease though its sensitivity and associated with respiratory chain defects. Certain clinical specificity are low. Hyperlactataemia is uncommon in adult features, such as progressive external ophthalmoplegia, are so onset respiratory chain disease apart from MELAS syndrome strongly suggestive of respiratory chain pathology that and mitochondrial myopathies. Hyperlactataemia seems to be investigation is warranted even in the absence of other more common in childhood and especially in infancy: raised features. Some investigation findings are equally suggestive lactate concentrations may reflect widespread disease, which (e.g. the MRI findings in Leigh disease3). The value of raised is likely to present early in life. Thus, Pearson syndrome, KSS lactate concentrations in blood or CSF will be discussed later. and CPEO are all associated with similar mtDNA Other features, such as cardiomyopathy, ataxia, myoclonus or rearrangements. Pearson syndrome, a multisystem disorder stroke-like episodes, should lead to a high index of suspicion that usually presents in infancy, is almost always associated but it is not feasible to investigate the respiratory chain in all with raised blood lactate concentrations. Raised levels are these patients unless there is an additional pointer to this also sometimes found in KSS, which presents later in aetiology. childhood or in young adults, but have not been described in (4) A final clinical clue to respiratory chain dysfunction is a CPEO. Again, cases of mtDNA depletion syndrome family history of mitochondrial disease. This may take the presenting in infancy tend to have hyperlactataemia, same form as in the index case but often is markedly different, whereas those presenting later do not6. Normal lactate particularly in cases caused by mtDNA mutations. For levels should not discourage investigation of the respiratory example, relatives of patients with MELAS syndrome have chain if the clinical picture is otherwise suggestive. been identified with myoclonus, pigmentary retinopathy or A raised blood lactate concentration strengthens the case deafness4. Obviously, a maternal pattern of inheritance is for respiratory chain disease but is far from specific. Other 218P particularly suggestive but any pattern may be found. causes of hyperlactataemia are summarized in Table 2. Many JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 88 April 1995 ofthese are easy to distinguish but others can cause diagnostic relevant family history. Measurement of the blood or CSF confusion. In general, the alternative diagnoses should be lactate, or the lactate to pyruvate ratio, can increase one's excluded first, as establishing the presence of a respiratory suspicion of respiratory chain disease but can neither prove it chain disorder is likely to be harder and the therapeutic nor exclude it. implications more limited. For example, hereditary

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