Deficiencia de Fumarasa

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, with 40 cases reported so far. Fumarase deficiency leads mainly to brain abnormalities, developmental delay, and great accumulation of fumaric acid in urine. This work presents the first case of fumaric aciduria described in Brazil, which presented with some interesting clinical and biochemical findings such as colpocephaly, hepatic alterations, and marked metabolic acidosis since birth. Common findings were ventriculomegaly, hypotonia, and microcephaly. Biochemically, besides the high urinary fumaric acid excretion, atypical elevation of plasma citrulline, tyrosine and methionine levels were also observed. In order to show all features and variants of fumaric aciduria, literature data of 40 patients was reviewed and compared with the case reported here. Findings in all these patients demonstrate that this disorder does not yet have its phenotype completely defined; it is important that more patients be described. Communicated by: Jan Smeitink Competing interest: None declared. 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, Universidade Federal do Rio de Janeiro (UFRJ), Cidade Universitária, Ilha do Fundão, Centro de Tecnologia, bloco A, 536 C, 21941 900 Rio de Janeiro, Brasil e-mail: [email protected] P. Correia : J. C. Llerena Jr Centro de Genética Médica, Instituto Fernandes Figueira, FIOCRUZ, Rio de Janeiro, Brasil Abbreviations AICAR 5-aminoimidazole-4-carboxamide ribotide AMP adenosine monophosphate AS argininosuccinase ASL adenylosuccinate lyase ASS argininosuccinic synthetase AST aspartate aminotransferase CPSI carbamoylphosphate synthetase I. FAH fumarylacetoacetate hydrolase FAICAR 5-formaminoimidazole-4-carboxamide ribotide FH fumarate hydratase GD glutamate dehydrogenase 4-HPPD 4-hydroxy-phenylpyruvate dioxygenase IMP inosine monophosphate MAI maleylacetoacetate isomerase ME malic enzyme MDH malate dehydrogenase OT ornithine transcarbamoylase PC pyruvate carboxylase PDHC pyruvate dehydrogenase complex SAICAR 5-aminoimidazole-(N-succinylcarboxiamide) ribotide SDH succinate dehydrogenase TAT tyrosine aminotransferase Introduction Fumaric aciduria, an autosomal recessive disorder, is caused by deficiency of the enzyme fumarate hydratase [fumarase (FH)]. The first patient with fumarase deficiency (OMIM 136850), presenting with lethargy, microcephaly, and hypotonia combined with high urinary fumaric acid excretion, was described by Zinn et al. (1986). Fumaric aciduria, however, had already been reported in 1983 by Cholestatic jaundice and hepatomegaly were noted since birth. FH (E. pCO2 25. alanine aminotransferase (ALT) 78 U/L. hooked nose. despite breast feeding and normal sucking. although being fed with breast milk and supplementary . adipic).. It is supposed that the cytosolic isoform processes fumaric acid from the urea cycle. This enzyme is homotetrameric. other dicarboxylic acids (suberic. There was a small weight gain. Hemotransfusion was performed due to anemia. and one premature sister. performed during one of these episodes. both being encoded by the same gene located on chromosome 1q.– and marked metabolic acidosis (pH 7. mild hyperammonemia. Fumaric aciduria is characterized by massive excretion of fumaric acid in urine. They only differ at the aminoterminal residue: pyroglutamic acid on the mitochondrial isoform and Nacetylalanine on the cytosolic one (Akiba et al 1984). pyloromyotomy was performed. respectively. Ultrasound images of the fourth child showed agenesis of the corpus callosum and mild bilateral pyelocaliceal dilatation. Birth weight was 2180 g (< 3rd percentile). showed lactic acidemia (4.1 mmHg. At one-and-a-half months of age.C. and slightly elevated appendicular tonus. alkaline leukocyte phosphatase (ALP) 267 U/L. since in the last 27 years.1 (Estevez et al 2002. she still presented with lactic acidemia (5. At this time. Immediately after birth and during the following 17 days. and purine metabolism. On the seventh and 25th days. HCO39. iron-dependent. she presented with hypoglycemic episodes difficult to control (glucose: 20–40 mg/dl). single transverse palmar crease on the left hand and postaxial polydactyly on the right hand. At 40 days of life. Other metabolites may also be altered in body fluids: Krebs cycle intermediates. two samples of urine and one of plasma were collected and sent for inborn errors of metabolism (IEM) screening. At 2 months and 4 days.2) catalyzes the stereospecific and reversible hydration/dehydration of fumarate to S-malate. normal range < 45 mmol/mol creatinine).20. USA. Urinary organic acid analyses by gas chromatography mass spectrometry (GCMS) (according to Tanaka et al 1980) showed massive excretion of fumaric acid (> 232 mmol/ mol creatinine. performed at 4 days of life. overriding sutures. Szep 2007). BE -17. Filiano 2006). posture of limbs flexion. camptodactyly of the fifth finger. mitochondrial and cytosolic. Neurologic exam. whereas the mitochondrial isoform originates from the Krebs cycle (Lehtonen 2006). 4. N 10–34 U/L.6 mEq/L. Further exams at this period revealed colpocephaly [cranial computed tomography (CT)]. remaining undernourished due to persistent vomiting and occasional diarrhea. both isoforms are affected. Remes et al 2004). motor dysfunction. the girl was discharged but continued to gain weight slowly. dysmorphic features were noted. General aminoaciduria was observed and some plasma amino acids were also altered (Table 1).0 µmol/ml). UK) amino acid analyzer. antibiotics were administered for one week due to suspicion of sepsis. a higher frequency can be observed at the border of northern Arizona and southern Utah. metabolic acidosis. and thermostable. and alterations in other organ systems. At 3 months and 5 days. hemoculture was positive for Staphylococcus epidermidis. the baby had extreme difficulty gaining weight. kidney.2. and she was treated with antibiotics for 14 days. reduced axial tonus. Cambridge. N 20–140 U/L. The same result was presented by a new urine sample collected at 40 days of life. One brother. N 0–51 U/L]. the fourth child of consanguineous parents (first cousins). Sample preparation and analysis were performed according to the manufacturer’s standard protocols. It exists in two isoforms. head circumference 30 cm (< 3rd percentile). was born at 38 weeks of gestation after a pregnancy complicated by polyhydramnios. Amino acid analyses were carried out on a Biochrom 20 (Biochrom Ltd.5 mEq/L). micrognathia. In fumarase deficiency. This is probably due to a founder effect in closed. At physical examination. infantile hypertrophic pyloric stenosis [abdominal ultrasound (US)] and interatrial communication (ECO). especially liver. Fumaric aciduria is classified into the group of disorders that involve metabolic energy.412 J Inherit Metab Dis (2010) 33:411–419 Whelan et al in a couple of siblings (Whelan et al 1983). length 47 cm (∼10th percentile). N: 0. such as hypertelorism. seizures. showed incomplete Moro reflex. only 40 cases have been reported in the literature. The disease is considered rare. amino acid. had both died 6 h(presumed perinatal asphyxia) and two days (cause not reported). born at term.0 µmol/ml. but vomiting episodes persisted. However.1. N 5–35 U/L. In this group are included mitochondrial disorders that may interfere in embryophetal development.5 µmol/ml). the following hepatic enzymes were altered: [aspartate aminotransferase (AST) 137 U/L. At 6 days of life. and APGAR score 8/9. but hepatic enzymes remained altered. and gammaglutamyltranspeptidase (γ–GT) 505 U/L.7–2. Laboratory exams. leading to developmental delay. and blood cells (Saudubray et al 2006. Case report A girl. At 1 month of age.42. and mild hyperammonemia. among which marriage between relatives seems to be frequent (Kerrigan et al 2000. and succinylpurine derivatives. The aim of this study was to report the first case of fumaric aciduria in Brazil and to review data from patients found in the literature. religious polygamist communities living in these regions. after birth. 13. 7–9. 9. 14–16 2. intense crying and pallor.J Inherit Metab Dis (2010) 33:411–419 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 . 11: Kerrigan et al 2000. 18. 12. pCO2 32 mmHg. 6–10. 6. 20 2. e reduced fetal movements. 12. 13: Kimonis et al 2000. 18 1– 4. 12. 14 2. 14. she presented with severe metabolic acidosis (pH 6. 12. 11. 8. 7. 14: Remes et al 1992 and 2004. 5–7. 7. 11. 6. 9: Coughlin et al 1998. 11. 10. she was readmitted owing to vomiting with traces of blood. 16 6. 9. 8: Bonioli et al 1998. 4: Gellera et al 1990. 9. 20: De Meirleir et al 2006 All types of convulsions included and two patients were not responsive to drug treatment. 15–17. 19. 16 1. 11–13. 19 4. and dehydration. hyperpyrexia. 16. USA formula. 13.45. Only two families. 16 11. d malrotation of the bowel and esophageal dysmotility.5 925. It was not possible to Table 2 Clinical features found in 36 patients with fumaric aciduria described in the literature and in the case presented here Clinical findings Global developmental delay Cerebral abnormalities Hypotonia Dysmorphism Convulsive disorders a Microcephaly Feeding difficulties Failure to thrive Do not follow or fix Hematologic alterations b Macrocephaly c Vomiting Lethargy Gastrointestinal abnormalities Gestational history Prematurity (33–36 weeks) Polyhydramnios Others e Patients 34/36 33/36 26/36 16/36 16/36 13/36 12/36 11/36 10/36 9/36 9/36 8/36 4/36 4/36 10/36 5/36 6/36 % 94 92 72 44 44 36 33 31 28 25 25 22 11 Present Case + + + + – + – + – References 1–20 1–19 2. f infantile hypertrophic pyloric stenosis c a . 3: Walker et al 1989. b Neonatal polycythemia in five patients from the same family. intrauterine growth retardation. 9. 19 d + – + – +f – + – 28 14 17 1: Whelan et al 1983. 10: Manning et al 2000. 4–10. Children’s Medical Center. and leakage of amniotic fluid. Vomiting episodes twice a day and occasional diarrhea persisted. Dallas. 7: Narayanan et al 1996. At 4 months and 9 days. BE –32 mEq/L) and bradycardia. 18 3. 16: Phillips et al 2006. 6: Bourgeron et al 1994. 7. 15: Loeffen et al 2005. 18: Zeng et al 2006. 17 2. which evolved to cardiac arrest and death. 14–19 3. 17: Deschauer et al 2006. 3. 12: Zeman et al 2000. 6. 18. 4–6.7 2683 2467 Metabolic Laboratory. 3. 13. excessive fetal weight. 8. 5: Elpeleg et al 1992. 9. 19: Maradin et al 2006. 7. Texas. Besides hepatosplenomegaly. 14 2.1m) (nmol/mg creatinine) 124–1118 248–2898 0–146 104–875 38–1373 81–923 47–200 28–402 133–1490 15–411 218–1795 365–2267 Plasma 1 (nmol/ml) 313 263 181 70 99 430 nd 66 257 77 107 130 413 Reference valuesa (0-1m) (nmol/ml) 90–329 99–395 10–45 10–60 29–132 376–709 17–98 48–160 55–147 48–211 92–325 30–138 Threonine Serine Citrulline Methionine Asparagine Glutamine Cystine Leucine Tyrosine Ornithine Lysine Histidine nd not detected a 10600 7350 5494 nd 4470 5120 1359 539 3690 1238 3652 6427 2262 3416 638 nd 207 1540 1564 177. 16. 2: Zinn et al 1986. 19 2.15. 14. HCO3– 2 mEq/L. dyspnea. 4.5 351. bleeding. 17 6. 15 4. 19 12. 11 12. 7. Clinical and biochemical data were described in 36 patients. 19 3. 11. 16 11. and their main clinical features and cerebral abnormalities are shown in Tables 2 and 3. 7. Cerebral abnormalities were observed in 33 patients and the three remaining were mentally impaired (Whelan et al 1983. b : 6 from the same family. 19 References according Table 2. Of these 36 patients. b monozygotic twins 13. 18 11. 19 2–5. 18. 11–16. a Described in one family with eight affected members (Kerrigan et al 2000). 18 19 13. 11.414 J Inherit Metab Dis (2010) 33:411–419 Table 3 Cerebral abnormalities found in 33 patients with reported neuroimaging and in the case presented here Cerebral abnormalities Ventriculomegaly/ Hydrocephaly Cerebral Atrophies Open Sylvian Operculum a Polymicrogyria a Small brain Stem b Agenesis/ Hypoplasia of corpus callosum Brain cysts c Hypomyelination Others d Patients 27/33 24/33 10/33 9/33 8/33 6/33 6/33 5/33 2/33 Percent 82 73 30 27 24 18 18 15 6 This case + + - References 1–9. 13. 18. It is important to stress that not all patients had complete description of clinical. 16 9. De Meirleir et al 2006). and mutational features in fumarase-deficient patients Data from the literature were compiled. Clinical findings The literature group consisted of 40 patients from 27 families. 20 were females and 16 males. 16–19 11. 14. 1 arachnoid cyst in the temporal fossa. These malformations in fumaric aciduria could be a result of Overview: clinical. compared with the case here reported. 1 cyst in occipital horn. 7. respectively. biochemical. 9–11. 11 16. Postmortem exam was not allowed by the parents. 16 16 16 16 16 13 12 13 13 10 – – – . laboratorial. 1 periventricular cysts. Bourgeron et al 1994. Table 4 Dysmorphic features described in 15 of 16 patients and in the case presented here Dysmorphic Features Depressed nasal bridge Frontal bossing Hypertelorism Notched/anteverted naresa Low-set/anteverted/prominent ears High-arched palatea Bitemporal narrowing Overridging sutures Metopic ridgingb Triangular lower fasciesb Brachycephaly b Dolichocephaly Micrognathia Hypotelorism Pointed chin Camptodactyly Polydactyly Colpocephaly Hooked nose Patients 12/15 10/15 9/15 5/15 4/15 3/15 3/15 2/15 2/15 2/15 2/15 1/15 1/15 1/15 1/15 1/15 – – – Percent 80 67 60 33 27 20 20 13 13 13 13 7 7 7 7 7 – – – Percent total 33 28 25 14 11 8 8 6 6 6 6 3 3 3 3 3 – – – This case – – + – – – – + – – – – + – – + + + + References 11. d : Dandy-Walker malformation and lissencephaly measure enzymatic activity and perform molecular analysis. since no laboratory in Brazil executed these exams. 16 3. c : 3 choroid plexus cysts. a : 8 from the same family.9. 12 Author’s references according Table 2. 18. and discussed. 8. enzymatic activity determined in 31. 16. and mutational data. and mutational data in 26. 11. one had only seizures and the other one died at 17 h of life (Coughlin et al 1998. Kerrigan et al 2000. five showing opisthotonus. 8. De Meirleir et al 2006. Abnormal posture was seen in seven hypotonic patients. 4 7 7 6. 8. Coughlin et al 1998. Global developmental delay was present in almost all patients reviewed in the literature. Zeng et al 2006). 4. 7. and others restricted to few words Fig. 13 3. From the two remaining patients. 15 2. choreoathetoid moveAICAR FAICAR IMP CYTOSOL ASPARTATE + GTP GDP + Pi MALEYLACETOACETATE MAI FUMARYL ACETOACETATE AMP ASL ADENYLOSUCCINATE HGO O2 FAH HOMOGENTISATE CO2 4HPPD ACETOACETATE S-MALATE ME FH SCS FUMARATE SDH SUCCINATE SUCCINYL-CoA CO2 2-CGDH MITOCHONDRION O2 p–OH–PHENYLPYRUVATE TAT PYRUVATE + CO2 FUMARATE FH AS -KETOGLUTARATE TYROSINE ARGININO SUCCINATE ARGININE KREBS CYCLE S-MALATE ME MDH CO2 ICDH GLUCOSE LACTATE ISOCITRATE AC CITRATE PYRUVATE PDHC ASS UREA CYCLE CITRULLINE OT ATP + HCO. 7 2–4. 15 2. spasticity.3 PC H2O UREA CS ACETIL-CoA ADP + Pi ASPARTATE ORNITHINE OXALOACETATE PYRUVATE + CO2 -KETOGLUTARATE AST GD AMINO ACID AMINOTRANSFERASE GLUTAMATE NH 3 CARBAMOYL PHOSPHATE CPSI -KETO ACID HCO. 13 4. Two patients presented with areflexia associated with hypotonia. 9. Other neurologic findings were bilateral Babinski sign. 6–8. Speech impairment was observed in 14 patients (from six different families). 7 15 +b Organic acid analyses were not performed in all patients b plasma aerobic energy loss during early embryogenesis (Phillips et al 2006).J Inherit Metab Dis (2010) 33:411–419 Table 5 Altered substances in physiological fluids reported in patients with fumaric aciduria Altered organic acid Number of patients Urine Fumaric Succinic 2-ketoglutaric Adipic Citric Latic Malic Pyruvic Suberic 3-OH-butyric 4-OH-phenylacetic Acetoacetic Methylmalonic References according to Table 2 CSF cerebral spinal fluid a 415 This case Plasmaa 5 – 1 – – 4 – 3 – – – 2 1 CSFa 1 – – – – 5 – 2 – – – – – + References 36/36 6/36 6/36 2/36 2/36 3/36 3/36 2/36 2/36 1/36 1/36 1/36 1/36 1–20 2–4. 4 2. 12. 1 Metabolic pathways involving fumarate SAICAR ASL (Whelan et al 1983. (Narayanan et al 1996. 12.3 + ATP ADP . Maradin et al 2006. Manning et al 2000). 17 4. 7. Manning et al 2000). 13. some being dysarthric. 6. 6. some being unable to speak. 1499G>A c. By the time of their respective reports.His402Cys p. and dystonic tetraplegia (Walker et al 1989.Asp425Val p. 477insLys Gln13Pro. Prematurity was a relevant gestational feature. and craniofacial dysmorphic features were present in all of them (Table 4).Gln376Pro p. 435insLys.His402Tyr – 7/26 5/26 3/26 2/26 2/26 2/26 2/26 2/26 1/26 1/26 1/26 1/26 1/26 1/26 1/26 1/26 1/26 1/26 1/26 1/26 1/26 a. Manning et al 2000. AAAins435 998A>C. 9: Pollard et al 2005.b DNA change* Protein mutation* Number of patients e a c d 1: Gellera et al 1994. 13: Maradin et al 2006. Loeffen et al 2005. 8: Loeffen et al 2005.Arg233His p.Leu303Ser – p. Gln333Pro. It must be observed that in disorders with abnormalities in cell energy production. which also contains the signal peptide of 43 amino acids. 10: Phillips et al 2006.922G>A c.521C>G c. the underlying mechanism in fumaric aciduria is unknown (Kerrigan et al 2000. these features are unique in study group (Kerrigan et al 2000). Gellera et al 1990. 11: Deschauer et al 2006.d siblings. Kimonis et al. dysmorphic features may occur.1084G>C c.689A>G – Exon 2 splice variant c. Remes et al 1992.a monozygotic twins with compound heterozygous mutation. 7. such as the case here reported.301C>T c. 3. Angulation of the frontal horns and optic nerve hypoplasia/pallor were described in a consanguineous family that had eight affected members.Arg233Cys p. Bonioli et al 1998. 7: Remes et al 2004.Lys66fs p.Lys230Arg p.Phe312Cys p. 3: Coughlin et al 1998. have being associated with polyhydramnios in two cases. The cause of death was described only in seven patients and in general was due to infections (3). In general. 12: Zeng et al 2006. However. 10 6. They were corrected for the mitochondrial isoform. 2000.c. 5: Zeman et al 2000. 8. musculoskeletal and the central nervous system (CNS) (Kyle et al.Trp500X p.1204C>T – p. 2: Bourgeron et al 1994.195_268del c. b.1127A>C c. 14: De Meirleir et al 2006 * Some of the reported FH mutations were traditionally based on the mature protein rather than the primary translation product. Peters and Kahler 2003). Of 11 patients with reported EEG.416 J Inherit Metab Dis (2010) 33:411–419 ments.1274A>T c. ten patients had died early (28%).Lys477dup p. 9 6 9 3 3 3 11 13 9 1 13 3 14 14 1302insAAA.1207C>T c. 1997). 11 5. the main fetal anomalies associated with polyhy- dramnios are a consequence of disorders that affect gastrointestinal.Pro369Ser p. for mitochondrial signaling. seven of them being younger than 1 year. Remes et al 2004. Narayanan et al 1996. Elpeleg et al 1992.1105C>T c. 9.His318Leu p. 12 10 2 8. Loeffen et al 2005. Table 6 Mutations found in 25 patients with fumarase deficiency (adapted from Bayley et al 2008) Original reference Original mutation description DNA 1. Maradin et al 2006).935T>G c. 9. Kerrigan et al 2000. Arg233His Asp383Val Lys187Arg Leu260Ser – – Ala265Thr Phe269Cys His275Leu Pro326Ser Arg58X Arg190Cys Gln343His/ 344delVal Trp458X – – c.953A>T c.698G>A c. ataxia. ten showed epileptiform features (Zinn et al 1986.1433insAAA. 492C>G 1078C>T 955G>C 698G>A 1148A>T 560A>G 779T>C 2-slice exon 2 66del74 793G>A 806T>G 824A>T 976C>T – – 1029_1031delAGT 1373G>A 1078C>T Intronic mutation c. Laboratorial findings Metabolite alterations in physiological fluids reported in the literature in patients with fumaric aciduria are described in Table 5.Ala308Thr p. or prolonged apnea (1). 1127A>C 392C>G.Pro174Arg p.1391-269A>G Protein 434insLys. Deschauer et al 2006. considered the canonic form.Arg101X p.1158_1060delAGT c. 6: Kimonis et al 2000. Sixteen patients from eight different families had some degree of dysmorphia. 9 3 3.697C>T c.1431_1433dup c.Gln386_ Val387delinsHis p. Phillips et al 2006). e one case of paternal partial isodisomy .Glu362Gln p. 4: Manning et al 2000. Gln376Pro Pro131Arg His360Cys Glu319Gln Arg190His. cardiac arrest (3). adenylosuccinate lyase (ASL. In one patient. showed altered results. This enzyme belongs to complex II and is part of the respiratory chain and Krebs cycle. The patient here reported showed an increased urinary excretion of several amino acids (Table 1). SAICAR. AMP. These findings were probably due to secondary enzymatic inhibition of succinate dehydrogenase (SDH). and glycine in blood and urine. was considered a potential neurotoxic agent to pyramidal neurons of rat hippocampus (Stone et al 1997). only urinary amino acids were altered. Another alternative pathway would be the mitochondrial and cytosolic malic enzyme converting pyruvic acid to malic acid.C. In the third patient. In one patient. which is converted to malic acid by malate dehydrogenase (MDH) (Gellera et al 1990). This bidirectional enzyme is highly stimulated when the mitochondrial levels of fumaric and succinic acids are increased (Taroni et al 1988) (Fig.J Inherit Metab Dis (2010) 33:411–419 417 The massive excretion of fumaric acid in urine is common to all patients (15. Some considerations regarding other metabolite changes in patients with fumaric aciduria are presented below. aids in tight regulation of cellular metabolism by controlling the amounts of available citric acid cycle intermediates and the Fig. and citrulline in plasma not 10 20 30 40 50 60 MYRALRLLAR SRPLVRAPAA ALASAPGLGG AAVPSFWPPN AARMASQNSF RIEYDTFGEL 70 80 90 100 110 120 KVPNDKYYGA QTVRSTMNFK IGGVTERMPT PVIKAFGILK RAAAEVNQDY GLDPKIANAI 130 140 150 160 170 180 MKAADEVAEG KLNDHFPLVV WQTGSGTQTN MNVNEVISNR AIEMLGGELG SKIPVHPNDH 190 200 210 220 230 240 VNKSQSSNDT FPTAMHIAAA IEVHEVLLPG LQKLHDALDA KSKEFAQIIK IGRTHTQDAV 250 260 270 280 290 300 PLTLGQEFSG YVQQVKYAMT RIKAAMPRIY ELAAGGTAVG TGLNTRIGFA EKVAAKVAAL 310 320 330 340 350 360 TGLPFVTAPN KFEALAAHDA LVELSGAMNT TACSLMKIAN DIRFLGSGPR SGLGELILPE 370 380 390 400 410 420 NEPGSSIMPG KVNPTQCEAM TMVAAQVMGN HVAVTVGGSN GHFELNVFKP MMIKNVLHSA 430 440 450 460 470 480 RLLGDASVSF TENCVVGIQA NTERINKLMN ESLMLVTALN PHIGYDKAAK IAKTAHKNGS 490 500 510 TLKETAIELG YLTAEQFDEW VKPKDMLGPK . fumaric acid elevation was not observed with the first symptoms but only appeared later (Narayanan et al 1996).2. and fumaric acid (Fig. Another interesting finding was the elevated levels of tyrosine.2) catalyzes two similar reactions producing 5-aminoimidazole-4-carboxamide ribotide (AICAR). these derivatives were not detected. necessary for cellular replication. 4. E. were found in cerebral spinal fluid (CSF). ASL could be affected by the increased amount of fumaric acid.to 1. Zeman and coworkers considered that the accumulation of these succinylpurine derivatives could have a profound effect on impairment of the CNS in fumaric aciduria (Zeman et al 2000). An unexpected finding from the literature was the presence of malic acid in three patients. 1). 1). Accumulation of fumaric acid due to FH deficiency may affect several other metabolic pathways. serine. In urine of two patients. Other organic acids were also shown to be altered in fumaric aciduria. which is a substrate for ASL. with urinary αketoglutaric and succinic acids being the most relevant besides fumaric acid (Table 5). two succinylpurine derivatives. alanine. 1).3. The reverse reaction is barely detectable in human cells and tissues in normal conditions (Brière et al 2005). threonine. From 12 literature cases in which amino acid analysis was performed. which is a weak and noncompetitive inhibitor of this enzyme (Barnes and Bishop 1975). The result is increased production of oxaloacetic acid. three patients.000-fold higher when compared with normal range). Bourgeron and coworkers reported that both siblings had slightly elevated phosphoethanolamine. Aspartate and asparagine were low in these two patients’ blood and elevated in urine of one of them (Bourgeron et al 1994). In purine de novo biosynthesis. methionine. it catalyzes the conversion of succinic acid to fumaric acid (Fig. 2 Mutations observed on fumarate hydratase enzyme (mitochondrial isoform) amount of free adenosine monophosphate (AMP) (Toth and Yeates 2000. two being siblings. This could be explained by the accumulation of acetyl-coenzyme A (CoA) in mitochondria that inhibits pyruvate dehydrogenase complex (PDHC) and stimulates pyruvate carboxylase (PC). valine. Zeman et al 2000). The purine nucleotide cycle. as such metabolites do not cross the blood-brain barrier (Elpeleg et al 1992. but these were not discriminated (Narayanan et al 1996). Tsai et al 2007). 5-aminoimidazole-(N-succinylcarboxiamide) ribotide (SAICAR) and adenylosuccinate. Djouadi F et al (2005) Succinate dehydrogenase deficiency in human. Favier J. Cell Mol Life Sci 62:2317–2324 Coughlin EM. such as observed in tyrosinemia type I. 4. regarding clinical features and abnormal metabolite levels in fumaric aciduria patients. splice site. BMC Med Genet 9:20 Bonioli E. Twelve patients were homozygous for the mutations Gln376Pro. Fourteen mutations were missense. tyrosine catabolic pathway. Pro174Arg. Int J Biochem 6:497–503 Bayley JP. and citric acid cycle. Peri V et al (1998) Fumarate hydratase deficiency. CMLS. common to urea cycle defects. Severe metabolic acidosis was present in the patient described here from birth and in only two literature patients (Gellera et al.1). Narayanan et al 1996). jaundice. References Akiba T. 1990. Glu362Gln.3.). J Biochem 26:189–195 Barnes LB. and Lys230Arg. although the great majority of patients present with global developmental delay and cerebral abnormalities. Mol Genet Metab 63:254–262 . J Inherit Metab Dis 21:435–436 Bourgeron T. renal Fanconi syndrome. Moreover. Mutation p. Zeman et al 2000). Some symptoms. by increased levels of fumaric acid (Fig. however. Kunz PL et al (1998) Molecular Analysis and prenatal diagnosis of human fumarase deficiency. The main features of this disease. Mutational findings Human FH gene consists of ten exons encoding 510 amino acids. Although organic acid analysis is the first and main step to be carried out in patients suspected of having fumaric aciduria. Luis Nelson L F Gomes. 2). 1). 2009). elevated excretion of fumaric acid has been found in all patients. such as hyperammonemia and vomiting. Di Stefano A. Biochemically. An interesting finding observed in the patient here reported was the alteration of several plasma and urinary amino acid levels. are presented. Acknowledgments We thank Francisco Radler de Aquino Neto.3. and most mutations are concentrated at the C-terminus of the FH enzyme (Fig. which would explain the significant plasma citrulline elevation (Fig. 1).C.2. being observed in seven heterozygous nonrelated patients (27%). Bishop SH (1975) Adenylosuccinate lyase from human erythrocytes. The mutations related to FH deficiency reported in the literature so far are shown in Table 6 (modified from Bayley et al 2008). being therefore considered a hallmark of this disorder. frameshift. and hepatic problems (hepatomegaly. Elevated tyrosine and methionine levels could be due to the secondary inhibition of the last enzyme of the tyrosine catabolic pathway. Heterozygous parents had the activity ranging from 30% to 74% of the control mean. it has been observed that fumaric acid excretion is not correlated with residual enzyme activity or severity of the clinical picture (Bonioli et al 1998). Tuboi S (1984) Intracellular distribution of fumarase in various animals. including de novo purine nucleotide biosynthesis.2. DLE (Diagnósticos Laboratoriais Especializados). E. J Clin Invest 93:2514–2518 Brière JJ.and neurotoxic metabolites. Final considerations It must be considered that some of the unusual findings of the patient here described could also be due to another genetic defect and not exclusively to fumaric aciduria. fumarylacetoacetate hydrolase (FAH. Asp425Val. It can be observed that FH genotype is very heterogeneous. The measured residual FH activity in the literature patients (n=31) ranged from not detectable to 36% of control mean (average ∼5%). and cholestasis) (Mitchell et al 2001). since the parents are consanguineous. The remaining mutations were nonsense. duplication. In two patients. The first exon (exon 0) encodes a mitochondrial localization signal peptide of 43 amino acids (UniProt. This inhibition could also result in elevation of several hepato.418 J Inherit Metab Dis (2010) 33:411–419 previously reported in the literature. Such changes allowed a few pertinent considerations that may expand the current knowledge of this rare disease. Walker et al 1989). were also presented by the patient here reported. The significant accumulation of fumaric acid due to FH deficiency may affect several metabolic pathways. Poggi-Bach J et al (1994) Mutation of fumarase gene in two sibilings with progressive encephalopathy and fumarase deficiency. Launonen V. Hiraga K.7. Markéta Tesařová and Jean-Pierre Bayley for their contribution to the study. urea cycle. Some possible explanations. Christensen E. and deletion/insertion.C. it is suggested that amino acid analysis in body fluids be also performed. Tomlinson IPM (2008) The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. El Ghouzzi V. However. were presented by the patient. Chretien D. only one allele mutation was found at the time of their reports (Coughlin et al 1998). and one of them also presented with jaundice and cholestasis (Walker et al 1989. E.1. it would be interesting to consider the hepatic picture owing to the signs described in the case presented here.Lys477dup was the most frequent. Hepatomegaly was described in two literature patients. Hyperammonemia was reported only in two patients from the literature (Zinn et al 1986. Twenty-one different mutations related with congenital fumarase deficiency were described. Fumaric aciduria has a broad spectrum of clinical manifestations. Another consequence of fumaric acid accumulation could be a diminished activity of argininosuccinase (AS. Valle D. 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