Xenia Dennett

Diagnostic criteria for respiratory chain disorders in adults and children

Background: Respiratory chain (RC) disorders are clinically, biochemically, and molecularly heterogeneous. The lack of standardized diagnostic criteria poses difficulties in evaluating diagnostic methodologies. Objective: To assess proposed adult RC diagnostic criteria that classify patients into “definite,” “probable,” or “possible” categories. Methods: The authors applied the adult RC diagnostic criteria retrospectively to 146 consecutive children referred for investigation of a suspected RC disorder. Data were collected from hospital, genetics, and laboratory records, and the diagnoses predicted by the adult criteria were compared with the previously assigned assessments. Results: The authors identified three major difficulties in applying the adult criteria:lack of pediatric-specific criteria; difficulty in segregating continuous data into circumscribed major and minor criteria; and lack of additivity of clinical features or enzyme tests. They therefore modified the adult criteria to allow for pediatric clinical and histologic features and for more sensitive coding of RC enzyme and functional studies. Reanalysis of the patients’ data resulted in congruence between the diagnostic certainty previously assigned by the authors’ center and that defined by the new general RC diagnostic criteria in 99% of patients. Conclusions: These general diagnostic criteria appear to improve the sensitivity of the adult criteria. They need further assessment in prospective clinical and epidemiologic studies.

Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder.

Objective: To define the spectrum of clinical and biochemical features in 51 children with isolated complex I deficiency. Background: Mitochondrial respiratory chain defects are one of the most commonly diagnosed inborn errors of metabolism. Until recently there have been technical problems with the diagnosis of respiratory chain complex I defects, and there is a lack of information about this underreported cause of respiratory chain dysfunction. Methods: A retrospective review of clinical features and laboratory findings was undertaken in all diagnosed patients who had samples referred over a 22-year period. Results: Presentations were heterogeneous, ranging from severe multisystem disease with neonatal death to isolated myopathy. Classic indicators of respiratory chain disease were not present in 16 of 42 patients in whom blood lactate levels were normal on at least one occasion, and in 23 of 37 patients in whom muscle morphology was normal or nonspecific. Ragged red fibers were present in only five patients. Tissue specificity was observed in 19 of 41 patients in whom multiple tissues were examined, thus the diagnosis may be missed if the affected tissue is not analyzed. Nine patients had only skin fibroblasts available, the diagnosis being based on enzyme assay and functional tests. Modes of inheritance include autosomal recessive (suggested in five consanguineous families), maternal (mitochondrial DNA point mutations in eight patients), and possibly X-linked (slight male predominance of 30:21). Recurrence risk was estimated as 20 to 25%. Conclusion: Heterogeneous clinical features, tissue specificity, and absence of lactic acidosis or abnormal mitochondrial morphology in many patients have resulted in underdiagnosis of respiratory chain complex I deficiency.

Quadriceps muscle wasting persists 5 months after total hip arthroplasty for osteoarthritis of the hip: a pilot study

Aims: To determine whether additional muscle fibre wasting of the ipsilateral vastus lateralis muscle occurs in the early postoperative period after total hip arthroplasty for osteoarthritis of the hip and whether there is an improvement in preoperative measures of quadriceps muscle thickness, strength, pain and function over a 5‐month postoperative period.

Benign acute childhood myositis: laboratory and clinical features.

Background: Benign acute myositis of childhood is a disorder of midchildhood, typically affecting boys. Symptoms include calf pain and difficulty walking after a viral illness. There is an epidemiologic association with influenza. Objectives: To describe the clinical and laboratory features of benign acute myositis. Results: Thirty-eight children (32 boys, 6 girls) were seen with 41 episodes of myositis between 1978 and 1997. Two were siblings and three had recurrent episodes. Mean age at onset of symptoms was 8.1 years. Children remained ambulant during 33 of 41 episodes. Two characteristic gaits were noted: toe-walking in 13, with a wide-based stiff-legged gait in another 7. Muscle tenderness was isolated to the gastrocnemius–soleus muscles in 82% of episodes. Recovery occurred within 1 week. Creatine kinase levels were elevated during all episodes. Viral studies were positive in 10 of 24 episodes, 5 because of influenza B. Conclusion: Benign acute myositis is a syndrome of midchildhood that can be differentiated from more serious causes of walking difficulty by the presence of calf tenderness, normal power, intact tendon reflexes, and elevated creatine kinase. The gait patterns noted may minimize power generation of the calf muscles by splinting the ankles. Onset in childhood may reflect an age-related response to viral infection, and occurrence primarily in boys may reflect a genetic predisposition or an as-yet unknown metabolic defect.

Partial cytochrome oxidase (aa3) deficiency in chronic progressive external ophthalmoplegia: Histochemical and biochemical studies☆

Biochemical and histochemical studies were carried out on 2 patients with chronic progressive external ophthalmoplegia (CPEO). Histological examination revealed prominent ragged-red fibres in the Gomori trichrome stain and cytochrome oxidase staining revealed partial depletion of cytochrome oxidase with negative staining in some fibres with prominent subsarcolemmal mitochondrial aggregations. Polarographic studies with isolated intact skeletal muscle mitochondria revealed low State III respiration rates with NAD- and FAD-linked substrates. Cytochrome aa3 levels were depressed in the one case where a cytochrome difference spectra was recorded. Cytochrome oxidase levels were greatly depressed in muscle homogenate, whereas monoamine oxidase levels were in the normal range, indicating a selective depletion of the former enzyme complex. It is possible that deficiency of cytochrome oxidase may arise as an epiphenomenon in degenerating mitochondria rather than a primary deficiency.

Respiratory chain failure in adult muscle fibres : relationship with ageing and possible implications for the neuronal pool

A histochemical analysis of mitochondrial enzyme activity was carried out in 103 human diaphragmatic skeletal muscles from 49 subjects of different ages, obtained either at the time of abdominal surgery or at necropsy. Evidence of respiratory failure (cytochrome oxidase negativity) was seen in occasional fibres from the fourth decade on with an approximate 10-fold increase between the fourth and ninth decade (0.16% to 2.85%). A similar incidence of mitochondrial failure in CNS neurones to that documented in skeletal muscle could easily account for attrition of 25% of neurones over a 50-year period as reported in the literature. Possible theoretical relationships between morphological markers of mitochondrial failure and cell attrition are explored. While the projections from muscle to neurone are somewhat speculative, it is clear that if a similar extent of mitochondrial pathology exists in the brain to that documented in skeletal muscle, this could easily account for neuronal loss in the ageing brain.

Progression from MERRF to MELAS phenotype in a patient with combined respiratory complex I and IV deficiencies

Identical twins developed myoclonic epilepsy in their teens. One twin remained mildly affected but the other went on to develop sensorineural deafness and ataxia with lactic acidosis and ragged red fibres leading to a diagnosis of mitochondrial encephalopathy. Multiple stroke-like episodes with hemiparesis followed, indicating progression from a MERRF to a MELAS phenotype. Biochemical studies revealed a severe deficiency of mitochondrial NADH-ubiquinone reductase and a moderate deficiency of cytochrome aa3. Western immunoblotting experiments using polyclonal antibodies raised against human placental cytochrome oxidase identified a similar profile of bands to those seen in controls, supporting the view that cytochrome aa3 deficiency in this case may be a secondary consequence of a failure of assembly related to a severe proximal respiratory chain defect.

Hypertrophic interstitial polyneuropathy in infancy. Clinical and pathologic features in two cases.

Two patients are described with hypertrophic intersticial polyneuropathy in infancy. The more severely affected infant presented in the neonatal period and the other infant, late in the first year of life. Each had delay in motor development, small muscles, weakness, hypotonia, absent tendon reflexes, elevated cerebrospinal fluid protein, and slow motor nerve conduction velocities. Peripheral nerves and spinal nerve roots showed well-developed “onion bulb” formations. The clinical and pathologic features suggest a primary disorder of myelination commencing as early as intrauterine life.

Mitochondrial theory of senescence: Respiratory chain protein studies in human skeletal muscle

In view of a previously demonstrated negative correlation between stage III respiratory activity in human mitochondria and increasing age, the relationship between human respiratory chain complex protein content and age was investigated. Quantitative immunoblot studies were carried out using holo complex I, III and IV antibody probes in human skeletal muscle mitochondrial homogenate from patients of varying ages. No significant negative correlation between increased age and respiratory complex chain protein content was seen for either total complex activity or for any of the subunits which could be reliably identified. As respiratory complex protein content is preserved with ageing, the decrease in respiratory efficiency is likely to follow aggregation of mutations in structural mitochondrial (mt) DNA genes which do not interfere with mt DNA transcription and protein translation rather than mutations in mt tRNA or ribosomal RNA genes. This is consistent with the fact that mt genes involved in protein translation only occupy a fairly small percentage of the mitochondrial genome.

Biochemical and morphological studies of skeletal muscle in experimental chronic alcoholic myopathy

Abstract Experimental alcoholic myopathy was induced in rats by a combination of prolonged alcohol intake (mean 15.3 g ethanol/kg/day for up to 10 weeks) and a short fast. In view of literature evidence for impairment of both glycolytic and oxidative metabolism in alcoholic myopathy, we combined histological and histochemical observations with biochemical studies comprising assay of all glycolytic enzymes and measurement of respiration rates and cytochrome content in isolated intact mitochondria. The predominant histological finding was type IIb fibre atrophy, while levels of the glycolytic enzymes aldolase, pyruvate kinase and lactate dehydrogenase were significantly depressed. Evidence of rhabdomyolysis was seen in a minority of animals. Mean mitochondrial respiratory rates were significantly lower with the Site I substrate glutamate in alcohol‐treated animals. It is postulated that chronic alcoholic myopathy is associated with glycolytic deficiency and that acute rhabdomyolysis may arise from a superimposed mitochondrial failure, resulting in a severe energy crisis in muscle.