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Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency.
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BackgroundGlutaryl-CoA dehydrogenase deficiency (GDD) is. recessively inheritedneurometabolic disorder associated with encephalopathic crises andsevere extrapyramidal symptoms. Treatment regimens including glucoseand electrolyte infusions during acute illnesses, oral carnitinesupplementation and/or a low-protein or lysine-restricted diet havebeen recommended, but their efficacy has been documented only on ananecdotal basis.Subjects and methodsWe conducted a retrospective analysis of 57 patients with provenGDD-relating appearance and severity of neurological disease to age andclinical status at diagnosis, glutaric acid levels in body fluids, anddifferent treatment regimens.ResultsThirty-six patients were diagnosed after the onset of neurologicaldisease (symptomatic group), twenty-one before (presymptomatic group).Carnitine levels were found to be reduced in all patients at diagnosis.In the symptomatic group, macrocephaly had been present around birthand was followed by rapid postnatal head growth in 70 % of thechildren. The patients often showed symptoms such as hypotonia,irritability, and jitteriness followed by an acute encephalopathiccrisis occurring on average at 12 months of age. Common neuroimagingfindings included frontotemporal atrophy, subependymal pseudocysts,delayed myelination, basal ganglia atrophy, chronic subdural effusionsand hematomas. In four patients the latter two findings were initiallymisinterpreted as resulting from child abuse. Other importantmisdiagnoses in older siblings who were affected and went undiagnosedinclude postencephalitic cerebral palsy, dystonic cerebral palsy andsudden infant death syndrome. Metabolic treatment did not convincinglyimprove the neurological disease, although it may have preventedfurther deterioration. Symptomatic treatment with baclofen orbenzodiazepines was effective in reducing muscle spasms.Children in the presymptomatic group were diagnosed because offamiliarity for the disease (n = 13), macrocephaly and/or additionalminor neurological signs in infancy (n = 6), or acute encephalopathy,which was fully reversible after prompt treatment (n = 2). Afterdiagnosis, all children were treated with oral carnitine, fluidinfusion during intercurrent illnesses and, in addition, a diet wasstarted in 13 of the 21 children. All 21 children except one (bornprematurely at 31 weeks) have continued to develop normally up to now.Mean age at report is 6.3 years with a range from 6 months to 14.8years. In older patients, the neuroradiological changes, present ininfancy as in the symptomatic patients, became less prominent and inone girl disappeared.ConclusionsIn presymptomatic children with GDD, the onset of neurological diseasecan be prevented by vigorous treatment of catabolic crises duringillnesses together with carnitine supplementation. The importance ofdietary therapy remains unclear and needs further evaluation. Thepotential treatability of GDD calls for increased attention to earlypresenting signs in order to recognize the disorder and to initiatetreatment before the onset of irreversible neurological disease.
Adolescent, Amino Acid Metabolism, Inborn Errors/enzymology, Amino Acid Metabolism, Inborn Errors/genetics, Atrophy, Brain/pathology, Brain Diseases, Metabolic/enzymology, Brain Diseases, Metabolic/genetics, Carnitine/administration & dosage, Child, Child, Preschool, Combined Modality Therapy, Diet, Protein-Restricted, Female, Follow-Up Studies, Glutaryl-CoA Dehydrogenase, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Neurologic Examination, Oxidoreductases/deficiency, Oxidoreductases/genetics, Oxidoreductases Acting on CH-CH Group Donors, Tomography, X-Ray Computed
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