Dados do Trabalho

Título

Arginase 1 Deficiency: An important mimicking of early-onset hereditary spastic paraplegia

RESUMO

Clinical case: A 19 years-old male patient, born from consanguineous parents, presented with an insidious complaint of progressive weakness and frequent falls since the age of nine. At fourteen he needed bilateral assistance to walk, and at eighteen he already needed the use of a wheelchair. His mother highlighted that the patient never liked meat and that he had a lack of appetite and frequent vomiting since childhood. She has also noticed that he has greater learning difficulties, is more childlike than people of the same age, and is more irritable and anxious. Neurological examination shows MRC grade II weakness and severe spasticity in the lower limbs, in addition to being unable to stand in an orthostatic posture. Brain MRI showed diffuse cortical and cerebellar atrophy. Whole-exome sequencing revealed a homozygous pathogenic variant mutation p.Arg308Gln in the ARG1 gene. Discussion: Arginase-1 deficiency (OMIM #207800) is a rare autosomal recessive genetic disorder caused by mutations in the ARG1 gene, resulting in partial or complete loss of enzyme function that affects the liver-based urea cycle. ARG1-deficient patients mainly exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, and persistent growth retardation. Early symptoms include irritability, global developmental delay, failure to thrive, recurrent vomiting, feeding/ protein aversion, and anorexia. Spastic paraparesis with onset in early childhood is the most obvious sign of the disease. Brain imaging may reveal cerebral atrophy and cerebellar atrophy may also occur. The ARG1 gene sits on chromosome 6 (6q23) composed of eight exons and there are at least 43 potentially disease-causing variants in ARG1 with the majority being missense/nonsense mutations and small deletions. In this case, a rare homozygous missense mutation was identified. Approximately half of the reported subjects are homozygous with a moderate number of cases arising from consanguineous relation, as in this case. Final Comments: This case shows that progressive loss of mental and motor skills, increasingly more severe spasticity, and pyramidal tract signs are the hallmarks of the disease caused by ARG1 deficiency, and this is an important differential diagnosis of childhood-onset hereditary spastic paraplegia.