Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment

Kripps, Kimberly A.; Sremba, Leighann; Larson, Austin; Hove, Johan L.K. Van; Nguyen, Hoanh; Wright, Erica; Mirsky, David M.; Watkins, David; Rosenblatt, David S.; Ketteridge, David; Berry, Susan A.; McCandless, Shawn E.; Baker, Peter R.

doi:10.1002/jimd.12448

Cited by 14 publications

(10 citation statements)

References 32 publications

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“…However, cobalamin deficiency can occur at the cellular level even with normal serum cobalamin concentrations, 26 and cobalamin supplementation can improve HCC even in patients without overt hypocobalaminemia. 27 Serum folate concentrations were below the lower limit of the reference interval (7.7 μg/L) in approximately 55% (16 of 29) of the healthy Greyhounds in our study. Although not significantly different from controls, serum folate concentrations were inversely correlated with serum HCy concentrations.…”

Section: Discussioncontrasting

confidence: 57%

“…In our Greyhounds, however, only 1 dog had a serum cobalamin concentration below the lower limit of the reference interval, suggesting that low serum cobalamin concentrations are unlikely to be the primary driver of HHC in Greyhounds. However, cobalamin deficiency can occur at the cellular level even with normal serum cobalamin concentrations, 26 and cobalamin supplementation can improve HCC even in patients without overt hypocobalaminemia 27 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Potential mechanism for hyperhomocysteinemia in Greyhound dogs

Johnson

Tiedeman

Peterson

et al. 2023

Veterinary Internal Medicne

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Background: Greyhounds have been reported to have hyperhomocysteinemia (HHC), but the underlying mechanisms and clinical implications are unclear.Hypothesis: Our primary aim was to assess serum concentrations of homocysteine (HCy) and related analytes in Greyhounds and to identify a likely metabolic pathway for HHC. A secondary aim was to determine whether HHC is associated with evidence of oxidative stress.Animals: Healthy pet Greyhounds (n = 31) and non-sighthound control dogs (n = 15).Methods: Analysis of serum HCy, cobalamin, folate, and methionine, and plasma cysteine, glutathione, and total 8-isoprostane concentrations.Results: Homocysteine concentrations were higher in Greyhounds (median, 25.0 μmol/L) compared to controls (13.9 μmol/L; P < .0001). Cobalamin concentrations were lower in Greyhounds (median, 416 ng/L) compared to controls (644 ng/L; P = .004) and were inversely correlated with HCy (r = À0.40, P = .004). Serum concentrations of folate, which is regenerated when HCy is converted to methionine, also were inversely correlated with HCy (r = À0.47, P = .002). Serum methionine concentrations were more than 4-fold lower in Greyhounds (median, 3.2 μmol/L) compared to controls (median, 15.0 μmol/L), but this difference was not significant (P = .3). Plasma cysteine, glutathione, and 8-isoprostane concentrations did not differ significantly between groups.Conclusions and Clinical Importance: Our findings suggest a primary defect in conversion of HCy to methionine in Greyhounds, with related impaired folate generation. Ineffective cycling by methionine synthase could lead to secondary cobalamin depletion. Notably, low serum folate and cobalamin concentrations can be observed

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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Potential mechanism for hyperhomocysteinemia in Greyhound dogs

Johnson

Tiedeman

Peterson

et al. 2023

Veterinary Internal Medicne

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“…Metabolite set enrichment analysis in Gad2 Fgf13 KO vs. WT (Supplemental Table 1) revealed that the most enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway among upregulated metabolites was glycolysis (P=4.29E-6), also consistent with data obtained in patients in status epilepticus (Hanin, Chollet et al 2024). The most downregulated pathway was methionine metabolism (P=9.88E-4), consistent with methionine synthase deficiency-an inborn error of metabolism-that present with seizures (Kripps, Sremba et al 2022). Thus, this metabolomic analysis supported the severity of the seizure phenotype observed in Gad2 Fgf13 KO mice.…”

Section: Inhibitory Neuron Knockout Of Fgf13 Recapitulates Spontaneou...mentioning

confidence: 63%

Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism

Lin,

Gade,

Wang

et al. 2024

Preprint

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Developmental and Epileptic Encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13 were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because FGF13 is expressed in both excitatory and inhibitory neurons, FGF13 undergoes extensive alternative splicing producing multiple isoforms with distinct functions, and the overall roles of FGF13 in neurons are incompletely cataloged. To overcome these challenges, we generated a set of novel cell type-specific conditional knockout mice. Interneuron-targeted deletion of Fgf13 led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of Fgf13 caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Nav) regulator, we observed no effect of Fgf13 ablation in interneurons on Navs but rather a marked reduction in K+ channel currents. Re-expressing different Fgf13 splice isoforms could partially rescue deficits in interneuron excitability and restore K+ channel current amplitude. These results enhance our understanding of the molecular mechanisms that drive the pathogenesis of Fgf13-related seizures and expand our understanding of FGF13 functions in different neuron subsets.

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“…As shown in the proband, it has previously been reported that the cblG phenotype can be present with neurological symptoms (43)(44)(45)(46)(47). Komulainen-Ebrahim et al and Kripps et al observed the neurological symptoms as a result of methionine synthase deficiency, along with the need for early treatment to reduce the neurological symptoms (48,49).…”

Section: Discussionmentioning

confidence: 91%

Novel WDR62 and MTR Variants in a Patient With Autosomal Recessive Primary Microcephaly-2 With Polymicrogyria and Homocystinuria-Megaloblastic Anemia

et al. 2022

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Background: Autosomal recessive primary microcephaly-2 (MCPH2) is a rare genetic disorder with clinical and genetic heterogeneity. This study aimed to perform high-throughput whole-exome sequencing (WES) to facilitate the diagnosis of the genetic variants responsible for MCPH2 and the comorbidities. Materials and Methods: The WES was performed for a 3-year-old boy with primary microcephaly-2 and homocystinuria-megaloblastic anemia in a consanguineous family. Sequencing and variant calling was conducted by standard bioinformatics tools. Filtering was performed to prioritize novel variants. Finally, the effect of variants on the protein structure and function was assessed using web prediction tools. Results: Using WES, two novel homozygous variants and three novel homozygous variants were identified in the WDR62 and MTR genes as the causes of MCPH2 and homocystinuria-megaloblastic anemia in the affected child, respectively. These frameshift insertion variants are classified as pathogenic and affect the structure and feature of the WDR62 and MTR proteins by changing amino acid sequence and causing nonsense-mediated RNA decay (NMD). Conclusion: Magnetic resonance imaging (MRI) supported polymicrogyria and impaired cerebral cortical development in the affected child. WDR62 as a causative gene plays an essential role in cerebral cortical development, and its pathogenic disease-causing variants are considered as causing factors for MCPH2. Homocystinuria-megaloblastic anemia was a comorbidity associated with microcephaly in this patient, and its variants were confirmed by WES. Overall, performing WES is a necessary and accurate way to rapidly identify the exact causative genetic variants in MCPH2 and the homocystinuria-megaloblastic anemia and manage the disease.

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Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment

Cited by 14 publications

References 32 publications

Potential mechanism for hyperhomocysteinemia in Greyhound dogs

Potential mechanism for hyperhomocysteinemia in Greyhound dogs

Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism

Novel WDR62 and MTR Variants in a Patient With Autosomal Recessive Primary Microcephaly-2 With Polymicrogyria and Homocystinuria-Megaloblastic Anemia

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