Neonatal presentation of coenzyme Q10 deficiency

Neonatal presentation of coenzyme Q10 deficiency Shamima Rahman, MRCP, Iain Hargreaves, PhD, Peter Clayton, MD, FRCP, and Simon Heales, PhD, MRCPath

We report a neonate with ubiquinone deficiency. Skeletal muscle analysis revealed markedly diminished mitochondrial complex II + III activity that could be restored by addition of a ubiquinone analogue. Ubiquinone deficiency was confirmed by high-performance liquid chromatography. Oral ubiquinone therapy was not associated with clinical improvement; the patient died at 2 years. (J Pediatr 2001;139:456-8)

Defects of the mitochondrial respiratory chain represent a relatively common group of inborn errors of metabolism.1 Respiratory chain defects are not amenable to treatment; a possible exception is ubiquinone (CoQ10) deficiency.2 CoQ10 acts as a redox carrier, transferring reducing equivalents from respiratory chain complexes I and II to complex III.3 CoQ10 deficiency appears to be extremely rare. Four patients from 3 families presented with mitochondrial encephalomyopathies4-6; systemic features have been described in only one family.2 We now report a severe neonatal presentation of CoQ10 deficiency with systemic features and poor clinical response to CoQ10 therapy. From the Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, and Departments of Neurochemistry and Clinical Biochemistry, Institute of Neurology and National Hospital, London, United Kingdom.

Submitted for publication Dec 29, 2000; revisions received Mar 6, 2001, and May 4, 2001; accepted May 25, 2001. Reprint requests: Simon Heales, PhD, Department of Clinical Biochemistry (Neurometabolic Unit), 9th Floor–Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/22/117575 doi:10.1067/mpd.2001.117575

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PATIENT AND METHODS Clinical Details and Initial Investigations The patient, a boy, was the seventh child of healthy unrelated Pakistani parents and was delivered by elective cesarean section after a normal pregnancy, possibly complicated by reduced fetal movements in the last trimester. Five older siblings, 4 girls and 1 boy, are well but another sibling died on day 1 of life with seizures, aminoaciduria, and acidosis. The mother had previously had 5 first-trimester miscarriages. The patient presented at 6 hours of age with poor feeding, hypothermia, and “shaking of both arms.” Examination revealed a passive neonate, unresponsive to his immediate environment, with a weak cry. There were no dysmorphic features. He had generalized increase of peripheral tone with reduced truncal tone. Initial investigations demonstrated lactic acidosis (plasma lactate 19.4 mmol/L, reference range 0.9 to 1.9 mmol/L), renal tubulopathy (tubular reabsorption of phosphate 60%, reference range >85%), and mild left ventricular hypertrophy with global hypokinesia on echocardiogram. Chest radiograph showed diffuse haze consistent with mild interstitial edema. Mag-

netic resonance imaging of the brain demonstrated generalized cerebral and cerebellar atrophy and abnormal parenchyma, and an electroencephalogram showed bilateral paroxysmal activity. He had mild clotting abnormalities (activated partial thromboplastin time 44.1 seconds, reference range 29 to 40; thrombin time 15.1 seconds, reference range 8 to 12). However, there was no evidence of jaundice; and hepatic transaminase, blood glucose, and ammonia levels were normal. He received formula feeds. Open muscle biopsy was deferred until 10 months. At this time he was more stable, although still requiring continuous administration of oxygen. CoQ10 Ubiquinone CoQ1 Ubiquinone-1

He had a severe seizure disorder, and development continued to be grossly delayed. His head control was poor, he was unable to sit unsupported, and he had minimal fine motor movements. He did not fix and follow, smile, or babble. Weight was on the 91st percentile and head circumference on the 0.4th percentile for age (United Kingdom growth charts). Examination revealed a dystonic movement disorder with generalized hyperreflexia. Repeat plasma lactate level was 4.1 mmol/L.

Enzyme Assays and Coenzyme Q10 Determination The skeletal muscle biopsy specimen (50 mg) was frozen immediately and stored at –70°C until analysis. Analysis of the mitochondrial complexes was conducted as previously described.7 Muscle CoQ10 concentration was de-

RAHMAN ET AL

THE JOURNAL OF PEDIATRICS

VOLUME 139, NUMBER 3 Table. Muscle mitochondrial respiratory chain enzyme activities and ubiquinone concentration

Assay Complex I Complex II + III Complex II + III + CoQ1 Complex IV Complex II Complex III CoQ10 (pmol/mg protein)

Patient value

Pediatric reference range

0.163