Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome.

L eigh syndrome is a subacute necrotising encephalomyelopathy characterised by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs. The main laboratory findings are raised lactate in the blood and cerebrospinal fluid, but the diagnosis is only confirmed by the presence of bilateral symmetrical lesions in the basal ganglia, thalamus, brain stem, and cerebellum. Leigh syndrome can result from a number of different defects in mitochondrial energy metabolism, most commonly deficiencies of cytochrome oxidase (COX), pyruvate dehydrogenase, NADH-ubiquinone oxidoreductase (Complex I) and ATP synthase. In patients with Leigh syndrome and cytochrome oxidase deficiency, the underlying genetic defect is usually a mutation in the SURF1 gene, which maps to chromosome 9q34 and encodes a cytochrome oxidase assembly factor. 3 In a small number of cases, Leigh syndrome and cytochrome oxidase deficiency have been found in patients with mutations in mitochondrial DNA (mtDNA) 5 and in one patient with mutations in the COX10 gene. Cytochrome oxidase is the terminal complex of the electron transport chain. It transfers electrons from cytochrome c to molecular oxygen and contributes to the proton motive force used in the generation of ATP. The mammalian complex is composed of thirteen subunits, three encoded in mtDNA and ten in nuclear DNA. Some of the nuclear subunits have different isoforms, which are coded by multigene families and are expressed in different tissues and at different stages of development. The cytochrome oxidase complex contains four prosthetic groups, haeme a, haeme a3, CuA and CuB, which are essential for the redox reaction. Therefore, generation of a fully functional complex in the inner mitochondrial membrane requires: (a) transcription and translation of 13 proteins in two different compartments of the cell, (b) correct assembly in the inner mitochondrial membrane with prosthetic groups, and (c) regulation of activity according to specific tissue and developmental requirements. As a consequence of this complexity, it is not surprising that cytochrome oxidase deficiency is genetically and phenotypically highly heterogeneous. At present, a specific genetic diagnosis is made in only <50% of patients and the majority of these belong to the SURF1 deficiency group. Mutations in other nuclear genes whose products are necessary for cytochrome oxidase biogenesis, such as SCO1, 17 SCO2, COX10, COX15, LRPPRC, TK-2, DGK-2, and thymidine phosphorylase, appear to be much less common. They have been associated with lactic acidosis and non-specific encephalopathy, in some cases co-existing with dysfunctions of other highly metabolic organs, such as heart, liver, kidney, and muscle. We describe a patient who presented with Leigh syndrome as a result of cytochrome oxidase deficiency, in whom the underlying cause is a mutation in the COX15 gene, which codes for an enzyme involved in haeme a biosynthesis. This is only the second patient described with a mutation at this locus and the clinical presentation differs significantly from the previously reported case, suggesting that this condition may be more variable in presentation than other defects of cytochrome oxidase assembly.