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Clinical and laboratory findings in referrals for mitochondrial DNA analysis
  1. A C J HUTCHESSON, Consultant Chemical Pathologist
  1. Royal Bolton Hospital
  2. Bolton BL4 0JR, UK

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Editor,—The paper by Lamont and colleagues1 is a valuable survey of the findings associated with mitochondrial DNA mutations. However, DNA analysis is time consuming and expensive, and there is a need for a screening test to identify those who merit further investigation. Measurement of lactate has been proposed, and it was disappointing that this study found it lacked specificity. However, two issues need discussion.

Lamont et al state (table 2) that 11 of 13 patients had raised lactate concentrations in blood or cerebrospinal fluid (CSF); however, the data they present refers only to plasma concentrations.1 Lactate is more stable in CSF than in plasma,2 ,3 and increased concentrations specifically reflect central nervous system disease. The sensitivity reported for plasma lactate in detecting mitochondrial disease is similar to that previously reported by us.3 We found the sensitivity of CSF lactate was similar to that of plasma lactate in this role, but were unable to assess its specificity. It would be valuable to know if Lamont et al are able to address this point as CSF lactate measurement is increasingly being requested.

Despite the poor specificity of plasma lactate, it may still have a role in screening for mitochondrial disease. Although the specificity was only 51%, the negative predictive value of a concentration < 2 mmol/l was 97%.1 The overall cost of measuring lactate in our laboratory is less than £5, compared to £68–200 for mitochondrial DNA studies at our regional centre. Furthermore, the result is available in two hours rather than a week or more. Thus, measurement of plasma lactate is a cost effective and timely procedure for identifying children who are unlikely to merit further investigation. CSF lactate measurement may be even more cost effective, depending on its specificity.


Dr Lamont and colleagues comment:

Hutchesson’s letter raises several valuable points. Our paper was retrospective and so subject to the difficulties inherent in that form of information collection. Few of the 190 subjects had a CSF lactate value recorded. This made separate analysis of CSF lactate specificity in mitochondrial disorders impossible.

Mitochondrial DNA mutations are one cause of inborn errors of the mitochondrial electron transport chain, thereby reducing NADH disposal by oxidation. The equilibrium concentration of lactate is directly related to the concentration of NADH and NAD+. It follows that lactate accumulation may occur as a result of accumulation of pyruvate, NADH or electrons. Lactate concentration in arterial blood and CSF is generally more reliable than venous plasma, being less prone to spurious increases.1-1 However, the specificity of raised CSF lactate for mtDNA mutations, as opposed to other conditions such as pyruvate dehydrogenase deficiency, is unlikely to be good given that tissues outside the nervous system are often involved. These include skeletal muscle, cardiac muscle, liver or pancreas and would not contribute to CSF lactate concentrations.

The conclusion from our paper was that muscle biopsy was the only investigation providing specific evidence of an underlying mtDNA mutation. That conclusion is now challenged by the discovery that the mutated protein in both Friedreich’s ataxia and autosomal recessive hereditary spastic paraplegia are mitochondrial, and that ragged red fibres and cytochrome C oxidase deficiency have been reported in muscle biopsies of patients with both conditions.1-2 A simple screening test for mtDNA mutation diseases is still to be found.


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