Autism Spectrum Disorders and Inborn Errors of Metabolism: an Update

Pediatric Neurology 49 (2013) 232e236

Contents lists available at ScienceDirect

Pediatric Neurology

journal homepage: www.elsevier.com/locate/pnu

Topical Review Autism Spectrum Disorders and Inborn Errors of Metabolism: An Update

Mohammad Ghaziuddin MD *, Mohammed Al-Owain MD

University of Michigan, Ann Arbor, Michigan, and King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

abstract

BACKGROUND: Autism spectrum disorder is characterized by social communicative deficits with restricted interests occurring in about 1% of the population. Although its exact cause is not known, several factors have been implicated in its etiology, including inborn errors of metabolism. Although relatively uncommon, these disorders frequently occur in countries with high rates of consanguinity and are often associated with behavioral problems, such as hyperactivity and aggression. The aim of this review is to examine the association of autism with these conditions. METHOD: A computer-assisted search was performed to identify the most common inborn errors of metabolism associated with autism. RESULTS: The following disorders were identified: phenylketonuria, glucose-6- phosphatase deficiency, propionic acidemia, adenosine deaminase deficiency, SmitheLemlieOpitz syndrome and mitochondrial disorders, and the recently described branched chain ketoacid dehydrogenase kinase deficiency. CONCLUSION: The risk of autistic features is increased in children with inborn errors of metabolism, especially in the presence of cognitive and behavioral deficits. We propose that affected children should be screened for autism.

Introduction categories. The former group usually begins in the first 2-3 years of life and may present in metabolic crisis (intoxica- Autism spectrum disorder (ASD) is a behavioral syn- tion), whereas the latter may come to medical attention at drome characterized by social communication deficits with any time and have a more insidious course. Metabolic dis- rigid restricted interests, occurring in about 1% of the pop- orders with intoxication often present with acute enceph- ulation.1,2 Although ASD and autism are often used inter- alopathy associated with acidosis, hyperammonemia, and/ changeably, the former more correctly refers to a group of or hypoglycemia.5 Several behavioral and neuropsychiatric disorders of varying degrees of severity. At least 10% of abnormalities can occur in children with metabolic disor- patients with ASD suffer from comorbid disorders, such as ders.6 These stem from the involvement of the central tuberous sclerosis and fragile X syndrome.3 nervous system and include learning disability, social defi- ASD can also occur with inborn errors of metabolism, cits, hyperactivity, aggression, catatonia, psychosis, and sometimes referred to as inherited metabolic disorders, depression.7 Because most metabolic disorders are auto- which occur in 1 in 800 live births.4 These conditions, which somal recessive,8 they are more common in countries with have become increasingly important because of the prog- high rates of consanguinity, where they are associated with ress made in their diagnosis and management,5 occur when a significant degree of morbidity and mortality.9 an enzyme or a transport protein deficiency causes a block Increased awareness of both autism and of inherited in a metabolic pathway resulting either in a harmful accu- metabolic disorders has increased the focus on the comor- mulation of the substrate behind the block or in a deficiency bidity between them. Although, the exact rate of autism in of the product. They can be divided into acute and chronic patients with inherited metabolic disorders is not known, the rate of the latter in patients with autism is said to be around 2%. For example, in a study of 222 Greek children Article History: with autism, 2.7% suffered from a metabolic disorder.10 Received 15 February 2013; Accepted 31 May 2013 However, given that the correct diagnosis of an inborn er- * Communications should be addressed to: Dr. Ghaziuddin; Depart- ror of metabolism requires both clinical and technological ment of Psychiatry; University of Michigan; Ann Arbor, MI 48109-0277. 11 E-mail address: [email protected] expertise, this figure is probably closer to 5%.

There have been no recent reviews of the association of out had low BCAA levels in plasma and in the brain and exhibited autism with metabolic disorders since the last review by neurological impairments typical of autism. BCKDH-knockout mice fed a Manzi and colleagues.12 Since then, several new reports diet enriched in BCAAs showed neurological improvements. However, the clinical significance of this report is unclear. Even if plasma BCAAs are have described the occurrence of autism in patients with normalized, patients might be beyond the critical periods for developing inherited metabolic disorders. For example, a novel meta- social and language skills typical of autism.13 bolic entity (branched chain ketoacid dehydrogenase kinase deficiency) was recently described in multiple consan- Organic acidurias guineous families with autism, epilepsy, and intellectual 13 disability. The aim of this review is to describe the asso- Propionic acidemia ciation between the two conditions with particular refer- Propionic acidemia is a common form of organic aciduria resulting ence to publications since the review by Manzi et al.12 from the deficiency of propionyl-Coenzyme A carboxylase. It is characterized by frequent and potentially lethal episodes of metabolic acidosis often accompanied by hyperammonemia.19 The incidence of this disor- Method der in countries such as Saudi Arabia is relatively high, with an estimated frequency of 1:2000-5000 live births20 partly resulting from tribal A computer-assisted PubMed search was performed with the keywords founder mutation.9 It is initially diagnosed by performing an acylcarni- “autism,”“autism spectrum disorders,”“pervasive developmental tine profile and analysis of urine organic acids. Further confirmation is disorders,”“metabolic diseases,”“metabolic disorders,” and “inborn errors done by enzyme assay or gene testing. Psychiatric symptoms such as of metabolism.” Through cross-references, reviews and book chapters were visual hallucinations21 have been reported, as well as autism.22 Inter- also examined. The following disorders were most commonly identified. estingly, recent reports have suggested that propionic acid administered by an intracerebroventricular injection or systemically may induce an 23-25 Aminoacidopathies animal model of autism. Therefore, in countries with high rates of recessive disorders, autism should be considered in the differential Phenylketonuria diagnosis whenever a patient with propionic acidemia presents with Phenylketonuria (PKU) is a common autosomal recessive disorder of behavioral symptoms. amino acid metabolism, occurring in about 1 in 10,000 people. It is caused by a dysfunction in the metabolism of phenylalanine resulting 3-methyl-crotonyl-CoA carboxylase deficiency either from a deficiency of the enzyme phenylalanine hydroxylase or of This is a disorder of leucine metabolism. Some reports have described its essential cofactor tetrahydrobiopterin. Because phenylalanine is not the occurrence of mental retardation and developmental disorders in fi fi metabolized, it accumulates in the body and causes reduction of myelin children with this enzyme de ciency at the time of birth and identi ed and neuronal loss.14 If PKU is not treated immediately after birth, irre- by neonatal screening. One report has mentioned the presence of autism fi versible brain damage may occur, and, one of its features may include in a child identi ed in a retrospective analysis of 35 patients. Another autism. child was said to suffer from obsessive-compulsive disorder and was The exact prevalence rate of autism in PKU is not known. However, placed in a gifted program. However, details about the diagnosis were fi fi the association between the two disorders is well-documented in single not given. It is dif cult to say to what extent this de ciency contributed 26 case reports and case series. Chen and Hsaio15 described autistic features to the presence of autism. in an adolescent who was later diagnosed with classical PKU. Treatment with a low-phenylalanine diet started after the diagnosis of PKU did not Pyridoxine dependency Pyridoxine dependency epilepsy is a form of organic aciduria char- decrease the autistic symptoms. The authors emphasized the need for acterized by early-onset epileptic encephalopathy responsive to large excluding PKU as a cause of autism in those countries where neonatal dosages of pyridoxine. It is caused by antiquitin (a-aminoadipic-semi- screening is not done systematically. In a relatively recent Italian study, aldehyde dehydrogenase) deficiency. In addition, most patients have Baleili and colleagues16 examined the features of autism in a group of 97 intellectual disability despite good seizure control. Antiquitin is coded by patients with classical PKU. Sixty-two were diagnosed early based on the gene ALDH7A1. Presentations include late-onset of seizures and neonatal screening and were receiving treatment. None in this group autism. In a large cohort with pyridoxine dependency epilepsy, Mills met the criteria of autism. In the remaining 35 patients, who were et al. reported that a single patient (F19) who had both seizures and diagnosed late, two patients (5.7%) met the full criteria of autism. Pa- autistic features responded to treatment with pyridoxine.27 The diag- tients in the former group were of normal intelligence, whereas those in nosis is generally confirmed by measurement of a-aminoadipic semi- the latter group were in the mentally disabled range.16 aldehyde and gene testing.28 Although the exact cause of autism in untreated PKU is not clear, it probably results from the accumulation of phenylalanine causing brain damage. Several other neuropsychological abnormalities have been Purine and pyrimidine disorders described in persons with PKU, including those who have been treated. Some of these include executive function deficits and problems with Adenosine deaminase (ADA) deficiency attention and impulsivity.17,18 Once the diagnosis of autism in children Adenosine deaminase plays an important role in the regulation of the with PKU is established, treatment should consist of incorporating neurotransmitters such as dopamine and serotonin and also in the educational and behavioral interventions focusing on the social and functioning of the immune system. Absence of the enzyme ADA leads to communication deficits. the accumulation of deoxyadenosine, which is toxic to the lymphocytes resulting in immunodeficiency. The disorder can be of early or late onset, Disorders of branched-chain amino acids with a range of clinical features depending on the level of deficiency of Branched chain amino acids (BCAAs, leucine, isoleucine, and valine) the enzyme.29 A few case reports have described autistic features in are essential amino acids required by the body. In a recent report,13 in- patients with reduced levels of ADA.30,31 Stubbs and colleagues found vestigators examined three consanguineous families of Middle Eastern that the level of ADA was decreased in children with autism compared origin with autism, intellectual disability, and seizure disorder (or an with normal, intellectually disabled and children with cerebral palsy.32 abnormal electroencephalograph). They found that affected persons In an Italian study, Bottini et al.33 compared 118 autistic children with with the three disorders had low levels of BCAAs, which were corrected 126 controls. The autistic group had increased levels of the variants of after the administration of the amino acids. The cause was the occur- the enzyme that are associated with reduced activity. However, Het- rence of mutations in the branched-chain ketoacid dehydrogenase ki- tinger et al.34 could not find evidence of disturbed enzyme activity in a nase gene (BCKDH), which encodes a protein involved in inactivating the study of 126 families in a North American sample. There is no evidence to branched-chain ketoacid dehydrogenase complex, the deficiency of suggest that treatment of ADA deficiency can lead to improvement of which causes maple syrup urine disease. Mice with this gene knocked autistic features. 234 M. Ghaziuddin, M. Al-Owain / Pediatric Neurology 49 (2013) 232e236

Adenylosuccinate lyase deficiency Altered mitochondrial gene expression has been reported in some Adenylosuccinate lyase deficiency is an autosomal recessive disorder psychiatric disorders using array-based technology. A few case of purine synthesis characterized by increased levels of succinylami- reports have also described the occurrence of autism in mitochondrial noimidazole carboxamide riboside and succinyladenosine. Clinical fea- disorders. In a study of 12 children with hypotonia, epilepsy, autism, and 35 tures include autistic symptoms, seizures, and mental retardation. The developmental delay, Fillano et al.48 found evidence of mitochondrial cause of autism in this syndrome is not known, but is probably mediated abnormalities in a significant number of children. These included through the presence of mental retardation. abnormal appearance of mitochondrial organelles and mitochondrial DNA deletions. Ezuga et al.49 described a 12-year-old boy with autism, fi Dihydropyrimidine dehydrogenase and dihydropyrimidinase de ciencies mental retardation, leg weakness, and dysmorphic features. A buccal These two enzymes in the pyrimidine metabolic pathway are swab electron transport chain analysis revealed a reduction in complex required sequentially to catalyze the conversion of uracil/thymine to IV and complex I activities, whereas a molecular cytogenetic study dihydrouracil/dihydrothymine followed by ß-ureidopropionate and ß- showed a small deletion involving the 5q14.3 region. Because most of the ureido isobutyrate. Symptoms may include psychomotor retardation and reports describing autism in mitochondrial disorders were based on 36 epileptic encephalopathy. Autistic features can be seen in both the small numbers, they can only be regarded as preliminary. disorders.37 Diagnosis relies on measurement of uracil/thymine and fl dihydrouracil/dihydrothymine in the body uids. Other disorders

Disorders of vitamins and cofactors Glucose 6-phosphate dehydrogenase (G6PD) deficiency G6PD converts glucose-6-phosphate to ribose-5-phosphate, which is Biotinidase deficiency a precursor of molecules such as RNA and DNA. The enzyme deficiency Biotin is a cofactor for all carboxylases in the body including increases the risk of the red blood cells to oxidative stress. It is the most propionyl-CoA carboxylase, pyruvate carboxylase, and 3-methyl-cro- common human enzyme defect, being present in more than 400 million tonyl-CoA carboxylase. The urine organic acid analysis and acylcarnitine people around the world. Symptoms include acute hemolytic anemia, profile may suggest the diagnosis; however confirmation requires bio- chronic hemolytic anemia, and neonatal hyperbilirubinemia. G6PD tinidase enzyme assay and/or gene testing. Besides a skin rash, the deficiency is particularly common in people of African and Mediterra- enzyme deficiency causes a neurological disease (poor hearing and nean origin, especially in areas endemic to malaria against which it 38 vision, seizures, and developmental and behavioral disturbances). A provides some protection.50 Al-Salehi and Ghaziuddin51 described two single patient with partial biotinidase deficiency with autism has been boys with autism and G6PD deficiency from a case series in Saudi Arabia. 39 reported. Both patients had severe language delay with mental retardation, and one also had a seizure disorder. The authors postulated that the one fi Cerebral folate de ciency factor leading to autism in patients with this enzyme deficiency might be fl Characterized by low cerebrospinal uid folates (especially 5- the development of kernicterus resulting from hyperbilirubinemia. Thus, methyltetrahydrofolate) and normal peripheral folate metabolism, ce- a subgroup of children with kernicterus may be vulnerable to developing fi rebral folate de ciency is increasingly being recognized in various autism, especially in developing countries, where a contributing factor is neurological disorders. It is associated with folate receptor autoimmu- G6PD deficiency. nity and the deficiency of one of several enzymes involved in folate 40,41 metabolism. Patients may exhibit autistic features in addition to SmitheLemlieOpitz syndrome psychomotor retardation, seizures, movement disorder, and visual and hearing impairment. If treated early, patients may show a favorable This is a recessive disorder in which the body does not metabolize 42 response to folinic acid. Diagnosis may be challenging and requires the cholesterol properly, leading to increased serum levels of 7- assay of cerebrospinal fluid neurotransmitters and specific enzymes. dehydrocholesterol. The symptoms range from isolated intellectual disability to severe physical and mental deficits incompatible with life. Disorders of mitochondrial energy metabolism Some of the physical features include microcephaly, ptosis, short stature, and abnormalities of the second and third toes.52 Neurodevelopmental Disorders of creatine metabolism symptoms may consist of hyperactivity and autistic symptoms with The hallmark of these disorders is the deficiency of creatine in the stereotyped behaviors that may be specific to the syndrome. Among brain. Collectively called creatine deficiency syndrome, they include L- stereotyped behaviors of SmitheLemlieOpitz patients, two may be arginine:glycine amidinotransferase deficiency, guanidinoacetate relatively specific: a characteristic upper body movement (opisthoki- methyltransferase deficiency, and X-linked creatine transporter defect. nesis) and stereotypic stretching motion of the upper body accompanied Autism is seen in all of these disorders. Cerebral creatine deficiency by by hand flicking.53 Treatment of the autistic features is symptomatic magnetic resonance spectroscopy of the brain is the characteristic although some patients seem to respond to a supplementary diet of feature of all of these disorders. Measurement of guanidinoacetate, cholesterol.53 creatine, and creatinine in body fluids (urine, serum, and cerebrospinal fluid) is also useful as a screening test. Enzymatic assay and/or gene Succinic semialdehyde dehydrogenase deficiency testing are required for confirmation.43,44 Succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric Mitochondrial disorders aciduria) is caused by a defect in the catabolic pathway of the inhibi- Mitochondria are intracellular structures that play an important role tory neurotransmitter g-aminobutyric acid. Urine organic acid analysis in protein and lipid metabolism. They participate in the production of reveals the elevations of g-hydroxybutyric acid. Clinically, the disorder is cell energy and modulate other functions such as signaling, cellular characterized by psychomotor retardation, hypotonia, ataxia, ASD, and differentiation, and cellular death. Monoamine oxidase enzymes A and B, seizures. Other behavioral manifestations (hyperkinetic behavior, which have been implicated in a variety of psychiatric disorders, are aggression, self-injurious behaviors, hallucinations, and sleep distur- 45 localized in the outer mitochondrial membrane. Mitochondrial disor- bances) are seen in nearly half of all patients, more commonly in ders have been reported predominantly with depression but also with older individuals. Patients with this disorder are treated with vigabatrin, other psychiatric disorders. In a review of the literature, Fattal and col- an anticonvulsant that irreversibly blocks g-aminobutyric acid tran- 46,47 leagues found 19 patients with mitochondrial disorders and asso- saminase.54 ciated psychiatric abnormalities such as bipolar disorder, anxiety disorders, and schizophrenia. For example, electron microscopic studies Sanfilippo syndrome (mucopolysaccharidosis type III) have revealed abnormalities in the size and density of mitochondria in the postmortem brains of patients with schizophrenia. Positron emission The deficiencies of four enzymes involved in the degradation of tomography studies have shown altered brain metabolism resulting heparan sulfate cause Sanfilippo syndrome, a lysosomal storage disease from mitochondrial dysfunction in schizophrenia and bipolar disorder. characterized by severe neurodegenerative course with minimal somatic M. Ghaziuddin, M. Al-Owain / Pediatric Neurology 49 (2013) 232e236 235 features.55 Several behavioral disturbances, including autism, have been as in the case of phenylketonuria. Screening for autism 56 reported in Sanfilippo syndrome. should be done when metabolic disorders occur with Assessment and treatment cognitive and behavioral problems. Treatment should address the symptoms resulting from both the inborn Clinicians working in countries with a high prevalence of errors of metabolism and the autism spectrum disorder. recessive conditions should rule out autism in patients with inborn errors of metabolism, especially in children with References behavioral problems. Common behavioral problems that 1. Kanner L. Autistic disturbances of affective contact. Nervous Child. suggest a need for screening for autism include speech and 1943;2:217-250. language abnormalities, hyperactivity and impulsivity, dif- 2. Nazeer A, Ghaziuddin M. Autism spectrum disorders: clinical fea- ficulty in interacting with peers, suggestion of intellectual tures and diagnosis. Pediatr Clin N Am. 2012;59:19-25. disability, and presence of excessive interests and ritualistic 3. Rutter M, Bailey A, Bolton P, LeCouteur A. Autism and known behaviors. There is a general consensus that the earlier the medical conditions: myth and substance. J Child Psychol Psychiatry. 1994;35:311-322. diagnosis of autism, the better the long-term outcome. In 4. Pampols T. Inherited metabolic rare disease. Adv Exp Med Biol. 2010; addition, a timely diagnosis is also necessary for accessing 686:397-431. the right kind of educational and psychological services and 5. Saudubray JM, Sedel FN, Walter JH. Clinical approach to treatable also for educating the parents about autism and its likely inborn metabolic diseases: an introduction. J Inherit Metab Dis. 2006;29:261-274. outcome. 6. Sedel FN, Baumann N, Turpin JC, et al. Psychiatric manifestations Screening measures and rating scales for autism should revealing inborn errors of metabolism in adolescents and adults. be used, and complex cases should be referred to a J Inherit Metab Dis. 2007;30:631-641. specialist. Conversely, clinicians working in autism assess- 7. Estrov Y, Scaglia F, Bodamer OA. Psychiatric symptoms of inherited ment centers should rule out comorbid metabolic disorders, metabolic disease. J Inherit Metab Dis. 2000;23:2-6. 8. Zecavati N, Spence SJ. Neurometabolic disorders and dysfunction in especially in patients with mental retardation/intellectual autism spectrum disorders. Curr Neurol Neurosci Rep. 2000;9: disability, seizure disorder, and dysmorphic features and in 129-136. those with a family history of these conditions. In consul- 9. Al-Owain MH, Al-Zaidan J, Al-Hassnan Z. Map of autosomal reces- tation with an expert in metabolic disorders, screening sive genetic disorders in Saudi Arabia: concepts and future di- rections. Am J Med Genet A. 2012;158A:2629-2640. should be done for serum amino acids, lactate, ammonia, 10. Ververi A, Vargiami E, Papadopoulou V, Tryfonas D, Zafeiriou DI. acylcarnitine, urine mucopolysaccharides, and organic Clinical and laboratory data in a sample of Greek children with acids. An amino acid analysis, a urine organic acid screen, autism spectrum disorders. J Autism Dev Disord. 2011;42: and an acylcarnitine profile are the most widely used 1470-1476. screening tests for the evaluation of suspected metabolic 11. Dykens EM, Volkmar FR. Medical conditions associated with autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive disorders. These tests collectively have a high detection rate Developmental Disorders. New York: Wiley; 1997. of many aminoacidopathies (e.g., phenylketonuria), organic 12. Manzi B, Loizzo AL, Giana G, et al. Autism and metabolic diseases. acidurias (e.g., propionic acidemia), and urea cycle defects. J Child Neurol. 2008;23:307-314. Confirmation of the diagnosis usually requires an enzyme 13. Novarino G, El-Fishawy P, Kayserili H, et al. Mutations in BCKD- kinase lead to a potentially treatable form of autism with epi- assay and/or gene testing. However, routine testing for lepsy. Science. 2012;338:394-397. metabolic disorders in all patients with autism is not indi- 14. Mitchell JJ. Phenylalanine hydroxylase deficiency. In: Pagon RA, cated.57 This is partly because the yield of metabolic disor- Bird TD, Dolan CR, et al., eds. GeneReviews (Internet). Seattle: University ders in children with ASD is less than 5%.11 At this stage, of Washington; 2000. http://www.ncbi.nlm.nih.gov/books/NBK therefore, as recommended by the American College of 1504/. Accessed May 13, 2013. 15. Chen CH, Hsiao KJ. A Chinese classic phenylketonuria manifested as Medical Genetics, selective metabolic screening/consulta- autism. Br J Psychiatry. 1989;155:251-253. tion should be considered only on the basis of clinical 16. Balieli S, Pavone L, Meli C, Fiumara A, Coleman M. Autism and findings.57 Possible clinical indications include a history of phenylketonuria. J Autism Dev Disorders. 2003;33:201-204. fi lethargy, cyclic vomiting, early seizures, dysmorphic fea- 17. Azadi B, Seddigh A, Tehrani-Doost M, Alaghband-Rad J, Ashra MR. Executive dysfunction in treated phenylketonuric patients. Eur Child tures, intellectual disability, concerns about newborn Adolesc Psychiatry. 2009;18:360-368. screening, or birth outside the United States, suggesting 18. Leuzzi V, Pansini M, Sechi E, et al. Executive function impairment in problems with maternal public health measures.58 early-treated PKU subjects with normal mental development. Depending on the age of the child, dietary treatment for J Inherit Metab Dis. 2004;27:115-125. the metabolic disorder should be considered in addition to 19. Dionisi-Vici C, Deodato F, Roschinger W, et al. Classical organic fi acidurias, propionic aciduria, methylmalonic aciduria and isovaleric autism-speci c interventions such as social skills training, aciduria: long-term outcome and effects of expanded newborn speech therapy, and educational placement. screening using tandem mass spectrometry. J Inherit Metab Dis. 2006;29:383-389. Conclusion 20. Rashed M, Ozand PT, Al-Aqeel A, Gascon GG. Experience of King Faisal Specialist Hospital and Research Center with Saudi organic Autistic symptoms occur in a variety of inborn errors of acid disorders. Brain Dev. 1994;16:1-6. 21. Shuaib T, Al-Hashmi N, Ghaziuddin M, et al. Propionic acidemia metabolism. These are more likely to occur in certain associated with visual hallucinations. J Child Neurol. 2011;27: countries, such as in the Middle East, where recessive 799-803. conditions are common because of consanguinity. The as- 22. Al-Owain M, Kaya N, Al-Shamrani, et al. Autism spectrum disorder sociation of autism with metabolic disorders underscores in a child with propionic acidemia. JIMD Rep. 2013;7:63-66. 23. MacFabe DF, Cain DP, Rodriguez-Capote K, et al. Neurobiological that autism can be the end result of a variety of insults and effects of intraventricular propionic acid in rats: possible role of injuries. The severity of the autistic symptoms varies with short chain fatty acids on the pathogenesis and characteristics of the timing of the diagnosis and the subsequent treatment, autism spectrum disorders. Behav Brain Res. 2007;176:149-169. 236 M. Ghaziuddin, M. Al-Owain / Pediatric Neurology 49 (2013) 232e236

24. MacFabe DF, Cain NE, Boon F, et al. Effects of the enteric bacterial 42. Ramaekers VT, Blau N, Sequeira JM, Nassogne MD, Quadros EV. metabolic product propionic acid on object-directed behavior, Folate receptor autoimmunity and cerebral folate deficiency in social behavior, cognition, and neuroinflammation in adolescent low-functioning autism with neurological deficits. Neuropediatrics. rats: Relevance to autism spectrum disorder. Behav Brain Res. 2011; 2007;38:276-281. 217:47-54. 43. Sykut-Cegielska J, Gradowska W, Mercimek-Mahmutoglu S, Stöck- 25. Shams S, Kavaliers M, Foley KA, et al. Social deficits, anxiety-like ler-Ipsiroglu S. Biochemical and clinical characteristics of creatine behavior and hypoactivity following systemic administration of pro- deficiency syndromes. Acta Biochim Pol. 2004;51:875-882. pionic acid in juvenile rats. Abstract [#436.6]. Chicago, IL: Society for 44. Nasrallah F, Feki M, Kaabachi N. Creatine and creatine deficiency Neuroscience; 2009. syndromes: biochemical and clinical aspects. Pediatr Neurol. 2010; 26. Arnold GL, Salazar D, Neidich JA, et al. Outcome of infants diagnosed 42:163-171. with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn 45. Shao L, Martin MV, Watson SJ, et al. Mitochondrial involvement in screening. Mol Genet Metab. 2012;106:439-441. psychiatric disorders. Ann Med. 2008;40:281-295. 27. Mills PB, Footitt EJ, Mills KA, et al. Genotype and phenotypic spec- 46. Fattal O, Budur K, Vaughan AJ, Franco K. Review of the literature on trum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). major mental disorders in adult patients with mitochondrial dis- Brain. 2010;133:2148-2159. eases. Psychosomatics. 2006;47:1-7. 28. Stockler S, Plecko B, Gospe SM, et al. Pyridoxine dependent epilepsy 47. Fattal O, Link J, Quinn K, Cohen BH, Franco K. Psychiatric comor- and antiquitin deficiency: clinical and molecular characteristics and bidity in 36 adults with mitochondrial cytopathies. CNS Spectrums. recommendations for diagnosis, treatment and follow-up. Mol 2007;12:429-438. Genet Metab. 2011;104:48-60. 48. Fillano JJ, Goldenthal MJ, Rhodes CH, Marin-Garcia J. Mitochondrial 29. Hershfield M. Adenosine deaminase deficiency. In: Pagon RA, dysfunction in patients with hypotonia, epilepsy, autism, and Bird TD, Dolan CR, et al., eds. GeneReviews (Internet). Seattle: Uni- developmental delay: HEADD syndrome. J Child Neurol. 2002;17: versity of Washington. http://www.ncbi.nlm.nih.gov/books/ 435-439. NBK1504/. Accessed May 13, 2013. 49. Ezugha H, Goldenthal M, Valencia I, Anderson CE, Legido A, 30. Stone RL, Aimi J, Barshop BA, et al. A mutation in adenylosuccinate Marks H. 5q14.3 deletion manifesting as mitochondrial disease and lyase associated with mental retardation autistic features. Nat autism: case report. J Child Neurol. 2010;25:1232-1235. Genet. 1992;1:59-63. 50. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase 31. Stathis SL, Cowley DM, Broe D. Autism and adenylosuccinase defi- deficiency. Lancet. 2008;371:64-74. ciency. J Am Acad Child Adolesc Psychiatry. 2000;39:274-275. 51. Al-Salehi SM, Ghaziuddin M. G6PD deficiency in autism: a case- 32. Stubbs G, Litt M, Lis E, et al. Adenosine deaminase activity decreased series from Saudi Arabia. Eur Child Adolesc Psychiatry. 2009;18: in autism. J Am Acad Child Adolesc Psychiatry. 1982;21:71-74. 227-230. 33. Bottini N, De Luca D, Saccucci P, et al. Autism: evidence of associ- 52. Kelley RI. Inborn errors of cholesterol biosynthesis. Adv Pediatr. ation with adenosine deaminase genetic polymorphism. Neuro- 2000;47:1-53. genetics. 2001;3:111-113. 53. Tierny E, Nwokoro NA, Porter FD, et al. Behavior phenotype in the RSH/ 34. Hettinger JA, Liu X, Holden JJ. The G22A polymorphism of the ADA SmitheLemlieOpitz syndrome. Am J Med Genet. 2001;98:191-200. gene and susceptibility to autism spectrum disorders. J Autism Dev 54. Pearl PL, Reehal T, Drillings I, et al. Succinic semialdehyde dehy- Disord. 2008;38:14-19. drogenase deficiency. In: Pagon RA, Bird TD, Dolan CR, et al., eds. 35. Micheli V, Camici M, Tozzi MG, et al. Neurological disorders of GeneReviews [Internet]. Seattle: University of Washington, Seattle; purine and pyrimidine metabolism. Curr Top Med Chem. 2011;11: 1993. Available from: http://www.ncbi.nlm.nih.gov/books/ 923-947. NBK1195/. Accessed May 13, 2013. 36. Nyhan WL. Disorders of purine and pyrimidine metabolism. Mol 55. Valstar MJ, Ruijter GJ, van Diggelen OP, et al. Sanfilippo syndrome: a Genet Metab. 2005;86:25-33. mini-review. J Inherit Metab Dis. 2008;31:240-252. 37. van Gennip AH. Defects of pyrimidine degration: clinical, molecular 56. Nidiffer FD, Kelly TE. Developmental and degenerative patterns and diagnostic aspects. Adv Exp Biol. 2000;486:233-241. associated with cognitive, behavioural and motor difficulties in the 38. Wolf B. Biotinidase deficiency. Genet Med. 2012;14:565-575. Sanfilippo syndrome: an epidemiological study. J Ment Defic Res. 39. Zaffanello M, Zamboni G, Fontana E, Zoccante L, Tato L. A case of 1983;27:185-203. partial biotinidase deficiency associated with autism. Child Neuro- 57. Curry CJ, Stevenson RE, Aughton D, et al. Evaluation of mental psychol. 2003;9:184-188. retardation: recommendations of a Consensus Conference: Amer- 40. Mangold S, Blau N, Opladen T, et al. Cerebral folate deficiency: a ican College of Medical Genetics. Am J Med Genet. 1997;72:468-477. neurometabolic syndrome? Mol Genet Metab. 2011;104:369-372. 58. Filipek PA, Accardo PJ, Baranek GT, et al. The screening and diag- 41. Hyland K, Shoffner J, Heales SJ. Cerebral folate deficiency. J Inherit nosis of autistic spectrum disorders. J Aut Dev Disorders. 1999;29: Metab Dis. 2010;33:563-570. 439-484.