Cytochrome c Oxidase Partial Deficiency-Associated Leigh Disease Presenting as an Extrapyramidal Syndrome

Abstract

Leigh disease is a subacute neurodegenerative disorder characterized by symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optical nerves and caused by altered oxidative phosphorylation. We describe the clinical, biochemical, neuroimaging, and molecular studies of a 19-year-old boy with early-onset Leigh disease manifesting as severe extrapyramidal disorder with generalized dystonia and choreoathetosis. He was born of healthy parents after an uneventful pregnancy and delivery. At the age of 2 1/2 years, after a minor respiratory infection, he developed unstable, broad-based gait and tremor of the hands. These symptoms persisted for the next several years, when ataxia became more prominent. Difficulty in swallowing, dysarthria, trunk dystonia, and marked dyskinesia of the arms and hands gradually developed. Nystagmus, transient ptosis, and strabismus also appeared. Abnormal laboratory findings included elevated plasma and cerebrospinal fluid lactate and pyruvate, with an abnormal lactate/pyruvate ratio. Cranial computed tomography and magnetic resonance imaging demonstrated signs of cerebellar atrophy, bilateral and symmetric hypodensities in the lentiform nucleus and thalamus, and transient hyperintensities of cerebral peduncles in T2-weighted sequences suggestive of Leigh disease. Muscle biopsy revealed isolated fiber atrophy, necrotic fibers undergoing phagocytosis, and no ragged-red fibers. The measured catalytic activity of cytochrome c oxidase in skeletal muscle homogenates demonstrated a partial cytochrome c oxidase deficiency No abnormalities in the mitochondrial genome and in the SURF-1 gene were found. The boy is currently receiving levodopa therapy, creatine monohydrate, and a high dosage of thiamine and lipoic acid, his condition is stabilized, and extrapyramidal symptoms are less pronounced.

Leigh's Disease: The Acute Clinical Course of a Two-Year-Old Child with Subacute Necrotizing Encephalomyelopathy

“…Congenital cytochrome-c-oxidase deficiency, pyruvate-dehydrogenase deficiency as well as biotinidase deficiency are known to cause these clinical symptoms [4, 7, 8]. These states probably have an autosomal-recessive inheritance although mitochondrial and maternal inheritance are being discussed and sporadic cases are known [3, 4].…”

“…These states probably have an autosomal-recessive inheritance although mitochondrial and maternal inheritance are being discussed and sporadic cases are known [3, 4]. Genetic irregularities could only be found in approximately 50% of all patients, showing that there are many other biochemical irregularities which could lead to the clinical syndrome of Leigh's disease [8]. …”

“…The use of coenzyme Q10, thiamine, and carnitine may cause a decrease in severity of symptoms in a few cases [6]. Cacic et al report that a 19-year-old man symptoms were kept stable for at least four years by a therapy including levodopa, carbidopa, and creatinine monohydrate [8]. …”