Lately, microdeletions of the 22q region, responsible for DiGeorge syndrome or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorder. These manifestations seem to be related to certain genes located in the hemideleted region such as the proline dehydrogenase (PRODH) and the catechol-o-methyltransferase (COMT) genes. We describe a teenager who started his adolescent psychiatric care presenting cognitive impairment, irritable mood and aggressive behaviour with schizophrenia-like symptoms that scored 153 in the Positive and Negative Symptoms Scale (PANSS) assessment. Worsening of symptoms when the patient was treated with valproic acid, and plasma aminoacids showing an increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Mild dysmorphic features also suggested a possible 22q11 deletion syndrome that was confirmed. A mutation for Hyperprolinemia type I was also detected. Knowledge of the correct diagnosis was crucial for an adequate treatment.info:eu-repo/semantics/publishedVersio

Afonso, J

Antunes, D

Correia, H

Duarte, M

Ferreira, C

Marques, M

Moreira, A

Sequeira, S

Duarte, Marco

Afonso, Joana

Moreira, Ana

Antunes, Diana

Ferreira, Cristina

Correia, Hildeberto

Sequeira, Silvia

Repositório Científico do Instituto Nacional de Saúde

www.elsevier.com/locate/braindevBrain & Development xxx (2017) xxx–xxxCase ReportHyperprolinemia as a clue in the diagnosis of a patientwith psychiatric manifestationsMarco Duarte a,⇑, Joana Afonso a, Ana Moreira b, Diana Antunes c, Cristina Ferreira d,Hildeberto Correia d, Margarida Marques a, Sı´lvia Sequeira eaChild and Adolescent Psychiatric Department, Hospital de Dona Estefaˆnia, Lisbon, PortugalbNeuropaediatric Department, Hospital de Dona Estefaˆnia, Lisbon, PortugalcGenetic Department, Hospital de Dona Estefaˆnia, Lisbon, PortugaldUnit of Cytogenetics of the Human Genetic Department, INSA, Lisbon, PortugaleMetabolic Unit, Hospital de Dona Estefaˆnia, Lisbon, PortugalReceived 25 October 2016; received in revised form 18 January 2017; accepted 19 January 2017AbstractLately, microdeletions of the 22q region, responsible for DiGeorge syndrome or velocardiofacial syndrome, have been increas-ingly related to neuropsychiatric disorders including schizophrenia and bipolar disorder. These manifestations seem to be related tocertain genes located in the hemideleted region such as the proline dehydrogenase (PRODH) and the catechol-o-methyltransferase(COMT) genes.We describe a teenager who started his adolescent psychiatric care presenting cognitive impairment, irritable mood and aggres-sive behaviour with schizophrenia-like symptoms that scored 153 in the Positive and Negative Symptoms Scale (PANSS)assessment.Worsening of symptoms when the patient was treated with valproic acid, and plasma aminoacids showing an increase in alanineand proline, suggested a mitochondrial involvement of the proline metabolic pathway. Mild dysmorphic features also suggested apossible 22q11 deletion syndrome that was conﬁrmed. A mutation for Hyperprolinemia type I was also detected.Knowledge of the correct diagnosis was crucial for an adequate treatment. 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.Keywords: Hyperprolinemia type I; PRODH gene; 22q11 deletion syndrome; Schizophrenia; Valproic acid1. IntroductionPatients with a 22q11.2 deletion syndrome, usuallypresent developmental delay, poor growth, distinctivefacial features, microcephaly, cleft palate, heart abnor-malities and immunological problems. Recent studieshttp://dx.doi.org/10.1016/j.braindev.2017.01.0080387-7604/ 2017 The Japanese Society of Child Neurology. Published by E⇑ Corresponding author at: Centro Hospitalar Psiquia´trico deLisboa, Avenida do Brasil 53, 1700-063 Lisboa, Portugal. Fax: +351217 952 989.E-mail address: marcoduarte@chpl.min-saude.pt (M. Duarte).Please cite this article in press as: Duarte M et al. Hyperprolinemia as a cluDev (2017), http://dx.doi.org/10.1016/j.braindev.2017.01.008show that some are likely to develop psychotic symp-toms, depression, anxiety and bipolar disorder [1]. Theloss of one copy of susceptible genes located in the22q11del region such as the COMT gene, an intracellu-lar postsynaptic enzyme that modulates dopamineclearance, and PRODH gene may ultimately lead to apsychiatric dysfunction [2].The PRODH gene encodes proline dehydrogenase orproline oxidase (POX), a mitochondrial enzyme involvedin proline catabolic pathway converting proline tolsevier B.V. All rights reserved.e in the diagnosis of a patient with psychiatric manifestations. BrainFig. 1. Proline metabolism. P5C: pyrroline-5-carboxylate; POX: proline oxidase; HPI: Hyperprolinemia type I; HPII: Hyperprolinemia type II.2 M. Duarte et al. / Brain & Development xxx (2017) xxx–xxxdelta-1-pyrroline-5-carboxylate (D1-P5C) [3]. Prolineplays a role in urea cycle where it can be endogenouslysynthesized (Fig. 1). Several disorders in proline metabo-lism have been identiﬁed, such as deﬁciency of POX orHyperprolinemia type I (HPI) and deﬁciency of the activ-ity of D1-P5C dehydrogenase or Hyperprolinemia type II(HPII). Both rare diseases, inherited as autosomal reces-sive disorders and characterized biochemically by highproline levels [4–6]. Although the neuropsychiatric phe-notype has been primarily associated with HPII [6,7], agrowing number of patients with these features, in partic-ular schizophrenia, have been documented for HPI [8].2. Case reportWe describe a 17-year-old male patient, whose rele-vant family history includes only a maternal great-uncle with schizophrenia.He presented mild hypotonia in infancy and later ondiﬃculties in motor coordination (but walking indepen-dently at the age of 14 months) and language delay (ﬁrstwords at 3 years and joining words at the age of 4) requir-ing physiotherapy and speech therapy with subsequentlearning diﬃculties.Karyotype and fragile-X studies werenormal. As he grew older, he started showing some man-ifestations in daily life suggesting obsessive behaviourleading sometimes to bullying and refusal to go to school.When he had his ﬁrst observation in the PsychiatricOutpatient Unit at the age of 15, he presented compul-sive and obsessive symptoms, anxiety, a mixed depres-sive/irritable mood and aggressive behaviour. Thespeech was impaired, with some diﬃculty in articulatingPlease cite this article in press as: Duarte M et al. Hyperprolinemia as a cluDev (2017), http://dx.doi.org/10.1016/j.braindev.2017.01.008words. Paranoid and reference delusions were suspected.Wechsler Intelligence Scale for Children (WISC) III wasperformed and scored medium low in the Verbal IQ andvery low in the Non-Verbal IQ.Themood, irritability, anxiety anddisruptedbehaviourimproved with the prescription of quetiapine but over thefollowing months he revealed a disorganized behaviourwith paranoid, reference and grandiose delusions.When admitted to the Inpatient Unit at the age of 17,he appeared to be restless, tense, with an irritable moodand auditory hallucinations. The Positive and NegativeSymptoms Scale (PANSS) performed at admissionscored 153: 33 for Positive Symptoms, 45 for NegativeSymptoms and 75 for General Symptoms Subscale. Rou-tine blood tests, including calcemia and investigations forpsychosis were within normal range. BrainMRI revealedonly non-speciﬁc ﬁndings and EEG was unremarkable.Olanzapine caused partial improvement of hispsychotic symptoms and aggressive behaviour but hemaintained an irritable mood. Valproic acid was thenadded but during the increase to therapeutic values, hedeteriorated (aggressive behaviour, long periods of iso-lation and drowsiness) leading to the discontinuationof this drug. As liver function tests showed normalvalues, a valproate intoxication was excluded and amitochondrial disorder was suspected.Treatment with lithium and olanzapine led toimprovement in behaviour and psychotic symptoms.Further investigations revealed normal lactic acidand ammonia values, elevation in proline (511 and403 lM/L; RV:51–271 lM/L) and alanine (623.7 and594 lM/L; RV < 400 lM/L) levels. Urinary organice in the diagnosis of a patient with psychiatric manifestations. BrainM. Duarte et al. / Brain & Development xxx (2017) xxx–xxx 3acids showed no pyroline-5-carboxylate (P5C), leadingto the diagnosis of a possible HPI.Considering slightly dysmorphic features (low set earsand hirsute eyebrows) despite normal growth and nomajor abnormalities and the knowledge that HPI islocated on chromosome 22q11, a multiplex ligation-dependent probe ampliﬁcation (MLPA) test was per-formed using the probemix P250-B1 (MRC-Holland,Amsterdam,TheNetherlands) that conﬁrmed a heterozy-gous 22q11 deletion from gene CLTCL1 to gene LZTR1.Another probemix, P324-A2 (MRC-Holland, Amster-dam, The Netherlands) that contains three probes forPRODH gene conﬁrmed this deletion spanning from17,298,536 to 19,779,435 bp (hg18), comprising both thePRODH and the COMT genes. Cardiac evaluation wasnormal.The high proline levels are not usually observed inpatients with 22q11 deletions and as HPI and HPIIare autosomal recessive disorders, molecular studiesfor the investigation of the PRODH gene, were per-formed and revealed a p.L289M (c.1865T > A) muta-tion in heterozygosity.3. DiscussionMost patients with the 22q11 deletion have congenitalabnormalities which is not the case of this patient thatmanifests solely mild dysmorphic features. As describedpreviously our patient had hypotonia, psychomotor andlanguage delay but unlike most of the described patientscould speak ﬂuently and attended normal schooling [9].Also, our case had lower values of proline when com-pared with a similar case described (930–1000 lmol/L[9] and didn’t had any cardiac abnormalities.Nevertheless the cognitive and psychological impair-ment he presents are not so well known. Most genes inchromosome loci 22q11 are expressed in the brain andhypothetically related to executive functions [2,3].A metabolic disorder was suspected due to the pres-ence of the cognitive delay associated with psychotic fea-tures as well as deterioration after the initiation ofvalproic acid as normal liver function excluded toxicity.Valproate metabolization occurs primarily in the livermitochondria, and thus should be avoided in cases ofmitochondrial disorders, as it may stress vital pathwaysthat intensify the genetic damage [10].The knowledge that HPI is caused by mutations inthe chromosome 22q11 led to further investigations thatconﬁrmed the 22q11 deletion. Nevertheless, consideringthe moderate elevation of proline and that HPI is auto-somal recessive, these ﬁndings could not be explainedsolely by the detected deletion. Complementary investi-gations showed heterozygous p.L289M (c.1865T > A)mutation in the PRODH gene already described in schi-zophrenic patients and that may lead to a decrease of a30% activity of POX [11,12].Please cite this article in press as: Duarte M et al. Hyperprolinemia as a cluDev (2017), http://dx.doi.org/10.1016/j.braindev.2017.01.008The 22q11 deletion that includes the PRODH generegion and a heterozygous mutation on the PRODHgene on the other allele may somehow result in a com-posed heterozygosity of this gene and have a moderateeﬀect on POX activity [3,12].This decreased activity could inﬂuence the proline/glutamate levels related with apoptosis in selected neu-rons [2,3]. It is possible that the overall phenotype ofcognitive and psychiatric anomalies could be a conse-quence of several genes aﬀected in this locus deletionor their interaction.This case is also clear evidence that knowing the aeti-ology of psychiatric manifestations is important in themanagement of patients preventing use of deleteriousdrugs or creating new therapeutic approaches. It alsoshows that it may be diﬃcult to diagnose chromosomalabnormalities in patients with no clear malformationsand mild dysmorphic features as the pleiotropism ofthe gene/deletion could probably lead to diﬀerentphenotypes.References[1] Schneider M, Debbane´ M, Bassett AS, Chow EW, Fung WL, vanden Bree M, et al. Psychiatric disorders from childhood toadulthood in 22q11.2 deletion syndrome: results from theinternational consortium on brain and behavior in 22q11.2deletion syndrome. Am J Psychiatry 2014;171:627–39.[2] Karayiorgou M, Simon TJ, Gogos JA. 22q11.2 microdeletions:linking DNA structural variation to brain dysfunction andschizophrenia. Nat Rev Neurosci 2010;11:402–16.[3] Di Rosa G, Nicotera AG, Lenzo P, Spano M, Tortorella G.Long-term neuropsychiatric follow-up in hyperprolinemia type I.Psychiatr Genet 2014;24:172–5.[4] Schafer IA, Scriver CR, Efron ML. Familial hyperprolinemia,cerebral dysfunction and renal anomalies occurring in a familywith hereditary nephropathy and deafness. N Engl J Med1962;267:51–60.[5] Mitsubuchi H, Nakamura K, Matsumoto S, Endo F. Inbornerrors of proline metabolism. J Nutr 2008;138:2016S–20S.[6] Phang JM, Hu CA, Valle D. Disorders of proline and hydrox-yproline metabolism. New York: McGraw Hill; 2001.[7] van de Ven S, Gardeitchik T, Kouwenberg D, Kluijtmans L,Wevers R, Morava E. Long-term clinical outcome, therapy andmild mitochondrial dysfunction in hyperprolinemia. J InheritMetab Dis 2014;37:383–90.[8] Guilmatre A, Legallic S, Steel G, Willis A, Di Rosa G,Goldenberg A, et al. Type I hyperprolinemia: genotype/pheno-type correlations. Hum Mutat 2010;31:961–5.[9] Afenjar A, Moutard ML, Doummar D, Gue¨t A, Rabier D,Vermersch AI, et al. Early neurological phenotype in 4 childrenwith biallelic PRODH mutations. Brain Dev 2007;29:547–52.[10] Silva MF, Aires CC, Luis PB, Ruiter JP, IJlst L, Duran M, et al.Valproic acid metabolism and its eﬀects on mitochondrial fattyacid oxidation: a review. J Inherit Metab Dis 2008;31:205–16.[11] Bender HU, Almashanu S, Steel G, Hu CA, Lin WW, Willis A,et al. Functional consequences of PRODH missense mutations.Am J Hum Genet 2005;76:409–20.[12] Jacquet H, Raux G, Thibaut F, Hecketsweiler B, Houy E,Demilly C, et al. PRODH mutations and hyperprolinemia in asubset of schizophrenic patients. Hum Mol Genet2002;11:2243–9.e in the diagnosis of a patient with psychiatric manifestations. Brain

Hyperprolinemia as a clue in the diagnosis of a patient with psychiatric manifestations

Repository of the Hospital Center of Central Lisbon

Hyperprolinemia as a Clue in the Diagnosis of a Patient with Psychiatric Manifestations

Repositório do Centro Hospitalar de Lisboa Central, EPE

www.elsevier.com/locate/braindevBrain & Development 39 (2017) 539–541Case ReportHyperprolinemia as a clue in the diagnosis of a patientwith psychiatric manifestationsMarco Duarte a,⇑, Joana Afonso a, Ana Moreira b, Diana Antunes c, Cristina Ferreira d,Hildeberto Correia d, Margarida Marques a, Sı´lvia Sequeira eaChild and Adolescent Psychiatric Department, Hospital de Dona Estefaˆnia, Lisbon, PortugalbNeuropaediatric Department, Hospital de Dona Estefaˆnia, Lisbon, PortugalcGenetic Department, Hospital de Dona Estefaˆnia, Lisbon, PortugaldUnit of Cytogenetics of the Human Genetic Department, INSA, Lisbon, PortugaleMetabolic Unit, Hospital de Dona Estefaˆnia, Lisbon, PortugalReceived 25 October 2016; received in revised form 18 January 2017; accepted 19 January 2017AbstractLately, microdeletions of the 22q region, responsible for DiGeorge syndrome or velocardiofacial syndrome, have been increas-ingly related to neuropsychiatric disorders including schizophrenia and bipolar disorder. These manifestations seem to be related tocertain genes located in the hemideleted region such as the proline dehydrogenase (PRODH) and the catechol-o-methyltransferase(COMT) genes.We describe a teenager who started his adolescent psychiatric care presenting cognitive impairment, irritable mood and aggres-sive behaviour with schizophrenia-like symptoms that scored 153 in the Positive and Negative Symptoms Scale (PANSS)assessment.Worsening of symptoms when the patient was treated with valproic acid, and plasma aminoacids showing an increase in alanineand proline, suggested a mitochondrial involvement of the proline metabolic pathway. Mild dysmorphic features also suggested apossible 22q11 deletion syndrome that was conﬁrmed. A mutation for Hyperprolinemia type I was also detected.Knowledge of the correct diagnosis was crucial for an adequate treatment. 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.Keywords: Hyperprolinemia type I; PRODH gene; 22q11 deletion syndrome; Schizophrenia; Valproic acid1. IntroductionPatients with a 22q11.2 deletion syndrome, usuallypresent developmental delay, poor growth, distinctivefacial features, microcephaly, cleft palate, heart abnor-malities and immunological problems. Recent studieshttp://dx.doi.org/10.1016/j.braindev.2017.01.0080387-7604/ 2017 The Japanese Society of Child Neurology. Published by E⇑ Corresponding author at: Centro Hospitalar Psiquia´trico deLisboa, Avenida do Brasil 53, 1700-063 Lisboa, Portugal. Fax: +351217 952 989.E-mail address: marcoduarte@chpl.min-saude.pt (M. Duarte).show that some are likely to develop psychotic symp-toms, depression, anxiety and bipolar disorder [1]. Theloss of one copy of susceptible genes located in the22q11del region such as the COMT gene, an intracellu-lar postsynaptic enzyme that modulates dopamineclearance, and PRODH gene may ultimately lead to apsychiatric dysfunction [2].The PRODH gene encodes proline dehydrogenase orproline oxidase (POX), a mitochondrial enzyme involvedin proline catabolic pathway converting proline tolsevier B.V. All rights reserved.Fig. 1. Proline metabolism. P5C: pyrroline-5-carboxylate; POX: proline oxidase; HPI: Hyperprolinemia type I; HPII: Hyperprolinemia type II.540 M. Duarte et al. / Brain & Development 39 (2017) 539–541delta-1-pyrroline-5-carboxylate (D1-P5C) [3]. Prolineplays a role in urea cycle where it can be endogenouslysynthesized (Fig. 1). Several disorders in proline metabo-lism have been identiﬁed, such as deﬁciency of POX orHyperprolinemia type I (HPI) and deﬁciency of the activ-ity of D1-P5C dehydrogenase or Hyperprolinemia type II(HPII). Both rare diseases, inherited as autosomal reces-sive disorders and characterized biochemically by highproline levels [4–6]. Although the neuropsychiatric phe-notype has been primarily associated with HPII [6,7], agrowing number of patients with these features, in partic-ular schizophrenia, have been documented for HPI [8].2. Case reportWe describe a 17-year-old male patient, whose rele-vant family history includes only a maternal great-uncle with schizophrenia.He presented mild hypotonia in infancy and later ondiﬃculties in motor coordination (but walking indepen-dently at the age of 14 months) and language delay (ﬁrstwords at 3 years and joining words at the age of 4) requir-ing physiotherapy and speech therapy with subsequentlearning diﬃculties.Karyotype and fragile-X studies werenormal. As he grew older, he started showing some man-ifestations in daily life suggesting obsessive behaviourleading sometimes to bullying and refusal to go to school.When he had his ﬁrst observation in the PsychiatricOutpatient Unit at the age of 15, he presented compul-sive and obsessive symptoms, anxiety, a mixed depres-sive/irritable mood and aggressive behaviour. Thespeech was impaired, with some diﬃculty in articulatingwords. Paranoid and reference delusions were suspected.Wechsler Intelligence Scale for Children (WISC) III wasperformed and scored medium low in the Verbal IQ andvery low in the Non-Verbal IQ.Themood, irritability, anxiety anddisruptedbehaviourimproved with the prescription of quetiapine but over thefollowing months he revealed a disorganized behaviourwith paranoid, reference and grandiose delusions.When admitted to the Inpatient Unit at the age of 17,he appeared to be restless, tense, with an irritable moodand auditory hallucinations. The Positive and NegativeSymptoms Scale (PANSS) performed at admissionscored 153: 33 for Positive Symptoms, 45 for NegativeSymptoms and 75 for General Symptoms Subscale. Rou-tine blood tests, including calcemia and investigations forpsychosis were within normal range. BrainMRI revealedonly non-speciﬁc ﬁndings and EEG was unremarkable.Olanzapine caused partial improvement of hispsychotic symptoms and aggressive behaviour but hemaintained an irritable mood. Valproic acid was thenadded but during the increase to therapeutic values, hedeteriorated (aggressive behaviour, long periods of iso-lation and drowsiness) leading to the discontinuationof this drug. As liver function tests showed normalvalues, a valproate intoxication was excluded and amitochondrial disorder was suspected.Treatment with lithium and olanzapine led toimprovement in behaviour and psychotic symptoms.Further investigations revealed normal lactic acidand ammonia values, elevation in proline (511 and403 lM/L; RV:51–271 lM/L) and alanine (623.7 and594 lM/L; RV < 400 lM/L) levels. Urinary organicM. Duarte et al. / Brain & Development 39 (2017) 539–541 541acids showed no pyroline-5-carboxylate (P5C), leadingto the diagnosis of a possible HPI.Considering slightly dysmorphic features (low set earsand hirsute eyebrows) despite normal growth and nomajor abnormalities and the knowledge that HPI islocated on chromosome 22q11, a multiplex ligation-dependent probe ampliﬁcation (MLPA) test was per-formed using the probemix P250-B1 (MRC-Holland,Amsterdam,TheNetherlands) that conﬁrmed a heterozy-gous 22q11 deletion from gene CLTCL1 to gene LZTR1.Another probemix, P324-A2 (MRC-Holland, Amster-dam, The Netherlands) that contains three probes forPRODH gene conﬁrmed this deletion spanning from17,298,536 to 19,779,435 bp (hg18), comprising both thePRODH and the COMT genes. Cardiac evaluation wasnormal.The high proline levels are not usually observed inpatients with 22q11 deletions and as HPI and HPIIare autosomal recessive disorders, molecular studiesfor the investigation of the PRODH gene, were per-formed and revealed a p.L289M (c.1865T > A) muta-tion in heterozygosity.3. DiscussionMost patients with the 22q11 deletion have congenitalabnormalities which is not the case of this patient thatmanifests solely mild dysmorphic features. As describedpreviously our patient had hypotonia, psychomotor andlanguage delay but unlike most of the described patientscould speak ﬂuently and attended normal schooling [9].Also, our case had lower values of proline when com-pared with a similar case described (930–1000 lmol/L[9] and didn’t had any cardiac abnormalities.Nevertheless the cognitive and psychological impair-ment he presents are not so well known. Most genes inchromosome loci 22q11 are expressed in the brain andhypothetically related to executive functions [2,3].A metabolic disorder was suspected due to the pres-ence of the cognitive delay associated with psychotic fea-tures as well as deterioration after the initiation ofvalproic acid as normal liver function excluded toxicity.Valproate metabolization occurs primarily in the livermitochondria, and thus should be avoided in cases ofmitochondrial disorders, as it may stress vital pathwaysthat intensify the genetic damage [10].The knowledge that HPI is caused by mutations inthe chromosome 22q11 led to further investigations thatconﬁrmed the 22q11 deletion. Nevertheless, consideringthe moderate elevation of proline and that HPI is auto-somal recessive, these ﬁndings could not be explainedsolely by the detected deletion. Complementary investi-gations showed heterozygous p.L289M (c.1865T > A)mutation in the PRODH gene already described in schi-zophrenic patients and that may lead to a decrease of a30% activity of POX [11,12].The 22q11 deletion that includes the PRODH generegion and a heterozygous mutation on the PRODHgene on the other allele may somehow result in a com-posed heterozygosity of this gene and have a moderateeﬀect on POX activity [3,12].This decreased activity could inﬂuence the proline/glutamate levels related with apoptosis in selected neu-rons [2,3]. It is possible that the overall phenotype ofcognitive and psychiatric anomalies could be a conse-quence of several genes aﬀected in this locus deletionor their interaction.This case is also clear evidence that knowing the aeti-ology of psychiatric manifestations is important in themanagement of patients preventing use of deleteriousdrugs or creating new therapeutic approaches. It alsoshows that it may be diﬃcult to diagnose chromosomalabnormalities in patients with no clear malformationsand mild dysmorphic features as the pleiotropism ofthe gene/deletion could probably lead to diﬀerentphenotypes.References[1] Schneider M, Debbane´ M, Bassett AS, Chow EW, Fung WL, vanden Bree M, et al. Psychiatric disorders from childhood toadulthood in 22q11.2 deletion syndrome: results from theinternational consortium on brain and behavior in 22q11.2deletion syndrome. Am J Psychiatry 2014;171:627–39.[2] Karayiorgou M, Simon TJ, Gogos JA. 22q11.2 microdeletions:linking DNA structural variation to brain dysfunction andschizophrenia. Nat Rev Neurosci 2010;11:402–16.[3] Di Rosa G, Nicotera AG, Lenzo P, Spano M, Tortorella G.Long-term neuropsychiatric follow-up in hyperprolinemia type I.Psychiatr Genet 2014;24:172–5.[4] Schafer IA, Scriver CR, Efron ML. Familial hyperprolinemia,cerebral dysfunction and renal anomalies occurring in a familywith hereditary nephropathy and deafness. N Engl J Med1962;267:51–60.[5] Mitsubuchi H, Nakamura K, Matsumoto S, Endo F. Inbornerrors of proline metabolism. J Nutr 2008;138:2016S–20S.[6] Phang JM, Hu CA, Valle D. Disorders of proline and hydrox-yproline metabolism. New York: McGraw Hill; 2001.[7] van de Ven S, Gardeitchik T, Kouwenberg D, Kluijtmans L,Wevers R, Morava E. Long-term clinical outcome, therapy andmild mitochondrial dysfunction in hyperprolinemia. J InheritMetab Dis 2014;37:383–90.[8] Guilmatre A, Legallic S, Steel G, Willis A, Di Rosa G,Goldenberg A, et al. Type I hyperprolinemia: genotype/pheno-type correlations. Hum Mutat 2010;31:961–5.[9] Afenjar A, Moutard ML, Doummar D, Gue¨t A, Rabier D,Vermersch AI, et al. Early neurological phenotype in 4 childrenwith biallelic PRODH mutations. Brain Dev 2007;29:547–52.[10] Silva MF, Aires CC, Luis PB, Ruiter JP, IJlst L, Duran M, et al.Valproic acid metabolism and its eﬀects on mitochondrial fattyacid oxidation: a review. J Inherit Metab Dis 2008;31:205–16.[11] Bender HU, Almashanu S, Steel G, Hu CA, Lin WW, Willis A,et al. Functional consequences of PRODH missense mutations.Am J Hum Genet 2005;76:409–20.[12] Jacquet H, Raux G, Thibaut F, Hecketsweiler B, Houy E,Demilly C, et al. PRODH mutations and hyperprolinemia in asubset of schizophrenic patients. Hum Mol Genet2002;11:2243–9.

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Hyperprolinemia as a clue in the diagnosis of a patient with psychiatric manifestations

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