Nonketotic Hyperglycinemia: Two Case Reports and Review

Poothrikovil, Rajesh P.; Thihli, Khalid Al; Futaisi, Amna Al; Murshidi, Fathiya Al

doi:10.1080/21646821.2019.1645549

Cited by 14 publications

(12 citation statements)

References 9 publications

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“…The loss of function of different genes in the same biochemical pathway may lead to clinically indistinguishable phenotypes as has been observed in disorders of peroxisomal biogenesis (at least 13 genes) [ 33 ], Maple Syrup Urine Disease (OMIM #248600, 3 genes) [ 34 ], glycine encephalopathy (OMIM #605899, 3 genes) [ 35 ], and many others. For other biochemical pathways, phenotypes are distinct among defects at different steps in the same pathway, such as among different disorders of cholesterol biosynthesis, or deficiencies in the catabolism of tyrosine, mucopolysaccharides, or sphingolipids.…”

Section: Discussionmentioning

confidence: 99%

Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy

et al. 2020

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We describe a novel type of ribosomopathy that is defined by deficiency in diphthamidylation of translation elongation factor 2. The ribosomopathy was identified by correlating phenotypes and biochemical properties of previously described patients with diphthamide biosynthesis gene 1 (DPH1) deficiencies with a new patient that carried inactivating mutations in both alleles of the human diphthamide biosynthesis gene 2 (DPH2). The human DPH1 syndrome is an autosomal recessive disorder associated with developmental delay, abnormal head circumference (microcephaly or macrocephaly), short stature, and congenital heart disease. It is defined by variants with reduced functionality of the DPH1 gene observed so far predominantly in consanguineous homozygous patients carrying identical mutant alleles of DPH1. Here we report a child with a very similar phenotype carrying biallelic variants of the human DPH2. The gene products DPH1 and DPH2 are components of a heterodimeric enzyme complex that mediates the first step of the posttranslational diphthamide modification on the nonredundant eukaryotic translation elongation factor 2 (eEF2). Diphthamide deficiency was shown to reduce the accuracy of ribosomal protein biosynthesis. Both DPH2 variants described here severely impair diphthamide biosynthesis as demonstrated in human and yeast cells. This is the first report of a patient carrying compound heterozygous DPH2 loss-of-function variants with a DPH1 syndrome-like phenotype and implicates diphthamide deficiency as the root cause of this patient’s clinical phenotype as well as of DPH1-syndrome. These findings define “diphthamide-deficiency syndrome” as a special ribosomopathy due to reduced functionality of components of the cellular machinery for eEF2-diphthamide synthesis.

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Section: Discussionmentioning

confidence: 99%

Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy

et al. 2020

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“…These effects occur due to the accumulation of glycine in different parts of the brain that have glycine receptors. Glycine receptors in the cerebrum and cerebellum have stimulating effects, and accumulation of glycine in these areas leads to the development of seizures, myoclonus, and encephalopathy [8]. Our patient presented with similar complaints of lethargy and reluctance to feed.…”

Section: Discussionmentioning

confidence: 54%

Neonatal Nonketotic Hyperglycinemia: A Rare Case from Pakistan

Arif

Ahmed

Malik

et al. 2020

Cureus

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Nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder caused by a defect in glycine cleavage enzyme. It leads to the accumulation of glycine in the body tissues, blood, and cerebrospinal fluid (CSF). Most NKH cases are diagnosed during the natal period of life and are fatal if not promptly diagnosed and managed. Here we present a case of a two-day-old child who presented with reluctant feeding and lethargy. She had reduced tone in all four limbs and a Glasgow Coma Scale score of 9. Keeping an infectious etiology in mind, she was started on cefotaxime and amikacin. The patient was shifted to the neonatal intensive care unit; however, no improvement in the patient's condition was seen and antibiotics were changed to linezolid and meropenem along with initiation of acyclovir. The patient's blood and CSF cultures were negative. Serum amino acid chromatography showed elevated levels of glycine, and a diagnosis of NKH was made. The patient was managed symptomatically but expired on the 22nd day of admission. The case highlights the importance of prompt diagnosis and management of aminoacidopathies. Nearly all metabolic disorders have similar clinical presentations, and an early diagnosis can improve the outcome in patients.

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“…The metabolism of glycine is completed by the glycine lyase system (EC2.1.2.10) in the mitochondria in the body ( Kure et al, 2001 ; Leung et al, 2020 ), which is composed of four protein components as follows: P protein ( Kure et al, 2006 ), also known as pyridoxal phosphate-dependent glycine decarboxylase, which is produced by GLDC (OMIM: 238300) gene encoding; H protein ( Poothrikovil et al, 2019 ), a lipoic acid-containing protein, encoded by the GCSH (OMIM: 238330) gene; T protein ( Toone et al, 2003 ), also known as amino methyltransferase, is a kind of tetrahydrofolate-dependent transfer. The methyl enzyme is encoded by the AMT (OMIM: 238310) gene; the L protein ( Bravo-Alonso et al, 2017 ), which is a lipoic acid dehydrogenase, is encoded by the DLD (OMIM: 238331) gene.…”

Section: Discussionmentioning

confidence: 99%

The Mutation Analysis of the AMT Gene in a Chinese Family With Nonketotic Hyperglycinemia

et al. 2022

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Background: Nonketotic hyperglycinemia is a metabolic disease with autosomal recessive inheritance due to the glycine cleavage system (GCS) defect leading to the accumulation of glycine that causes severe and fatal neurological symptoms in the neonatal period.Methods: Genomic DNA was extracted from the peripheral blood of the female proband and her family members. The AMT variation was detected in the patient by whole-exome sequencing (WES), and the variant was validated by Sanger sequencing.Results: The WES showed that there were novel compound heterozygous frameshift variations c.977delA (p.Glu326Glyfs*12) and c.982_983insG (p.Ala328Glyfs*22) in exon eight of the AMT gene (NM_000481.4) in the proband. Genetic analysis showed that the former was inherited from the mother, and the latter was inherited from the father.Conclusion: We report the novel compound heterozygous variation of the AMT gene in a Chinese girl with NKH by WES, which has never been reported previously. Our case expanded the AMT gene mutation spectrum, further strengthened the understanding of NKH, and deepened the genetic and clinical heterogeneity of the disease. However, the study of treatment and prognosis is still our future challenge and focus.

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Nonketotic Hyperglycinemia: Two Case Reports and Review

Cited by 14 publications

References 9 publications

Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy

Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy

Neonatal Nonketotic Hyperglycinemia: A Rare Case from Pakistan

The Mutation Analysis of the AMT Gene in a Chinese Family With Nonketotic Hyperglycinemia

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