Arginase 1 deficiency presenting as complicated hereditary spastic paraplegia

Abstract

Argininemia or arginase deficiency is a metabolic disorder caused by pathogenic variants in ARG1 and consists of a variable association of progressive spastic paraplegia, intellectual disability, and seizures. Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder characterized by lower limb spasticity. This study presents seven patients with arginase 1 deficiency from six different families, all with an initial diagnosis of complicated HSP. We evaluated the clinical data of seven patients belonging to six independent families who were diagnosed with hyperargininemia in a neurogenetics outpatient clinic. All patients had lower limb spasticity and six had global developmental delay. Five individuals had intellectual disability and two had epilepsy. Psychiatric abnormalities were seen in two patients. In two participants of this study, magnetic resonance imaging (MRI) disclosed thinning of the corpus callosum. Molecular diagnosis was made by whole-exome sequencing. All variants were present in homozygosis; we identified two novel missense variants, one novel frameshift variant, and one previously published missense variant. A clinical diagnosis of early-onset complicated hereditary spastic paraplegia was made in all patients. Two patients were initially suspected of having SPG11 because of thinning of the corpus callosum. As argininemia may present with a highly penetrant phenotype of spastic paraplegia associated with additional symptoms, this disease may represent a specific entity among the complicated HSPs.