J Inherit Metab Dis (2010) 33:411–419 DOI 10.1007/s10545-010-9134-2 ORIGINAL ARTICLE Fumaric aciduria: an overview and the first Brazilian case report Gabriella Allegri & Marcia J. Fernandes & Fernanda B. Scalco & Patricia Correia & Ruth E. Simoni & Juan C. Llerena Jr & Maria L. Costa de Oliveira Received: 18 January 2010 /Revised: 5 May 2010 /Accepted: 12 May 2010 /Published online: 15 June 2010 # SSIEM and Springer 2010 Abstract Fumaric aciduria is a rare metabolic disease, Abbreviations with 40 cases reported so far. Fumarase deficiency leads AICAR 5-aminoimidazole-4-carboxamide ribotide mainly to brain abnormalities, developmental delay, and AMP adenosine monophosphate great accumulation of fumaric acid in urine. This work AS argininosuccinase presents the first case of fumaric aciduria described in ASL adenylosuccinate lyase Brazil, which presented with some interesting clinical ASS argininosuccinic synthetase and biochemical findings such as colpocephaly, hepatic AST aspartate aminotransferase alterations, and marked metabolic acidosis since birth. CPSI carbamoylphosphate synthetase I. Common findings were ventriculomegaly, hypotonia, and FAH fumarylacetoacetate hydrolase microcephaly. Biochemically, besides the high urinary FAICAR 5-formaminoimidazole-4-carboxamide ribotide fumaric acid excretion, atypical elevation of plasma FH fumarate hydratase citrulline, tyrosine and methionine levels were also GD glutamate dehydrogenase observed. In order to show all features and variants of 4-HPPD 4-hydroxy-phenylpyruvate dioxygenase fumaric aciduria, literature data of 40 patients was IMP inosine monophosphate reviewed and compared with the case reported here. MAI maleylacetoacetate isomerase Findings in all these patients demonstrate that this ME malic enzyme disorder does not yet have its phenotype completely MDH malate dehydrogenase defined; it is important that more patients be described. OT ornithine transcarbamoylase PC pyruvate carboxylase PDHC pyruvate dehydrogenase complex SAICAR 5-aminoimidazole-(N-succinylcarboxiamide) Communicated by: Jan Smeitink ribotide SDH succinate dehydrogenase Competing interest: None declared. TAT tyrosine aminotransferase G. Allegri (*) : M. J. Fernandes : F. B. Scalco : R. E. Simoni : M. L. C. de Oliveira Laboratório de Erros Inatos do Metabolismo (LABEIM), Departamento de Bioquímica, Instituto de Química, Introduction Universidade Federal do Rio de Janeiro (UFRJ), Cidade Universitária, Ilha do Fundão, Centro de Tecnologia, Fumaric aciduria, an autosomal recessive disorder, is bloco A, 536 C, 21941 900 Rio de Janeiro, Brasil caused by deficiency of the enzyme fumarate hydratase e-mail: [email protected] [fumarase (FH)]. The first patient with fumarase deficiency : (OMIM 136850), presenting with lethargy, microcephaly, P. Correia J. C. Llerena Jr and hypotonia combined with high urinary fumaric acid Centro de Genética Médica, Instituto Fernandes Figueira, FIOCRUZ, excretion, was described by Zinn et al. (1986). Fumaric Rio de Janeiro, Brasil aciduria, however, had already been reported in 1983 by 412 J Inherit Metab Dis (2010) 33:411–419 Whelan et al in a couple of siblings (Whelan et al 1983). sutures, hooked nose, micrognathia, camptodactyly of the Fumaric aciduria is characterized by massive excretion of fifth finger, single transverse palmar crease on the left hand fumaric acid in urine. Other metabolites may also be and postaxial polydactyly on the right hand. Immediately altered in body fluids: Krebs cycle intermediates, other after birth and during the following 17 days, she presented dicarboxylic acids (suberic, adipic), and succinylpurine with hypoglycemic episodes difficult to control (glucose: derivatives. The disease is considered rare, since in the 20–40 mg/dl). Laboratory exams, performed during one of last 27 years, only 40 cases have been reported in the these episodes, showed lactic acidemia (4.0 µmol/ml; N: literature. However, a higher frequency can be observed 0.7–2.5 µmol/ml), mild hyperammonemia,– and marked - at the border of northern Arizona and southern Utah, metabolic acidosis (pH 7.20; pCO2 25.1 mmHg; HCO3 USA. This is probably due to a founder effect in closed, 9.6 mEq/L; BE -17.5 mEq/L). Neurologic exam, per- religious polygamist communities living in these regions, formed at 4 days of life, showed incomplete Moro reflex, among which marriage between relatives seems to be posture of limbs flexion, reduced axial tonus, and frequent (Kerrigan et al 2000,Szep2007). Fumaric slightly elevated appendicular tonus. At 6 days of life, aciduria is classified into the group of disorders that antibiotics were administered for one week due to involve metabolic energy. In this group are included suspicion of sepsis. On the seventh and 25th days, two mitochondrial disorders that may interfere in embryophe- samples of urine and one of plasma were collected and tal development, leading to developmental delay, seizures, sent for inborn errors of metabolism (IEM) screening. motor dysfunction, and alterations in other organ systems, Amino acid analyses were carried out on a Biochrom 20 especially liver, kidney, and blood cells (Saudubray et al (Biochrom Ltd., Cambridge, UK) amino acid analyzer. 2006; Filiano 2006). Sample preparation and analysis were performed accord- FH (E.C. 4.2.1.2) catalyzes the stereospecific and ingtothemanufacturer’s standard protocols. General reversible hydration/dehydration of fumarate to S-malate. aminoaciduria was observed and some plasma amino This enzyme is homotetrameric, iron-dependent, and acids were also altered (Table 1). Urinary organic acid thermostable. It exists in two isoforms, mitochondrial and analyses by gas chromatography mass spectrometry (GC- cytosolic, both being encoded by the same gene located on MS) (according to Tanaka et al 1980) showed massive chromosome 1q.42.1 (Estevez et al 2002, Remes et al excretion of fumaric acid (> 232 mmol/ mol creatinine, 2004). They only differ at the aminoterminal residue: normal range < 45 mmol/mol creatinine). The same result pyroglutamic acid on the mitochondrial isoform and N- was presented by a new urine sample collected at 40 days acetylalanine on the cytosolic one (Akiba et al 1984). In of life. fumarase deficiency, both isoforms are affected. It is At 1 month of age, despite breast feeding and normal supposed that the cytosolic isoform processes fumaric acid sucking, the baby had extreme difficulty gaining weight, from the urea cycle, amino acid, and purine metabolism, remaining undernourished due to persistent vomiting and whereas the mitochondrial isoform originates from the occasional diarrhea. Cholestatic jaundice and hepatomegaly Krebs cycle (Lehtonen 2006). were noted since birth. At 40 days of life, the following The aim of this study was to report the first case of hepatic enzymes were altered: [aspartate aminotransferase fumaric aciduria in Brazil and to review data from patients (AST) 137 U/L, N 10–34 U/L; alanine aminotransferase found in the literature. (ALT) 78 U/L, N 5–35 U/L; alkaline leukocyte phosphatase (ALP) 267 U/L, N 20–140 U/L, and gamma- glutamyltranspeptidase (γ–GT) 505 U/L, N 0–51 U/L]. Case report Further exams at this period revealed colpocephaly [cranial computed tomography (CT)], infantile hypertrophic pyloric A girl, the fourth child of consanguineous parents (first stenosis [abdominal ultrasound (US)] and interatrial com- cousins), was born at 38 weeks of gestation after a munication (ECO). At one-and-a-half months of age, pregnancy complicated by polyhydramnios. Birth weight pyloromyotomy was performed, but vomiting episodes was 2180 g (< 3rd percentile), length 47 cm (∼10th persisted. At this time, she still presented with lactic percentile), head circumference 30 cm (< 3rd percentile), acidemia (5.0 µmol/ml), metabolic acidosis, and mild and APGAR score 8/9. One brother, born at term, and one hyperammonemia. Hemotransfusion was performed due to premature sister, had both died 6 h(presumed perinatal anemia. At 2 months and 4 days, hemoculture was positive asphyxia) and two days (cause not reported), respectively, for Staphylococcus epidermidis, and she was treated with after birth. Ultrasound images of the fourth child showed antibiotics for 14 days. There was a small weight gain, but agenesis of the corpus callosum and mild bilateral pyelo- hepatic enzymes remained altered. At 3 months and 5 days, caliceal dilatation. At physical examination, dysmorphic the girl was discharged but continued to gain weight slowly, features were noted, such as hypertelorism, overriding although being fed with breast milk and supplementary J Inherit Metab Dis (2010) 33:411–419 413 Table 1 Urinary and plasma amino acid analysis by ion-exchange chromatography of the patient here reported Amino acid Urine 1 (nmol/mg creatinine) Urine 2 (nmol/mg creatinine) Reference valuesa (0 - 1m) Plasma 1 Reference valuesa (nmol/mg creatinine) (nmol/ml) (0-1m) (nmol/ml) Threonine 10600 2262 124–1118 313 90–329 Serine 7350 3416 248–2898 263 99–395 Citrulline 5494 638 0–146 181 10–45 Methionine nd nd 104–875 70 10–60 Asparagine 4470 207 38–1373 99 29–132 Glutamine 5120 1540 81–923 430 376–709 Cystine 1359 1564 47–200 nd 17–98 Leucine 539 177.5 28–402 66 48–160 Tyrosine 3690 351.5 133–1490 257 55–147 Ornithine 1238 925.7 15–411 77 48–211 Lysine 3652 2683 218–1795 107 92–325 Histidine 6427 2467 365–2267 130 30–138 nd not detected a Metabolic Laboratory, Children’s Medical Center, Dallas, Texas, USA formula. Vomiting episodes twice a day and occasional dehydration. Besides hepatosplenomegaly,