Early-onset cerebellar ataxia, myoclonus and hypogonadism in a case of mitochondrial complex III deficiency treated with vitamins K3 and C.

A 16-year-old girl presented with early-onset cerebellar ataxia, myoclonus, elevated lactic acidosis and hypogonadotropic hypogonadism. Muscle biopsy specimens revealed fibres with a "ragged" appearance with increased mitochondria and lipid droplets. Biochemical investigation revealed a deficiency of complex bc1 (complex III) of the mitochondrial respiratory chain. Genetic analysis did not show either deletions or known mutations of mitochondrial DNA (mtDNA). Phosphorus magnetic resonance spectroscopy (31P-MRS) showed defective energy metabolism in brain and gastrocnemius muscle. A decreased phosphocreatine (PCr) content was found in the occipital lobes accompanied by normal inorganic phosphate (Pi) and cytosolic pH. These findings represented evidence of a high cytosolic adenosine diphosphate concentration and a relatively high rate of metabolism accompanied by a low phosphorylation potential. Muscle 31P-MRS showed a high Pi content at rest, abnormal exercise transfer pattern and a low rate of PCr post-exercise recovery. These findings suggested a deficit of mitochondrial function. Therapy with vitamins K3 and C normalized brain 31P-MRS indices, whereas it did not affect muscle bioenergetic metabolism. In this patient, the endocrinological disorder is putatively due to a mitochondrial cytopathy. Although an unknown mtDNA mutation cannot be ruled out, the genetic defect may lie in the nuclear genome.

Cardiovascular autonomic dysfunction in multiple sclerosis is likely related to brainstem lesions.

Impairment of cardiovascular autonomic reflexes has been described in multiple sclerosis (MS), and believed reflecting dysfunction of reflex pathways located within the central nervous system. A battery of cardiovascular autonomic tests were performed in 40 patients with definite MS: R-R interval variation test, deep breathing, Valsalva manoeuvre, blood pressure and heart rate responses to standing, sustained handgrip. The results were evaluated by Bayesian analysis, a pattern recognition technique. The patients had also magnetic resonance imaging (MRI) of brain and in 19 subjects of cervical spinal cord. Deep breathing test and sustained handgrip test produced most frequently abnormal results (17.5% and 40%, respectively). However, only 4 patients (10% had two or more tests abnormal, with a very variable pattern. Evaluation by Bayesian analysis revealed 7 patients (17.5%) with definite autonomic dysfunction. A correlation was found between the confidence level obtained by Bayesian analysis, as index of autonomic function, and the Kurtzke brainstem FS score (r = 0.43, P < 0.01). There was a significant association between presence of autonomic dysfunction and clinical (P < 0.02) and MRI (P < 0.005) evidence of brainstem lesions.

Late-onset mitochondrial neuromyopathy: an age-related phenomenon?

Peripheral neuropathy has been described in a number of cases of mitochondrial diseases. In these patients the onset of neuropathy varies from childhood to adulthood, whereas late onset is quite rare. We report here three males, ranging from 71 to 75 years with onset of peripheral neuropathy between 64 and 74 years of age. They complain of ataxic gait, muscle aches, weakness and mild muscle atrophy, sensory impairment with predominant glove and stocking distribution, reduced or absent deep tendon reflexes. Neurophysiological examinations and sural nerve biopsy studies showed a sensorimotor neuropathy with axonal degeneration in two cases and demyelination in one. Peroneus brevis muscle biopsy revealed, apart from frank neurogenic changes, presence of ragged-red fibers and cytochrome c oxidase negative fibers. Electron microscopy confirmed an abnormally increased presence of subsarcolemmal and intermyofibrillar mitochondria in muscle samples. These morphological features suggested a mitochondrial disease that was confirmed by biochemical investigations on muscle homogenate showing that the mitochondrial respiratory chain (MRC) enzyme activities were all reduced when compared to citrate synthase activity. In addition the presence of a partially inactive cytochrome c oxidase protein by ELISA was demonstrated in two cases. According to a recent "mitochondrial theory of aging", we think that a progressive decline of MRC function has affected either skeletal muscle or peripheral nerves in our patients. Being energy-requiring processes, muscle metabolism as well as active axonal transport may become progressively defective with age resulting in a late-onset neuropathy.