Handbook of Clinical Neurology, Vol. 113 (3rd series) Pediatric Neurology Part III O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved Chapter 181 Defects in amino acid catabolism and the urea cycle GEORG F. HOFFMANN* AND STEFAN KO¨ LKER Department of General Pediatrics, University Children’s Hospital Heidelberg, Heidelberg, Germany INTRODUCTION organizations can offer support. Since treatment is time- and cost-intensive, often lifelong, and mostly Defects in amino acid catabolism and the urea cycle performed at home, regular training and support of result in an accumulation of metabolites upstream of patients and their families is essential. Unfortunately, as the defective enzyme (amino acids (AAs), organic acids for all chronic diseases, average compliance with recom- and/or ammonia) causing intoxication. Phenylketonuria mendations has been found as low as 50%, e.g., in PKU. (PKU) is the most frequent AA disorder (AAD) in Individual defects in AA catabolism and the urea Caucasians. Breakdown of AAs results in the release cycle usually have a low prevalence except for some of ammonia that is detoxified by the urea cycle. Hyper- communities with high consanguinity rates. However, ammonemia is the biochemical hallmark of urea cycle the cumulative prevalence of these disorders is consider- defects (UCDs). able (i.e., at least> 1:2000 newborns; Schulze et al., After an uneventful pregnancy and an initially asymp- 2003). Detailed information on diagnosis, genetic test- tomatic period, the onset of symptoms in these disorders ing, treatment and follow-up is available at the following varies from neonatal metabolic decompensation to late online databases: onset in adulthood. In childhood, metabolic decompensa- OMIM (http://www.ncbi.nlm.nih.gov/omim) tions are triggered by excess intake of protein and, impor- This is the online version of “Mendelian Inheritance in tantly, secondary to breakdown of body protein during Man,” the oldest and most widely used database of catabolic episodes. Treatment includes: (1) reduction of genetic disorders, founded by Victor A. McKusick. toxic metabolites by dietary restriction of precursor The number allocated to entries in the OMIM catalogue AAs, prevention of catabolism, stimulation of residual is used in scientific publications worldwide for the exact enzyme activity and detoxification strategies, and (2) sub- identification of individual genetic disorders. stitution with depleted substrates, vitamins and cofactors, GeneClinics (http://www.geneclinics.org) such as biotin or cobalamin. However, treatment efficacy This expert-written, peer-reviewed medical database is often low if patients are diagnosed after the onset of contains information on diagnosis, treatment and genetic symptoms. As a consequence, in many countries newborn testing of genetic disorders. screening programs have been established for some of Orphanet (http://www.orphanet.infobiogen.fr) these disorders. Neurological disease is common, particu- This database contains peer-reviewed information on a larly in untreated patients, and the manifestations are var- large number of genetic and non-genetic conditions. ied. The most frequent are: (1) mental defect, (2) epilepsy, The information is available in English and French. and (3) movement disorders. Successful treatment of affected individuals is often CLINICAL SPECTRUM AND DIAGNOSTIC challenging and requires careful supervision by metabolic WORK-UP centers involving an experienced interdisciplinary team. Evaluation and treatment of neurological symptoms A careful (family) history may reveal important clues to should be performed by a neuropediatrician and/or later diagnosis. Most disorders are inherited as autosomal on by a neurologist. In addition, parent and patient recessive traits which may be suspected if the parents *Correspondence to: Professor Dr. Georg F. Hoffmann, University Children’s Hospital Heidelberg, Department of General Pedi- atrics, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany. Tel: þ49-6221-564002, Fax: þ49-6221-564388, E-mail: Georg. [email protected] 1756 G.F. HOFFMANN AND S. KO¨ LKER are consanguineous or the family has a confined ethnic abnormalities, cortical or cerebellar atrophy, and injury or geographic background. They may be more frequent of the basal ganglia, can be derived from cranial mag- in certain communities (e.g., Amish), ethnic groups (e.g., netic resonance imaging (MRI). Ashkenazi Jews, Arabic tribes) or countries that have seen little immigration over many centuries (e.g., INDIVIDUAL DISORDERS Finland). Urea cycle defects Many disorders already manifest in the first days of life with progressive irritability or drowsiness. Most typ- Hyperammonemia (plasma ammonia: >80 mmol/L in ically, a young infant may vomit or refuse to feed and newborns; >50 mmol/L after the newborn period) is then rapidly deteriorates. The initial erroneous diagnoses caused by decreased detoxification of ammonia (NH3) are usually neonatal sepsis or intracranial hemorrhage. and/or increased production (e.g., by intestinal urease- A presumptive diagnosis of an inborn error of metabo- producing bacteria). Decreased detoxification results lism (IEM) of AA catabolism or urea cycle within 24–48 from inherited or acquired deficiency of key enzymes hours of the onset of symptoms is indispensable for a and transporters of the urea cycle (Fig. 181.1), or bypasses satisfactory outcome. Timely and correct intervention of the liver (e.g., open ductus hepaticus). Secondary during the initial presentation of metabolic imbalance impairment of NH3 detoxification results from condi- and during later episodes is an important prognostic tions where glutamate or acetyl-CoA are decreased, factor. Evaluation of metabolic parameters including such as in OADs, b-oxidation defects, carnitine deple- analyses of blood gases, serum glucose and lactate, tion, or valproate therapy, or where toxic acyl-CoAs plasma ammonia and AAs, acylcarnitine profiling in are increased, such as in propionic, methylmalonic, or dried blood spots, and organic acid analysis in urine isovaleric aciduria. should be performed on an emergency basis in every Hyperammonemia is neurotoxic resulting in brain patient presenting with symptoms of unexplained meta- edema, convulsions, and coma. A particular injury to bolic crisis, intoxication, or encephalopathy (Blau et al., the bilateral lentiform nuclei and the deep sulci of the 2003, 2005). Routine clinical chemistry alone is often insular and perirolandic regions occurring in the new- unrevealing. born has been reported (Takanashi et al., 2003) A substantial number of patients present differently (Fig. 181.2). Neuropathological evaluation reveals an with acute encephalopathy or chronic and fluctuating alteration of astrocyte morphology including cell swell- progressive neurological disease. The so-called cerebral ing (acute hyperammonemia) and Alzheimer type II organic acid disorders (OADs) (e.g., glutaric aciduria astrocytosis (chronic hyperammonemia) with ulegyria type I) present with (progressive) neurological symp- in the most severe cases, which can build up within a toms, such as ataxia, myoclonus, extrapyramidal symp- few weeks (Kornfeld et al., 1985). Mild cerebral and cer- toms, and “metabolic stroke” (Hoffmann et al., 1994). ebellar atrophy and infarct at bilateral posterior putamen Important diagnostic clues, such as white matter and insular cortex localization on conventional MRI NAGS N-acetylglutamate Glutamate + Ammonia Orotic acid CPS1 Carbamyl- Orotidine − phosphate HCO3 Uracil Citrulline OTC Aspartate Mitochondrion T ASS Cytosol Urea Ornithine Cycle Argininosuccinate Urea ASL Arginase Arginine T = Ornithine transporter Fumarate Fig. 181.1. The urea cycle. CPS1, carbamylphosphate synthase; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarba- mylase; ASS, argininosuccinate synthase; ASL, argininosuccinate lyase; T, ornithine transporter. (Adapted with permission from Zschocke and Hoffmann 2011.) DEFECTS IN AMINO ACID CATABOLISM AND THE UREA CYCLE 1757 Fig. 181.2. A 13-day-old child with citrullinemia revealed by coma and hyperammonemia. MRI (T1) shows bilateral insular and perirolandic cortical hypersignal. (Courtesy of Professor Boddaert.) images and elevated choline/creatine ratios and abnor- cellular transport including transporter proteins for the mal peak at 3.8 ppm, most likely representing arginine dibasic amino acids ornithine (HHH syndrome) and deposition (Gung€ or€ et al., 2008). Centropontine myelino- aspartate (citrullinemia II) primarily result in neurolog- lysis has also been reported (Mattson et al., 1995). Brain ical disease. relies on energy-dependent glutamine synthesis by astro- Onset of symptoms may occur at any age; however, it cytic glutamine synthase for the removal of excess NH3. is particularly frequent during the neonatal period, in As a consequence, increased brain NH3 is considered to late infancy, and in puberty, and is precipitated by excess amplify glutamatergic signaling, redistribution of cere- protein or episodes that induce catabolism such as infec- bral blood flow and metabolism, impairment of brain tious diseases, trauma, or steroid therapy. Neonatal pre- energy metabolism affecting the glutamate/glutamine sentation starts after a short asymptomatic interval with cycle, and increased serotonin secretion. Hyperammone- poor feeding, vomiting, lethargy, tachypnea and/or irri- mia exerts reversible (mostly serotonergic) as well as tability which cannot be