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The argininosuccinate synthetase deficiency, a rare inborn error of arginine metabolism, is considered to be a disorder of arginine catabolism. To characterize the neurological manifestations in patients with this disorder, we have characterized the clinical, biochemical and genetic features of eight patients from six unrelated families with the argininosuccinate synthetase deficiency. All patients showed symptoms of neurological impairment (hypotonia and epilepsy) and hepatopathy at birth. Brain magnetic resonance imaging (MRI) showed a low signal intensity in the basal ganglia on the T1-weighted images. MRI at follow-up showed progressive atrophy of the basal ganglia and brainstem, especially in patients with severe hypotonic-hyporeflexia. Liver function tests were abnormal in all patients, and fibrosis was seen on liver histology. The patients demonstrated an isolated deficiency of the enzyme argininosuccinate synthetase. Missense mutations were identified in the region of the argininosuccinate synthetase gene that encodes the highly conserved arginine binding site of the enzyme. The patients presented with atypical symptoms in the first few months of life