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D-2-hydroxyglutaric (DL-2-hydroxyglutaric) aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The product 4-hydroxybutyric acid is also neuropharmacologically active, as illustrated by patients with 4-hydroxybutyric aciduria which is due to succinic semialdehyde dehydrogenase deficiency (Chapter 13). The elevated levels of GABA in the CSF in patients with D-2-hydroxyglutaric aciduria would be consistent with abnormalities in this pathway. Fibroblasts derived from patients with D-2-hydroxyglutaric aciduria have been found to have normal transhydrogenase activity; on the other hand, it is likely that this enzyme is responsible for the occurrence of D-2-hydroxyglutaric aciduria in patients with 4-hydroxybutyric aciduria (Chapter 13). In patients with multiple acylCoA dehydrogenase deficiency (glutaric aciduria type 2) [39] (Chapter 45), 2-hydroxyglutaric acid excretion is elevated, and it is the D-isomer that is predominant. Of course, in glutaric aciduria type 2, any hydroxyl acid accumulated might lead to the formation of D-2-hydroxyglutaric aciduria in the presence of 2-oxoglutarate in a transhydrogenase reaction.
Glutamine, Glutamate, and GABA in Human Diseases
Published in Elling Kvamme, Glutamine and Glutamate in Mammals, 1988
Table 4 also lists the circumstances in which brain GABA contents may be elevated in humans. In patients dying with idiopathic Parkinson’s disease, GABA content is significnatly increased in the putamen,56,57 presumably as a secondary effect of nigrostriatal neuronal death and decreased release of dopamine in the striatum. Patients with the rare autosomal recessive disorder succinic semialdehyde dehydrogenase deficiency show marked reduction in the activity of this enzyme in lymphocytes isolated from blood, and they accumulate 7- hydroxybutyric acid in blood, urine, and CSF.58 Although amounts of GABA, the immediate precursor of succinic semialdehyde, have not yet been reported for the CSF and brain of such patients, it would not be surprising if they eventually prove to be elevated.
Role of Tandem Mass Spectrometry in Diagnosis and Management of Inborn Errors of Metabolism
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Kannan Vaidyanathan, Sandhya Gopalakrishnan
MS has led to the identification of many new diseases. New methods for lipid analysis have opened up the fields ofinbornerrorsof cholesterol synthesis, bile acid synthesis and leukotriene synthesis. Developments in TMS allowed it to be used for determination of the amino acid sequence and post-translational modifications of proteins [10]. Short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) has been differentiated from isovalericaciduria [11]. Janzen et al. used UPLC with C18 column and gradient elution with MS/MS in ESI+ mode for the identification of C5 acyl carnitine species. This technique helps to reduce false positives and also helps differentiation between isovalericaciduria and 2 methyl butyryl CoA dehydrogenase deficiency [12]. Scott et al. have used MS/MS for the simultaneous detection of lysosomal storage disorders and mucopolysaccharidosis (Fabry, Pompe, and MPS-I) [13]. UPLC along with ESI-MS/MS can be used for the diagnosis of different types of mucopolysaccharidoses [14]. MS is important for structural glycomics and study of diseases like-congenital disorders of glycosylation, lysosomal storage diseases, autoimmune diseases, and cancer [15]. LaMarca et al. developed an LC-MS/MS method for the simultaneous determination of succinylacetone, tyrosine, phenylalanine, methionine, and NTBC for the diagnosis and treatment of tyrosinemia Type I [16]. 4-hydroxy-butyrate elevation and succinic semialdehyde dehydrogenase deficiency was diagnosed in three infants from China using organic acid analysis by GC/MS. 3-hydroxyisovaleric acid was used to detect biotin deficiency by UPLC-MS/MS [17].
Stargardt macular dystrophy and evolving therapies
Published in Expert Opinion on Biological Therapy, 2018
Rehan M. Hussain, Thomas A. Ciulla, Audina M. Berrocal, Ninel Z. Gregori, Harry W. Flynn, Byron L. Lam
Vision Medicine’s VM200 molecule for STGD1 is currently in preclinical trials. This oral aldehyde trap sequesters the toxic compound, all-trans retinal, to potentially prevent retinal cell death [39]. Specifically, VM200 is a primary amine that reacts with the aldehyde group of all-trans retinal to form an inactive Schiff base, thus making it unable to form A2E. VM200 was shown to preserve retinal structure in ABCA4−/− Rdh8−/− mice, as measured by SD-OCT. According to unpublished data from Case Western Reserve University, VM200 has also demonstrated ability to preserve retinal function, as mice treated with it were noted to have increased concentration of 11-cis-retinal (a biomarker of intact photoreceptors) compared to controls [40]. No significant toxicities were noted in 2-week and 13-week long studies. The molecule of VM200 is an enantiomer of pregabalin, which is used to treat neuropathic pain, though its affinity for the pregabalin target is 10-fold less than that of pregabalin. VM200 could also have therapeutic potential in other inborn errors of aldehyde metabolism including Sjogren-Larsson Syndrome, Best Disease, and Succinic semialdehyde-dehydrogenase deficiency. Preclinical studies are continuing [40].
Pharmacotherapy of retinal disease with visual cycle modulators
Published in Expert Opinion on Pharmacotherapy, 2018
Rehan M. Hussain, Ninel Z. Gregori, Thomas A. Ciulla, Byron L. Lam
Vision Medicine’s VM200 molecule for SMD is currently in preclinical trials. This oral aldehyde trap sequesters the toxic compound, all-trans-retinal, to prevent retinal cell death [49]. Specifically, VM200 is a primary amine that reacts with the aldehyde group of all-trans-retinal to form an inactive Schiff base, thus making it unable to form A2E. VM200 was shown to preserve retinal structure in ABCA4−/− Rdh8−/− mice, as measured by SD-OCT. According to unpublished data from Case Western Reserve University, VM200 has also demonstrated ability to preserve retinal function, as mice treated with it were noted to have increased concentration of 11-cis retinal (a biomarker of intact photoreceptors) compared to controls [50]. No significant toxicities were noted in 2-week and 13-week long studies. The molecule of VM200 is an enantiomer of pregabalin, which is used to treat neuropathic pain, though its affinity for the pregabalin target is 10-fold less than that of pregabalin. VM200 is also indicated for other inborn errors of aldehyde metabolism including Sjogren–Larsson syndrome, best disease, and succinic semialdehyde-dehydrogenase deficiency. Preclinical studies are ongoing [50].
Ocular abnormalities in a patient with congenital disorder of glycosylation type Ig
Published in Ophthalmic Genetics, 2019
Hamed Esfandiari, Marilyn B. Mets, Katherine H. Kim, Sudhi P. Kurup
A 23-month-old male first presented to our institution with concerns of failure to thrive, intrauterine and postnatal growth retardation, and developmental delays. The patient was born at term in Pakistan to parents who are first cousins. Family history was significant for a female paternal first cousin who died in infancy, a male paternal first cousin who was born prematurely and had visual impairment, and a paternal great uncle who was born prematurely and died in infancy. Pregnancy was notable for reportedly decreased fetal movements in the third trimester and oligohydramnios that required prenatal treatment and emergency Cesarean section. Neurologic evaluation at presentation noted severe global developmental delays and spastic quadriparesis. Initial eye exam was only revealing of dysmorphic facies with deep-set eyes, intermittent exotropia, and mild myopic astigmatism. Magnetic resonance imaging (MRI) of the brain showed simplified gyral pattern with moderately diminished white matter volume, paucity of tertiary sulcation, and microcephaly. Genetics evaluation revealed elevation of monoglycosylated transferrin with normal N- and O-glycan profiles on multiple carbohydrate-deficient transferrin (CDT) assays, consistent with CDG type I. Urine organic acids demonstrated elevated 4-hydroxybutyric acid lactone, which was suggestive of succinic semialdehyde dehydrogenase deficiency (SSADH); however, ALDH5A1 analysis was negative. Ultimately, whole exome sequencing (WES) of our patient identified a homozygous, likely pathogenic, variant (p.Cys188Tyr/c.563G>A) in ALG12, which is consistent with autosomal recessive CDG type Ig. Both parents were confirmed to be heterozygous for this variant. WES also revealed an additional variant of unknown significance (m.10845C>T/p.Thr29Ile) in the mitochondrial MT-ND4 gene at 100% homoplasmy. The patient’s mother had the same mitochondrial variant at 100% homoplasmy but no signs or symptoms of mitochondrial disease. The importance of this variant is unknown since it alters a position in an amino acid that is not highly conserved.