Epilepsy and Argininosuccinic Aciduria

The first patients affected by argininosuccinic aciduria (ASA) were reported 60 years ago. The clinical presentation was initially described as similar to other urea cycle defects, but increasing evidence has shown overtime an atypical systemic phenotype with a paradoxical observation, that is, a higher rate of neurological complications contrasting with a lower rate of hyperammonaemic episodes. The disappointing long-term clinical outcomes of many of the patients have challenged the current standard of care and therapeutic strategy, which aims to normalize plasma ammonia and arginine levels. Interrogations have raised about the benefit of newborn screening or liver transplantation on the neurological phenotype. Over the last decade, novel discoveries enabled by the generation of new transgenic argininosuccinate lyase (ASL)-deficient mouse models have been achieved, such as, a better understanding of ASL and its close interaction with nitric oxide metabolism, ASL physiological role outside the liver, and the pathophysiological role of oxidative/nitrosative stress or excessive arginine treatment. Here, we present a collaborative review, which highlights these recent discoveries and novel emerging concepts about ASL role in human physiology, ASA clinical phenotype and geographic prevalence, limits of current standard of care and newborn screening, pathophysiology of the disease, and emerging novel therapies. We propose recommendations for monitoring of ASA patients. Ongoing research aims to better understand the underlying pathogenic mechanisms of the systemic disease to design novel therapies.Carmen Diez-Fernandez and Shaul Lerner contributed equally to this study.

Section: Biochemical Presentation/ Diagnosismentioning

confidence: 99%

“…Abnormal neurodevelopment is usually diagnosed around 24 months of age. 30,31,38,39 Epilepsy, observed in 40% of patients, 30 presents with tonic clonic, clonic or myoclonic seizures. 39 Electroencephalography can be abnormal even in nonsymptomatic patients, displaying an aspecific pattern.…”

Section: Systemic Diseasementioning

confidence: 99%

Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects

Baruteau

Dı́ez-Fernández

Lerner³

et al. 2019

“…1 ASA is known as a complex disorder, involving mechanisms beyond the ureagenesis defect: independently of the clinical picture severity and the effectiveness of treatment, patients, differently from other UCD, show unique signs like liver disease with fibrosis and cirrhosis, epilepsy, cognitive delay, hypertension and elevated triglycerides. [2][3][4][5][6] In our experience, most ASA, and not the other UCD patients, have a tendency to develop central adiposity and hypertriglyceridemia, although treated with apparently adequate energy intake.…”

Section: Introductionmentioning

confidence: 68%

Resting energy expenditure in argininosuccinic aciduria and in other urea cycle disorders

Brambilla

Bianchi

Cancello

et al. 2019

No data are available on the specific energy needs of patients affected with Urea Cycle disorders (UCD) and especially argininosuccinic aciduria (ASA). In our experience, ASA patients tend to develop central adiposity and hypertriglyceridemia when treated with apparently adequate energy intake, while the other UCD do not. The aim of this study was to evaluate anthropometric parameters, body composition, risk of metabolic syndrome (MS) and resting energy expenditure (REE), both by indirect calorimetry (IC) and predictive equations, in UCD patients. Hypertension (5/13), pathological waist circumference-to-height ratio (WtHr) (6/13), hypertriglyceridemia (12/13), reduced HDL cholesterol (12/13), and MS (5/13) were found in ASA group. In the ASA cohort, the mean and median IC-REE were 88% of what was predicted by Food and Agriculture Organization of the United Nations and Harris-Benedict equations. The "other UCD" cohort did not show hypertension, dyslipidaemia nor MS; IC-REE was similar to the REE predicted by equations. A significant difference was seen for the presence of hypertension, dyslipidaemia, pathological WtHr, MS and IC-REE/predictive equations-REE in the two cohorts. ASA patients have a risk of overfeeding if their energy requirement is not assessed individually with IC. Excessive energy intake might increase the cardiovascular risk of ASA patients. We suggest to test ASA individuals with IC every year if the patient is sufficiently collaborative. We speculate that most of the features seen in ASA patients might Abbreviations: ASA, argininosuccinic aciduria; ASL, argininosuccinate lyase; ATP, adult treatment panel; BMI, body mass index; DXA, dualenergy X-ray absorptiometry; FAO, Food and Agriculture Organization of the United Nations; FAO-REE, resting energy expenditure estimated by FAO equation; FM, fat mass; HB-REE, resting energy expenditure estimated by Harris-Benedict equation; HOMA, homeostatic model assessment; IC, indirect calorimetry; IC-REE, resting energy expenditure measured by indirect calorimetry; IC-REE/FAO-REE, ratio of IC-REE to prediction by FAO equation; IC-REE/HB-REE, ratio of IC-REE to prediction by Harris-Benedict

“…A retrospective analysis compared neuropsychological outcomes between individuals with neonatal‐onset (n = 8) and late‐onset (n = 3) ASLD . Among neonatal‐onset individuals, the DQ/IQ score was near normal at diagnosis but declined slowly thereafter, stabilizing after the age of 4‐6 years.…”

Section: Resultsmentioning

confidence: 99%

Neuropsychological attributes of urea cycle disorders: A systematic review of the literature

Waisbren

Stefanatos

Kok

et al. 2019