Arginase 1 deficiency presenting as complicated hereditary spastic paraplegia.

Abstract

Introduction: 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 7 patients with arginase 1 deficiency from 6 different families, all with an initial diagnosis of complicated HSP. Methods: We evaluated the clinical data of 7 patients belonging to six independent families who were diagnosed with hyperargininemia in a neurogenetics outpatient clinic. Results: 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, 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. Discussion: Clinical diagnosis of early onset complicated hereditary spastic paraplegia was made in all patients. Two patients were initially suspected of having SPG11 due to 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 amongst the complicated HSPs.

Argininemia: Pathophysiology and Novel Methods for Evaluation of the Disease

“…Various cases have been described, for instance, the case of a 46-year-old female patient who had a history of frequent falls, and delayed development of speech ability at the age of 1 with subsequent progressive lower limbs spasticity, and dependency on a wheelchair by the age of 14. In contrast, there are cases such as that of a 16-year-old girl who also had a history of frequent falls, spastic gait, repetitive vomiting, and global developmental delay at the age of 1, followed by epileptic seizures at the age of 5, but after treatment with sodium benzoate, and a low-protein diet demonstrated no further clinical deterioration [11].…”

“…Neurological symptoms associated with this syndrome encompass motor signs such as progressive spastic diplegia/paraparesis-which constitutes the hallmark of the disease and typically begins in the first decade of life [11,12]. Motor symptoms can also present between 1 to 5 years as hyperreflexia, clonus, toe walking, and other gait abnormalities, with 80% of the patients showing upper motor neuron involvement.…”

Hereditary spastic paraparesis: not always HSP!

“…Although arginase deficiency is an inherited disorder characterised by spastic paraparesis, it is not classified as one of the hereditary spastic paraplegias (HSP), a group of clinically and genetically heterogeneous disorders due to length‐dependent damage to upper motor neurones 4 . However, arginase deficiency does feature in the differential diagnosis of HSP and should be considered in any patient with childhood‐onset complicated spastic paraparesis, since misdiagnosis as HSP has been reported 5 . Cerebellar atrophy on magnetic resonance imaging of the brain may point towards arginase deficiency, although this neuroimaging finding has been reported in some cases of childhood‐onset HSP 6 …”

“…4 However, arginase deficiency does feature in the differential diagnosis of HSP and should be considered in any patient with childhood-onset complicated spastic paraparesis, since misdiagnosis as HSP has been reported. 5 Cerebellar atrophy on magnetic resonance imaging of the brain may point towards arginase deficiency, although this neuroimaging finding has been reported in some cases of childhood-onset HSP. 6 The symptom complex of early onset physical and learning disability in this patient might initially have suggested the non-specific diagnostic category of 'cerebral palsy' but the neuroimaging and genetic characterisation allowed a more fine-grained diagnosis -arginase deficiency -hence opening up the opportunity for genetic counselling of the family.…”