Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation

Rymen, Daisy; Lindhout, M.J.; Spanou, Maria; Ashrafzadeh, Farah; Benkel, Ira; Betzler, Cornelia; Coubes, Christine; Hartmann, Hans; Kaplan, Julie; Ballhausen, Diana; Koch, Johannes; Lotte, J; Mohammadi, Mohammad Hasan; Rohrbach, Marianne; Dinopoulos, Argirios; Wermuth, Marieke; Willis, Daniel N.; Brugger, Karin; Wevers, Ron A.; Boltshauser, Eugen; Bierau, Jörgen; Mayr, Johannes A.; Wortmann, Saskia B.

doi:10.1038/s41436-020-0933-z

Cited by 25 publications

(42 citation statements)

References 20 publications

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“…This deficiency can be compensated by an alternative mechanism, whereby pyrimidine is recycled from uridine, giving rise to the treatment option of uridine supplementation with antiepileptic effect attributed to the salvage pathway (Nyhan, 2005). Following the discovery of the first patient with biallelic CAD mutations in 2015, and with a more recent retrospective series published of 20 subjects in Rymen et al (2020) Genetic Medicine 2020, there remains a lack of detailed depictions of the clinical picture of CAD deficiency prior to or post uridine treatment (Ng et al, 2015;Koch et al, 2017;Del Caño-Ochoa et al, 2020;Rymen et al, 2020;Zhou et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Case Report: Rapid Treatment of Uridine-Responsive Epileptic Encephalopathy Caused by CAD Deficiency

et al. 2020

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We present two unrelated Chinese patients with CAD deficiency manifesting with a triad of infantile-onset psychomotor developmental delay with regression, drug-refractory epilepsy, and anaemia with anisopoikilocytosis. Timely translation into uridine supplementation, within 2-months of disease onset, allowed us to stop conventional anti-epileptic drugs and led to dramatic improvement in the clinical symptoms, with prompt cessation of seizures, resolution of anaemia, developmental progress, and prevention of development of severe and non-reversible manifestations. The remarkable recovery and prevention of advanced disease with prompt treatment, highlights the need to act immediately upon genetic diagnosis of a treatable disease. This further reinforces CAD deficiency as a treatable neurometabolic disorder and emphasises the need for a biomarker or genetic new born screening for early identification.

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Section: Introductionmentioning

confidence: 99%

Case Report: Rapid Treatment of Uridine-Responsive Epileptic Encephalopathy Caused by CAD Deficiency

et al. 2020

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“…58,[72][73][74][75][76] The course of the disease can be lethal, with most untreated cases not surviving beyond 4.5-9 years of age. 73 However, oral supplementation with uridine or UMP replenish the pyrimidine levels through the salvage pathway (Figure 1) and leads to significant improvement, with immediate cessation of seizures, and progression from a minimally conscious state to communicate and move without assistance after several weeks of treatment. 58,[73][74][75][76] An early treatment can prevent irreversible damage, 58 but the diagnosis is difficult since there are no biomarkers for screening and symptoms are easily confused or masked by nutritional factors.…”

Section: Defects In Cad Cause a Rare Neurometabolic Diseasementioning

confidence: 99%

“…Then, in 2015, the first case of a child with a rare inborn error of metabolism and biallelic mutations in CAD was reported, 72 and was shortly followed by a second study describing four similar cases from three unrelated families 58 . This CAD‐deficiency (OMIM #616457), also known as early infantile epileptic encephalopathy‐50 (EIEE‐50) or CAD congenital disorder of glycosylation, typically manifests at an early age as a progressive refractory epilepsy with loss of skills, global developmental delay, intellectual disability and movement disorders, anemia and abnormal red blood cells 58,72–76 . The course of the disease can be lethal, with most untreated cases not surviving beyond 4.5–9 years of age 73 .…”

Section: Defects In Cad Cause a Rare Neurometabolic Diseasementioning

confidence: 99%

Deciphering CAD: Structure and function of a mega‐enzymatic pyrimidine factory in health and disease

Caño-Ochoa

Ramón‐Maiques

2021

Protein Science

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CAD is a 1.5 MDa particle formed by hexameric association of a 250 kDa protein divided into different enzymatic domains, each catalyzing one of the initial reactions for de novo biosynthesis of pyrimidine nucleotides: glutaminasedependent Carbamoyl phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase. The pathway for de novo pyrimidine synthesis is essential for cell proliferation and is conserved in all living organisms, but the covalent linkage of the first enzymatic activities into a multienzymatic CAD particle is unique to animals. In other organisms, these enzymatic activities are encoded as monofunctional proteins for which there is abundant structural and biochemical information. However, the knowledge about CAD is scarce and fragmented. Understanding CAD requires not only to determine the threedimensional structures and define the catalytic and regulatory mechanisms of the different enzymatic domains, but also to comprehend how these domains entangle and work in a coordinated and regulated manner. This review summarizes significant progress over the past 10 years toward the characterization of CAD's architecture, function, regulatory mechanisms, and cellular compartmentalization, as well as the recent finding of a new and rare neurometabolic disorder caused by defects in CAD activities. K E Y W O R D Saspartate transcarbamoylase, carbamoyl phosphate synthetase, de novo pyrimidine biosynthesis, dihydroorotase, multienzymatic protein, nucleotide metabolism, rare diseases | INTRODUCTIONPyrimidine nucleotides are building blocks of DNA and RNA and key activators of intermediate metabolites in a number of cellular processes, including glycosylation and carbohydrate and phospholipid synthesis. 1,2 The cells obtain the supply of pyrimidines through two different metabolic pathways (Figure 1). Slowly dividing or differentiated cells use preferentially salvage pathways to uptake preformed nucleosides (e.g., uridine) from the diet or from the breakdown of nucleic acids, whereas, proliferating cells, whether normal (e.g., activated lymphocytes) or tumoral, depend on de novo ("of new") synthesis of pyrimidine nucleotides. The de novo pathway consists of six enzymatic steps yielding uridine 5-monophosphate (UMP), from which all other pyrimidine nucleotides are made (Figure 1). 3 In a first step, carbamoyl phosphate synthetase (CPS; EC 6.3.5.5) makes

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“…This disorder is associated with global developmental delay, epileptic encephalopathy, and anemia with anisopoikilocytosis. Although this disorder is rare, it is worth mentioning since it can respond to uridine supplementation, ameliorating seizures and improving the neurological phenotype ( 75 , 76 ).…”

Section: Congenital Disorders Of Glycosylationmentioning

confidence: 99%

Metabolic Seizures

et al. 2021

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Metabolic diseases should always be considered when evaluating children presenting with seizures. This is because many metabolic disorders are potentially treatable and seizure control can be achieved when these diseases are appropriately treated. Seizures caused by underlying metabolic diseases (metabolic seizures) should be particularly considered in unexplained neonatal seizures, refractory seizures, seizures related to fasting or food intake, seizures associated with other systemic or neurologic features, parental consanguinity, and family history of epilepsy. Metabolic seizures can be caused by various amino acids metabolic disorders, disorders of energy metabolism, cofactor-related metabolic diseases, purine and pyrimidine metabolic diseases, congenital disorders of glycosylation, and lysosomal and peroxisomal disorders. Diagnosing metabolic seizures without delay is essential because the immediate initiation of appropriate therapy for many metabolic diseases can prevent or minimize complications.

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Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation

Cited by 25 publications

References 20 publications

Case Report: Rapid Treatment of Uridine-Responsive Epileptic Encephalopathy Caused by CAD Deficiency

Case Report: Rapid Treatment of Uridine-Responsive Epileptic Encephalopathy Caused by CAD Deficiency

Deciphering CAD: Structure and function of a mega‐enzymatic pyrimidine factory in health and disease

Metabolic Seizures

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