Biomedical subjects
Mikko Kärppä
Publications and source records attributed to Mikko Kärppä.
Spectrum of myopathic findings in 50 patients with the 3243A>G mutation in mitochondrial DNA.
Myopathy is a typical clinical finding among patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), but the variability in such findings has not been properly established. We have previously determined the prevalence of patients with 3243A>G in a defined population in northern Finland and characterized a group of patients who represent a good approximation to a population-based cohort. We report here on examinations performed on patients belonging to this cohort in order to determine the frequency of myopathy and to evaluate the clinical, histological, ultrastructural and single fibre mtDNA variability in muscle involvement. Fifty patients with 3243A>G underwent a thorough structured interview and clinical examination. Muscle histology, ultrastructure and single fibre analysis were examined in a subset of patients. A clinical diagnosis of myopathy was made in 50% of cases [95% confidence interval (CI), 36-64] and abnormalities in muscle histology were found in 72% (95% CI, 55-86). Moderate limb weakness leading to functional impairment was the most common myopathic sign, but mild weakness, ptosis and external ophthalmoplegia could also be found. The presence of intramitochondrial crystals and cytochrome c oxidase (COX)-negative fibres and variation in mitochondrial size and shape were more common in the muscles of the myopathic patients. Longitudinal variations in mutation heteroplasmy were examined in single muscle fibres from two severely affected patients. Although the total variation in mutation heteroplasmy along four ragged red fibres (RRFs) was small, the mutation heteroplasmy in five 10 microm segments was clearly lower (median 68%, range 64-74%) than that in the neighbouring segments. There were also segments with deviant mutation load in histologically normal fibres in one patient. The highest incidence of myopathy was in the fifth decade of life, but, apart from age, no other clinical variables such as gender, muscle heteroplasmy, physical inactivity or diabetes were associated with an increased risk of myopathy. The clinical presentation of myopathy is highly variable in patients with 3243A>G.
Muscle computed tomography patterns in patients with the mitochondrial DNA mutation 3243A>G.
Computed tomography provides a sensitive method for investigating skeletal muscle changes in neuromuscular diseases, but this method has not been applied to mitochondrial myopathies. We characterized the pattern of muscle involvement in patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), the common MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) mutation. Twenty-four patients, age 19-73 years, with 3243A>G were examined. Clinical evaluation included assessment of muscle strength and functional capacity. All the patients underwent muscle computed tomography, and muscle samples from 17 of them were examined for the presence of ragged red fibres and for the 3243A>G heteroplasmy. Venous blood lactate at rest and serum creatine kinase were determined. Clinical myopathy was found in six patients, while nine showed mild muscle weakness and nine had normal muscle function. The upper and lower limbs were equally affected, but the proximal muscles were more severely affected than the distal ones. CT revealed abnormalities in the muscles of 13 patients (54%; 95% confidence interval, 33-76%), including the six with clinical myopathy and seven without clinical myopathy. Myopathic changes were found most frequently in the pelvic muscles, with predominant involvement of the gluteus maximus. These data show that CT reveals frequent abnormal findings in the muscle of patients with the 3243A>G mtDNA mutation. Muscle CT is a useful adjunct to clinical evaluation in these patients.
Peripheral neuropathy in patients with the 3243A>G mutation in mitochondrial DNA.
Peripheral neuropathy is one of the clinical manifestations of the MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome, but its frequency and phenotypic variability have not been properly characterised. We therefore studied the clinical and electrophysiological features of peripheral neuropathy in 32 patients with the 3243A > G mutation in mitochondrial DNA by using clinical examination, assessment of Neuropathy Symptom Score, Neuropathy Disability Score, and electrophysiological examinations. Seven patients (22 %; 95 % confidence interval, 9-40 %) fulfilled the electrodiagnostic criteria for polyneuropathy. Mixed axon loss and demyelinating sensorimotor neuropathy was the most common type of polyneuropathy, while one patient presented with uniform demyelinating sensorimotor polyneuropathy. Sensory more than motor neuropathy was diagnosed in four patients. Clinically and electrophysiologically confirmed carpal tunnel syndrome (CTS) occurred in three patients (9.4 %), suggesting a higher prevalence than in the general population. Patients with neuropathy were in general more severely affected than those without neuropathy, although no correlation was found between the presence of neuropathy and the degree of mutant heteroplasmy in muscle. Higher age and male gender were associated with an increased risk of neuropathy. Our results show that peripheral neuropathy is not uncommon in patients with the 3243A > G mutation, and they also may have an increased risk of CTS.
A mutation in mitochondrial DNA-encoded cytochrome c oxidase II gene in a child with Alpers-Huttenlocher-like disease.
OBJECTIVE: Cytochrome c oxidase (COX) deficiency has been demonstrated in some patients with Alpers-Huttenlocher disease, but no genetic background has been identified. Our objective was to determine the molecular defect underlying the mitochondrial respiratory chain deficiency in a child with Alpers-Huttenlocher-like progressive cerebrohepatic disease. METHODS: The entire coding region of mitochondrial DNA was analyzed by conformation-sensitive gel electrophoresis and sequencing. Biochemical and morphologic investigations were performed on tissue biopsy material, including oximetric and spectrophotometric analyses of oxidative phosphorylation, histochemistry, and electron microscopy. RESULTS: Postmortem histologic examination revealed a marked loss of neurons in the olivary nuclei and a spongy change in the calcarine cortex, fatty infiltration and micronodular cirrhosis of the liver, and atrophic ovaries. A novel heteroplasmic 7706G>A mutation was found in the COX II gene. The median degree of the mutant heteroplasmy was 90% in 5 tissues examined but was lower in the blood of asymptomatic maternal relatives. The distribution of the mutant heteroplasmy was skewed to the left in single muscle fibers of the proband and her mother. The 7706G>A mutation converts a hydrophobic alanine in a conserved transmembrane segment to hydrophilic threonine. CONCLUSIONS: The 7706G>A mutation is pathogenic and may lead to impaired dioxygen transfer to the active site of COX. The clinical phenotype of this patient resembled that in Alpers-Huttenlocher disease, suggesting that analysis of mitochondrial DNA is worthwhile in patients with a progressive cerebrohepatic disease.