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Nutrition Therapy of Inborn Errors of Metabolism
Published in Fima Lifshitz, Childhood Nutrition, 2020
Kimberlee Michals-Matalon, Reuben Matalon
The binding of toxic substances produced by the metabolic block is yet another mode of therapy. Isovaleric acidemia is caused by a deficiency of the enzyme isovaleryl Co-A dehydrogenase which is in the leucine degradative pathway. The abnormal accumulation of isovalerylglycine is diagnostic. Most patients develop vomiting, acidosis, lethargy, and coma in the newborn period, while others have these symptoms only associated with an underlying illness. Isovaleric acidemia responds well to treatment with supplemental glycine (250 mg/kg) which binds with the isovaleric acid and is excreted as isovalerylglycine.27 Carnitine supplementation (100 mg/kg) may also be added to the treatment regimen as a binding agent.
Isovaleric acidemia
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
Isovaleric acidemia is an autosomal recessive disease caused by deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase. Assay of the enzyme in fibroblasts of a series of patients revealed considerable heterogeneity and residual activity, as much as 13 percent of the control level [51, 52–54]. The enzyme may also be assayed in leukocytes. Prenatal diagnosis has been approached in the same manner [55], however the assay is not generally available. An accurate method for the gas chromatographic-mass spectrometric (GCMS) analysis of 3-hydroxyisovaleric acid [56] or isovalerylglycine permits rapid prenatal diagnosis via direct detection in the amniotic fluid [57]. Isovalerylglycine appears to be the metabolite of choice; it has been diagnostic as early as 12 weeks of gestation. Prenatal diagnosis has also been made by the incorporation of labeled isovaleric acid in chorionic villus material [58], and by electrospray ionization tandem mass spectrometry analysis of acylcarnitines in amniotic fluid (elevated levels of isovalerylcarnitine from 3.12 to 12 μM compared to control values from 0.59 to 0.99 μM) [59], but now predominantly by mutation analysis in informative families.
Neonatal Seizures
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Of the large number of inborn errors of metabolism, only a few cause very early seizures. Phenylketonuria has almost lost its significance by virtue of routine newborn screening and early treatment (27). Deficiencies of branched-chain ketoacids (maple-syrup disease being the most common) can trigger seizures within 1 to 3 weeks of birth, with feeding problems, hypotonia alternating with opisthotonic crisis, true convulsions, and coma. Hypoglycemia (often leucine-induced) may trigger the seizures, but ketoacids also directly affect nerve cells and myelination. Screening for urine dinitrophenylhydrazine (DNPH) allows early diagnosis. Repeated exchange transfusions and strict dietary measures are required. Propionic acidemia, isovaleric acidemia, methylmalonic acidemia, and other rare disorders of amino acids produce a variety of neurologic symptoms. Characteristic, frequent, abnormal movements can be taken for convulsive seizures, but these are in fact rare in the newborn period. Biotinidase deficiency may cause early seizures, which improve with biotin therapy. Disorders causing hyperglycinemia present with seizures after a short period of no apparent CNS problem. They are often myoclonic or focal tonic but also may present with clonic and autonomic components and are resistant to common AEDs. The course is usually downhill with severe hypotonia, lethargy, and coma. Ketonuria, thrombocytopenia, acidosis, and elevated ammonia are diagnostic clues. The nonketotic variety is the most common (we encountered 10 (0.9%) cases in our prospective studies). The deficit seems to be due to lack of a glycine cleavage enzyme. Therapies with sodium benzoate, strychnine, and other agents have failed to arrest this condition. Acute, severe hyperammonemia (secondary to urea cycle disorders or to primary hepatic disorders) may trigger early seizures. We have seen two cases of carbamylphosphate synthetase deficiency and one of arginosuccinase deficiency. Sporadic cases of neonatal seizures have been reported in babies with congenital lysine intolerance and in babies with citrillinemia. The role of elevated ammonia in causing seizures is debatable, since elevated serum ammonia is found in other conditions without seizures. Premature babies show transient but marked hyperammonemia; some exhibit CNS derangements, including seizures, while others escape without sequelae. Diseases with abnormalities of glycogen or lipid storage disorders almost never exhibit seizures in the newborn period. One exception in our earliest series was a baby with infantile Gm, gangliosidosis type 1 (who had clusters of tonic spasms) and another with glycogen synthetase deficiency (with erratic myoclonic seizures).
A pilot study on machine learning approach to delineate metabolic signatures in intellectual disability
Published in International Journal of Developmental Disabilities, 2021
Vidya Nikam, Suvidya Ranade, Naushad Shaik Mohammad, Mohan Kulkarni
The analytes were correlated with demographic characters using Kendall–Tau matrix. 3-Hydroxyisovalerylcarnitine (C5OH) is an indicator for diagnoses of 3-methylcrotonyl-CoA carboxylase deficiency reported to be associated with mild developmental delay (Maeda et al.2008). Decreased levels of acylcarnitines were reported to be associated with neurodegenerative disorders with a major impact on the motor function (Saiki et al.2017). Glutamate results from proline catabolism by aldehyde dehydrogenase and via an aminotransferase enzyme helps in the synthesis of alanine. Glutamate is a main excitatory neurotransmitter and abnormal glutamate signaling is thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders (Fedder and Sabo 2015). This could be explained why subjects with elevated proline and alanine would be having an early onset of ID. Elevated levels of C5 acylcarnitine are characteristic of isovaleric acidemia with clinical features suggestive of significant motor delay (Ensenauer et al.2011). Glycine is an inhibitory neurotransmitter of the central nervous system and its upsurge blood levels are delineated to be a cause of glycine encephalopathy with seizures and speech delay as the major clinical manifestations (Hennermann 2006). The study indicates that Kendall–Tau matrix could efficiently correlate analytes and demographic milestones which match with the reported literature.
Inherited hyperammonemias: a Contemporary view on pathogenesis and diagnosis
Published in Expert Opinion on Orphan Drugs, 2018
Evelina Maines, Giovanni Piccoli, Antonia Pascarella, Francesca Colucci, Alberto B. Burlina
The majority of OAs causing hyperammonemia results from a defect in the branched-chain amino acids (BCAAs) catabolism. The most important are propionic acidemia (PA, OMIM #606054), methylmalonic acidemia (MMA, OMIM #251000), and isovaleric acidemia (IVA, OMIM #243500). Hyperammonemia may be also a feature of severe forms of maple syrup urine disease (MSUD, OMIM #248600) [74]. The diagnosis of these disorders is based on acylcarnitines profiles identified by primary biomarkers [75–78] and in some cases by second-tier testing to improve the positive predictive value of NBS [78,79].
EEG Pattern in Neonatal Maple Syrup Urine Disease: Description and Clinical Significance
Published in The Neurodiagnostic Journal, 2021
Rajesh P. Poothrikovil, Khalid Al Thihli, Amna Al Futaisi
Similar central rhythms in alpha and theta ranges were reported in normal and abnormal infants with metabolic disorders such as methylmalonic aciduria, isovaleric aciduria, hyperlactemia (Hayakawa et al. 1987; Mises et al. 1983). However, these rhythms appear in short bursts and less frequent when compared to those in MSUD patients. Also, the background tends to be abnormal in MSUD patients and consists of generalized and focal spike wave discharges and burst-suppression pattern.