title: Central hypoventilation syndrome in pyruvate dehydrogenase complex deficiency.
abstract: The presentation and treatment of a central hypoventilation syndrome in a boy with pyruvate dehydrogenase complex (PDHC) deficiency are reported. Dephosphorylated PDHC was assayed in disrupted fibroblasts after pretreatment with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor. Maximal specific activity of activated patient PDHC was 10% to 30% of control values. Patient PDHC activity was not increased by alterations in concentrations of pyruvate or cofactors (thiamine pyrophosphate [TPP], coenzyme A [CoA], oxidized form of nicotinamide adenine dinucleotide [NAD+]). Clinically, normalization of plasma lactate by a high-lipid diet did not prevent slowly progressive neurologic decline. The patient manifested intermittent ataxia, episodic profound weakness, moderate psychomotor retardation, ophthalmoplegia, and retinal pigment epithelial changes. A true central hypoventilation syndrome was documented on the basis of rigorous radiologic, electrophysiologic, and pulmonary function criteria. Theophylline, progesterone, and ritalin neither altered ventilatory response to CO2 nor permitted weaning from the ventilator. In contrast, peripheral chemoreceptor stimulants (intravenous doxapram; oral almitrine) effected an acute doubling of minute ventilation with appropriate decreases in PaCO2. However, a positive response to long-term therapy with almitrine could not be unequivocally shown. It was concluded that measurement of disrupted fibroblast PDHC following dichloroacetate activation constitutes an accurate assay for PDHC deficiency. PDHC deficiency must be considered in the differential diagnosis of the central hypoventilation syndrome; this appears to be the first report of such an association. Finally, a therapeutic trial of a peripheral chemoreceptor agonist is warranted in the management of central hypoventilation syndrome.
mesh_terms: D015765:Almitrine; D002478:Cells, Cultured; D002628:Chemoreceptor Cells / Q000187:drug effects; D002648:Child; D003653:Decarboxylation; D004315:Doxapram / Q000627:therapeutic use; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008297:Male; D010879:Piperazines / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D012121:Respiration, Artificial; D012891:Sleep Apnea Syndromes / Q000201:enzymology* / Q000628:therapy; D014140:Tracheotomy
chemical_list: D007773:Lactates; D010879:Piperazines; D011773:Pyruvates; D019344:Lactic Acid; D019289:Pyruvic Acid; D004315:Doxapram; D015765:Almitrine