Remimazolam Anesthesia for a Pediatric Patient With Glutaric Aciduria Type I: A Case Report.

Glutaric aciduria type I (GA-1) is a rare metabolic disorder caused by an autosomal, recessive, inherited deficiency of glutaryl-CoA dehydrogenase. Reports on the anesthetic management of patients with GA-1 are limited. It has been suggested that inhalation anesthesia is safer than propofol due to the mitochondrial dysfunction inherent in GA-1. However, inhalation anesthesia poses a risk, albeit rare, of malignant hyperthermia, which can result in severe neurological damage in GA-1 patients. Therefore, we considered that management using remimazolam might be effective and, provided a successful general anesthesia using it for a pediatric patient with GA-1. We report a case of a four-year-old girl with GA-1 who underwent a laparoscopic gastrostomy under general anesthesia. Remimazolam was used for both induction and maintenance of anesthesia. Our perioperative management also included measures to prevent a hypercatabolic condition such as adequate hydration and blood glucose control. The patient had an uneventful perioperative course and was discharged on postoperative day 7. Thus, remimazolam is proposed as a new option for anesthetic management in patients with GA-1. Additionally, tailored perioperative management that addresses the unique characteristics of GA-1 is crucial for favorable outcomes.

Determination of the Protein and Amino Acid Content of Fruit, Vegetables and Starchy Roots for Use in Inherited Metabolic Disorders.

Amino acid (AA)-related inherited metabolic disorders (IMDs) and urea cycle disorders (UCDs) require strict dietary management including foods low in protein such as fruits, vegetables and starchy roots. Despite this recommendation, there are limited data on the AA content of many of these foods. The aim of this study is to describe an analysis of the protein and AA content of a range of fruits, vegetables and starchy roots, specifically focusing on amino acids (AAs) relevant to AA-related IMDs such as phenylalanine (Phe), methionine (Met), leucine (Leu), lysine (Lys) and tyrosine (Tyr). AA analysis was performed using high-performance liquid chromatography (HPLC) on 165 food samples. Protein analysis was also carried out using the Dumas method. Foods were classified as either 'Fruits', 'Dried fruits', 'Cruciferous vegetables', 'Legumes', 'Other vegetables' or 'Starchy roots'. 'Dried fruits' and 'Legumes' had the highest median values of protein, while 'Fruits' and 'Cruciferous vegetables' contained the lowest median results. 'Legumes' contained the highest and 'Fruits' had the lowest median values for all five AAs. Variations were seen in AA content for individual foods. The results presented in this study provide useful data on the protein and AA content of fruits, vegetables and starchy roots which can be used in clinical practice. This further expansion of the current literature will help to improve diet quality and metabolic control among individuals with AA-related IMDs and UCDs.

Whole exome sequencing reveals a dual diagnosis of BCAP31-related syndrome and glutaric aciduria III.

Background: Biochemical testing is a common first-tier approach in the setting of genetic evaluation of patients with unexplained developmental delay. However, results can be unclear, and a plan for second-tier analysis must be determined based on the patient's biochemical results and clinical presentation - in many cases, triggering a diagnostic odyssey. Case presentation: A male patient from the United States presenting with unexplained developmental delay, microcephaly, hypotonia, and feeding difficulties was referred for clinical genetic evaluation at age 8 months. Biochemical testing revealed an isolated marked elevation of glutaric acid on urine organic acid profile, without elevations of related metabolites. Further testing included GCDH sequencing, a neurometabolic gene panel, chromosomal microarray, Prader Willi/Angelman testing, and lysosomal disease enzyme panel, all of which were non-diagnostic. The patient had persistent developmental delay and hypotonia, dystonia, sensorineural hearing loss, and abnormal brain myelination on magnetic resonance imaging. Whole exome sequencing (WES) was performed and revealed a dual diagnosis of glutaric aciduria III (GA III) and BCAP31-related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant. Conclusions: GA III has historically been considered clinically benign, with few reported cases. This patient's presenting symptoms were similar to those commonly seen in GA I and GA II, however the biochemical abnormalities were not consistent with these disorders, prompting additional molecular and biochemical testing. Ultimately, WES confirmed a diagnosis of BCAP31-related syndrome, a rare neurological disorder, which explained the patient's presenting symptoms. WES also identified a secondary diagnosis of GA III. We present a patient with two rare genetic conditions, highlighting the importance of deep phenotyping and the utility of WES in the setting of a patient with dual genetic diagnoses.

Clinical features and GCDH gene variants in three Chinese families with glutaric aciduria type 1: A case series and literature review.

Aim: To analyze the clinical phenotype and genetic etiology of three cases of glutaric aciduria type 1 (GA1) in Chinese children. Methods: We performed genetic and metabolic testing using tandem mass spectrometry (MS/MS) and gas chromatography-mass spectrometry (GC/MS), followed by trio whole-exome sequencing (trio-WES) and Sanger sequencing. A literature review on glutaric aciduria type 1 (GA1) in Chinese patients was also conducted. Results: Sequencing results showed each case had compound heterozygous variants in GCDH(NM_000159.4): c.214C > G (p.Arg72Gly) and c.411C > G (p.Tyr137Term) (Case 1), c.214C > G (p.Arg72Gly) and c.1204C > T (p.Arg402Trp) (Case 2), and c.1228G > T (p.Val410Leu) and c.395G > A (p.Arg132Gln) (Case 3). These variants were inherited from their respective parents. Notably, the c.214C > G variant found in two children was a novel variant not previously reported. A review of the literature revealed that, clinically, the majority of patients experienced onset in infancy and early childhood (82%). Additionally, 38.36% were diagnosed through newborn screening, with the primary reasons for the initial visit being delayed development (32.43%) and infections (21.61%). The most common clinical manifestations included increased head circumference (77.19%) and motor developmental delay (65.15%). Biochemically, patients exhibited significant elevations in C5DC (98.51%) and C5DC/C8 (94.87%) in blood, as well as GA (94.37%) and 3OHGA (69.39%) in urine. Radiographically, patients showed a high prevalence of abnormalities in cranial MRI (86.15%) and EEG (73.33%). Genetically, 67 distinct GCDH gene variants were identified among 73 patients, with missense variants being the most prevalent type (73.97%). The most frequent variant was c.1244-2 A > C, observed in 17.12% of cases. Additionally, the majority of variant sites were located in exons 11 (25.37%) and 6 (22.39%). Conclusion: GCDH variants were identified as the causative factors in the three children. The discovery of the novel variant (c.214C > G) expands the spectrum of pathogenic GCDH variants. These findings facilitate the diagnosis and treatment of affected children and provide a basis for genetic counseling and prenatal diagnosis for their families.

A compound heterozygote case of glutaric aciduria type II in a patient carrying a novel candidate variant in ETFDH gene: A case report and literature review on compound heterozygote cases.

BACKGROUND: Glutaric aciduria type II (GA2) is a rare genetic disorder inherited in an autosomal recessive manner. Double dosage mutations in GA2 corresponding genes, ETFDH, ETFA, and ETFB, lead to defects in the catabolism of fatty acids, and amino acids lead to broad-spectrum phenotypes, including muscle weakness, developmental delay, and seizures. product of these three genes have crucial role in transferring electrons to the electron transport chain (ETC), but are not directly involve in ETC complexes. METHODS: Here, by using exome sequencing, the cause of periodic cryptic gastrointestinal complications in a 19-year-old girl was resolved after years of diagnostic odyssey. Protein modeling for the novel variant served as another line of validation for it. RESULTS: Exome Sequencing (ES) identified two variants in ETFDH: ETFDH:c.926T>G and ETFDH:c.1141G>C. These variants are likely contributing to the crisis in this case. To the best of our knowledge at the time of writing this manuscript, variant ETFDH:c.926T>G is reported here for the first time. Clinical manifestations of the case and pathological analysis are in consistent with molecular findings. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant. ETFDH:c.926T>G is reported here for the first time in relation to the causation GA2. CONCLUSION: Given the milder symptoms in this case, a review of GA2 cases caused by compound heterozygous mutations was conducted, highlighting the range of symptoms observed in these patients, from mild fatigue to more severe outcomes. The results underscore the importance of comprehensive genetic analysis in elucidating the spectrum of clinical presentations in GA2 and guiding personalized treatment strategies.

Long-term use of investigational ß-Hydroxybutyrate salts in children with multiple acyl-CoA dehydrogenase or pyruvate dehydrogenase deficiency.

Several disorders of energy metabolism have been treated with exogenous ketone bodies. The benefit of this treatment is best documented in multiple acyl-CoA dehydrogenase deficiency (MADD) (MIM#231680). One might also expect ketone bodies to help in other disorders with impaired ketogenesis or in conditions that profit from a ketogenic diet. Here, we report the use of a novel preparation of dextro-ß-hydroxybutyrate (D-ßHB) salts in two cases of MADD and one case of pyruvate dehydrogenase (PDH) deficiency (MIM#312170). The two patients with MADD had previously been on a racemic mixture of D- and L­sodium hydroxybutyrate. Patient #1 found D-ßHB more palatable, and the change in formulation corrected hypernatraemia in patient #2. The patient with PDH deficiency was on a ketogenic diet but had not previously been given hydroxybutyrate. In this case, the addition of D-ßHB improved ketosis. We conclude that NHS101 is a good candidate for further clinical studies in this group of diseases of inborn errors of metabolism.

Getting the diagnostic clue, role of MRI in the diagnosis of type 1 Glutaric aciduria in resource-limited settings.

Glutaric aciduria type 1 is a rare autosomal recessive disorder caused by a deficiency of glutaryl-CoA dehydrogenase, which is the key mitochondrial enzyme involved in the final degradation of lysine, L-hydroxylysine, and L-tryptophan. It is an inherited organic acidemia characterized by macrocephaly and dystonia, which results in high morbidity and mortality. In resource-limited countries like Nepal, where enzyme assays are not available, MRI has a great role to play in supporting diagnosis in such situations. Here, we present 2 cases of glutaric aciduria type 1 in brothers from the same parent that were diagnosed by MRI, and subsequent diet modification and L-carnitine therapy led to improvement of clinical symptoms.

Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model.

Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disorder caused by a deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), with accumulation of neurotoxic metabolites, resulting in a complex movement disorder, irreversible brain damage, and premature death in untreated individuals. While early diagnosis and a lysine restricted diet can extend survival, they do not prevent neurological damage in approximately one-third of treated patients, and more effective therapies are required. Here we report the efficacy of adeno-associated virus 9 (AAV9)-mediated systemic delivery of human GCDH at preventing a high lysine diet (HLD)-induced phenotype in Gcdh -/- mice. Neonatal treatment with AAV-GCDH restores GCDH expression and enzyme activity in liver and striatum. This treatment protects the mice from HLD-aggressive phenotype with all mice surviving this exposure; in stark contrast, a lack of treatment on an HLD triggers very high accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, with about 60% death due to brain accumulation of toxic lysine metabolites. AAV-GCDH significantly ameliorates the striatal neuropathology, minimizing neuronal dysfunction, gliosis, and alterations in myelination. Magnetic resonance imaging findings show protection against striatal injury. Altogether, these results provide preclinical evidence to support AAV-GCDH gene therapy for GA1.

Molecular genetic analysis of candidate genes for glutaric aciduria type II in a cohort of patients from Queensland, Australia.

Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.

Dried Blood Spot Postmortem Metabolic Autopsy With Genotype Validation for Sudden Unexpected Deaths in Infancy and Childhood in Hong Kong.

Background Inborn errors of metabolism (IEM) are collectively rare but potentially preventable causes of sudden unexpected death (SUD) in infancy or childhood, and metabolic autopsy serves as the final tool for establishing the diagnosis. We conducted a retrospective review of the metabolic and molecular autopsy on SUD and characterized the biochemical and genetic findings. Methodology A retrospective review of postmortem metabolic investigations (dried blood spot acylcarnitines and amino acid analysis, urine metabolic profiling where available, and next-generation sequencing on a panel of 75 IEM genes) performed for infants and children who presented with SUD between October 2016 and December 2021 with inconclusive autopsy findings or autopsy features suspicious of underlying IEM in our locality was conducted. Clinical and autopsy findings were reviewed for each case. Results A total of 43 infants and children aged between zero days to 10 years at the time of death were referred to the authors' laboratories throughout the study period. One positive case of multiple acyl-CoA dehydrogenase deficiency was diagnosed. Postmortem reference intervals for dried blood spot amino acids and acylcarnitines profile were established based on the results from the remaining patients. Conclusions Our study confirmed the importance of metabolic autopsy and the advantages of incorporating biochemical and genetic testing in this setting.

The evaluation of inherited metabolic diseases presenting with rhabdomyolysis from Turkey: Single center experience.

Aim: It was aimed to identify markers that would indicate which cases presenting with rhabdomyolysis are more likely to be associated with inherited metabolic diseases. Methods: We analyzed 327 children who applied to our Hospital Pediatric Nutrition and Metabolic Diseases Clinic with rhabdomyolysis. The diagnosis of rhabdomyolysis was made by measuring the serum creatinine kinase level in cases presenting with muscle pain, weakness and dark urine. Results: Metabolic disease was detected in 29 (16/13, M/F) patients from 26 different families. 298 patients (165/133, M/F) had normal metabolic work-up. We detected glutaric aciduria type 2 in 13 patients (44,6%), glycogen storage disease type 5 in three patients (10,3%), MCAD deficiency in three patients(10,3%), mitochondrial disease in three patients (10,3%), glycogen storage disease type 9 in one patient (3,5%), VLCAD deficiency in one patient (3,5%), LCHAD deficiency in one patient (3,5%), CPT2 deficiency in one patient(3,5%), Tango2 deficiency in one patient (3,5%), lipin-1 deficiency in one patient (3,5%) and primary carnitine deficiency in one patient (3,5%). Conclusion: In our study, consanguineous marriage, developmental delay, and intellectual disability were found more frequently in patients with metabolic disease. In addition, CK levels above 2610 U/L was found to be significantly correlated with metabolic disease.

Navigating the Diagnostic Journey in Pediatric Gastroenterology: Decoding Recurrent Vomiting and Epigastric Pain in a Child with Glutaric Aciduria Type II.

BACKGROUND: Glutaric aciduria type II (GA II), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is a rare autosomal recessive metabolic disorder with varied manifestations and onset ages. CASE REPORT: This study presents a distinctive case of a 10-year-old girl who experienced episodic, intermittent vomiting and epigastric pain, particularly aggravated by high-fat and sweet foods. Despite inconclusive physical examinations and routine laboratory tests, and an initial suspicion of cyclic vomiting syndrome, the persistence of recurrent symptoms and metabolic abnormalities (metabolic acidosis and hypoglycemia) during her third hospital admission necessitated further investigation. Advanced diagnostic tests, including urinary organic acid analysis and genetic testing, identified heterozygous pathogenic variants in the ETFDH gene, confirming a diagnosis of GA IIc. The patient showed a positive response to a custom low-protein, low-fat diet supplemented with carnitine and riboflavin. SIGNIFICANCE: This case emphasizes the diagnostic challenges associated with recurrent, nonspecific gastrointestinal symptoms in pediatric patients, particularly in differentiating between common gastrointestinal disorders and rare metabolic disorders like GA II. It highlights the importance of considering a broad differential diagnosis to enhance understanding and guide future medical approaches in similar cases.

Comprehensive metabolomics analysis reveals novel biomarkers and pathways in falsely suspected glutaric aciduria Type-1 newborns.

BACKGROUND: Glutaric aciduria type-1 (GA-1) is a rare metabolic disorder due to glutaryl coenzyme A dehydrogenase deficiency, causing elevated levels of glutaryl-CoA and its derivatives. GA-1 exhibits symptoms like macrocephaly, developmental delays, and movement disorders. Timely diagnosis through genetic testing and newborn screening is crucial. However, in some cases, transiently elevated level of glutarylcarnitine (C5DC) challenges accurate diagnosis, highlighting the need for alternative diagnostic methods, like mass spectrometry-based untargeted metabolomics, to identify additional biomarkers for distinguishing falsely suspected GA-1 from healthy newborns. METHODOLOGY: DBS samples from falsely suspected GA-1 newborns (n = 47) and matched control were collected through the NBS program. Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was performed to enable biomarker and pathway investigations for significantly altered metabolites. RESULTS: 582 and 546 were up- and down-regulated metabolites in transient GA-1. 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-palmitoylcysteine, heptacarboxyporphyrin, 3-hydroxylinoleoylcarnitine, and monoacylglyceride (MG) (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient elevated C5DC levels in DBS samples. CONCLUSIONS: A distinct metabolic pattern linked to the transient C5DC elevation in newborns was reported to enhance the prediction of the falsely positive cases, which could help avoiding unnecessary medical treatments and minimizing the financial burdens in the health sector.

Fatal cervical myelopathy in a child with glutaric aciduria type 1.

We report the case of a Syrian female refugee with late diagnosis of glutaric aciduria type 1 characterised by massive axial hypotonia and quadriplegia who only started adequate diet upon arrival in Switzerland at the age of 4 years, after a strenuous migration journey. Soon after arrival, she died from an unexpected severe upper cervical myelopathy, heralded by acute respiratory distress after a viral infection. This was likely due to repeated strains on her hypotonic neck and precipitated by an orthotopic os odontoideum who led to atlanto-axial subluxation. This case reminds us not to omit handling patients with insufficient postural control and hypotonia with great care to avoid progressive cervical myelopathy.

Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period. The aim was to extensively profile the clinical, biochemical, and genomic characteristics of MADD in this understudied population. METHODS: Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations. RESULTS: Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH, with SA population-specific allele frequencies of < 0.00067-0.00084%. CONCLUSIONS: This study reveals the first extensive genotype-phenotype profile of a MADD patient cohort from the diverse and understudied SA population. The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.

Compilation of Genotype and Phenotype Data in GCDH-LOVD for Variant Classification and Further Application.

Glutaric aciduria type 1 (GA-1) is a rare but treatable autosomal-recessive neurometabolic disorder of lysin metabolism caused by biallelic pathogenic variants in glutaryl-CoA dehydrogenase gene (GCDH) that lead to deficiency of GCDH protein. Without treatment, this enzyme defect causes a neurological phenotype characterized by movement disorder and cognitive impairment. Based on a comprehensive literature search, we established a large dataset of GCDH variants using the Leiden Open Variation Database (LOVD) to summarize the known genotypes and the clinical and biochemical phenotypes associated with GA-1. With these data, we developed a GCDH-specific variation classification framework based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. We used this framework to reclassify published variants and to describe their geographic distribution, both of which have practical implications for the molecular genetic diagnosis of GA-1. The freely available GCDH-specific LOVD dataset provides a basis for diagnostic laboratories and researchers to further optimize their knowledge and molecular diagnosis of this rare disease.

Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1.

Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. We aimed to elucidate the molecular basis of protein loss of function in GA1 by performing a parallel analysis in a large panel of GCDH missense variants using different biochemical and biophysical methodologies. Thirteen GCDH variants were investigated in regard to protein stability, hydrophobicity, oligomerization, aggregation, and activity. An altered oligomerization, loss of protein stability and solubility, as well as an augmented susceptibility to aggregation were observed. GA1 variants led to a loss of enzymatic activity, particularly when present at the N-terminal domain. The reduced cellular activity was associated with loss of tetramerization. Our results also suggest a correlation between variant sequence location and cellular protein stability (p < 0.05), with a more pronounced loss of protein observed with variant proximity to the N-terminus. The broad panel of variant-mediated conformational changes of the GCDH protein supports the classification of GA1 as a protein-misfolding disorder. This work supports research toward new therapeutic strategies that target this molecular disease phenotype.

"Liver Failure in an Infant of Late-Onset Glutaric Aciduria Type II": Case Report.

Glutaric aciduria type II, also known as Multiple acyl-CoA Dehydrogenase Deficiency, results from a defect in the mitochondrial electron transport chain resulting in an inability to break down fatty-acids and amino acids. There are three phenotypes- type 1 and 2 are of neonatal onset and severe form, with and without congenital anomalies, respectively, and presents with acidosis, severe hypotonia, cardiomyopathy, hepatomegaly, and non-ketotic hypoglycemia. Type 3 or late-onset Multiple acyl-CoA Dehydrogenase Deficiency usually presents in the adolescent or adult age group with phenotype ranging from mild forms of myopathy and exercise intolerance to severe forms of acute metabolic decompensation on its chronic course. Type 3 Multiple acyl-CoA Dehydrogenase Deficiency rarely presents in infancy and in liver failure. We present a five-month-old developmentally normal female child with acute encephalopathy, hypotonia, non-ketotic hypoglycemia, metabolic acidosis, and liver failure, with a history of sibling death of suspected inborn error of metabolism. The blood acyl-carnitine levels in Tandem Mass Spectrometry and urinary organic acid analysis through Gas Chromatography-Mass Spectrometry were unremarkable. The patient initially responded to riboflavin, CoQ, and supportive management but ultimately succumbed to sepsis with shock and multi-organ dysfunction. The clinical exome sequencing reported a homozygous missense variation in exon 11 of the ETFDH gene (chr4:g.158706270C > T) that resulted in the amino acid substitution of Leucine for Proline at codon 456 (p.Pro456Leu) suggestive of Glutaric aciduria type IIc (OMIM#231,680).

Breastfeeding and Inborn Errors of Amino Acid and Protein Metabolism: A Spreadsheet to Calculate Optimal Intake of Human Milk and Disease-Specific Formulas.

Human milk (HM) offers important nutritional benefits. However, except for phenylketonuria (PKU), there are little data on optimal levels of consumption of HM and a special formula free of disease-related amino acids (SF-AA) in infants with inborn errors of metabolism of amino acids and proteins (IEM-AA-P). We designed a spreadsheet to calculate the amounts of SF-AA and HM required to cover amino acid, protein, and energy needs in patients with the nine main IEM-AA-P in infants aged under 6 months. Upon entering the infant's weight and the essential amino acid or intact protein requirements for the specific IEM, the spreadsheet calculates the corresponding required volume of HM based on the amino acid concentration in HM. Next, the theoretical daily fluid intake (typical range, 120-200 mL/kg/day) is entered, and the estimated daily fluid intake is calculated. The required daily volume of SF-AA is calculated as the difference between the total fluid intake value and the calculated volume of HM. The spreadsheet allows for the introduction of a range of requirements based on the patient's metabolic status, and includes the option to calculate the required volume of expressed HM, which may be necessary in certain conditions such as MMA/PA and UCD. In cases in which breastfeeding on demand is feasible, the spreadsheet determines the daily amount of SF-AA divided over 6-8 feeds, assuming that SF-AA is administered first, followed by HM as needed. Intake data calculated by the spreadsheet should be evaluated in conjunction with data from clinical and nutritional analyses, which provide a comprehensive understanding of the patient's nutritional status and help guide individualized dietary management for the specific IEM.

Update current understanding of neurometabolic disorders related to lysine metabolism.

Lysine, as an essential amino acid, predominantly undergoes metabolic processes through the saccharopine pathway, whereas a smaller fraction follows the pipecolic acid pathway. Although the liver is considered the primary organ for lysine metabolism, it is worth noting that lysine catabolism also takes place in other tissues and organs throughout the body, including the brain. Enzyme deficiency caused by pathogenic variants in its metabolic pathway may lead to a series of neurometabolic diseases, among which glutaric aciduria type 1 and pyridoxine-dependent epilepsy have the most significant clinical manifestations. At present, through research, we have a deeper understanding of the multiple pathophysiological mechanisms related to these diseases, including intracerebral accumulation of neurotoxic metabolites, imbalance between GABAergic and glutamatergic neurotransmission, energy deprivation due to metabolites, and the dysfunction of antiquitin. Because of the complexity of these diseases, their clinical manifestations are also diverse. The early implementation of lysine-restricted diets and supplementation with arginine and carnitine has reported positive impacts on the neurodevelopmental outcomes of patients. Presently, there is more robust evidence supporting the effectiveness of these treatments in glutaric aciduria type 1 compared with pyridoxine-dependent epilepsy.