Letter to the editor ‘Pyruvate dehydrogenase deficiency presenting as dystonia and responding to levodopa’ SIR–We read with much interest the recent article of Head et al.,1 in which they described two cases of pyruvate dehydrogenase (PDH) deficiency presenting during childhood with dystonia. We fully agree with the authors’ findings as we have also encountered two brothers with confirmed PDH deficiency (partial defect in E1 subunit) who presented to us with severe dystonia, which remained the prominent clinical sign. The elder brother presented at the age of 3 months when parents noted attacks of chin tremors and states of sudden unresponsiveness, later confirmed to be of epileptic origin. He was first examined at the age of 9 months when psychomotor delay was found with severe head lag, dyskinetic posturing with increased muscle tone, and exaggerated deep tendon reflexes. On a few occasions, the investigations revealed increased plasma lactate levels (up to 6.5mmol/l) while lactate level in cerebrospinal fluid (CSF) was 1.8mmol/l. Urinary organic acid and plasma aminoacid profiles were normal. Brain magnetic resonance imaging (MRI) revealed diffuse brain atrophy, while electromyography and nerve conduction study were normal as well as visual evoked potentials and electroretinography. Somatosensory evoked potentials demonstrated diminished amplitudes of cortical responses after median nerve stimulation. Electroencephalogram (EEG) was abnormal and revealed diffuse background activity, slowing and frequent generalized discharges of fast spikes and spike and wave complexes, sometimes accompanied by myoclonic seizures during sleep. Muscle biopsy specimen was performed at Clinical Genetics Centre, Metabolic Division in Nijmegen, the Netherlands and revealed decreased activities of PDH complex (1.9mU per mg protein; control range: 2.7–8.2mU per mg protein), and especially E1 subunit (0.046 – control range: 0.083 – 0.25mU per mg protein), while fibroblast culture revealed normal basal and total PDH complex activities, thus, reflecting tissue-specific expression, the phenomenon being frequently encountered in many patients with PDH deficiency. The patient is now 15 years old and is cared for in an institution, is quite emaciated, however he still has some preservation of psychosocial contact, but is bed-ridden with severe dystonic and spastic posturing. He has occasional generalized myoclonic seizures despite regular valproate and vigabatrin treatment. His younger brother presented to us at the age of 4 months because his parents noted similar clinical signs to those of his elder sibling: chin tremors, hand fisting, and unusual posturing of feet and hands. On examination, poor eye-to-eye contact was noted with slightly decreased muscle tone, especially in the axial muscles, and dystonia of feet and hands with dystonic facial expressions. At age 7 months, the parents sought a second opinion from the Institute of Child Health, London, UK, where it was confirmed that the younger brother probably had a similar disorder to his elder brother. However, as he did not exhibit seizures at that age (although he did 2 years later) and had shown reduced CSF
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homovanillic acid, treatment with combined levodopa and carbidoba was suggested, and some beneficial response was found thereafter. Brain MRI revealed only delay in myelination with a little myelin developed in the posterior limb of the capsules and central corona as well as the brain stem. The highest serum lactate level noted was 3.9 mmol/l, while CSF lactate was 1.5 mmol/l. Muscle biopsy was not done as the parents did not agree to sign informed consent. The child later developed myoclonic seizures (with similar EEG abnormalities as in his elder brother) which responded well to a combination of valproate and vigabatrine. He is now 8 years old and is cared for at home and at a kindergarten for disabled children, he has severe motor and cognitive impairments and exhibits dyskinetic-dystonic syndrome. A reliable diagnosis of mitochondrial disorder in the paediatric population is quite difficult, and, therefore, diagnostic criteria for childhood mitochondrial disorders have been modified.2 We also know that paediatric mitochondrial disorders can be accompanied by normal muscle morphology, normal plasma and/or CSF lactate, normal mitochondrial enzymes in skeletal muscle, normal mitochondrial DNA mutation screening, and a nonclassical clinical presentation.1,2 We also believe that our two patients fit the category of PDH deficiency presenting with dystonia, although in the younger brother it has not been confirmed as the muscle biopsy was not permitted by the parents. Both brothers presented with dystonia, had a slowly progressive course with prolonged survival and no changes in basal ganglia on MRI and, thus, both contribute to the change of our clinical view that dystonia can be a prominent feature of PDH deficiency. However, we are aware of the fact that the diagnosis would be more firmly established if a primary mutation in PDH subunits could be confirmed, however the parents did not give us the consent for further specific investigations. Our first patient also confirms that if there is sufficient residual enzyme activity, the course of the disease will be slower and the survival prolonged, while our second patient confirms that some improvement can be seen with levodopa and carbidopa treatment. DOI: 10.1017/S0012162205000988
David Neubauer PhD* Jana Frelih MD Nezˇa Zˇupanc ˇic ˇ MD ˇStefan Kopac ˇ MD Lada Cindro-Heberle MD Department of Child, Adolescent and Developmental Neurology, University Children’s Hospital, Ljubljana, Slovenia *Correspondence to:
[email protected] References: 1. Head RA, de Goede CGEL, Newton RWN, Walter JH, McShane MA, Brown RM, Brown GK. (2004) Pyruvate dehydrogenase deficiency presenting as dystonia in childhood. Dev Med Child Neurol 46: 710–712. 2. Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EOB, Neish SR, Ware SM, Hunter JV, Fernbach SD, Vladutiu GD, Wong LJC, Vogel H. (2004) Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 114: 925–931.
