Impact of newborn screening for fatty acid oxidation disorders on neurological outcome: A Belgian retrospective and multicentric study.

Fatty acid oxidation (FAO) disorders are autosomal recessive genetic disorders affecting either the transport or the oxidation of fatty acids. Acute symptoms arise during prolonged fasting, intercurrent infections, or intense physical activity. Metabolic crises are characterized by alteration of consciousness, hypoglycemic coma, hepatomegaly, cardiomegaly, arrhythmias, rhabdomyolysis, and can lead to death. In this retrospective and multicentric study, the data of 54 patients with FAO disorders were collected. Overall, 35 patients (64.8%) were diagnosed after newborn screening (NBS), 17 patients on clinical presentation (31.5%), and two patients after family screening (3.7%). Deficiencies identified included medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (75.9%), very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (11.1%), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3.7%), mitochondrial trifunctional protein (MTP) deficiency (1.8%), and carnitine palmitoyltransferase 2 (CPT 2) deficiency (7.4%). The NBS results of 25 patients were reviewed and the neurological outcome of this population was compared with that of the patients who were diagnosed on clinical presentation. This article sought to provide a comprehensive overview of how NBS implementation in Southern Belgium has dramatically improved the neurological outcome of patients with FAO disorders by preventing metabolic crises and death. Further investigations are needed to better understand the physiopathology of long-term complications in order to improve the quality of life of patients and to ensure optimal management.

Clinical characteristics and related gene mutations of infants with short-chain acyl-CoA dehydrogenase deficiency by neonatal screening in Beijing.

OBJECTIVE: To investigate the clinical characteristics of infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) and related gene mutations in Beijing. METHODS: The acylcarnitine levels in the blood samples of 100 603 neonates in Beijing during August 2014 and March 2022 were measured by tandem mass spectrometry (MS/MS). The suspected SCADD neonates were rechecked by MS/MS, urine gas chromatography-mass spectrometry (GC/MS) and next-generation sequencing (NGS) for diagnosis. The clinical, biochemical and gene mutation characteristics of infants with SCADD were analyzed; the growth and intellectual development of these patients were observed regularly. RESULTS: Among 100 603 live births, the elevated C4 concentration or elevated C4/C3 ratio were detected in the initial screening from 196 neonates, and 131 were recalled. Five cases of SCADD were diagnosed with an incidence rate of 4.97/100 000 (1/20 121). There was no significant abnormality in clinical manifestations, however, the blood butyrylcarnitine (C4) level and the ratio of C4 to propionylcarnitine (C3) were raised in all diagnosed cases. Urinary organic acids were analyzed in 4 cases, all of whom had increased ethyl malonate acid levels. Seven mutations were detected in the ACADS gene, all of which were known missense mutations. One patient had homozygous mutation, and the others showed compound heterozygous mutations. No clinical symptoms were observed, and the physical and intellectual development was normal in all patients at a median age of 33 (4-40) months during follow-up. CONCLUSIONS: The incidence rate of SCADD was 1/20 121 in Beijing. Neonates with early diagnosis and without clinical symptoms usually have good prognosis.

Screening and follow-up results of neonate medium-chain acyl-CoA dehydrogenase deficiency in Zibo, Shandong province.

OBJECTIVE: To analyze the incidence, phenotype, genotype and prognosis of neonatal medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in Zibo city of Shandong province. METHODS: A total of 241 297 neonates were screened for MCADD in Zibo city of Shandong province from November 2013 to January 2022. Non-derivatized tandem mass spectrometry was used to detect blood free carnitine and acylcarnitine profiles in neonatal screening. Neonates with octanoylcarnitine (C8)≥0.25 µmol/L, or combined with C8/decanoylcarnitine (C10)≥1.5 were recalled, and second-generation high-throughput sequencing was performed for genetic diagnosis. RESULTS: Among 241 297 neonates, 6 cases of MCADD were screened, including 2 boys and 4 girls, with an incidence of 1/40 216. Two mutation sites of ACADM gene were identified in all MCADD infants, and 12 mutation with 8 types were detected in total. The hot spot mutations were c.449_452del (p.T150Rfs*4) and c.387+1delG， and exon 11 c.1076C>T (p.A359V) was a newly detected mutation. No phenotype-genotype correlation was found. One case died on day 4 after birth; 5 cases were followed up for 2 to 60 months, none of them received special diet treatment. The growth and intellectual development of the surviving cases were normal, and no abnormality was found in routine biochemical indicators. CONCLUSIONS: The incidence of MCADD in Zibo city seems to be higher than that in other areas in China. The ACADM gene mutations c.449_452del (p.T150Rfs*4) and c.387+1delG are common, and a new mutation c.1076C>T (p.A359V) has been detected. No phenotype-genotype correlation has been found. Early diagonsis and treatment are effective measures to reduce poor prognosis.

Newborn screening and genetic variation of medium chain acyl-CoA dehydrogenase deficiency in the Chinese population.

OBJECTIVES: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of the fatty acid oxidative metabolism. This study aimed to investigate the epidemiological characteristics, the spectrum of variation, clinical phenotype, and prognosis of MCADD in Chinese newborns. METHODS: We retrospectively analysed newborn screening (NBS) data in the Zibo area from January 2016 to March 2022 and summarized 42 cases recently reported in Chinese neonates. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and next-generation sequencing (NGS) were used to detect the concentrations of carnitine in the blood spots and for diagnosis. RESULTS: A total of 183,082 newborns were detected, and six patients were diagnosed with MCADD (1/3,0514). The primary octanoylcarnitine (C8) and the octanoylcarnitine/decanoylcarnitine ratio (C8/C10) were elevated in all patients. Gene analysis revealed four known and four novel variants of the ACADM gene. Five patients were asymptomatic and developed normally under dietary guidance. One child died of vaccination-induced MCADD, presenting with hypoglycemia and elevated acylcarnitines. CONCLUSIONS: The incidence of MCADD in Chinese newborns varies geographically from 1/222,903 to 1/30,514, and the most common pathogenic variant is c.449_452 del CTGA (p. T150Rfs∗4) in ACADM gene with a frequency of 27.7%. HPLC-MS/MS and genetic analysis are beneficial for early prevention and good prognosis of MCADD.

Analysis of gene mutations of medium-chain acyl-coenzyme a dehydrogenase deficiency (MCADD) by next-generation sequencing in Henan, China.

BACKGROUND: Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a rare inherited metabolic disorder of fatty acid ß-oxidation and one of the most common inborn errors of metabolism. The incidence of MCADD varies among regions and ethnic groups. To date, few cases of MCADD have been documented in China. OBJECTIVE: The present study aimed to find out the novel genetic pathogenic variants in the Chinese patients and evaluate the detection rate of the disease of high-frequency ACADM pathogenic variants in different regions of China. METHODS: 6 cases of MCADD were screened by tandem mass spectrometric (MS/MS) among 245 054 newborns. We performed next-generation sequencing on 6 families of infants with MCADD. We used the REVEL method to predict the protein function of the detected missense variants and used SPDBV 4.10 to predict the protein 3D structure model. We identified pathogenic variants of ACADM gene in 6 cases of MCADD, and then assessed these variants through Sanger sequencing and association analysis. RESULTS: The incidence of neonatal MCADD was 1/40,842 in Henan province. Among the 6 patients, five cases were compound heterozygous variants, one case was homozygous variants. DNA sequencing revealed 4 known (c.449_452del, c.1085G > A, c.1229 T > C, c.589A > G) and 3 novel mutations (c.849 + 5_849 + 8del, c.427A > G, c.1181C > T) in the ACADM gene. Mutation c.1085G > A (p.G362E) was most frequent among Henan people and shows obvious differences between North and South of China. CONCLUSION: MCADD is relatively rare in China, and c.1085G > A (p.G362E) is a common mutation in Henan population. Our findings, especially novel variants, will help improve the understanding of the genetic background and have facilitated clinical diagnosis and genetic counseling for the affected families.

Sudden neonatal death in individuals with medium-chain acyl-coenzyme A dehydrogenase deficiency: limit of newborn screening.

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial ß-oxidation of fatty acids resulting in hypoketotic hypoglycemia, hepatopathy, and often fatal outcome in undiagnosed children. Introduction of tandem mass spectrometry-based newborn screening programs in the late 1990s has significantly reduced morbidity and mortality in MCAD deficiency; however, neonatal death in individuals with early disease manifestation and severe hypoglycemia may still occur. We describe the fatal disease course in eight newborns with MCAD deficiency, aiming to raise awareness for early clinical symptoms and the life-saving treatment, and promote systematic post-mortem protocols for biochemical and genetic testing, necessary for correct diagnosis and counselling of the family if unexpected death occurred in the neonatal period.Conclusion: Early newborn screening and awareness for clinical symptoms is lifesaving in MCAD deficiency, which may present with fatal neonatal crisis. Systematic post-mortem diagnostic protocols are needed for sudden neonatal deaths.

Impact of Newborn Screening and Early Dietary Management on Clinical Outcome of Patients with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency and Medium Chain Acyl-CoA Dehydrogenase Deficiency-A Retrospective Nationwide Study.

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD/MTPD) and medium chain acyl-CoA dehydrogenase deficiency (MCADD) were included in the expanded neonatal screening program (ENBS) in Czechia in 2009, allowing for the presymptomatic diagnosis and nutritional management of these patients. The aim of our study was to assess the nationwide impact of ENBS on clinical outcome. This retrospective study analysed acute events and chronic complications and their severity in pre-ENBS and post-ENBS cohorts. In total, 28 children (12 before, 16 after ENBS) were diagnosed with LCHADD/MTPD (incidence 0.8/100,000 before and 1.2/100,000 after ENBS). In the subgroup detected by ENBS, a significantly longer interval from birth to first acute encephalopathy was observed. In addition, improvement in neuropathy and cardiomyopathy (although statistically non-significant) was demonstrated in the post-ENBS subgroup. In the MCADD cohort, we included 69 patients (15 before, 54 after ENBS). The estimated incidence rose from 0.7/100,000 before to 4.3/100,000 after ENBS. We confirmed a significant decrease in the number of episodes of acute encephalopathy and lower proportion of intellectual disability after ENBS (p < 0.0001). The genotype-phenotype correlations suggest a new association between homozygosity for the c.1528C > G variant and more severe heart involvement in LCHADD patients.

Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8.

BACKGROUND: Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder resulting from variants in ACAD8, and is poorly understood, as only dozens of cases have been reported previously. Based on a newborn screening program, we evaluated the incidence, phenotype and genotype of IBDD as well as the prognosis. Moreover, we reviewed the variant spectrum in ACAD8 associated with IBDD. METHODS: Forty unrelated patients with IBDD were retrospectively screened for newborns between Jan 2012 and Dec 2020. Tandem mass spectrometry (MS/MS) was used to determine the concentrations of C4-acylcarnitine, C4/C2 (acetylcarnitine), and C4/C3 (propionylcarnitine). All suspected cases were genetically tested by metabolic genes panel. RESULTS: The incidence of IBDD here was 1: 62,599. All patients presented continuously elevated C4-acylcarnitine levels with higher ratios of C4/C2 and C4/C3. Isobutyrylglycine occurred in only 8 patients. During follow-up, four patients had a transient motor delay, and two patients had growth delay. Notably, one case harbored both ACAD8 compound heterozygous variants and a KMT2A de novo variant (c.2739del, p.E914Rfs*35), with IBDD and Wiedemann-Steiner syndrome together, had exact severe global developmental delay. All patients were regularly monitored once they were diagnosed, and each patient gradually had a normal diet after 6 months of age. After 3-108 months of follow-up, most individuals were healthy except the case harboring the KMT2A variant. A total of 16 novel variants in ACAD8, c.4_5delCT, c.109C > T, c.110-2A > T, c.236G > A, c.259G > A, c.381-14G > A, c.413delA, c.473A > G, c.500delG, c.758 T > G, c.842-1G > A, c.911A > T, c.989G > A, c.1150G > C, c.1157A > G and c.1165C > T, were identified. Along with a literature review on 51 ACAD8 variants in 81 IBDD patients, we found that the most common variant was c.286G > A (27.2%), which has been observed solely in the Chinese population to date, followed by c.1000C > T (8.6%), c.1176G > T (3.7%) and c.455 T > C (3.1%). CONCLUSION: The concentration of C4-acylcarnitine in NBS plus subsequent genetic testing is necessary for IBDD diagnosis. Both the genotypes and ACAD8 variants in IBDD are highly heterogeneous, and no significant correlations between genotype and phenotype are present here in patients with IBDD. Our IBDD cohort with detaied clinical characteristics, genotypes and long-term prognosis will be helpful for the diagnosis and management of patients with IBDD in the future.

Development and characterization of a mouse model for Acad9 deficiency.

Acyl CoA Dehydrogenase 9 (ACAD9) is a member of the family of flavoenzymes that catalyze the dehydrogenation of acyl-CoAs to 2,3 enoyl-CoAs in mitochondrial fatty acid oxidation (FAO). Inborn errors of metabolism of all family members, including ACAD9, have been described in humans, and represent significant causes of morbidity and mortality particularly in children. ACAD9 deficiency leads to a combined defect in fatty acid oxidation and oxidative phosphorylation (OXPHOS) due to a dual role in the pathways. In addition to its function in mitochondrial FAO, ACAD9 has a second function as one of 14 factors responsible for assembly of complex I of the electron transport chain (ETC). Considerable controversy remains over the relative role of these two functions in normal physiology and the disparate clinical findings described in patients with ACAD9 deficiency. To better understand the normal function of ACAD9 and the pathophysiology of its deficiency, several knock out mouse models were developed. Homozygous total body knock out appeared to be lethal as no ACAD9 animals were obtained. Cre-lox technology was then used to generate tissue-specific deletion of the gene. Cardiac-specific ACAD9 deficient animals had severe neonatal cardiomyopathy and died by 17 days of age. They had severe mitochondrial dysfunction in vitro. Muscle-specific mutants were viable but exhibited muscle weakness. Additional studies of heart muscle from the cardiac specific deficient animals were used to examine the evolutionarily conserved signaling Intermediate in toll pathway (ECSIT) protein, a known binding partner of ACAD9 in the electron chain complex I assembly pathway. As expected, ECSIT levels were significantly reduced in the absence of ACAD9 protein, consistent with the demonstrated impairment of the complex I assembly. The various ACAD9 deficient animals should serve as useful models for development of novel therapeutics for this disorder.

Core Outcome Sets for Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Phenylketonuria.

BACKGROUND: Evidence to guide treatment of pediatric medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) is fragmented because of large variability in outcome selection and measurement. Our goal was to develop core outcome sets (COSs) for these diseases to facilitate meaningful future evidence generation and enhance the capacity to compare and synthesize findings across studies. METHODS: Parents and/or caregivers, health professionals, and health policy advisors completed a Delphi survey and participated in a consensus workshop to select core outcomes from candidate lists of outcomes for MCAD deficiency and PKU. Delphi participants rated the importance of outcomes on a nine-point scale (1-3: not important, 4-6: important but not critical, 7-9: critical). Candidate outcomes were progressively narrowed down over 3 survey rounds. At the workshop, participants evaluated the remaining candidate outcomes using an adapted nominal technique, open discussion, and voting. After the workshop, we finalized the COSs and recommended measurement instruments for each outcome. RESULTS: There were 85, 61, and 53 participants across 3 Delphi rounds, respectively. The candidate core outcome lists were narrowed down to 20 outcomes per disease to be discussed at the consensus workshop. Voting by 18 workshop participants led to COSs composed of 8 and 9 outcomes for MCAD deficiency and PKU, respectively, with measurement recommendations. CONCLUSIONS: These are the first known pediatric COSs for MCAD deficiency and PKU. Adoption in future studies will help to ensure best use of limited research resources to ultimately improve care for children with these rare diseases.

Variants in the ethylmalonyl-CoA decarboxylase (ECHDC1) gene: a novel player in ethylmalonic aciduria?

Ethylmalonic acid (EMA) is a major and potentially cytotoxic metabolite associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency, a condition whose status as a disease is uncertain. Unexplained high EMA is observed in some individuals with complex neurological symptoms, who carry the SCAD gene (ACADS) variants, c.625G>A and c.511C>T. The variants have a high allele frequency in the general population, but are significantly overrepresented in individuals with elevated EMA. This has led to the idea that these variants need to be associated with variants in other genes to cause hyperexcretion of ethylmalonic acid and possibly a diseased state. Ethylmalonyl-CoA decarboxylase (ECHDC1) has been described and characterized as an EMA metabolite repair enzyme, however, its clinical relevance has never been investigated. In this study, we sequenced the ECHDC1 gene (ECHDC1) in 82 individuals, who were reported with unexplained high EMA levels due to the presence of the common ACADS variants only. Three individuals with ACADS c.625G>A variants were found to be heterozygous for ECHDC1 loss-of-function variants. Knockdown experiments of ECHDC1, in healthy human cells with different ACADS c.625G>A genotypes, showed that ECHDC1 haploinsufficiency and homozygosity for the ACADS c.625G>A variant had a synergistic effect on cellular EMA excretion. This study reports the first cases of ECHDC1 gene defects in humans and suggests that ECHDC1 may be involved in elevated EMA excretion in only a small group of individuals with the common ACADS variants. However, a direct link between ECHDC1/ACADS deficiency, EMA and disease could not be proven.

Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China.

OBJECTIVES: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. METHODS: From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. RESULTS: Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). CONCLUSIONS: These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.

Coexistence of medium chain acyl-CoA dehydrogenase deficiency (MCADD) and type 1 diabetes (T1D): a management challenge.

Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive fatty acid ß-oxidation defect. The enzyme, medium chain acyl-CoA dehydrogenase is important in the breakdown of medium chain fats into acetyl-CoA to produce ketones. Ketones are used as an alternative energy source when glucose or hepatic glycogen stores become depleted during prolonged fasting. In MCADD during periods of fasting or acute illness, there are insufficient ketones to compensate for the glucose energy deficit, resulting in an hypoketotic hypoglycaemia alongside a build-up of fatty acids. This build-up of fatty acids can be neurotoxic and lead to altered brain function and even unexpected death. Management includes avoiding prolonged periods of starvation, consuming high carbohydrate drinks during periods of illness and in symptomatic patients, reversal of catabolism and sustained anabolism by provision of simple carbohydrates by mouth or intravenously. Coexistence of MCADD and type 1 diabetes (T1D) is rare, there is no causal association though there are some documented cases. A key goal of management in T1D is achievement of good glycaemic control to reduce risk of long-term complications. This can in some cases increase the risk of hypoglycaemia which can be catastrophic in the presence of MCAD.

The Genetics of Sudden Infant Death Syndrome-Towards a Gene Reference Resource.

Sudden infant death syndrome (SIDS) is the unexpected death of an infant under one year of age that remains unexplained after a thorough investigation. Despite SIDS remaining a diagnosis of exclusion with an unexplained etiology, it is widely accepted that SIDS can be caused by environmental and/or biological factors, with multiple underlying candidate genes. However, the lack of biomarkers raises questions as to why genetic studies on SIDS to date are unable to provide a clearer understanding of the disease etiology. We sought to improve the identification of SIDS-associated genes by reviewing the SIDS genetic literature and objectively categorizing and scoring the reported genes based on the strength of evidence (from C1 (high) to C5 (low)). This was followed by analyses of function, associations between genes, the enrichment of gene ontology (GO) terms, and pathways and gender difference in tissue gene expression. We constructed a curated database for SIDS gene candidates consisting of 109 genes, 14 of which received a category 4 (C4) and 95 genes received the lowest category of C5. That none of the genes was classified into the higher categories indicates the low level of supporting evidence. We found that genes of both scoring categories show distinct networks and are highly diverse in function and involved in many GO terms and pathways, in agreement with the perception of SIDS as a heterogeneous syndrome. Genes of both scoring categories are part of the cardiac system, muscle, and ion channels, whereas immune-related functions showed enrichment for C4 genes. A limited association was found with neural development. Overall, inconsistent reports and missing metadata contribute to the ambiguity of genetic studies. Considering those parameters could help improve the identification of at-risk SIDS genes. However, the field is still far from offering a full-pledged genetic test to identify at-risk infants and is still hampered with methodological challenges and misunderstandings of the vulnerabilities of vital biological mechanisms.

Genotype and residual enzyme activity in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: Are predictions possible?

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of mitochondrial ß-oxidation. Confirmation diagnostics after newborn screening (NBS) can be performed either by enzyme testing and/or by sequencing of the ACADM gene. Here, we report the results from enzyme testing in lymphocytes with gene variants from molecular analysis of the ACADM gene and with the initial acylcarnitine concentrations in the NBS sample. From April 2013 to August 2019, in 388 individuals with characteristic acylcarnitine profiles suggestive of MCADD the octanoyl-CoA-oxidation was measured in lymphocytes. In those individuals with residual activities <50%, molecular genetic analysis of the ACADM gene was performed. In 50% of the samples (195/388), MCADD with a residual activity ranging from 0% to 30% was confirmed. Forty-five percent of the samples (172/388) showed a residual activity >35% excluding MCADD. In the remaining 21 individuals, MCAD residual activity ranged from 30% to 35%. The latter group comprised both heterozygous carriers and individuals carrying two gene variants on different alleles. Twenty new variants could be identified and functionally classified based on their effect on enzyme function. C6 and C8 acylcarnitine species in NBS correlated with MCAD activity and disease severity. MCADD was only confirmed in half of the cases referred suggesting a higher false positive rate than expected. Measurement of the enzyme function in lymphocytes allowed fast confirmation diagnostics and clear determination of the pathogenicity of new gene variants. There is a clear correlation between genotype and enzyme function underlining the reproducibility of the functional measurement in vitro.

Unexpected elevation in valproic acid concentration and agranulocytosis in a patient with short-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an autosomal recessive metabolic disorder or condition of fatty acid ß-oxidation, caused by mutations in the gene encoding SCAD (ACADS). We report an infant with SCAD deficiency who unexpectedly exhibited an extremely high blood concentration of valproic acid (VPA) and agranulocytosis. CASE REPORT: An 8-month-old girl was diagnosed with West syndrome (infantile spasms), and VPA was administered at the standard level of 25 mg/kg/day. However, the blood concentration of VPA rose unexpectedly to 230 µg/mL (two- to three-fold higher than the expected value), and continued to remain relatively high even after the dosage was reduced (7 mg/kg/day, blood concentration of 88 µg/mL). Furthermore, she presented with a high-grade fever with agranulocytosis (neutrophil 231/µL). The abnormal pharmacokinetics and toxicity of VPA raised the suspicion of possible inborn errors of metabolism in the fatty acid ß-oxidation pathway. Blood tandem mass spectrometry revealed a transient elevation of C4, and urine gas chromatography-mass spectrometry revealed a continuous elevation of ethylmalonate. Finally, gene analysis revealed compound heterozygous mutations, c.625G > A (p.G209S) and c.1031A > G (p.E344G), in ACADS. CONCLUSION: VPA should be avoided if a patient is suspected to have inborn errors of ß-oxidation including SCAD deficiency.

Isobutyryl-CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report.

BACKGROUND: Isobutyryl-CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched-chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl-CoA dehydrogenase deficiency (IBDD), which is identified by increased C4-acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. METHODS: Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature. RESULTS: To assess whether a phenotype-genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4-acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups. CONCLUSION: As in our proband, trio whole exome sequencing did not establish an alternative secondary genetic diagnosis for autism, and reported long-term follow-up of IBDD patients is limited, it is possible that autism spectrum disorders could be one of the disease-associated features. Further long-term follow-up is suggested in order to delineate the full clinical spectrum associated with IBDD.