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.
CONCLUSIONS: 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.

The white matter is an important constituent of the central nervous system, containing axons, oligodendrocytes, and its progenitor cells, astrocytes, and microglial cells. Oligodendrocytes are central for myelin synthesis, the insulating envelope that protects axons and allows normal neural conduction. Both, oligodendrocytes and myelin, are highly vulnerable to toxic factors in many neurodevelopmental and neurodegenerative disorders associated with disturbances of myelination. Here we review the main alterations in oligodendrocytes and myelin observed in some organic acidurias/acidemias, which correspond to inherited neurometabolic disorders biochemically characterized by accumulation of potentially neurotoxic organic acids and their derivatives. The yet incompletely understood mechanisms underlying the high vulnerability of OLs and/or myelin in glutaric acidemia type I, the most prototypical cerebral organic aciduria, are particularly discussed.

GCDH encodes for the enzyme catalyzing the sixth step of the lysine degradation pathway. Autosomal recessive variants in GCDH are associated with glutaric aciduria type I (GA1), of which a wide genotypic spectrum of pathogenic variants have been described. In this study, hiPSC lines derived from four GA1 patients with different genotypes were generated and fully characterized. Two patients carry compound heterozygous variants in GCDH, while the other two patients carry a variant in homozygosis. These hiPSC lines can significantly contribute to better understand the molecular mechanism underlying GA1 and provide excellent models for the development of new therapeutic strategies.

Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1.

OBJECTIVE: To evaluate the clinical, radiological, and biochemical features of glutaric aciduria Type 1 (GA1) patients identified through urine organic acid testing at a biochemical genetics laboratory (BGL) in Pakistan.
METHODS: Observational study. Place and Duration of the Study: Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan, from January 2013 to December 2022.
METHODS: Medical charts and urine organic acid (UOA) chromatograms of the patients presenting at the BGL from January 2013 to December 2022 were reviewed. Brain imaging was obtained where available. Variables were noted as per the objective and descriptive statistics were obtained.
RESULTS: GA1 was found in 64 (0.4%) patients out of a total of 16,094 UOA requests for high-risk screening cases. The age of diagnosis ranged between one month and three years. The brain MRI findings revealed characteristic abnormalities such as cerebral atrophy, expanded CSF spaces, white matter abnormalities, and a distinct bat wings appearance, in cohesion with the results of biochemical testing.
CONCLUSIONS: Sixty-four cases of GA1 from a single centre indicate a high frequency of the disorder in Pakistan. Late diagnosis emphasises the need for increased clinical awareness and preferably newborn screening to ensure optimal outcomes.
BACKGROUND: Glutaric aciduria Type 1 (GA1), Brain imaging, UOA analysis, Glutaryl-CoA dehydrogenase (GCDH), Pakistan.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare autosomal recessive disease characterized by elevated levels of hydroxyglutaric acid in the body fluids and brain with abnormal white matter. We present two siblings with psychomotor retardation and quadriparesis. Their brain imaging showed diffuse bilateral symmetrical involvement of the cerebral cortex, white matter, basal ganglia and cerebellum. The whole exome sequence studies revealed a homozygous likely pathogenic variant on chromosome 14q22.1 (NM_024884.2: c.178G > A; pGly60Arg) in the gene encoding for L-2-hydroxyglutarate dehydrogenase (L2HGDH) (OMIM #236792). Therefore, using the L2HGDH gene study is beneficial for L2HGA diagnosis.

OBJECTIVE: To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the SLC25A1 gene.
METHODS: Patients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing.
RESULTS: In this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink.
CONCLUSIONS: Our pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease.

BACKGROUND: . Neonatal screening of glutaric aciduria type 1 (GA-1) has brought radical changes in the course and outcomes of this disease. This study analyses the outcomes of the first 5 years (2015-2019) of the AGA1 neonatal screening programme in our autonomous community.
METHODS: . We conducted an observational, descriptive and retrospective study. All neonates born between January 1, 2015 and December 31, 2019 that participated in the neonatal screening programme were included in the study. The glutarylcarnitine (C5DC) concentration in dry blood spot samples was measured by means of tandem mass spectrometry applying a cut-off point of 0.25 µmol/L.
RESULTS: . A total of 30 120 newborns underwent screening. We found differences in the C5DC concentration based on gestational age, type of feeding and hours of life at sample collection. These differences were not relevant for screening purposes. There were no differences between neonates with weights smaller and greater than 1500 g. Screening identified 2 affected patients and there were 3 false positives. There were no false negatives. The diagnosis was confirmed by genetic testing. Patients have been in treatment since diagnosis and have not developed encephalopathic crises in the first 4 years of life.
CONCLUSIONS: . Screening allowed early diagnosis of two cases of GA-1 in the first 5 years since its introduction in our autonomous community. Although there were differences in C5DC levels based on gestational age, type of feeding and hours of life at blood extraction, they were not relevant for screening.

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, autosomal recessive neurometabolic disease, which presents with elevated L-2-hydroxyglutarate acid. Generally, L2HGA appear as slowly progressing central nervous system function deterioration during infancy, and a rapid progression in adulthood is uncommon for the syndrome\'s classic phenotype.

BACKGROUND: Uraemia causes a generalised encephalopathy as its most common neurological complication. Isolated brainstem uraemic encephalopathy is rare. We report a case of fatigable ptosis and complex ophthalmoplegia in brainstem uraemic encephalopathy.
METHODS: A 22-year-old Sri Lankan man with end stage renal failure presented with acute onset diplopia and drooping of eyelids progressively worsening over one week. The patient had not complied with the prescribed renal replacement therapy which was planned to be initiated 5 months previously. On examination, his Glasgow coma scale score was 15/15, He had a fatigable asymmetrical bilateral ptosis. The ice-pack test was negative. There was a complex ophthalmoplegia with bilateral abduction failure and elevation failure of the right eye. The diplopia did not worsen with prolonged stare. The rest of the neurological examination was normal. Serum creatinine on admission was 21.81 mg/dl. The repetitive nerve stimulation did not show a decremental pattern. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse midbrain and pontine oedema with T2 weighted/FLAIR hyperintensities. The patient was haemodialyzed on alternate days and his neurological deficits completely resolved by the end of the second week of dialysis. The follow up brain MRI done two weeks later demonstrated marked improvement of the brainstem oedema with residual T2 weighted/FLAIR hyperintensities in the midbrain.
CONCLUSIONS: Uraemia may rarely cause an isolated brainstem encephalopathy mimicking ocular myasthenia, which resolves with correction of the uraemia.