The many clinical faces of cytochrome c oxidase deficiency.

Cytochrome c oxidase (COX) catalyzes the last step in respiration, transferring electrons from cytochrome c to molecular oxygen and coupling electron transfer with proton translocation from the mitochondrial matrix to the intermembrane space. COX is composed of 13 subunits, three larger catalytic subunits encoded by mitochondrial DNA (mtDNA) and ten subunits encoded by nuclear DNA. Clinically heterogeneous human diseases were attributed to COX deficiency since the 1970s, mostly based on histochemical or biochemical data in muscle biopsies. Here, we revisit the COX deficiencies described before the molecular era, assess the value of COX histochemistry in conjunction with succinate dehydrogenase (SDH) stain, and review the clinical presentations of primary COX deficiencies defined at the molecular level. In general, mutations in mtDNA COX genes are associated with milder and later onset clinical syndromes, probably due to heteroplasmy. Mutations affecting nuclear-encoded COX subunits ("direct hits") are extremely rare whereas mutations affecting assembly proteins ("indirect hits") account for most COX deficiencies and the list keeps growing. Onset is generally in infancy and survival into adolescence or adult life is infrequent. The most common neurological disorder is Leigh syndrome, either alone or associated with cardiopathy, hepatopathy, or nephropathy.

Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, increasing in prevalence with age. Most patients who develop AD have an unknown cause, but characteristic neuropathological features include the deposition of extracellular amyloid beta and of intraneuronal hyperphosphorylated tau protein. Researchers have previously implicated mitochondrial dysfunction in AD. We previously showed an increase in neurons displaying a mitochondrial biochemical defect-cytochrome-c oxidase (COX) deficiency-in the hippocampus in patients with sporadic AD compared with age-matched controls. COX deficiency is well described as a marker of mitochondrial (mt) DNA dysfunction. This present study analyzed the mtDNA in single neurons from both COX normal and COX-deficient cells. Analysis of the mtDNA revealed that COX deficiency is caused by high levels of mtDNA deletions which accumulate with age. Future research is needed to clarify the role mtDNA deletions have in normal aging and investigate the relationship between mtDNA deletions and the pathogenesis of sporadic AD.

High prevalence of SURF1 c.845_846delCT mutation in Polish Leigh patients.

Leigh syndrome is a neuropathological disorder with typical morphological changes in brain, appearing regardless of diverse molecular background. One of the most common enzymatic defects in Leigh patients is cytochrome c oxidase deficiency associated with recessive mutations in the SURF1 gene. To assess the SURF1 mutation profile among Polish patients we studied 41 affected children from 34 unrelated families by PCR-SSCP and sequencing. Four novel mutations, c.39delG, c.752-1G>C, c.800_801insT, c.821A>G, and five described pathogenic changes, c.311_312insAT312_321del10, c.688C>T, c.704T>C, c.756_757delCA, c.845_846delCT, were identified in 85.3% of analysed probands. One mutation, c.845_846delCT, was identified in 77.6% of SURF1 alleles. Up to now, it has been reported only in 9% of alleles in other parts of the world. The deletion was used as LS(SURF1-) marker in population studies. Eight heterozygous carriers of the mutation were found in a cohort of 2890 samples. The estimated c.845_846delCT allele frequency is 1:357 (0.28+/-0.2%), and the lowest predicted LS(SURF1-) frequency in Poland 1:126,736.births. Relatively high frequency of LS(SURF1-) in Poland with remarkable c.845_846delCT mutation dominance allows one to start the differential diagnosis of LS in each patient of Polish (and probably Slavonic) origin from the direct search for c.845_846delCT SURF1 mutation.

Clinical presentations of mitochondrial cardiomyopathies.

UNLABELLED: To determine the clinical manifestations and interfamilial variability of patients diagnosed with a mitochondrial cardiomyopathy, we reviewed the charts of 14 patients with cardiomyopathy out of 59 patients with mitochondrial disorders who attended the mitochondrial disease clinic at Wolfson Medical Center from 1996 to 2001. All patients underwent a metabolic evaluation including blood lactate, pyruvate, carnitine, and amino acids and urine organic acids. Respiratory chain enzymes were assessed in 10 patients. The mitochondrial DNA (mtDNA) was assessed for mutations. The age at presentation ranged between 6 months and 24 years. Six of the patients died, 5 from heart failure. The cardiomyopathy was hypertrophic in 10 and dilated in 4. Conduction and rhythm abnormalities were present in 6. Eleven patients had family members with mitochondrial disorders. All the patients had additional involvement of one or more systems. Seven patients exhibited a deficiency of a respiratory chain enzyme in the muscle. The MELAS mtDNA point mutation (3243) was found in one patient. Blood lactic acid levels were increased in 5. Brain MRI abnormalities were observed in 4. CONCLUSIONS: Mitochondrial dysfunction frequently affects the heart and may cause both hypertrophic and dilated cardiomyopathy. The cardiomyopathy is usually a part of a multisystem involvement and may rarely be isolated. The course may be stable for many years, but rapid deterioration may occur. Understanding the biochemical and genetic features of these diseases will enable us to comprehend the clinical heterogeneity of these disorders.