Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study.

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.

A retrospective biochemical, molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria.

A retrospective review was compiled of 54 patients with argininosuccinic aciduria who were either identified through the Saudi National Newborn Screening Program or diagnosed clinically from January 2000 to December 2015. The duration of follow-up is from 2 to 19 years. The majority of patients (65%) originated from the central province of Saudi Arabia. The mean patient age at review was 10 years (2-19 years), 92% received an early diagnosis (<28 days of age) and most were symptomatic at the time of the diagnosis (n = 34). Normal ammonia at diagnosis was reported in 30% of patients, who were detected under the newborn metabolic screen (n = 5/16). A very high rate of consanguinity was observed in our cohort (98%). Developmental delay was the most detectable long term neurocognitive consequence followed by seizure disorder; 90.7% (n = 49) and 62.9% (n = 34) respectively. As expected, the severe neonatal form was the major presentation. The most common variant identified in this cohort was the previously reported founder c.1060C > T; p.(Gln354*) nonsense mutation in the ASL gene. In addition, the frequency of hyperammonemia was higher in patients homozygous for c.1060C > T; p.(Gln354*) compared to the other mutations. Interestingly, frequent thrombocytosis with the mean level of 717 × 109/L (range = 457-1169 × 109/L) was observed in 96% of the patients with no clear explanation.

Argininosuccinic Aciduria-A Rare Indication for Liver Transplant: Report of Two Cases.

Argininosuccinic aciduria is a urea cycle disorder caused by an argininosuccinate lyase enzyme deficiency that ends with nitrogen accumulation as ammonia. Argininosuccinic aciduria patients are at risk for long-term complications including poor neurocognitive outcome, hepatic disease, and systemic hypertension despite strict pharmacologic and dietary therapy. As the liver is the principle site of activity of the urea cycle, it is logical that a liver transplant should be an option, with careful patient selection, even in the absence of cirrhosis. We present 2 pediatric argininosuccinic aciduria patients who underwent a living-donor liver transplant from their mothers. After the liver transplant, the general well-being of the patients and their quality of life improved significantly. Liver transplant should be an option for argininosuccinic aciduria patients to prevent further neurologic deterioration and improve the patient's quality of life.

Histopathological findings in livers of patients with urea cycle disorders.

BACKGROUND: Urea cycle disorders (UCD) are caused by genetic defects in enzymes that constitute the hepatic ammonia detoxification pathway. Patients may present with variable clinical manifestations and with hyperammonaemia. Liver abnormalities have been associated with UCD, but only a few reports on the histopathological findings in the liver of UCD patients have been published. METHODS: We conducted a retrospective review of liver biopsies, ex-planted livers and livers at post-mortem of patients with UCD. A single pathologist reviewed all specimens. RESULTS: There were 18 liver samples from 13 patients with confirmed UCD: four ex-planted livers from patients with Ornithine Transcarbamylase (OTC) (n=3) and Carbamoyl Phosphate Synthetase 1 (CPS 1) (n=1) deficiencies, eight post-mortem samples from patients with CPS 1 (n=2), OTC (n=4), Argininosuccinate Synthetase (ASS) (n=1) and Argininosuccinate Lyase (ASL) (n=1) deficiencies, and six liver biopsies, three of which came from one patient with ASL deficiency. The other three liver biopsies were from patients who subsequently received liver transplantation. Histopathological findings in samples from neonates were non-specific. Samples from three late onset OTC deficient and one ASL deficient patients showed thin fibrous septa with portal to portal bridging fibrosis and focal marked enlargement and pallor of the hepatocytes due to accumulation of glycogen particles, resembling glycogenosis and resulting in a prominent nodular pattern. Serial liver biopsies in four UCD patients with interval between samples ranging from 1 year 2 months to 17 years showed progression in fibrosis in one OTC and one ASL deficient patients. Moderate fatty changes to no progression in liver disease were noted in the two patients (OTC=1 and CPS=1). A variety of non-specific features such as fatty change, mild inflammation, cholestasis and focal necrosis were seen in the other UCD patients. CONCLUSIONS: Histopathological changes in livers from neonates with UCD are non-specific. Older patients with UCD seem to show variable hepatic fibrosis compared to those who died early. Some of these patients also show focal and superficial resemblance to a glycogen storage disorder and cirrhosis. However, progression of these changes seems to be slow. To clarify the long term consequence of these changes, more extensive periods of follow up in a larger population series is needed.

Urea cycle disorder--argininosuccinic lyase deficiency.

An increased level of ammonia in the bloodstream, or hyperammonemia, is a symptom associated with metabolic disorders referred to as inborn errors of metabolism. Urea cycle disorder is a congenital abnormality or absence of one of the six enzymes involved in the elimination of ammonia. Administration of certain medications, high protein diet, excessive exercise, surgical procedures, or trauma can precipitate symptoms of mental confusion, seizure-like activity, and ataxia. This paper reviews the literature with insight into current treatment and management options of the disorder and modification of treatment for the dental patient.

Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria.

Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition.

Hyperammonemia in review: pathophysiology, diagnosis, and treatment.

Ammonia is an important source of nitrogen and is required for amino acid synthesis. It is also necessary for normal acid-base balance. When present in high concentrations, ammonia is toxic. Endogenous ammonia intoxication can occur when there is impaired capacity of the body to excrete nitrogenous waste, as seen with congenital enzymatic deficiencies. A variety of environmental causes and medications may also lead to ammonia toxicity. Hyperammonemia refers to a clinical condition associated with elevated ammonia levels manifested by a variety of symptoms and signs, including significant central nervous system (CNS) abnormalities. Appropriate and timely management requires a solid understanding of the fundamental pathophysiology, differential diagnosis, and treatment approaches available. The following review discusses the etiology, pathogenesis, differential diagnosis, and treatment of hyperammonemia.

Epilepsy and argininosuccinic aciduria.

BACKGROUND: We have reviewed the occurrence of epilepsy in our patients with argininosuccinic aciduria (ASA) (OMIM 207900) and the possible relationship of late epilepsy to symptomatic seizures in the neonatal period, hyperammonaemia and treatments. METHODS: We retrospectively analysed 11 ASA patients (8 neonatal onset and 3 late onset), 6 of whom had developed epilepsy. RESULTS: Epilepsy in our sample was frequent (55 %). It developed after a seizure-free period from the onset of the metabolic disease and seizures were responsive to treatment in all cases. Arginine plasma levels were kept in the same range for the 2 groups of patients with and without epilepsy. CONCLUSIONS: Although epilepsy is reported to be common among patients with ASA, very few long-term follow-up studies are available. The pathophysiological mechanism of epileptogenesis remains unclear. Neither hyperammonaemia nor acute symptomatic seizures at birth seem to be predictive of late epilepsy. Excessive arginine dosages as a cause of epilepsy could be reasonably excluded since our 3 late onset patients developed epilepsy before the diagnosis of ASA, at a time when they were likely to be arginine deficient. Arginine deficiency may not be excluded as cause of epilepsy, but further studies are needed to define its role.

Experience with the treatment of argininosuccinic aciduria during pregnancy.

We present the details of the management and the outcome of a pregnancy of a woman affected with argininosuccinic aciduria. Management with a closely monitored, protein-restricted diet, supplemented with L-arginine, resulted in the birth of a healthy infant boy and an uneventful perinatal course for the mother.