Molecular Genetics and Metabolism

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1 Molecular Genetics and Metabolism 96 (2009) Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: Citrin defciency, a perplexing global disorder David Dimmock a,1,2, Bruno Maranda b,2, Carlo Dionisi-Vici c, Jing Wang a, Soledad Kleppe d, Giuseppe Fiermonte e, Renkui Bai a, Bryan Hainline f, Ada Hamosh g, William E. O Brien a, Fernando Scaglia a, *, Lee-Jun Wong a a Depart ment of Molec u lar and Human Genet ics, Bay lor Col lege of Med i cine, One Bay lor Plaza, BCM225, Hous ton, TX 77030, USA b Ser vice de Géné tique Médi cale, Cen tre Hos pit a lier Uni vers i taire de Qué bec, Uni ver sité La val, Ste-Foy, Qué bec, Can ada c Divi sion of Metab o lism, Chil dren s Hos pi tal Bam bino Gesù, Rome, Italy d Divi sion Gene ti ca, CE MIC, Bue nos Aires, Argen tina e Depart ment of Phar maco-biol ogy, Uni ver sity of Bari, Bari, Italy f Depart ment of Med i cal and Molec u lar Genet ics, Indi ana Uni ver sity School of Med i cine, Indi a nap o lis, IN, USA g Insti tute of Genetic Med i cine, Johns Hop kins Uni ver sity School of Med i cine, Bal ti more, MD, USA article info Article history: Received 2 August 2008 and in revised form 14 October 2008 Accepted 14 October 2008 Available online 25 November 2008 Key words: Cit rul line mia CTLN2 NIC CD Ther apy New born screen ing Intra he patic cho le sta sis Bipo lar dis or der Hepatic ste a to sis abstract Cit rin deficiency, caused by muta tions in SLC25A13, can pres ent with neo na tal intra he patic cho le sta sis or with adult onset neu ro psy chi at ric, hepatic and pan cre atic dis ease. Until recently, it had been thought to be found mostly in indi vid u als of East Asian ances try. A key diag nos tic fea ture has been the deficient argi ni nosuc ci nate syn the tase (ASS) activ ity (E.C ) in liver, with nor mal activ ity in skin fbro blasts. In this series we describe the clin i cal pre sen ta tion of 10 patients referred to our lab o ra to ries for sequence anal y sis of the SCL25A13 gene, includ ing sev eral patients who pre sented with ele vated cit rul line on new born screen ing. In addi tion to sequence anal y sis per formed on all patients, ASS enzyme activ ity, cit rul line incor po ra tion and Western blot anal y sis for ASS and cit rin were per formed on skin fbro blasts if avail able. We have found 5 unreported muta tions includ ing two appar ent foun der muta tions in three unre lated French-Cana dian patients. In marked con trast to pre vi ous cases, these patients have a mark edly reduced ASS activ ity in skin fbro blasts. The pres ence of cit rin pro tein on Western blot in three of our cases reduces the sen si tiv ity of a screen ing test based on pro tein immu no blot ting. The fnd ing of cit rin muta tions in patients of Ara bic, Paki stani, French Cana dian and North ern Euro pean ori gins sup ports the con cept that cit rin deficiency is a pan eth nic dis ease Published by Elsevier Inc. Intro duc tion Cit rin, the mito chon drial aspar tate/glu ta mate car rier (AGC2) plays a sig nif cant role in nitro gen metab o lism by vir tue of its shut tle activ ity. Deficiency of this pro tein has pre vi ously been described as the cause of cit rul line mia type 2 (CTLN2) [1]. CTLN2 was ini tially described as an adult onset hepatic and neu ro log i cal dis or der in indi vid u als of Jap a nese ances try. CTLN2, was orig i nally dif fer en ti ated from clas si cal cit rul line mia by a tis sue spe cifc defi ciency of argi ni no suc ci nate syn the tase (ASS) activ ity (E.C ) in the liver but nor mal enzy matic activ ity in renal tis sue or skin fbro blast cul ture [2]. Cit rin deficiency has sub se quently been shown to be a cause of neo na tal intra he patic cho le sta sis through mech a nisms that are not well under stood [3,4]. Although ini tially reported among indi vid u als of East Asian ances try, sev eral recent * Cor re spond ing author. Fax: address: fsca (F. Scaglia). 1 Cur rent address: Depart ment of Pedi at rics, Med i cal Col lege of Wis con sin, Mil wau kee, WI, USA. 2 Joint frst authors. reports have described indi vid u als with liver dis ease sec ond ary to cit rin deficiency from other eth nic groups [5 8]. Cit rin deficiency is a di f icult met a bolic dis or der to reli ably dis tin guish from other causes of hepatic dis ease, par tic u larly as the char ac ter is tic plasma amino acid profile is not con sis tently pres ent [9 11]. How ever, in Tai wan, cit rin deficiency has been shown to be the lead ing cause of hepatic ste a to sis in infants [11]. There fore, rapid and inex pen sive diag nos tic test ing is of sig nif cant value in eval u at ing chil dren with hepatic ste a to sis or intra he patic cho le sta sis. Con se quently, more recent efforts have focused on using Western blot to diag nose patients, as all muta tions reported to date have resulted in no detect able pro tein [12]. Meth ods Sequenc ing Clin i cal sam ples on patients with sus pected cit rin deficiency were referred to the Med i cal Genet ics lab o ra to ries at Bay lor College of Med i cine, Hous ton, Texas for DNA anal y sis of the SCL25A /$ - see front matter 2008 Published by Elsevier Inc. doi: /j.ymgme

2 D. Dim mock et al. / Molecular Genetics and Metabolism 96 (2009) gene (cases 1 6 and 8 10) or in Dr Palm i eri s lab o ra tory at the Uni ver sity of Bari, Italy (case 7) (see Table 1). The entire cod ing exons and at least 50 bases of the flank ing intron regions of the SCL25A13 gene were PCR amplified, fol lowed by auto mated DNA sequenc ing in both for ward and reverse directions using gene spe cifc prim ers (avail able upon request) linked to M13 universal sequence prim ers. The sequenc ing was per formed on an ABI3730XL auto mated DNA sequencer with Sequenc ing Analy sis Soft ware v5.1 (Applied Bio sys tems, Fos ter City, CA, USA). DNA sequences were ana lyzed using Muta tion Sur veyor ver sion (Soft Ge net ics, State Col lege, PA, USA) and the Gene bank sequence: NM_ , was used as the ref er ence sequence. In all cases, muta tions were confirmed on a sec ond DNA extraction. Trans-config u ra tion of muta tions was confirmed by sequence anal y sis of paren tal DNA sam ples. To exclude muta tions in the ASS1 gene, full sequenc ing was per formed as noted. Research test ing was per formed accord ing to pro to cols approved by Bay lor Col lege of Med i cine Insti tu tional Review Board and with the con sent of sub jects or legal guard ians where appro pri ate and in line with the Dec la ra tion of Hel sinki. Clin i cal details and his topa thol ogy reports were obtained from the refer ring insti tu tions. Western anal y sis Fibro blast cul tures were obtained from cases 1, 2 and 7. For cases 1 and 2 these were har vested and washed in phos phate buffered saline and then briefly son i cated in RIPA buffer (25 mm Tris HCl ph 7.6, 150 mm NaCl, 1% NP-40, 1% sodium deoxy cho late, 0.1% SDS). Pro tein con cen tra tion was deter mined by the Bio-Rad Protein Assay (Bio Rad, Her cu les, CA). Sam ples were diluted to 1 mg/ and then 5 20 lg were loaded onto a 12% SDS PAGE gel and transferred to 45 lm nitro cel lu lose mem brane. The mem brane was subse quently blocked for 1 h in 5% milk and then incu bated over night in primary anti body, washed and incu bated for 1 h with a sec ondary anti body. Immu no re ac tive bands were visu al ized using the ECL sys tem (Amersham Pharmacia). Mem branes were then stripped and reprobed with a mono clo nal anti-b-actin anti body pro duced in mouse (Sigma Aldrich A2228) as a load ing con trol. For case 7, mito chon dria were iso lated from patient and con trol fbro blasts using a com mer cial kit (Pierce) with the Halt pro te ase inhib i tors accord ing to the man u fac turer s instruc tions. An anti body to subunit IV of the cyto chrome c oxi dase was used as a load ing con trol. Anti-cit rin anti body was pro duced in rab bit uti liz ing KLH conju ga tion against pep tide KRA DPAELRTIFLK (posi tions p of the pre cur sor pro tein) by Open Bio sys tems (Hunts ville, AL) accord ing to their stan dard pro to cols. This anti body was val i dated on patient sam ples pre vi ously tested by Dr. Ke iko Ko bay ash i [6]. A com mercial anti-cit rin mouse mono clo nal anti body raised against amino acid posi tions 2 to 81 was also eval u ated (Gene tex GTX95185). Anti-ASS anti body pro duc tion has been pre vi ously described [13] and these results were confirmed using a com mer cial mono clo nal anti body to the C-ter mi nal of ASS (BD ). Bio chem i cal stud ies Plasma amino acid anal y sis was per formed on a Bio chrom 30 amino acid ana lyzer accord ing to man u fac turer s pro to cols. ASS enzyme activ i ties and cit rul line incor po ra tion stud ies were performed on cases 1 and 2 as pre vi ously described [13,14]. Real time PCR Total RNA was extracted from fbro blasts using TRI ZOL (Invit ro gen, Carls bad, Cal i for nia). Reverse tran scrip tion was performed using iscript (Bio rad, Her cu laes, Cal i for nia). Real time PCR was then per formed on cdna using spe cifc prim ers for ASS1 653 Table 1 Sum mary of eth nic ity and muta tions in SLC23A13. Case Eth nic ity Gen der Muta tion 1 Muta tion 2 1 French-Cana dian Female p.r43x p.r355x 2 French-Cana dian Male p.r43x p.r355x 3 French-Cana dian Female p.r43x p.r355x 4 French-Cana dian Female p.r43x p.r43x 5 South East Asian Female c.1660_c.1661dup23 c.1660_c.1661dup23 6 Han Male c.851delg TAT c.615+5g>a 7 Ara bic Male p.a25e p.a25e 8 Paki stani Male c.172_173del GT c.172_173del GT 9 Paki stani Female c.172_173del GT c.172_173del GT 10 Northern Euro pean Female c.848+3a>c p.t546r and for the beta 2 micro glob u lin as a ref er ence. A patient with two mis sense muta tions in ASS1 and a nor mal fbro blast line were used as con trols. Results Case reports Case 1, a 2 year old female, was born at term with a birth weight of 1767 g to non-con san guin e ous French-Cana dian par ents from the Bas-St-Lau rent region of Que bec. She pre sented with an ele vated cit rul line on uri nary new born screen ing [15]. She devel oped jaundice at 6 weeks with pro gres sive cho le sta sis. Her aspar tate amino trans fer ase (AST) was mod estly ele vated at 49 IU/L (ref er ence range: < 34 IU/L) with an increase in gamma glut am yl trans pepti dase (GGT) of 1042 IU/L (ref er ence range: <265 IU/L). Her ini tial plasma amino acids at 48 days of age revealed an ele vated methio nine of 90 lm (ref er ence range 9 45 lm) and Cit rul line of 235 lm (ref er ence range <41 lm) (Table 2). Her alpha feto pro tein (AFP) was sig nif cantly ele vated at 30,071 ku/l (ref er ence range: <3395 ku/l). Given the sig nif cant ele va tion in cit rul line, skin fbro blasts were sent for ASS assay. This revealed a com plete deficiency of ASS activ ity (0.0 nmol/min/mg pro tein, nor mal range nmol/ min/mg pro tein). Repeat anal y sis on re-derived cells yielded sim i- lar results. Clin i cal sequenc ing of the ASS1 gene revealed no mutations. She was man aged as a patient with ASS deficiency with a low pro tein diet and sodium ben zo ate. Her liver dis ease per sisted with recur rent hypo gly ce mia, hypo al bu mi ne mia, and fail ure to thrive. Abdom i nal ultra sound at one year of age showed an enlarged liver with ste a to sis and three echo genic foci. Due to the per sis tent ele va tion in plasma cit rul line (Table 2) and clin i cal pic ture of liver dis ease, a liver biopsy was per formed. The pathol ogy was sig nif cant for ste a to sis and giant cell hep a titis. Given the pre dom i nant hepatic phe no type, sequence anal y sis of SCL25A13 was per formed, that revealed two novel het ero zy gous muta tions: c.127c > T (p.r43x) and c.1063c > T (p.r355x). These muta tions have not been seen in over 300 con trol chro mo somes. She was also het ero zy gous for a novel var i ant c c > g, the pre vi ously reported SNPs: c A > G in cis with the p.r43x muta tion, and the c.1194 a > g (p.l398l) in cis with the p.r355x muta tion. Western anal y sis for cit rin using the rab bit poly clonal anti body revealed a 37 kda pro tein (Fig. 1), and this was rep li cated when the com mer cial mouse mono clo nal anti body was used (data not shown). The cit rul line incor po ra tion ratio was nor mal (26.99, ref er ence range 3 112). Western anal y sis of these fbro blasts revealed an almost total absence of ASS pro tein with increased mrna lev els (Fig. 2). A high-pro tein and low car bo hy drate diet was imple mented as pre vi ously described [6]. The liver func tion returned to nor mal and the infant remains clin i cally well. Case 2, a 2 year old male, was born at term to non- con san guine ous French-Cana dian par ents from the Bas-St-Lau rent region of Que bec. He pre sented with an ele vated cit rul line on uri nary

3 46 D. Dim mock et al. / Molecular Genetics and Metabolism 96 (2009) Table 2 Selected plasma amino acid profiles of selected cases in lm. Case Age/days Thre o nine Ser ine Glu ta mine Ala nine Cit rul line Valine Methi o nine Iso leu cine Leu cine Tyro sine Phe Or nith ine His ti dine Argi nine LLN ULN Key: LLN, lower limit of nor mal; ULN, upper limit of nor mal; Phe Phen yl al a nine;, Data not avail able. Fig. 1. (a) Western blot anal y sis in skin fbro blasts dem on strates a nor mal immuno re ac tive band in a con trol cell line and an approx i mately 37 kda band in cases 1 ( 1 ) and 2 ( 2 ), com pound het ero zy gous for a p.r355x and p.r43x muta tion; A is an unpub lished case. (b) Western blot anal y sis of mito chon dria from fbro blasts of a con trol (lane 1) and case 7 (lane 2); with anti-cit rin in the top panel, and antisub unit IV of the cyto chrome c oxi dase in the bot tom panel. Fig. 2. (a) Western blot anal y sis dem on strates that reduced ASS enzyme activ ity is as a result of a reduc tion in the ASS pro tein in case 1 ( 1 ) less mark edly in case 2 ( 2 ) com pared with con trols C1 and C2. (b) Quan ti ta tive RT-PCR of ASS1 nor malized to Beta-2 Micro glob u lin in patient fbro blasts dem on strates increased transcrip tion when com pared to a nor mal con trol (C) or a patient with clas si cal ASS deficiency (ASS). 654 new born screen ing. He sub se quently devel oped jaun dice with pro gres sive cho le sta sis. How ever, his liver func tion tests were all within the nor mal range. His alpha feto pro tein (AFP) and fer ri tin were not sig nif cantly ele vated. His ini tial plasma amino acids at birth were sig nif cant for an ele vated cit rul line and methi o nine with a mod est ele va tion of thre o nine (Table 2). Given the sig nifi cant ele va tion in cit rul line (492 lm), an ASS enzyme assay was per formed on cul tured fbro blasts. This assay revealed reduced ASS activ ity (0.5 nmol/min/mg pro tein nor mal range nmol/ min/mg pro tein). A low pro tein diet was imple mented but fail ure to thrive and liver dys func tion appeared. As a result of the con cur rent expe ri ence with case 1, sequenc ing of the SCL25A13 gene was per formed, which revealed the same novel het ero zy gous muta tions: p.r43x and p.r355x with the same novel var i ant and SNPs as case 1. Con sis tent with case 1, Western anal y sis for cit rin detected a 37 kda pro tein (Fig. 1). The cit rul line incorpo ra tion ratio was nor mal (27.98 ref er ence range 3 112). Western anal y sis of fbro blasts for ASS revealed a sig nif cant reduc tion in ASS pro tein with increased mrna (Fig. 2). A high pro tein, low carbo hy drate diet was pre scribed as pre vi ously described [6]. However this die tary approach has proved di f icult for the par ents to imple ment and he still has per sis tent fail ure to thrive. Case 3 is the 24 year old mother of case 2. She was diag nosed as a result of muta tion test ing to clar ify the config u ra tion of her son s muta tions. She was born at term and, by his tory, had no signif cant neo na tal cho le sta sis. She had an unevent ful child hood and per formed appro pri ately at school. She has a life long dis like of sim ple car bo hy drates and a pref er ence for pro tein rich foods. In adult hood she has exhib ited epi sodic con fu sion and a mood disor der. Although, at this point undi ag nosed, she had no sig nif cant com pli ca tions dur ing preg nancy and no postpartum decom pen sation. More recently she has pre sented with sig nif cant epi gas tric pain sec ond ary to pan cre a ti tis with a lipase of 1500 U/L (ref er ence range <190 U/L). Her ALT, AST, bil i ru bin, ammo nia and tri glyc er ides have always remained within nor mal range. Sequence anal y sis of the SCL25A13 gene revealed the same novel het ero zy gous mutations: p.r43x and p.r355x. Test ing of her par ents estab lished the trans config u ra tion of the muta tions with the same novel var i ant and SNPs as case 1. Case 4 is a 6 month old French-Cana dian female who pre sented with ele vated cit rul line on uri nary new born screen ing at three weeks of age. Reflex PAA revealed a pattern con sis tent with NIC DD with a cit rul line of 948 (see Table 2). Given pre vi ous expe ri ence, sequenc ing anal y sis of the cit rin gene was per formed and revealed

4 D. Dim mock et al. / Molecular Genetics and Metabolism 96 (2009) a homo zy gous p.r43x muta tion and the homo zy gos ity for the same c a > g SNP as seen in cases 1, 2, and 3. A skin biopsy was not per formed for clin i cal or research stud ies. She has sub sequently been man aged on a high-pro tein, low car bo hy drate diet as pre vi ously described [6]. She is grow ing well and has not developed clin i cally sig nif cant liver dis ease. Case 5, a 3 year old South East Asian child, pre sented with ele vated cit rul line (350 lm) with bor der line ele va tion in tyro sine on expanded new born screen ing. Plasma amino acids at 3 weeks of age showed a cit rul line of 850 lmol with ele va tions in tyro sine, methi o nine, thre o nine to ser ine ratio and argi nine (Table 2). She exhib ited sig nif cant cho le sta sis and deranged coag u la tion for over 8 weeks. The liver fail ure did not ini tially respond to the high pro tein, low car bo hy drate diet we have pre vi ously used [6]. Consis tent with another reported case, sig nif cant improve ment was seen after gal act ose was excluded from the diet [16]. Sequenc ing revealed a pre vi ously reported homo zy gous inser tion muta tion, c.1660_c.1661ins23 (c.1638_1660dup23) [1]. She was sub se quently lost to fol low up. Case 6, a 2 year old child, was born at 38 weeks, to non- consang u ous eth ni cally Han par ents in Bue nos Aires, Argen tina. He pre sented with a phen yl al a nine seven times the upper limit of nor mal on new born screen ing. On the sec ond screen he had a normal phen yl al a nine level but ele vated total gal act ose of 12.5 mg/dl, (cut off <11 mg/dl) rising to 40 mg/dl in a third sam ple with positive reduc ing sub stances in the urine. On ini tial eval u a tion he had a signif cant coag u lop a thy, which responded to IM vita min K. He also had sig nif cant intra he patic cho le sta sis with a total bil i ru bin of 15 mmol/l (ref er ence range mmol/l) and a direct bil i ru bin of 13 mmol/l (ref er ence range mmol/l). AST and ALT were three times the upper limit of nor mal with a GGT of 559 (ref er ence range: <265 IU/L). He was also noted to have ane mia, hypo pro teine mia (4.4 gm/dl; ref er ence range gm/dl) and hypo al bu mine mia (2.9 gm/dl; ref er ence range g/dl), ammo nia (71 lm; ref er ence range <50 lm) and lactate (5.0 mm; ref er ence range <2.2 mm) were ele vated with an increased anion gap met a bolic aci do sis. Reflex plasma amino acids revealed a profile char ac teris tic for NIC CD (Table 2). Sequenc ing revealed het er o zy gos ity for two pre vi ously described muta tions: c.851delg TAT and c G > A [1,17]. The cho le sta sis responded to a high pro tein, low carbo hy drate diet as pre vi ously described [6] with the exclu sion of gal act ose at about 1 month of age. He is grow ing well, with nor mal lab o ra tory val ues and has nor mal neu ro cog ni tive devel op ment at fol low up. Case 7 is the third child born to con san guin e ous Tuni sian par ents. He was breast-fed and, start ing at one month of age, he devel oped pro gres sive scleral jaun dice with hepa to meg aly while main tain ing nor mal growth. At 6 months of age lab o ra tory investi ga tions revealed raised trans am i nases, increased con ju gated bili ru bin, absent anti body ti tres against com mon viral infec tions, a nor mal serum alpha-1-anti tryp sin and nor mal sweat test. Liver ultra sound showed increased ech og e nic i ty. The child under went a liver biopsy that revealed cir rho sis with macr o ve sic u lar ste a tosis. He was dis charged with vita min K and ur so de oxy chol ic acid ther apy. His jaun dice resolved spon ta ne ously at 8 months of age. By 3 years of age he was grow ing well but had mild coarse facial fea tures, and mod est hepa to meg aly. Rou tine lab o ra tory and met a- bolic inves ti ga tions includ ing ammo nia, lactate, alpha-1-anti trypsin, alpha-feto pro tein, vita min A and E and plasma amino acids (cit rul line 29 lm, methi o nine 23 lm, tyro sine 53 lm) were nor mal. Liver biopsy showed incom plete sep tal cir rho sis with micr o ve si cular ste a to sis. Based on the pre vi ous his tory of tran sient cho le sta sis, cit rin deficiency was sus pected and molec u lar stud ies of SLC25A13 revealed a pre vi ously unde scribed homo zy gous mis sense mutation c. 74C>A (p. A25E). This muta tion was not found in 108 unrelated con trol chro mo somes. The sub sti tu tion of the non-polar to 655 polar amino acid is pre dicted to be path o genic by SIFT and Pol phen [18,19]. Western blot ting showed no dif fer ence in the amount or size of the cit rin pro tein (Fig. 1). Case 8 was the 6 lb 1 oz prod uct of an uncom pli cated ges ta tion and vag i nal deliv ery born to con san guin e ous (frst cousin) Paki stani par ents. He has two healthy older full sib lings. The ini tial Mary land state new born screen was per formed prior to su f icient milk feeds and was not reported. On day 11, the results of the sec ond screen revealed that the cit rul line was ele vated at 276 lm (cut off 100 lm). A repeat on day 19 was 298 lm. At ini tial clin i cal eval u a tion on day 26, he was mildly jaun diced and some what thin although he had regained birth weight. Plasma amino acids showed a char ac ter istic pattern for cit rin deficiency (Table 2). He also had a mod estly increased ammo nia of 86 lm with sig nif cant ele va tions of total bil i ru bin (7.6 g/dl, NR <2.2) and alka line phos pha tase 1347 (ULN 390) but with nor mal trans am i nases (AST 54, ALT 17). Given the clin i cal sus pi cion of cit rin deficiency, breast milk was dis con tinued and replaced with a soy based for mula. Sub se quently his liver sta tus improved and by 4 months of age, his cho le sta sis and GGT had nor mal ized. At 5 months of age, he is grow ing and devel op ing nor mally. Molec u lar stud ies of SLC25A13 revealed a homo zy gous frame shift muta tion, c.172_173del GT (p.v58gfsx24). This is predicted to result in a premature ter mi na tion codon. Both par ents are car ri ers for this muta tion. Case 9 is the clin i cally asymp tom atic sib ling of case 8. She was the full term prod uct of an uncom pli cated ges ta tion. Her cit rul line lev els were 146, 514 and 126 lm on three blood spot spec i mens at 2 days, 2 weeks, and 4 weeks of age respec tively. How ever, she was not referred for met a bolic eval u a tion at that time. She did not have any clin i cally detected jaun dice or liver dis ease in the newborn period and she was breast fed for 18 months. She craves protein at every meal and has a die tary avoid ance of fruits and rice. At 4 1/2 years of age, she is grow ing and devel op ing nor mally and has nor mal ammo nia, liver func tion tests and plasma amino acids except for a mod estly ele vated cit rul line of 53 lm (Table 2). Molecu lar test ing found her to be homo zy gous for the c.172_173del GT (p.v58gfsx24) frame shift muta tion. Case 10 is a 5 year old Cau ca sian female who was born with a birth weight of 2.2 kg. She was fed on cow milk based for mula, and passed her Indi ana state new born screen at less than 48 h but failed the sec ond screen at 8 days of age with an ele vated cit rul line and cit rul line to tyro sine ratio. Reflex plasma amino acids showed a sig nif cantly ele vated thre o nine (769 lm), cit rul line (325 lm), and methi o nine (578 lm) with an essen tially nor mal tyro sine (100 lm, ref er ence range <96). With the sus pi cion of cit rin deficiency, a galact ose free diet was insti tuted. She has not been on a high pro tein diet but growth has remained at the 50th per cen tile. She has not had any liver dys func tion and neu ro cog ni tive devel op ment remains on tar get. Sequenc ing revealed a pre vi ously reported splice site mutation, c.848+3a > c [6,20], and a het ero zy gous unclas sified var i ant, c.1637c > G (p.t546r). Thre o nine at this position is con served from yeast to human. SIFT and Poly Phen [18,19] pre dict this var i ant to be del e te ri ous. A dif fer ent sub sti tu tion, p.t546m, at the same amino acid position, has pre vi ously been reported in patients with cit rin deficiency [21]. Dis cus sion A total of 14 patients, that we are aware of, have been diag nosed in North Amer ica in the past 4 years with the addi tion of 2 cases from Texas (one Cau ca sian Amer i can reported else where [6] and one of Viet nam ese ances try) and 2 cases in Cal i for nia of Tai wan ese and Korean descent. The major ity of these patients are not of Asian ances try. It remains unclear to what extent this fnd ing reflects a dif fer ent prev a lence of this dis ease among dif fer ent eth nic groups. Nev er the less, from our data it is clear that cit rin deficiency

5 48 D. Dim mock et al. / Molecular Genetics and Metabolism 96 (2009) should be con sid ered in any infant pre sent ing with intra he patic cho le sta sis, ste a to sis or cir rho sis regard less of eth nic ity. The diag no sis of three new borns in Que bec with cit rin deficiency in the past 2 years would sug gest, if these years are rep re sen ta tive, a min i mum birth inci dence of 1 case per 50,000 live births. However, since all of these patients come from the same region, it is likely that the inci dence within the Bas-St-Lau rent region may be higher. Although we did not iden tify com mon ances tors, the common hap lo type and the rel a tively small geo graph i cally defned region of ori gin sug gests that these are foun der muta tions. Cit rin deficiency may be a sig nif cant cause of neo na tal liver dis ease in this region and fur ther inves ti ga tion will be required to deter mine if spe cifc screen ing for this con di tion in this pop u la tion is warranted. In addi tion, the diag no sis of this con di tion in a patient of Ara bic descent and another patient of Paki stani ori gin sug gests that this dis or der is truly a pan-eth nic con di tion and should be con sid ered when indi cated in all eth nic groups (see Table 1). To date 110 patients have been referred to the Med i cal Genet ics Lab o ra to ries at Bay lor Col lege of Med i cine Med i cal Genet ics Lab o rato ries for cit rin sequenc ing, and among them twelve cases (11%) have confirmed bi-alle lic muta tions. Although not sys tem at i cally eval u ated in all patients, 7 of the remain ing cases (7%) had confirmed mutations in ASS1. Five of these seven patients had an ele vated cit rul line in the range of lm on new born screen ing. As only two other genetic dis eases are cur rently asso ci ated with an ele vated cit rul line (pyru vate car box yl ase deficiency type B, OMIM # and argini no suc ci nate lyase deficiency, OMIM #207900) it is likely that the bio chem i cal phe no type seen in cit rin deficiency may also be caused by other, as yet undefined, path o log i cal pro cesses. It is note wor thy that one patient, with a sim i lar amino acid profile and cho le sta sis, had muta tions in the DGUOK gene and is pub lished else where [22]. The original reports of CTLN2, described a tis sue-spe cifc deficiency of ASS activ ity in the liver but not in skin fbro blasts [2] while subsequent stud ies have shown that this activ ity may be normal in the liver of some patients [23], the activ ity has always been nor mal in skin fbro blasts [1,2,6]. We con sid ered that this may be use ful diag nos tic dis tinc tion between this dis or der and primary ASS deficiency. How ever, in this paper we pres ent two French-Cana dian patients with reduced ASS activ ity in fbro blasts har bor ing the same novel muta tions in the SLC25A13 gene. In addi tion, the nor mal cit rulline incor po ra tion is con sis tent with results seen in patients with less severe muta tions in ASS1 [24]. It is unclear why cit rin deficiency alters ASS activ ity in the fbro blasts of our patients and why the reduc tion is restricted to the liver of the other patients pre vi ously described. Although metab o lite con cen tra tions, par tic u larly argi nine and cit rulline in the cul ture media may alter ASS activ ity, this change is medi ated by altered tran scrip tion [25]. As the ASS1 mrna lev els are not reduced in either of our patients fbro blasts, or in the liver of Jap a- nese patients with liver spe cifc ASS deficiency [2], it seems unlikely that this is the mech a nism. Sub se quently, reg u la tion of endo the lial, but not hepatic ASS through alter na tive trans la tion ini ti a tion sites of the 59 UTR has been described. These tran scripts can sup press ASS tran scrip tion [26]. How ever, as they are not expressed in the liver, it seems unlikely that this is the mech a nism of reduc tion of ASS activity. More recently, it has been shown that the NADPH to NADP + ratio directly alters the ASS activ ity and changes the asso ci a tion with the reg u la tory pro tein HSCARG [27]. Since these ratios are expected to be per turbed in our patients, this is the most plau si ble expla na tion to date. Fur ther stud ies will be required to eval u ate the role of this path way in cit rin deficiency. Addi tional cases are nec es sary to determine if the reduced ASS activ ity in fbro blasts in the French-Canadi ans is a result of the spe cifc muta tions in the SLC25A13 gene or a reflec tion of mod ifier genes. The ASS enzyme assay has been the stan dard diag nos tic test for primary ASS deficiency for over 25 years. These cases have sig nif cant impli ca tions for the diag no sis of primary ASS deficiency. 656 Our results dem on strate that primary ASS deficiency can not always be dis tin guished from cit rin deficiency by ASS assay. These fnd ings also sug gest the need for care ful re-eval u a tion of all patients with appar ent ASS deficiency on skin fbro blast test ing and only mod est ele va tions in cit rul line lev els, espe cially those not respond ing to, or wors en ing on, a low pro tein diet. Given that the ASS deficiency is not restricted to the liver, we would sug gest that the term CTLN2 is no longer used, as it is clear that our patients have cit rin (AGC2) deficiency but not CTLN2. Instead we would pro pose that the disease clas si f ca tion reflect the under ly ing met a bolic cause that is the deficiency of the cit rin pro tein. The di f iculty in dis tin guish ing hypomor phic ASS deficiency [28] from cit rin deficiency is fur ther compli cated by the almost iso lated, mark edly ele vated cit rul line seen in case 2 s pre sent ing chro mato gram and the sig nif cant ele va tion in case 4 (Table 2), sug gest ing that, at pre sen ta tion, amino acid profiles may not help dis tin guish one dis or der from another. The avail abil ity of die tary ther apy for this con di tion, and the sig nif cant wors en ing seen in cases 1 and 2 when pro tein was restricted, make it vital to dis tin guish these con di tions when a patient is detected with modest ele va tions of cit rul line on new born screen ing. This sug gests that molec u lar diag no sis by sequenc ing of SLC25A13 and ASS1 is essen tial in the prompt diag no sis and man age ment of such patients ascertained through the new born screen ing pro gram. Con sis tent with pre vi ous expe ri ence using blood spots where approx i mately half of all patients were not detected by expanded new born screen ing on blood [9], it is clear from case 7 that not all patients will be detected with an ele vated cit rul line. Addi tion ally, even at times of acute cri ses the plasma amino acid profile might be non-diag nos tic. The lack of symp tom atic dis ease in child hood of cases 3 and 9 must be con sid ered when decid ing if this dis ease would be an appro pri ate primary tar get for new born screen ing. Con se quently, fur ther muta tion-based stud ies will be required to eval u ate the true prev a lence and nat u ral his tory of this dis or der outside of Asia. The psy chi at ric fea tures of case 3 and the nat u- ral his tory of CTLN2 patients in Japan empha size the eti o logic role cit rin deficiency plays in organic psy chi at ric ill ness. How ever, further stud ies are needed to eval u ate how com mon this dis or der is amongst given pop u la tions before rec om mend ing rou tine eval u a- tion for this dis ease in patients with psy chi at ric ill ness. The muta tions observed in cases 7 and 10 empha size the emerg ing role of mis sense muta tions in this dis or der [7,8,29]. Since the muta tion in case 7 is in the N-ter mi nal domain, this muta tion would not affect the trans port activ ity of cit rin in our expres sion sys tem [30] How ever, this dis rup tive change in an amino acid, highly con served in the cal cium-bind ing domain of both ara lar (AGC1) and cit rin (AGC2), is expected to impair cal cium reg u la tion. Notice ably, since cases 1, 2 and 7 and a recently reported patient of Paki stani ori gin [7] (data not shown) have pro tein detected on Western blot ting, pro tein based screen ing [12] may not be as sensi tive as one would hope. In sum mary, we pres ent fve novel muta tions in SLC25A13, includ ing appar ent foun der muta tions in a French Cana dian popu la tion. Addi tional novel muta tions in patients of Tuni sian, Pakistani and Northern Euro pean descent sup port the notion that this is truly a pan-eth nic dis or der. Fur ther muta tion-based stud ies will be required to eval u ate the true prev a lence and nat u ral his tory of this dis or der outside of East Asia. Cit rin deficiency may pres ent with ele vated cit rul line on new born screen ing. More over, in contrast to pre vi ously described patients, ASS enzyme deficiency may be detected on skin fbro blast cul ture sug gest ing a piv otal role for DNA sequenc ing in these patients. Acknowl edg ments The authors wish to thank Jac que line Heid orn for assis tance with the ASS enzyme assay and cit rul line incor po ra tion, Rob ert

6 D. Dim mock et al. / Molecular Genetics and Metabolism 96 (2009) Trieu and Ye wei Ma for assis tance with the Western blot ting. The authors also wish to acknowl edge Steph a nie B. Gur non, MS, CGC, Rebecca Rob erts, MS, RD, V. Reid Sut ton, MD and the late Rebecca Wa pp ner, MD, for assis tance in obtain ing clin i cal infor ma tion and pro vid ing clin i cal care to our patients. This study was fund ing in part by an NIH fel low ship award to DD (K12 RR17665) and by grants from Min is te ro dell Uni ver sità e della Ric erca, Min is te ro della Salute to GF. Ref er ences [1] K. Ko bay ash i, D.S. Si na sac, M. Iij ima, A.P. Bo right, L. Begum, J.R. Lee, T. Yas uda, S. Ik e da, R. Hir ano, H. Ter az on o, M.A. Crack ow er, I. Kondo, L.C. Tsui, S.W. Scherer, T. Sa heki, The gene mutated in adult-onset type II cit rul li na emia encodes a puta tive mito chon drial car rier pro tein, Nat. Genet. 22 (2) (1999) [2] K. Ko bay ash i, N. Shah een, R. Ku mas hi ro, K. Tan ik a wa, W.E. O Brien, A.L. Beaudet, T. Sa heki, A search for the primary abnor mal ity in adult-onset type II citrul line mia, Am. J. Hum. Genet. 53 (5) (1993) [3] T. Sa heki, K. Ko bay ash i, Mito chon drial aspar tate glu ta mate car rier (cit rin) defi ciency as the cause of adult-onset type II cit rul line mia (CTLN2) and idi o pathic neo na tal hep a ti tis (NIC CD), J. Hum. Genet. 47 (7) (2002) [4] Y. Ta zawa, D. Abuk a wa, O. Sa kam ot o, I. Nag at a, J. Mura ka mi, T. Ii zuka, M. Okam ot o, A. Kim ura, T. Ku ro s a wa, K. Ii numa, K. Ko bay ash i, T. Sa heki, T. Oh ura, A pos si ble mech a nism of neo na tal intra he patic cho le sta sis caused by cit rin deficiency, Hep a tol. Res. 31 (3) (2005) [5] E. Ben-Sha lom, K. Ko bay ash i, A. Sha ag, T. Yas uda, H.Z. Gao, T. Sa heki, C. Bachmann, O. El pe leg, Infan tile cit rul line mia caused by cit rin deficiency with increased diba sic amino acids, Mol. Genet. Metab. 77 (3) (2002) [6] D. Dim mock, K. Ko bay ash i, M. Iij ima, A. Ta ba ta, L.J. Wong, T. Sa heki, B. Lee, F. Sca glia, Cit rin deficiency: a novel cause of fail ure to thrive that responds to a high-pro tein, low-car bo hy drate diet, Pedi at rics 119 (3) (2007) e773 e777. [7] G. Fier monte, D. Soon, A. Chau dh uri, E. Par a dies, P.J. Lee, S. Krywa wych, F. Palm i eri, R.H. Lach mann, An adult with type 2 cit rul line mia pre sent ing in Europe, N. Engl. J. Med. 358 (13) (2008) [8] A. Ta ba ta, J.S. Sheng, M. Ushi kai, Y.Z. Song, H.Z. Gao, Y.B. Lu, F. Okum ura, M. Iij ima, K. Mutoh, S. Kish ida, T. Sa heki, K. Ko bay ash i, Iden ti f ca tion of 13 novel muta tions includ ing a ret ro trans pos al inser tion in SLC25A13 gene and frequency of 30 muta tions found in patients with cit rin deficiency, J. Hum. Genet. 53 (6) (2008) [9] A. Tam a mor i, A. Fu jim ot o, Y. Ok ano, K. Ko bay ash i, T. Sa heki, Y. Ta gam i, H. Takei, Y. Shig ema tsu, I. Hata, H. Ozaki, D. Toku ha ra, Y. Ni shim ura, T. Yor ifuji, N. I gar ash i, T. Oh ura, T. Shi mizu, K. Inui, N. Sa kai, D. Abuk a wa, T. Mi yak a wa, M. Matsu mor i, K. Ban, H. Kane ko, T. Ya ma no, Effects of cit rin deficiency in the peri na tal period: fea si bil ity of new born mass screen ing for cit rin deficiency, Pe di atr. Res. 56 (4) (2004) [10] Y. Ta zawa, K. Ko bay ash i, D. Abuk a wa, I. Nag at a, S. Mais a wa, R. Su ma zaki, T. Ii zuka, Y. Ho soda, M. Okam ot o, J. Mura ka mi, S. Kaji, A. Ta ba ta, Y.B. Lu, O. Sa kamot o, A. Mat sui, S. Kan zaki, G. Tak ada, T. Sa heki, K. Ii numa, T. Oh ura, Clin i cal het er o ge ne ity of neo na tal intra he patic cho le sta sis caused by cit rin deficiency: case reports from 16 patients, Mol. Genet. Metab. 83 (3) (2004) [11] J.N. Yeh, Y.M. Jeng, H.L. Chen, Y.H. Ni, W.L. Hwu, M.H. Chang, Hepatic ste a to sis and neo na tal intra he patic cho le sta sis caused by cit rin deficiency (NIC CD) in Tai wan ese infants, J. Pe di atr. 148 (5) (2006) [12] D. Toku ha ra, M. Iij ima, A. Tam a mor i, T. Oh ura, J. Ta kaya, S. Mais a wa, K. Ko bayash i, T. Sa heki, T. Ya ma no, Y. Ok ano, Novel diag nos tic approach to cit rin defi ciency: anal y sis of cit rin pro tein in lym pho cytes, Mol. Genet. Metab. 90 (1) (2007) [13] T.S. Su, H.G. Bock, A.L. Beau det, W.E. O Brien, Molec u lar anal y sis of argi ni nosuc ci nate syn the tase deficiency in human fbro blasts, J. Clin. Invest. 70 (6) (1982) [14] H. North rup, A.L. Beau det, W.E. O Brien, Pre na tal diag no sis of cit rul li na emia: review of a 10-year expe ri ence includ ing recent use of DNA anal y sis, Pre nat. Di agn. 10 (12) (1990) [15] C. Au ray-blais, D. Cyr, R. Drou in, Que bec neo na tal mass uri nary screen ing programme: from mic ro mol e cules to mac ro mol e cules, J. Inherit. Metab. Dis. 30 (4) (2007) [16] E. Na i to, M. Ito, S. Matsu ura, Yo ko ta, T. Sai jo, Y. Og a wa, S. Ki tam ura, K. Ko bayash i, T. Sa heki, Y. Ni shim ura, N. Sak ura, Y. Ku roda, Type II cit rul li na emia (cit rin deficiency) in a neo nate with hy per ga lac to sa emia detected by mass screen ing, J. Inherit. Metab. Dis. 25 (1) (2002) [17] Y.B. Lu, K. Ko bay ash i, M. Ushi kai, A. Ta ba ta, M. Iij ima, M.X. Li, L. Lei, K. Kaw a b e, S. Taura, Y. Yang, T.T. Liu, S.H. Chiang, K.J. Hsiao, Y.L. Lau, L.C. Tsui, D.H. Lee, T. Sa heki, Fre quency and dis tri bu tion in East Asia of 12 muta tions iden tified in the SLC25A13 gene of Jap a nese patients with cit rin deficiency, J. Hum. Genet. 50 (7) (2005) [18] P.C. Ng, S. He nik off, Pre dict ing the effects of amino acid sub sti tu tions on protein func tion, Ann. Rev. Genom ics Hum. Genet. 7 (2006) [19] V. Ra men sky, P. Bork, S. Sun yaev, Human non-syn on y mous SNPs: server and sur vey, Nucleic Acids Res. 30 (17) (2002) [20] L.J. Wong, D. Dim mock, M.T. Ger a ghty, R. Quan, U. Lich ter-ko necki, J. Wang, E.K. Brun dage, F. Sca glia, A.C. Chi na ult, Util ity of oli go nu cleo tide array-based com par a tive geno mic hybrid iza tion for detec tion of tar get gene dele tions, Clin. Chem. 54 (7) (2008) [21] K. Ko bay ash i, Y. Bang Lu, M. Xian Li, I. Ni shi, K.J. Hsiao, K. Choeh, Y. Yang, W.L. Hwu, J.K. Re ic hardt, F. Palm i eri, Y. Ok ano, T. Sa heki, Screen ing of nine SLC25A13 muta tions: their fre quency in patients with cit rin deficiency and high car rier rates in Asian pop u la tions, Mol. Genet. Metab. 80 (3) (2003) [22] D.P. Dim mock, Q. Zhang, C. Di on is i-vici, R. Car rozzo, J. Shieh, L.Y. Tang, C. Truong, E. Sch mitt, M. Si fry-platt, S. Luc i o li, F.M. San tor el li, C.H. Fic i cio glu, M. Rodri guez, K. Wier enga, G.M. Enns, N. Lon go, M.H. Lip son, H. Val lance, W.J. Cra i gen, F. Sca glia, L.J. Wong, Clin i cal and molec u lar fea tures of mito chon drial DNA deple tion due to muta tions in deox y gua no sine kinase, Hum. Mutat. 29 (2) (2008) [23] T. Yas uda, N. Yam ag u chi, K. Ko bay ash i, I. Ni shi, H. Hor i nou chi, M.A. Ja lil, M.X. Li, M. Ushi kai, M. Iij ima, I. Kondo, T. Sa heki, Iden ti f ca tion of two novel mutations in the SLC25A13 gene and detec tion of seven muta tions in 102 patients with adult-onset type II cit rul line mia, Hum. Genet. 107 (6) (2000) [24] D. Dim mock, P. Tra pane, A. Fe i gen baum, C. Ke e gan, S. Ced er baum, J. Gib son, M. Gam bel lo, K. Vaux, P. Ward, G. Rice, J. Wolff, W. O Brien, P. Fang, The Role of Molec u lar Test ing and Enzyme Anal y sis in the Man age ment of Hypo mor phic Cit rul line mia Amer i can Jour nal of Med i cal Genet ics, in press. [25] M.J. Jack son, S.J. Allen, A.L. Beau det, W.E. O Brien, Metab o lite reg u la tion of argi ni no suc ci nate syn the tase in cul tured human cells, J. Biol. Chem. 263 (31) (1988) [26] L.C. Pendl eton, B.L. Good win, L.P. Sol o mon son, D.C. Eich ler, Reg u la tion of endo the lial argi ni no suc ci nate syn thase expres sion and NO pro duc tion by an upstream open read ing frame, J. Biol. Chem. 280 (25) (2005) [27] Y. Zhao, J. Zhang, H. Li, Y. Li, J. Ren, M. Luo, X. Zheng, An NADPH sen sor pro tein (HSCARG) down reg u lates nitric oxide syn the sis by asso ci a tion with argi ni nosuc ci nate syn the tase and is essen tial for epi the lial cell via bil ity, J. Biol. Chem. 283 (16) (2008) [28] J. Hab er le, S. Pa u l i, E. Schmidt, B. Schu lze-eilfing, C. Bern ing, H.G. Koch, Mild cit rul line mia in Cau ca sians is an alle lic var i ant of argi ni no suc ci nate syn the tase deficiency (cit rul line mia type 1), Mol. Genet. Metab. 80 (3) (2003) [29] N. Yam ag u chi, K. Ko bay ash i, T. Yas uda, I. Ni shi, M. Iij ima, M. Nak ag a wa, M. Osame, I. Kondo, T. Sa heki, Screen ing of SLC25A13 muta tions in early and late onset patients with cit rin deficiency and in the Jap a nese pop u la tion: Iden ti f- ca tion of two novel muta tions and estab lish ment of multiple DNA diag no sis meth ods for nine muta tions, Hum. Mutat. 19 (2) (2002) [30] L. Palm i eri, B. Pardo, F.M. La sorsa, A. del Arco, K. Ko bay ash i, M. Iij ima, M.J. Runs wick, J.E. Walker, T. Sa heki, J. Sa tru ste gui, F. Palm i eri, Cit rin and ara lar1 are Ca(2+)-stim u lated aspar tate/glu ta mate trans port ers in mito chon dria, EMBO J. 20 (18) (2001)

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