Cerebral white matter disease in children may be caused by mitochondrial respiratory chain deficiency.

Several mitochondrial diseases are known to occasionally involve the cerebral white matter, namely Leigh syndrome, Kearns-Sayre syndrome, and MELAS syndrome, but in these cases the major finding is alteration in the basal ganglia and brainstem. Here we report on severe diffuse white matter involvement and respiratory chain enzyme deficiency or mitochondrial DNA rearrangement in 5 unrelated families. It is interesting that white matter lesions were the only abnormal neuroradiologic feature in 3 of the 5 families, and multiple small cyst-like white matter lesions were found in 2 of 5 probands. Respiratory chain deficiency should be considered in the diagnosis of severe white matter involvement in childhood.

Late onset familial dystonia: could mitochondrial deficits induce a diffuse lesioning process of the whole basal ganglia system?

BACKGROUND: Striatal necrosis has been related to various clinical syndromes, with acute or chronic progression, and juvenile or late occurrence, but the most common type is Leigh's encephalopathy. METHODS: Between 1967 and 1995, six out of seven related patients with chronic familial dystonia were examined. MRIs were performed in four, between 1992-1994. The seven members, affected over three generations, were the father, three daughters (one surviving), and three surviving grandsons. RESULTS: The leading symptoms were gait disorders and dystonia in all, dysarthria in six, verbal and motor stereotypies in two, and parkinsonian and cerebellar signs in three. Optic neuropathy was found in three. A frontal lobe syndrome without amnesia occurred in two. Symptoms occurred between the second and the fifth decade, with progressive deterioration. Magnetic resonance imaging, performed in four, showed in the two patients with severe neurological signs diffuse striatopallidal abnormal hyposignal (comparable with CSF signal) in T1 weighted images, suggesting extensive necrosis of the striatum and pallidum, associated with thalamo-subthalamo-rubro-dentato-nigral and substantia innominata hypersignals in T2 weighted images suggesting gliosis in these respective areas. The same images were described to a lesser extent in a third patient. Concentrations of lactate in CSF and serum were normal in three. Muscle biopsy, performed in four, was shown to be normal. Enzyme histochemistry showed complex I, III, and IV deficiency in surviving patients. CONCLUSION: This familial dystonia of chronic progression may be related to basal ganglia necrosis or gliosis, associated with alterations in the respiratory chain. These metabolic alterations probably play a part in the pathophysiology of these unusual brain lesions.

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

Sarcoid myopathy and mitochondrial respiratory chain defects: clinicopathological, biochemical and molecular biological analyses.

We report on a 33-yr-old female patient with myalgia, CK values up to 3500 Ul-1 and proximal weakness. An initial muscle biopsy showed myositis. One year later an enlarged lymph node was investigated and sarcoidosis diagnosed. In a second muscle biopsy inflammatory cells and morphological characteristics of mitochondrial myopathy were found. Biochemical analyses indicated a 50% reduction in complex II activity of the respiratory chain. Due to failure in clinical improvement a third muscle biopsy was performed in 1990 where only 19% of normal complex II activity was present. Southern blot analysis of the mitochondrial genome was normal. Thus for the first time we describe a patient with sarcoid myopathy and a complex II deficiency. Our interpretation is that a pre-existing complex II defect became clinically relevant because of additional sarcoid myopathy.

Benign mitochondrial myopathy with decreased succinate cytochrome C reductase activity.

In most of the cases previously described, the defect on complex II was suggested by low activity of succinate cytochrome C reductase (SCCR). The clinical pattern of the previous 10 cases is heterogeneous and may be limited to one particular tissue or be of a more general nature. We report a 22-year-old-woman, daughter of consanguineous parents, with generalized muscle weakness, easy fatigability and benign course, who showed a decrease of SCCR activity in mitochondria of muscle fibers. Free carnitine (FC) concentration was decreased in muscle as well. The muscle biopsy showed a mild variation in fiber size, with fiber type I predominance, subsarcolemmal oxidative DPNH accumulations, excess of neutral lipids and abnormally large mitochondria with paracrystalline inclusions. A possible inheritance pattern is discussed. Coenzyme Q10 therapy in this patient induced a significant increase of global MRC index score and a decrease of the turns-mean amplitude ratio in the automatic analysis of the EMG.

Nuclear complementation restores mtDNA levels in cultured cells from a patient with mtDNA depletion.

We have studied cultured skin fibroblasts from a patient with a fatal mitochondrial disease manifesting soon after birth. These fibroblasts were found to grow only in the presence of pyruvate and uridine, a characteristic of cells lacking mtDNA (rho0 cells). Southern blot and PCR analyses confirmed that the patient's fibroblasts contained less than 2% of control levels of mtDNA. Biochemical analyses indicated that the activities of all the respiratory-chain enzymes were severely decreased in mitochondria isolated from these fibroblasts. In order to elucidate the underlying molecular defect, cell fusions were performed between enucleated fibroblasts from this patient and a human-derived rho0 cell line (rho0 A549.B2). The resulting cybrids were plated in medium lacking pyruvate and uridine, to select for the restoration of respiratory-chain function. Complementation was observed between the nuclear genome of the rho0 A549.B2 cells and the mtDNA of the patient's cells, restoring mtDNA levels and respiratory-chain function in the cybrid cells. These results indicate that mtDNA depletion in our patient is under the control of the nuclear genome.

Fatal combined defects in mitochondrial multienzyme complexes in two siblings.

A female child suffering from intrauterine growth retardation was born by caesarean section at 32 weeks. In the immediate newborn period there was a metabolic acidosis but this resolved. Hypotonia, muscular weakness and poor respiratory effort were evident and the child died at 6 days of age. A previous male sibling had died at 3 months of age after similar symptoms with seizures and a dysmyelination disorder. Post-mortem examination of both children showed damage to the basal ganglia. Defects in the activities of the pyruvate dehydrogenase complex, cytochrome oxidase and succinate cytochrome c reductase were found in cultured skin fibroblasts. Similar defects were found in isolated muscle mitochondria but not in isolated liver mitochondria from the patient. Immunoblotting for cytochrome oxidase showed that the multienzyme complex was not assembled in muscle and skin fibroblast mitochondria, but was assembled in liver mitochondria. Similar results were obtained in cultured skin fibroblast mitochondria for complex I of the mitochondrial respiratory chain. This is the first occasion that multiple defects have been demonstrated both in tissue and in culture skin fibroblasts in mitochondrial respiratory chain complexes.

Rett syndrome and mitochondrial enzyme deficiencies.

The etiology of Rett syndrome is unknown. Structural mitochondrial abnormalities have been described in muscle in patients with Rett syndrome. We report three children with Rett syndrome and normal muscle mitochondrial structure on light and electron microscopy. However, all had abnormalities in mitochondrial respiratory chain enzymes.

[Myopathy due to succinate cytochrome C oxidoreductase deficiency: possible defect of complex II of the respiratory chain]. / Miopatia por deficiência de succinato-citocromo-C-redutase: possível defeito no complexo II da cadeia respiratória.

The case of a 24 years-old woman with weakness since the teens and progressive loss of muscle strength is reported. The muscle biopsy showed increased number of mitochondria. In two occasions the respiratory chain enzymes showed important reduction of the succinate-cytochrome-C-reductase, suggesting a possible defect in the complex II of the respiratory chain. Large doses of vitamins C and K were prescribed. There was improvement of muscle strength. A discussion about the most common syndromes marked by mitochondrial abnormalities in muscle is made, as well as about the type of work-up that should be done in suspect cases of respiratory chain defects.

Miopatia por deficiência de succinato citocromo-c redutase: possível defeito no complexo 11 da cadeia respiratória / Myopathy due to succinate cytochrome-c reductase deficiency: possible deficiency in the complex 11 of the respiratory chain

Relato do caso de mulher de 24 anos de idade que apresentava astenia desde a puberdade, com agravamenteo nos últimos anos, cuja biópsia muscular revelou grande acúmulo de mitocôndrias. As dosagens dos enzimas mitocondriais mostrou importante reduçäo da succinato-citocromo-C-redutase, sugerindo defeito na cadeia respiratória a nível do complexo II. Medicada com altas doses de vitamina C e K, melhorou da força muscular. Säo feitas consideraçöes a respeito das principais síndromes com miopatias mitocondriais, bem como a respeito dos métodos de investigaçäo em defeitos da cadeia respiratória

Mitochondrial myopathy with lactic acidosis and deficient activity of muscle succinate cytochrome-c-oxidoreductase.

A male infant had severe muscular hypotonia from birth. Recurrent vomiting with dehydration and severe metabolic acidosis complicated the course. Elevated lactate (up to 12.3 mmol/l; n less than 2), pyruvate (0.4 mmol/l; n less than 0.05) and alanine levels were found in serum with an abnormal lactate/pyruvate ratio (greater than 30; n less than 15). In urine the concentrations of lactate, pyruvate, alanine and of several intermediates of the citric acid cycle were increased. In muscle, numerous disseminated "ragged red fibres" were found by light microscopy; muscle fibres were found to contain subsarcolemmal aggregates of mitochondria, lipid droplets and glycogen by electromicroscopical methods. Moreover, mitochondria with a typical circular arrangement of cristae were noticed. In liver homogenates normal activities of pyruvate carboxylase and pyruvate dehydrogenase complex were found; in liver mitochondria also succinate-cytochrome-c-oxidoreductase activity was normal. However, in muscle no succinate-cytochrome-c-oxidoreductase activity was detectable. The patient became increasingly lethargic and died because of sepsis at 5 months of age.

Histiocytoid cardiomyopathy of infancy: deficiency of reducible cytochrome b in heart mitochondria.

A 3-week-old girl with failure to thrive and cardiomegaly died of cardiac arrest at age 4 weeks. Morphologic studies of the heart showed enlarged muscle fibers with large accumulations of mitochondria, characteristic of histiocytoid cardiomyopathy. Biochemical studies showed markedly decreased succinate-cytochrome c reductase and rotenone-sensitive NADH-cytochrome c reductase activities, while other mitochondrial enzymes were normal. In isolated mitochondria, cytochrome spectra showed a severe defect of reducible cytochrome b and a less marked defect of cytochrome cc1, while the content of cytochrome aa3 (cytochrome c oxidase) was normal. Histiocytoid cardiomyopathy appears to be due to a defect of complex III (reduced coenzyme Q-cytochrome c reductase) in the respiratory chain of heart mitochondria.

Lactic acidosis and mitochondrial myopathy associated with deficiency of several components of complex III of the respiratory chain.

We have studied a 17-year-old girl with lactic acidosis (3-18 mEq/liter) and progressive muscle weakness since 9 years of age. Morphological findings in muscle were of a typical ragged red myopathy with multiple collections of bizarre mitochondria, some containing paracrystalline inclusions. The carnitine content of serum and muscle was normal, as were the activities of carnitine palmitoyltransferase, carnitine octanoyltransferase, and carnitine acetyltransferase in the patient's muscle. Measurement of the enzymes of oxidative phosphorylation in both crude muscle homogenates and mitochondrial fractions showed close to normal activities of cytochrome c oxidase, succinate dehydrogenase, and ATPase. In contrast, succinate cytochrome c reductase activity was greatly reduced in the patient, being 0.035 mumol/min/g tissue in whole muscle (controls 1.16 +/- 0.47 mumol/min/g tissue) and 8 nmol/min/mg protein in the mitochondria (control, 340 nmol/min/mg protein). Rotenonesensitive NADH-cytochrome c reductase was also undetectable in the patient's mitochondria. Spectral analysis of cytochromes showed decrease of reducible cytochrome b to 16% of the control. These results indicate a defect of ubiquinol-cytochrome c reductase or the cytochrome bc1 segment (complex III) of the electron transport chain. Antibody-binding studies of the individual components of complex III showed additional deficiencies of core proteins I and II and peptide VI, indicating a more widespread defect of complex III than was evident from spectral analysis and enzyme activity measurements alone. Urine organic acid analysis after fasting and following a medium chain triglyceride load showed unusually high levels of lactate and 3-hydroxybutyrate, lower than expected levels of acetoacetate and dicarboxylic acids, and the presence of several other metabolites suggesting a disturbed citric acid cycle and redox state.(ABSTRACT TRUNCATED AT 250 WORDS)