RESUMEN
Hyperargininaemia is a disorder of the last step of the urea cycle. It is an autosomal recessive disease caused by deficiency of liver arginase-1 and usually presents later in childhood with progressive neurological symptoms including marked spasticity. In contrast with other urea cycle disorders, hyperammonaemia is not usually present but can be a feature. A number of guanidine compounds may accumulate in the blood and cerebrospinal fluid of these patients, which could play an important pathophysiological role. Guanidinoacetate is of particular interest as a well-known potent epileptogenic compound in guanidinoacetate methyltransferase deficiency. We found markedly elevated guanidinoacetate levels in a patient with arginase deficiency, which dropped significantly in response to dietary and medical treatment. Measurement of guanidinoacetate and other guanidino compounds may, therefore, be important for therapeutic monitoring in arginase deficiency.
Asunto(s)
Benzoatos/farmacología , Creatina/farmacología , Glicina/análogos & derivados , Hiperargininemia/tratamiento farmacológico , Ornitina/farmacología , Benzoatos/administración & dosificación , Biomarcadores , Niño , Creatina/administración & dosificación , Glicina/sangre , Humanos , Hiperargininemia/dietoterapia , Hiperargininemia/fisiopatología , Masculino , Ornitina/administración & dosificación , Resultado del TratamientoRESUMEN
In areas without expanded newborn screening, instead of presenting neonatally, patients with arginase deficiency typically present with spastic paraplegia in early childhood. Diagnosis of this rare neurometabolic disease poses the first challenge because it is often misdiagnosed as cerebral palsy during initial stages. We describe arginase deficiency in a 20-year-old woman with spastic paraplegia, progressive dystonia, dementia, peripheral neuropathy, epilepsy, liver cirrhosis, and non-B/non-C hepatocellular carcinoma. A novel homozygous mutation NM_000045.2 (ARG1):c.673del (p.Arg225GlyfsX5) was detected. We suggest that all children presenting with progressive neurodegeneration or spastic paraplegia in the absence of risk factors for cerebral palsy should be screened for inborn errors of metabolism, including arginase deficiency. For monitoring urea cycle defects, noninvasive imaging screening for liver fibrosis and hepatocellular carcinoma can help ensure early detection, with potential treatment implications.
Asunto(s)
Arginasa/genética , Hiperargininemia/genética , Eliminación de Secuencia , Anticonvulsivantes/uso terapéutico , Arginasa/fisiología , Secuencia de Bases , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/etiología , Parálisis Cerebral/diagnóstico , Codón sin Sentido , Terapia Combinada , Contraindicaciones , Diagnóstico Tardío , Demencia/etiología , Errores Diagnósticos , Progresión de la Enfermedad , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Resultado Fatal , Femenino , Humanos , Hiperargininemia/diagnóstico , Hiperargininemia/dietoterapia , Hiperargininemia/tratamiento farmacológico , Hígado/enzimología , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/etiología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/etiología , Datos de Secuencia Molecular , Cuidados Paliativos , Fenotipo , Radiografía , Benzoato de Sodio/uso terapéutico , Ultrasonografía , Ácido Valproico , Adulto JovenRESUMEN
Newborn screening makes possible the early identification and treatment of asymptomatic ARG1-deficient patients; however, it is unknown whether early intervention prevents neurological insults. We identified a full-term Hispanic male infant with argininaemia by newborn screening with a serum arginine of 327 µmol/L (reference values 0-140); ARG1 was undetectable on enzyme assay. Sequence analysis of ARG1 revealed a heterozygous nonsense mutation, c.223A>T (p.K75X), and a novel heterozygous missense variant, c.425G>A (p.G142E). Dietary protein restriction began from age 3 months, with addition of sodium benzoate at 4 months, and carnitine from 14 months. For the past 6 years, his serum arginine concentrations were maintained between 268 and 763 µmol/L (reference values 10-140). He has normal development without spastic paraplegia, but with mild hepatomegaly and stable hepatic dysfunction. A full neurodevelopmental assessment was conducted at age 5 years. The BASC-2 rated the patient's behaviours as age-appropriate. The Leiter-R assessed his 'Fundamental Visualization', 'Sequential Order', and 'Picture Concept' at 'Average', 'Form Completion' and 'Matching' at 'Low Average', and 'Figure Ground' and 'Repeated Patterns' in the 'Deficit' range. The full-scale IQ and the functioning ability presented in the 'Borderline' range and in the 'Low Average' range, respectively. The VABS/Survey - Spanish Version showed difficulty in receptive and written language and fine and gross motor skills, and his performance to be at younger than his chronological age. The Short Sensory Profile showed some difficulty with taste and smell sensitivity. Long-term observation over 6 years in a patient with early treated argininaemia shows promising neurodevelopmental results.