3-Methylglutaconyl-CoA hydratase deficiency (MGA1) is a defect in leucine catabolism, which causes the accumulation of urinary 3-methylglutaconate, with or without 3-hydroxyisovalerate and 3-methylglutarate. It is an ultra-rare condition, with <30 cases published in the literature. It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention. We reviewed the collective Australian experience of patients with confirmed MGA1, four of whom were diagnosed when asymptomatic through newborn screening (NBS). When our cohort is considered alongside the broader literature, there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder. Some patients have non-specific clinical features (such as autism spectrum disorder [ASD]); however, there are also other family members with ASD in the absence of MGA1, suggesting a multifactorial aetiology. Importantly, all four patients diagnosed through NBS (including three with over 18 years of clinical follow-up) remain asymptomatic in the absence of treatment. Based on the available literature, we suggest that MGA1 represents a biochemical phenotype, with an absence of a childhood clinical phenotype. The burdens of sustained treatment (particularly with intensive dietary leucine restriction) in asymptomatic individuals may be of little benefit, and likely to result in poor compliance. Longer-term follow-up of patients detected via NBS (or biochemical screening of large cohorts of asymptomatic adult individuals) will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy.

Three young patients with glutaric aciduria type I (age 6-23 years) of different ethnic origins, treated for their metabolic disease since early childhood, presented with malignant central nervous system tumors. We recommend continuing clinical follow-up, including monitoring of neurological manifestations and neuroradiological findings, in all patients with glutaric aciduria type I beyond early childhood, especially if adherence to diet is poor or the treatment was not started neonatally.

BACKGROUND:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the DHCR7 gene that result in reduced cholesterol biosynthesis. The aim of the study was to examine the biochemical and clinical features of SLOS in the context of the emerging evidence of the importance of cholesterol in morphogenesis and steroidogenesis.METHODS:We retrospectively reviewed the records of 18 patients (including four fetuses) with confirmed SLOS and documented their clinical and biochemical features.RESULTS:Seven patients had branchial arch abnormalities, including micrognathia, immune dysfunction and hypocalcemia. Thymic abnormalities were found in three fetuses. All four patients with a cholesterol level of ≤0.35 mmol/L died. They all had electrolyte abnormalities (hyperkalemia, hyponatremia, hypocalcemia), necrotizing enterocolitis, sepsis-like episodes and midline defects including the branchial and cardiac defects. Patients with cholesterol levels ≥1.7 mmol/L had milder features and were diagnosed at 9 months to 25 years of age. All 10 patients had intellectual disability. One patient was found to have a novel mutation, c.1220A>G (p.Asn407Ser).CONCLUSIONS:We suggest that screening for adrenal insufficiency and for hypoparathyroidism, hypothyroidism and immunodeficiency, should be done routinely in infants diagnosed early with SLOS. Early diagnosis and intervention to correct these biochemical consequences may decrease mortality and improve long-term outcome in these patients.

Ornithine Trans-Carbamylase (OTC) deficiency is the most common disorder of the urea cycle. Cognitive impairments in skills such as attention and executive function have been reported in individuals with OTC deficiency who are managed with medication. In some cases, children undergo liver transplantation (LTx) to correct the metabolic defect. The metabolic and medical outcomes of LTx are generally good. However, little is known about the impacts on cognition. In this study, four children (three female) completed detailed neuropsychological batteries prior to (n = 6) and following LTx (n = 8 assessments). Children's age at assessment ranged from 3 to 11 years. The battery included standardised, age-referenced measures of intellectual ability (IQ), attention, memory and educational ability. Additionally, parent measures of behaviour and executive function were administered. Generally, there was little change in overall IQ following LTx. Memory and academic skills were at expected levels for the three female patients and gains were made after LTx. Children showed ongoing impairments in attention and parent rated executive function. In conclusion, the immediate effect of LTx on cognition may not appear beneficial in the short-term and impairments in IQ, attention and behaviour persisted after the procedure. However, LTx seems to enable stabilisation to premorbid function in the longer term.

Objective: To explore the level of coping and management of parents of children with inherited metabolic disorders (IMD) and the relationship with children's cognitive, behavioural and social functioning. Methods: Parents of children (n = 22) with confirmed IMD (glutaric aciduria type I, methylmalonic aciduria, propionic aciduria, isovaleric aciduria, glycogen storage disease, maple syrup urine disease, ornithine transcarbamylase or very long-chain acyl-CoA dehydrogenase deficiency) completed standardised questionnaires regarding psychological distress, coping and family management. Children completed cognitive assessments and parents rated their behavioural and social functioning on standardised questionnaires. Scores were compared with normative data. Results: Most parents were coping well; 4/22 reported high levels of psychological distress. Exploratory analysis found that parent coping variables were correlated to the child's internalising symptoms, whereas family management was related to children's externalising behaviours and social skills. No relationship was found between parent variables and cognitive functioning. Conclusions: Parental coping and family management impact on the child's internalising symptoms and externalising behaviours, respectively. Early identification of issues in these domains may enhance referral for therapeutic interventions and family support programmes.

Aim: Phenylketonuria (PKU) is an inborn error of protein metabolism that results from perturbation in phenylalanine hydroxylase activity leading to elevated blood levels of phenylalanine (phe). We aimed to explore the relationships between dietary patterns (total-protein, natural-protein, amino-acid formula), and the ratio of protein to energy intake with growth and body composition.Method: Longitudinal prospective data (1-6 measurements) of growth, dietary intake and body composition in patients treated with phe-restricted diet only (D-PKU; n = 32), and tetrahydrobiopterin (BH4) phe-restricted diet (BH4-PKU; n = 5) were collected over a two-year period. Healthy siblings provided control data (n = 21).Results: There were no significant differences in weight-, height-, BMI z-score or percent body fat mass (% fatmass) between the D-PKU, BH4-PKU and control groups or between the all-types of PKU combined and controls, which confirmed 'normal' growth in the PKU cohort. Total-protein intake in the all-types of PKU group met or exceeded WHO safe protein recommendations. There were no significant relationships between anthropometric and dietary variables. Significant negative correlations were found in body composition: %fatmass and total-protein intake (r(s) = 0.690, p 0.001), natural-protein intake (r(s) = 0.534, p = 0.001), and AAF intake (r(s) = -0.510, p = 0.001). Age was significantly correlated with %fatmass (r(s) = 0.493, p = 0.002) A total-protein intake of 1.5-2.6 g/kg/day and natural-protein intake > 0.5 g/kg/day were associated with improved body composition. An apparent safe P:E ratio of 3.0-4.5 g protein/100 kcal was strongly associated with appropriate growth outcomes.Conclusions: Clinical decision-making needs to consider both the enhancement of natural-protein tolerance and the application of an apparent 'safe' protein to energy ratio to support optimal growth and body composition in PKU.

Journal of Inherited Metabolic DiseaseVolume 40, Issue 2 p. 307-307 Book Review Nenad Blau (ed.). Phenylketonuria and BH4 deficiencies 3rd Edition 2016; 112 pp; 39.80 Euro; ISBN 978-3-8374-1526-1 Avihu Boneh, Corresponding Author Avihu Boneh avihu.boneh@rch.org.au Department of Metabolic Medicine, Metabolic Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, 3052 Australia Department of Paediatrics, University of Melbourne, Melbourne, Australia avihu.boneh@rch.org.auSearch for more papers by this author Avihu Boneh, Corresponding Author Avihu Boneh avihu.boneh@rch.org.au Department of Metabolic Medicine, Metabolic Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, 3052 Australia Department of Paediatrics, University of Melbourne, Melbourne, Australia avihu.boneh@rch.org.auSearch for more papers by this author First published: 06 February 2017 https://doi.org/10.1007/s10545-017-0019-5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume40, Issue2March 2017Pages 307-307 RelatedInformation

Objectives To examine relationships between dietary intake, growth and body composition patterns in patients with inborn errors of intermediary protein metabolism and to determine a safe protein: energy ratio (P: E ratio) associated with optimal growth outcomes.Study design Retrospective longitudinal data of growth and dietary intake in patients (n = 75) with isovaleric acidemia (IVA; n = 7), methylmalonic acidemia/propionic acidemia (MMA/PA; n = 14), urea cycle defects (UCD; n = 44), classical maple syrup urine disease (MSUD; n = 10) were collected. Prospective longitudinal data of growth, dietary intake, and body composition from 21 patients: IVA (n = 5), MMA/PA (n = 6), UCD (n = 7), and MSUD (n = 3) were collected at clinic visits.Results Fifty-two of 75 (66%), 49 of 74 (68%), and 44 of 65 (68%) patients had a z-score of 0 (+/- 1) for lifetime weight, height, and body mass index, respectively. Patients with MMA/PA had the lowest median height and weight z-scores, and MSUD patients had highest median body mass index z- score at all ages. In IVA, MMA/PA, and UCD, total natural protein intake met or exceeded the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO)/United Nations University (UNU) recommended safe levels. Median percentage fat mass was 17.6% in IVA, 20.7% in MMA/PA, 19.4% in UCD, and 17.8% in MSUD. There was a significant negative correlation between percentage fat mass and total protein intake in IVA, MMA/PA, and UCD (r = -0.737; P=.010). The correlation between the P: E ratio and growth variables in IVA, MMA/PA, and UCD suggest a safe P: E ratio (> 1.5 to < 2.9) g protein: 100 kcal/day.Conclusion Growth outcomes in inborn errors of intermediary protein metabolism are not always ideal. Most patients with IVA, MMA/PA, and UCD consume sufficient natural protein to meet FAO/WHO/UNU recommendations. A P: E ratio range of (> 1.5 to < 2.9) g protein/100 kcal/day correlates with optimal growth outcomes.

AIM:To compare the measurement of total body water (TBW) and fat-free mass (FFM) using the criterion method of deuterium dilution space (2H2O) with bioelectrical impedance analysis (BIA) using a portable QuadScan 4000, Bodystat® in children and adolescents with phenylketonuria (PKU).METHODS:Sixteen patients with PKU, median age is 12.5 (range 5-20.6) years, were recruited into this cross-sectional study. TBW was measured by both deuterium dilution and BIA on the same occasion as per a standard protocol. FFM was estimated from predictive equations.RESULTS:There was no significant difference between TBWDeut and TBWBIA (p = 0.344) or FFMDeut and FFMBIA (p = 0.111). TBWDeut and TBWBIA were highly correlated (r = 0.990, p < 0.0001), as were FFMDeut and FFMBIA (r = 0.984, p < 0.0001). Bland-Altman plots demonstrated that there was no proportional bias between the criterion method, TBWDeut, and the test method TBWBIA, in estimating TBW (β = -0.056, adjusted r 2 = 0.069, p = 0.169) or FFM (β = -0.089, adjusted r 2 = 0.142, p = 0.083).CONCLUSION:Our results suggest that when compared with the criterion method, the QuadScan 4000, Bodystat® can reliably be used to predict TBW and FFM in patients with PKU. We suggest that due to the portability and non-invasive approach, this method can reliably be used to monitor body composition in the outpatient clinic setting, to further improve the monitoring and assessment of nutritional status in PKU.

Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of fatty acid oxidation. Treatment practices of the disorder have changed over the past 10-15 years since this disorder was included in newborn screening programs and patients were diagnosed pre-symptomatically. A genotype phenotype correlation has been suggested but the discovery of novel mutations make this knowledge limited. Herein, we describe our experience in treating patients (n = 22) diagnosed through newborn screening and mutational confirmation and followed up over a median period of 104 months. We report five novel mutations. In 2013 we formalised our treatment protocol, which essentially follows a European consensus paper from 2009 and our own experience. The prescribed low natural fat diet is relaxed for patients who are asymptomatic when reaching age 5 years but medium-chain triglyceride oil is recommended before and after physical activity regardless of age. Metabolic stability, growth, development and cardiac function are satisfactory in all patients. There were no episodes of encephalopathy or hypoglycaemia but three patients had episodes of muscle pain with our without rhabdomyolysis. Body composition studies showed a negative association between dietary protein intake and percent body fat.Larger patient cohort and longer follow up time are required for further elucidation of genotype-phenotype correlations and for establishing the role of dietary protein in metabolic stability and long-term healthier body composition in patients with VLCAD deficiency. (C) 2016 Elsevier Inc. All rights reserved.

Objective: To explore the level of coping and management of parents of children with inherited metabolic disorders (IMD) and the relationship with children’s cognitive, behavioural and social functioning. Methods: Parents of children (n 1⁄4 22) with confirmed IMD (glutaric aciduria type I, methylmalonic aciduria, propionic aciduria, isovaleric aciduria, glycogen storage disease, maple syrup urine disease, ornithine transcarbamylase or very long-chain acyl-CoA dehydrogenase deficiency) completed standardised questionnaires regarding psychological distress, coping and family management. Children completed cognitive assessments and parents rated their behavioural and social functioning on standardised questionnaires. Scores were compared with normative data. Results: Most parents were coping well; 4/22 reported high levels of psychological distress. Exploratory analysis found that parent coping variables were correlated to the child’s internalising symptoms, whereas family management was related to children’s externalising behaviours and social skills. No relationship was found between parent variables and cognitive functioning. Conclusions: Parental coping and family management impact on the child’s internalising symptoms and externalising behaviours, respectively. Early identification of issues in these domains may enhance referral for therapeutic interventions and family support programmes. Inherited metabolic disorders (IMD) are individually rare but overall are diagnosed in 1:318–1:3670 live births, depending on the population (Hutchesson et al. 1998; Dionisi-Vici et al. 2002; Aygen et al. 2014). The implementation of newborn screening and initiation of earlier treatment have decreased morbidity and mortality rates (Waisbren et al. 2003; Wilcken et al. 2009), yet some children remain vulnerable to ongoing ‘metabolic crises’. Parents need to constantly manage and monitor their children since poor management can affect physical and cognitive development (Hood et al. 2014), and some children may experience poor outcomes despite early treatment (Gr€unert et al. 2013; Waisbren et al. 2013). Thus, parents are faced with multiple stressors throughout the diagnosis period and beyond. Parents may experience a range of emotions at the diagnostic stage, such as guilt, anger, grief, sadness and worry for the future (Weber et al. 2012). Long-term burden includes changes in lifestyle due to dietary constraints, medication regimes and frequent visits to the medical centre – all of which affect family routines, relationships and parenting styles (Cederbaum et al. 2001; Hatzmann et al. 2009). IMD can lead to financial burden as much as emotional burden (Gramer et al. 2013). Some parents also report a type of ‘social burden’ regarding what friends, family and society may think about them and their parenthood Communicated by: Verena Peters Competing interests: None declared A. Brown (*) : L. Crowe :V. Anderson Murdoch Childrens Research Institute, Australian Centre for Child Neuropsychological Studies, Royal Children’s Hospital, Flemington Road, Parkville, Melbourne, VIC 3052, Australia e-mail: amy.brown@mcri.edu.au A. Brown :A. Boneh :V. Anderson Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia L. Crowe :V. Anderson Department of Psychology, Royal Children’s Hospital, Melbourne, VIC, Australia A. Boneh Metabolic Research, Murdoch Childrens Research Institute, Royal Childrens Hospital, Melbourne, VIC, Australia JIMD Reports DOI 10.1007/8904_2016_544

3-Hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is a rare inborn error of the valine catabolic pathway associated with Leigh-like disease. We report a female patient who presented at the age of 5months with hypotonia, developmental delay and cerebral atrophy on MRI. Pyruvate dehydrogenase deficiency was initially suspected and decreased activity was shown in fibroblasts. Urine tandem mass spectrometry screening showed large increases in the cysteine conjugate of methacrylate previously described in HIBCHD. 3-hydroxyisobutyryl-CoA hydrolase activity in fibroblasts was below the limit of detection of the enzymatic assay and two novel HIBCH mutations were identified (c.[129dupA];[1033G>A]). Urine metabolite investigations also showed increases in 3-hydroxyisobutyryl carnitine, 2,3-dihydroxy-2-methylbutyrate and several metabolites indicating accumulation and subsequent metabolism of methacrylyl-CoA and acryloyl-CoA. The metabolites derived from acryloyl-CoA were also increased in patients with inborn errors of propionyl-CoA metabolism, indicating the involvement of a secondary propionyl-CoA pathway utilising 3-hydroxyisobutyryl-CoA hydrolase. With the exception of 3-hydroxyisobutyryl carnitine, the metabolite abnormalities were essentially the same as those observed in patients with ECHS1 mutations, a recently described disorder that also affects valine metabolism. Our findings demonstrate the benefits of urine tandem mass spectrometry screening for diagnosing HIBCH and ECHS1 defects and that propionate metabolism may play a role in their pathogenesis. These disorders should be considered during the differential diagnosis of Leigh like-diseases and hypotonia.

BACKGROUND AND OBJECTIVE:Tandem mass spectrometry-based newborn screening (NBS) is a powerful screening tool. The NBS process includes sample collection, shipment, testing, analysis, reporting and communication with the infant's family. We explored the NBS programme-related factors that may delay diagnosis and may influence timely initiation of treatment in neonates who present before the screening results are available and therefore urgently need diagnosis and treatment. STUDY DESIGN:Detailed retrospective review of all data regarding sampling, shipment, testing and notification, contact with family and initiation of treatment of all neonates with disorders of fatty acid oxidation (FAO) and protein metabolism (PM), who presented clinically before NBS results were available, between 1-February-2002 and 31-January-2014. RESULTS:Of 847,418 newborns screened, 18 infants presented clinically before NBS results were available (FAO n = 9, median age 2.5 days; PM n = 9, median age 3 days). Samples were collected from 11 infants at age 48-72 h, as per instructions, and were received in the laboratory at a median age of 7 days (median 4 days from sample collection until receipt in the laboratory). Results were available within 24h in 16/18 infants. Treatment for a suspected metabolic disorder was initiated in seven infants before results were available. CONCLUSIONS:An audit of the programme procedures enabled the identification of issues that can be improved. Some patients benefited from the availability of results shortly after presentation. Good communication between the laboratory, the clinical metabolic specialist service and the primary treating team ensures timely initiation of treatment in these infants.

Steven Abman Anthony Absalom Thomas Abshire Wiliam Ackerman Margaret Adam Shawn K. Ahlfeld S.Faisal Ahmed Joseph L. Alcorn Eileen Steinle Alexander Omar Ali Geoffrey Ambler Istvan Arany J. Arciero Petra Clara Arck Moshe Arditi Guillaume Arlet H. Artac Stephen Ashwal Sara Aspberg Bakri Assas Chun Ting Au Renata Auricchio Richard Auten John E Baatz Tiziana Bachetti Carl Backes Praveen Ballabh Robert S. Baltimore Siddharth Banka Laura Banks Piers Barker James Barkovich Alberto Battezzati Beau Batton Olivier Baud Michel Baum Catherine Beauchemin S. Patricia Becerra Manon J. Benders Pere Berbel Anne Berg Ina bergheim Janet Elizabeth Berrington Carol Berseth Enrico Bertini Julia Beulertz Flavia Bezerra Vinod K Bhutani Marc B Bierings Stella Tracey Bjorkman Robert Black Heather Louise Blackmore Jorge Blanco Francis G Blankenberg David Bleich Joseph M. Bliss Jacky Bonaventure Avihu Boneh Riccardo Bonfanti Osvaldo Borrelli Arend F Bos Rodolfo Bracci Paolo Brambilla C Brendel Dora Brites Frank Brozovich David Elliott Brumbaugh Giacomina Brunetti Luc Bruyndonckx Karen Jane Bryson Vittoria Buccigrossi Sara Buckelew Daniel Bulte Giuseppe Buonocore David Burgner Jane C. Burns Will Bush Kara Calkins Angelo Salvatore Campanozzi Deborah Campbell Philippe Campeau Michael S. Caplan PJ Carey Waldemar A. Carlo Susan E. Carlson Virgilio P. Carnielli Marco Carotenuto David J Carr William J. Cashore Kevin A Cassady Gustavo Osvaldo Castaño Marco Castori Brian Catchpole Corrado Cecchetti Gediminas Cepinskas Lina F Chalak Wei-Chiao Chang Jennifer R Charlton Christiane Charriaut-Marlangue Raul Chavez-Valdez Fook-Choe Cheah Paul Checchia Henry Cheng Yiu Fai Cheung Terry W. Chin Valerie Y. Chock Rolando Cimaz Nevio Cimolai Tereza Cindrova-Davies Erika C. Claud Nelson Claure Pilar Codoñer-Franch Martine Cohen Solal John Connolly James Connor Giangennaro Coppola Luc Cornette Serena Counsell John M. Dagle Yun Dai Alexis S Davis Miles De Blasio Sarah D. De Ferranti Nicola De Luca Emanuella De Lucia Rolfe Linda S. de Vries Koert de Waal Charlotte Dean Justin Dean Sean Deane Roberta DeBiasi Tamas Decsi Andre Dejam Paul Delgado Olguin Christian Delles Eugene M. Dempsey Matthew Derrick Prasad Devarajan George A. Diaz Juliann DiFiore James DiNardo Lili Ding Jens Christian Djurhuus Franc C.L. Donkers Birgit Cornelia Donner Benard Dreyer Emma Gail Duerden Elia J. Duh Olivier Dulac Galit Dunietz Asim K K Duttaroy Michael B Dwinell David Eaton Danielle Ehret Barbara E Ehrlich Thomas Eiwegger Dawn Elder Maurizio Elia Nicholas Embleton Vibeke Ramsgaard Eriksen Erica A. Eugster Karen D. Fairchild Lir-Wan Fan Kathryn Noel Farrow Jia Feng Wu Rômulo Fernandes Mary S. Fewtrell Jeffrey R. Fineman Neil N. Finer I Fischbein Roslyn Holly Fitch V Flamand Brian W. Fleck Bobbi Fleiss Steven J. Fliesler Anna Forsberg P Forsythe William D. Foulkes Maria V. Fraga Mark Rohit Francis Axel Franz Mhoyra Fraser David Frommhold Richard Eugene Frye G Fueller Drude Fugelseth Ryoichi Fujiwara Camille Fung John Fuqua Sheila Gahagan Robert Galinsky Jorge Gallego Pediatr Res

s for the 39th Human Genetics Society of Australasia Annual Scientific Meeting Perth, Western Australia

Glutaric aciduria type I (GA-I) is an inherited metabolic disorder that may lead to severe motor disorder and cognitive impairment. GA-I is now included in the newborn screening programme in many countries as early detection allows for prompt treatment and effectively reduces the risk of poor developmental outcome. Information regarding the long-term neurodevelopmental outcome of children with GA-I treated early is sparse.We recruited children with a confirmed diagnosis of GAI diagnosed via newborn screening, treated in our centre and >3 years of age (n = 6). Children were assessed at two time points using a comprehensive neuropsychological test battery. Four of these had been the subject of a previous report. All participants were male, 3-6 years at the initial assessment and 6-12 years of age at the follow-up assessment.Fine motor skills were below average in all patients. Speech, which was affected in all four patients reported previously, improved following speech therapy. IQ scores remained generally stable within the normal range. Executive functioning was average to high average in four patients. Behaviour, as assessed through parental questionnaires, was problematic in two patients. Compounding factors included child neglect, family history of autism and multiple admissions to hospital (n = 1 in each).GA-I affects fine motor skills and speech, regardless of early treatment, but not IQ scores. Patients with GA-I should be referred for assessment and appropriate early intervention. Further research is needed to correlate specific neuropsychological deficits with neuroimaging.

Pyruvate dehydrogenase complex (PDHC) deficiency is a disorder of energy metabolism that leads to a range of clinical manifestations. We sought to characterise clinical manifestations and biochemical, neuroimaging and molecular findings in thiamine-responsive and nonresponsive PDHC-deficient patients and to identify potential pitfalls in the diagnosis of PDHC deficiency. We retrospectively reviewed all medical records of all PDHC-deficient patients (n - 19; all had PDHA1 gene mutations) and one patient with severe PDHC deficiency secondary to 3-hydroxyisobutyryl- CoA hydrolase deficiency managed at our centre between 1982 and 2012. Responsiveness to thiamine was based on clinical parameters. Seventeen patients received thiamine treatment: eight did not respond, four showed sustained response and the others responded temporarily/ questionably. Sustained response was noted at thiamine doses >400 mg/day. Age at presentation was 0-6 and 12-27 months in the nonresponsive (n - 8) and responsive n - 4) patients, respectively. Corpus callosum abnormalities were noted in 4/8 nonresponsive patients. Basal ganglia involvement (consistent with Leigh disease) was found in four patients (including 2/4 thiamine-responsive patients). Diagnosis through mutation analysis was more sensitive and specific than through enzymatic analysis. We conclude that patients presenting at age >12 months with relapsing ataxia and possibly Leigh syndrome are more likely to be thiamine responsive than those presenting with neonatal lactic acidosis and corpus callosum abnormalities. However, this distinction is equivocal and treatment with thiamine (>400 mg/day) should be commenced on all patients suspected of having PDHC deficiency. Mutation analysis is the preferable first-line diagnostic test to avoid missing thiamine-responsive patients and misdiagnosing patients with secondary PDHC deficiency.Short Summary: Thiamine responsiveness is more likely in patients presenting at age >12 months with relapsing ataxia and possibly Leigh syndrome than in those presenting with neonatal lactic acidosis and corpus callosum abnormalities. Thiamine doses >400 mg/day are required for sustained response. Mutation analysis is more sensitive and specific than enzymatic analysis as a first-line diagnostic test.