Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data

Huemer, Martina; Bürer, Céline; Ješina, Pavel; Kožich, Viktor; Landolt, Markus A.; Suormala, Terttu; Fowler, Brian; Augoustides‐Savvopoulou, Persephone; Blair, Ed; Brennerova, Katarina; Broomfield, Alexander; Meirleir, L. De; Gökçay, Gülden; Hennermann, Julia B.; Jardine, Philip; Koch, Johannes; Lorenzl, Stefan; Lotz-Havla, Amelie S.; Noss, J; Parini, Rossella; Peters, Heidi; Plecko, Barbara; Ramos, F J; Schlune, Andrea; Tsiakas, Konstantinos; Tanšek, Mojca Žerjav; Baumgartner, Matthias R.

doi:10.1007/s10545-014-9803-7

Cited by 42 publications

(60 citation statements)

References 26 publications

(28 reference statements)

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“…With the increasing number of reported patients, the natural history of these disorders becomes clearer. 12,[19][20][21] The majority of patients are diagnosed after being symptomatic (with rare exceptions, including siblings of known patients 22 or populations with high carrier frequency 4 ). Although the age of onset varies significantly, most of the patients with remethylation disorders present during the first 3 years of life with predominantly neurological manifestations.…”

Section: Resultsmentioning

confidence: 99%

“…Although the age of onset varies significantly, most of the patients with remethylation disorders present during the first 3 years of life with predominantly neurological manifestations. 1,19,21 In one series, 92% of patients with cblG and cblE defects had disease onset before 3 years of age, with peak during the first year of life (75%). 21 Similar data are reported for cases of severe MTHFR deficiency.…”

Section: Resultsmentioning

confidence: 99%

“…1,19,21 In one series, 92% of patients with cblG and cblE defects had disease onset before 3 years of age, with peak during the first year of life (75%). 21 Similar data are reported for cases of severe MTHFR deficiency. 19 Fatal outcomes, particularly in cases of severe MTHFR deficiencies, are not uncommon.…”

Section: Resultsmentioning

confidence: 99%

“…19 Remethylation disorders diagnosed later in life have also been described. 1,21 Many of them have been subjected to long diagnostic work-up for nonspecific predominantly neurologic symptoms until elevation of tHcy was detected. Several patients presenting with isolated hematologic abnormalities, 23 acute psychosis in adult patients, 24 or asymptomatic patients 12,22 have also been reported.…”

Section: Resultsmentioning

confidence: 99%

“…However, the delays in the diagnosis and treatment are recognized as the most important factor leading to residual morbidity in these patients. 1,4,20,21 In several cases specific therapy started very early in life or in asymptomatic patients 4,25 led to normal outcomes. The treatment of remethylation disorders is aimed at either bypassing the biochemical block or augmenting the residual activity with cofactors of the affected enzymes.…”

Section: Resultsmentioning

confidence: 99%

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Outcomes of four patients with homocysteine remethylation disorders detected by newborn screening

Wong

Tortorelli

Bishop

et al. 2016

Genetics in Medicine

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Purpose:We evaluated the clinical outcome in homocysteine remethylation disorders following newborn screening (NBS) and initiation of early specific treatment. Methods:Five patients with remethylation disorders were included in this study. Results:Two asymptomatic patients (one with cblG and one with cblE) were identified by NBS using an approach that combines a postanalytical interpretive tool (available on the Region 4 Stork (R4S) collaborative project website, http://www.clir-r4s.org) and a second-tier test for total homocysteine determination. Both the initial screening and the second-tier test are performed on the same blood spot, with no additional patient contact, resulting in no false-positive outcomes. Two additional patients with methylenetetrahydrofolate reductase deficiency were detected by NBS using low methionine as a marker.Although already symptomatic despite the early diagnosis, the latter two patients greatly improved with treatment and their outcomes are compared with that of another patient with methylenetetrahydrofolate reductase deficiency and significant morbidity who was diagnosed clinically at 3 months of age. Conclusion:Early detection by NBS and timely and specific treatment considerably improve at least short-term outcomes of homocysteine remethylation disorders. When a remethylation disorder is suspected, group-specific treatment could be started prior to the completion of in vitro confirmatory testing because all disorders from this group require similar intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Outcomes of four patients with homocysteine remethylation disorders detected by newborn screening

Wong

Tortorelli

Bishop

et al. 2016

Genetics in Medicine

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Prenatal Diagnosis of Inherited Disorders of Folate and Cobalamin Metabolism

Rosenblatt¹,

Watkins²

2021

Genetic Disorders and the Fetus

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The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

Huemer

Baumgartner

2019

J of Inher Metab Disea

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This review gives an overview of clinical characteristics, treatment and outcome of nutritional and acquired cobalamin (Cbl; synonym: vitamin B12) deficiencies, inborn errors of Cbl absorption and intracellular trafficking, as well as methylenetetrahydrofolate dehydrogenase (MTHFD1) and methylene tetrahydrofolate reductase (MTHFR) deficiencies, which impair Cbl‐dependent remethylation. Acquired and inborn Cbl‐related disorders and MTHFR deficiency cause multisystem, often severe disease. Failure to thrive, neurocognitive or psychiatric symptoms, eye disease, bone marrow alterations, microangiopathy and thromboembolic events are characteristic. The recently identified MTHFD1 defect additionally presents with severe immune deficiency. Deficient Cbl‐dependent enzymes cause reduced methylation capacity and metabolite toxicity. Further net‐effects of perturbed Cbl function or reduced Cbl supply causing oxidative stress, altered cytokine regulation or immune functions are discussed.

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Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data

Abstract: The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment.

Cited by 42 publications

References 26 publications

Outcomes of four patients with homocysteine remethylation disorders detected by newborn screening

Outcomes of four patients with homocysteine remethylation disorders detected by newborn screening

Prenatal Diagnosis of Inherited Disorders of Folate and Cobalamin Metabolism

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

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