CLINICAL COURSE, EARLY DIAGNOSIS, TREATMENT, AND PREVENTION OF DISEASE IN GLUTARYL-COA DEHYDROGENASE-DEFICIENCY

Background Glutaryl-CoA dehydrogenase deficiency (GDD) is. recessively inherited neurometabolic disorder associated with encephalopathic cri ses and severe extrapyramidal symptoms. Treatment regimens including g lucose and electrolyte infusions during acute illnesses, oral carnitin e supplementation and/or a low-protein or lysine-restricted diet have been recommended, but their efficacy has been documented only on an an ecdotal basis. Subjects and methods We conducted a retrospective analy sis of 57 patients with proven GDD-relating appearance and severity of neurological disease to age and clinical status at diagnosis, glutari c acid levels in body fluids, and different treatment regimens. Result s Thirty-six patients were diagnosed after the onset of neurological d isease (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 birth and was followed by rapid postnatal head growth in 70 % of the childr en. The patients often showed symptoms such as hypotonia, irritability , and jitteriness followed by an acute encephalopathic crisis occurrin g on average at 12 months of age. Common neuroimaging findings include d frontotemporal atrophy, subependymal pseudocysts, delayed myelinatio n, basal ganglia atrophy, chronic subdural effusions and hematomas. In four patients the latter two findings were initially misinterpreted a s resulting from child abuse. Other important misdiagnoses in older si blings who were affected and went undiagnosed include postencephalitic cerebral palsy, dystonic cerebral palsy and sudden infant death syndr ome. Metabolic treatment did not convincingly improve the neurological disease, although it may have prevented further deterioration. Sympto matic treatment with baclofen or benzodiazepines was effective in redu cing muscle spasms. Children in the presymptomatic group were diagnose d because of familiarity for the disease (n = 13), macrocephaly and/or additional minor neurological signs in infancy (n = 6), or acute ence phalopathy, which was fully reversible after prompt treatment (n = 2). After diagnosis, all children were treated with oral carnitine, fluid infusion during intercurrent illnesses and, in addition, a diet was s tarted in 13 of the 21 children. All 21 children except one (born prem aturely at 31 weeks) have continued to develop normally up to now. Mea n age at report is 6.3 years with a range from 6 months to 14.8 years. In older patients, the neuroradiological changes, present in infancy as in the symptomatic patients, became less prominent and in one girl disappeared. Conclusions In presymptomatic children with GDD, the onse t of neurological disease can be prevented by vigorous treatment of ca tabolic crises during illnesses together with carnitine supplementatio n. The importance of dietary therapy remains unclear and needs further evaluation. The potential treatability of GDD calls for increased att ention to early presenting signs in order to recognize the disorder an d to initiate treatment before the onset of irreversible neurological disease.