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

Waisbren, Susan E.; Stefanatos, Arianna K.; Kok, Teresa M Y; Hismi, Burcu

doi:10.1002/jimd.12146

Cited by 30 publications

(17 citation statements)

References 110 publications

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“…This is not surprising, as patients with distal UCDs, especially those inclusive of the NBS population, tend to have milder disease courses less prone to hyperammonemia than the average proximal UCD patient. While some patients with “milder” disease may not need nitrogen scavenging therapy, studies have suggested that nitrogen scavenging therapy may confer some long-term neurocognitive benefits [ 31 ]. However, this was not evaluated in this study and represents a limitation to the data provided.…”

Section: Discussionmentioning

confidence: 99%

Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

Longo

Diaz

Lichter‐Konecki

et al. 2021

Molecular Genetics and Metabolism

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Background/Aims: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. Methods: This was an open-label study in UCD patients aged 0 – 2 months, consisting of an initiation/transition period (1 – 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 μmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. Results: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 μmol/L at baseline and 50.4 μmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. Conclusions: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.

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Section: Discussionmentioning

confidence: 99%

Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

Longo

Diaz

Lichter‐Konecki

et al. 2021

Molecular Genetics and Metabolism

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“…8 Arginase deficiency, which is among this group of diseases, has been reported much less frequently (1:950000). 9 Rapid-onset hyperammoniemia attacks are not characteristic for argininemia, they follow a slower clinical course. It may often present with growth retardation and pronounced progressive spasticity in the lower extremities.…”

Section: Discussionmentioning

confidence: 99%

“…If appropriate treatment is not initiated, patients will rapidly deteriorate and will be lost with cardiovascular collapse, respiratory failure and renal failure. 5,[8][9][10] This case was presented to draw attention to the case of argininemia, which was followed up with a diagnosis of cerebral palsy for a long time and lost the chance of early diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Late Diagnosed Argininemia

et al. 2021

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Ammonia; It is a toxic molecule for the central nervous system resulting from the catabolism of proteins. Its excretion is provided with the urea cycle. Argininemia is a rare subtype of urea cycle disorders. Arginase enzyme catalyzes the last stage of the urea cycle, arginine; urea and ornithine are broken down. The decrease in arginase 1 (ARG1) enzyme activity is responsible for argininemia. The most common presenting symptoms of patients diagnosed with argininemia are progressive spastic diplegia, regression in developmental stages, choreoathetosis, hepatomegaly and seizures. The diagnosis of the disease can be made by detecting the elevation of arginine in body fluids together with the increase in serum ammonia. Neurological findings of these patients can be confused with cerebral palsy. In this case report, we wanted to present a patient with argininemia who was followed up with a diagnosis of cerebral palsy for a long time. Early diagnosis, restricted protein and arginine diet are life-saving in this disease. Argininemia should be kept in mind in patients with unexplained neuromotor retardation.

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“…Ornithine Transcarbamylase (OTC) deficiency is an uncommon X‐linked inborn error of metabolism [1]. One study reported an incidence of in ~1 in 56,500 individuals [2]. Although it is rare, OTC deficiency represents the most common disorder of the urea cycle.…”

Section: Introductionmentioning

confidence: 99%

Late‐onset of ornithine transcarbamylase deficiency: A rare medical examiner case

Gitto

Fuller

Calleo

et al. 2021

Journal of Forensic Sciences

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Ornithine Transcarbamylase (OTC) is an enzyme of the urea cycle, which converts ammonia into urea in the liver cells. OTC plays a crucial role in the breakdown and removal of nitrogen in the body. OTC deficiency is a rare X-linked recessive disorder that classically presents in early life with signs of hyperammonemia and progressive central nervous system involvement resulting in seizures, coma, and death. Sentinel presentation in adulthood is quite rare. A 29-year-old man developed altered mental status after receiving an epidural steroid injection 3 days earlier for back pain. He presented to the emergency department severely agitated, and his workup revealed an elevated ammonia level of 125 µmol/L. He refused admission and was discharged against medical advice. The following day, his mentation deteriorated, he developed status epilepticus, and was transported to another emergency department. He was admitted with worsening hyperammonemia (levels rising to over 700 µmol/L). His clinical condition progressive deteriorated, and he developed encephalopathy and diffuse cerebral edema. Liver function testing indicated progressive liver damage, and amino acids were detected in his blood and urine. Clinical and laboratory findings suggested undiagnosed OTC enzyme deficiency. He died 2 days after admission.An autopsy showed an 1890 g liver with diffuse yellow discoloration and softening.Histology and electron microscopy revealed findings suggestive of urea cycle disorder, such as microvesicular steatosis, apoptosis, and scattered mitosis, clusters of clear hepatocytes at the PAS stain, and mitochondria abnormalities. Genetic analysis revealed a hemizygous pathogenic variant of the OTC gene (c.622G>A). OTC deficiency should be suspected in subjects with hyperammonemic encephalopathy. If a genetic mutation is identified in the deceased, surviving family members should be screened to prevent potential life-threatening complications.

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

Cited by 30 publications

References 110 publications

Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

Late Diagnosed Argininemia

Late‐onset of ornithine transcarbamylase deficiency: A rare medical examiner case

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