Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A>G and c.413G>A)

2019 ◽  
Vol 72 (6) ◽  
pp. 393-398 ◽  
Author(s):  
Rashmi Dongerdiye ◽  
Pranoti Kamat ◽  
Punit Jain ◽  
Prashant Warang ◽  
Rati Devendra ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Adenylate Kinase ◽  
Structural Changes ◽  
Psychomotor Retardation ◽  
Red Cell ◽  
Missense Mutations ◽  
Rare Disorders ◽  
Pathogenic Variants ◽  
Cell Enzyme ◽  
Next Generation Sequencing Ngs

Adenylate kinase (AK) deficiency is a rare erythroenzymopathy associated with hereditary nonspherocytic haemolytic anaemia along with mental/psychomotor retardation in few cases. Diagnosis of AK deficiency depends on the decreased level of enzyme activity in red cell and identification of a mutation in the AK1 gene. Until, only eight mutations causing AK deficiency have been reported in the literature. We are reporting two novel missense mutation (c.71A > G and c.413G > A) detected in the AK1 gene by next-generation sequencing (NGS) in a 6-year-old male child from India. Red cell AK enzyme activity was found to be 30% normal. We have screened a total of 32 family members of the patient and showed reduced red cell enzyme activity and confirm mutations by Sanger’s sequencing. On the basis of Sanger sequencing, we suggest that the proband has inherited a mutation in AK1 gene exon 4 c.71A > G (p.Gln24Arg) from paternal family and exon 6 c.413G > A (p.Arg138His) from maternal family. Bioinformatics tools, such as SIFT, Polymorphism Phenotyping v.2, Mutation Taster, MutPred, also confirmed the deleterious effect of both the mutations. Molecular modelling suggests that the structural changes induced by p.Gln24Arg and p.Arg138His are pathogenic variants having a direct impact on the structural arrangement of the region close to the active site of the enzyme. In conclusion, NGS will be the best solution for diagnosis of very rare disorders leading to better management of the disease. This is the first report of the red cell AK deficiency from the Indian population.

scholarly journals Mitochondrial Encephalomyopathy Associated with Pyruvate Dehydrogenase Complex Deficiency: Eight Clinical Cases

2020 ◽  
pp. 12-17
Author(s):  
Ekaterina A. Nikolaeva ◽  
Svetlana Ya. Volgina ◽  
Chulpan D. Khaliullina ◽  
Sergey V. Bochenkov ◽  
Maria A. Danceva
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Perinatal Period ◽  
Psychomotor Retardation ◽  
Mitochondrial Encephalomyopathy ◽  
Missense Mutations ◽  
Pathogenic Variants ◽  
Dehydrogenase Complex

Background. Defects in pyruvate dehydrogenase complex (PDC), involved in the glycolysis products integration into the cells’ energy metabolism, are one of the reasons of mitochondrial pathology development. The diagnosis of this condition can be pretty complicated also due to the lack of description of such patients with encephalomyopathy associated with PDC deficiency in Russian population.Clinical Case Description. We have performed the analysis of clinical manifestations polymorphism of progressive mitochondrial encephalomyopathy caused by pathogenic variants in nuclear X linked gene, PDHA1 (encodes alpha subunit of pyruvate dehydrogenase), in 8 boys aged from 1 to 8 years. The adverse perinatal period was mentioned in all cases. The major features of symptom complex by the time of hospital examination were psychomotor retardation, ataxy, myopathic manifestations. Dystonic attacks were observed in 2 sibs. All patients had changes on brain magnetic resonance imaging: in basal ganglia in 6 children and ventriculomegaly in 2 children. All children had lactic acidosis. Clinical examination has shown that 4 patients had severe damage of nervous system, other 4 patients had moderate damage. Missense mutations in the PDHA1 gene were revealed in 6 children, insertions and duplications including 6 and 16 base pairs — in 2 children. The moderate positive dynamics was noticed as a result of complex treatment of children: stabilization of the overall condition, no metabolic crises, decrease in frequency of dystonic attacks.Conclusion. The clinical polymorphism of mitochondrial encephalomyopathy associated with PDC deficiency is described. The differences in manifestations of severe and moderate forms of disease are shown. The presented description may be useful for medico-genetic counseling and providing medicogenetic care for families.

Red cell enzyme activity during blood storage and reactivation of phosphofructokinase

1982 ◽  
Vol 13 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Nancy A. Noble ◽  
Kouichi R. Tanaka ◽  
Byron A. Myhre ◽  
Delores E. Johnson
Keyword(s):  
Enzyme Activity ◽  
Red Cell ◽  
Blood Storage ◽  
Cell Enzyme

The World Distribution of Electrophoretic Variants of the Red Cell Enzyme Adenylate Kinase

1971 ◽  
Vol 21 (3) ◽  
pp. 302-304 ◽  
Author(s):  
D. Tills ◽  
J.L. Van den Branden ◽  
V.R. Clements ◽  
A.E. Mourant
Keyword(s):  
Adenylate Kinase ◽  
Red Cell ◽  
Electrophoretic Variants ◽  
Cell Enzyme ◽  
The World ◽  
World Distribution

scholarly journals Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Hana Pavlu-Pereira ◽  
Maria João Silva ◽  
Cristina Florindo ◽  
Sílvia Sequeira ◽  
Ana Cristina Ferreira ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
In Silico Analysis ◽  
Psychomotor Retardation ◽  
Missense Mutations ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Genes Encoding ◽  
Biochemical Analyses ◽  
Dehydrogenase Complex

Abstract Background The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype–phenotype correlations. Results The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.

CHANGES IN RED CELL ENZYME ACTIVITY IN RELATION TO RED CELL SURVIVAL IN INFANCY

PEDIATRICS ◽  
1963 ◽  
Vol 32 (3) ◽  
pp. 371-375
Author(s):  
Eugene Kaplan ◽  
J. Tyson Tildon
Keyword(s):  
Enzyme Activity ◽  
Life Span ◽  
Cell Survival ◽  
Cell Population ◽  
The Other ◽  
Red Cell ◽  
Term Infants ◽  
Cell Life ◽  
Cell Enzyme ◽  
Red Cell Survival

The change in activity of red cell G6PDH and AChE in normal full term infants forms a pattern which parallels that of Cr51 red cell life span in the first months of life. These two phenomena, one relating to erythrocyte biochemistry and the other to erythrocyte function, are in keeping with the hypothesis that reduced erythropoiesis after birth results in an older red cell population.

scholarly journals Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes

2020 ◽  
Author(s):  
Hana Pavlu-Pereira ◽  
Maria João Silva ◽  
Cristina Florindo ◽  
Sílvia Sequeira ◽  
Ana Cristina Ferreira ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
In Silico Analysis ◽  
Psychomotor Retardation ◽  
Missense Mutations ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Genes Encoding ◽  
Biochemical Analyses ◽  
Dehydrogenase Complex

Abstract Background : Pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA which ultimately generates ATP. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits, and the resulting phenotype, though very heterogeneous, mainly affects the neuro-encephalic system. The aim of this study is to describe and discuss the clinic, metabolic and genotypic profiles of thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results : The mutational spectrum revealed that seven patients (54 %) carry mutations in the PDHA1 gene , encoding the E1α subunit, five patients (38 %) carry mutations in the PDHX gene, encoding the E3 binding protein, and the remaining patient (8 %) harbors mutations in the DLD gene, encoding the E3 subunit. These data corroborate PDHA1 mutations as the predominant cause of PDC deficiency, though revealing a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying a seemingly private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas de ratio L/P was under 16; enzymatic activities, when compared to control values, revealed to be independent from the genotype and ranged from 8.5% to 30% which may be considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed developmental delay/psychomotor retardation, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially go through the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, the in silico analysis of the missense mutations present in this PDC deficient population allowed to understand the molecular mechanism underlying these pathogenic variants. Conclusion : The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allows to get insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.

The World Distribution of Electrophoretic Variants of the Red Cell Enzyme Adenylate Kinase

1970 ◽  
Vol 20 (5) ◽  
pp. 517-522 ◽  
Author(s):  
D. Tills ◽  
J.L. Van den Branden ◽  
V.R. Clements ◽  
A.E. Mourant
Keyword(s):  
Adenylate Kinase ◽  
Red Cell ◽  
Electrophoretic Variants ◽  
Cell Enzyme ◽  
The World ◽  
World Distribution

scholarly journals Rare hereditary nonspherocytic hemolytic anemia caused by a novel homozygous mutation, c.301C > A, (Q101K), in the AK1 gene in an Indian family

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Rashmi Dongerdiye ◽  
Abhilasha Sampagar ◽  
Rati Devendra ◽  
Prashant Warang ◽  
Prabhakar Kedar
Keyword(s):  
Hemolytic Anemia ◽  
Adenylate Kinase ◽  
Novel Mutation ◽  
Psychomotor Retardation ◽  
Molecular Testing ◽  
Homozygous Mutation ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
The Family ◽  
And Control

Abstract Background Adenylate kinase (AK) deficiency is a rare red cell enzymopathy associated with moderate to severe congenital nonspherocytic hemolytic anemia, along with mental and psychomotor retardation (in exceptional cases). Only ten mutations have been detected in the AK1 gene to date. In this study, we aimed to diagnose the unexplained issue of haemolytic anaemia and offer antenatal screening to the family. Methods Genomic DNA was isolated from whole blood by a standard protocol. Targeted next-generation sequencing (t-NGS) was performed to identify pathogenic variants in the patient and control samples. A chronic villus sample was collected at 11 weeks of gestation from the mother, and molecular testing was performed. Genetic confirmation was concluded by Sanger DNA sequencing. Bioinformatics tools predicted the pathogenicity of the variant. Results t-NGS revealed a homozygous variant (c.301C > A, p. Gln101Lys) in the AK1 gene in the patient and heterozygosity in the fetus and parental samples. The prediction tools SIFT, Polyphen2, Provean, PMUT, Mutation taster, and Mutation Assessor, confirmed the damaging effect of the variant on the AK1 protein structure Conclusion We have presented a novel mutation in the AK1 gene (p. Gln101Lys) associated with adenylate kinase deficiency. It is the first prenatal diagnosis of AK deficiency in India, where heterogeneity is exceptionally high.

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