Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency

Banka, Siddharth; Blom, Henk J.; Walter, John H.; Aziz, Majid; Urquhart, Jill; Clouthier, Christopher M.; Rice, Gillian I.; Brouwer, Arjan P.M. de; Hilton, Emma; Vassallo, Grace; Will, Andrew; Smith, Desirée E.C.; Smulders, Yvo M.; Wevers, Ron A.; Steinfeld, Robert; Heales, Simon; Crow, Yanick J.; Pelletier, Joelle N.; Jones, Simon A.; Newman, William G.

doi:10.1016/j.ajhg.2011.01.004

Cited by 94 publications

(67 citation statements)

References 36 publications

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“…Treatment with folinic acid led to improvement of anemia and CSF 5-methylTHF levels, and seizure control. However, the neurodevelopmental improvement was less than that reported in patients with FOLR1 mutations or FR autoantibodies [ 44 ]. CFD was also reported in patients with megaloblastic anemia who were heterozygous for the DHFR A458T polymorphism [ 80 ].…”

Section: Cerebral Folate Deficiencymentioning

confidence: 71%

“…DHFR deficiency caused megaloblastic anemia, normal total Hcy (tHcy), and low tetrahydrobiopterine in the CSF [ 44 ]. DNA sequencing revealed a homozygous DHFR C238T (Leu80Phe) missense mutation [ 44 ]. Treatment with folinic acid led to improvement of anemia and CSF 5-methylTHF levels, and seizure control.…”

Section: Cerebral Folate Deficiencymentioning

confidence: 99%

“…Furthermore, CFD has been found in patients with single nucleotide polymorphisms (SNPs) in the DHFR gene in two recent studies [ 44 , 80 ]. DHFR deficiency caused megaloblastic anemia, normal total Hcy (tHcy), and low tetrahydrobiopterine in the CSF [ 44 ]. DNA sequencing revealed a homozygous DHFR C238T (Leu80Phe) missense mutation [ 44 ].…”

Section: Cerebral Folate Deficiencymentioning

confidence: 99%

“…Several inherited disorders of folate metabolism and transport have been described: MTHFR deficiency, MTR deficiency (either caused by mutations in MTR gene or MTRR gene), cerebral folate deficiency (CFD) caused by FOLR1 mutation, hereditary folate malabsorption, and glutamate formiminotransferase (FTCD) deficiency [ 44 ] ( Table 1 ). In addition, several putative inherited disorders related to folate metabolism are discussed in the literature like DHFR deficiency, cellular uptake defects, and the 5,10-methyleneTHF cyclohydrolase [part of the trifunctional enzyme 5,10-methyleneTHF dehydrogenase 1 (MTHFD1, EC 1.5.1.5)] deficiency [ 66 ].…”

Section: Inherited Disorders Of Folate Metabolism and Transportmentioning

confidence: 99%

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Genetic defects in folate and cobalamin pathways affecting the brain

Kirsch

Herrmann

Obeid

2012

Clinical Chemistry and Laboratory Medicine (CCLM)

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Folate and cobalamin are necessary for early brain development and function. Deficiency of folate or cobalamin during pregnancy can cause severe malformation in the central nervous system such as neural tube defects. After birth, folate and cobalamin deficiency can cause anemia, failure to thrive, recurrent infections, psychiatric and neurological symptoms. The folate and the homocysteine metabolic pathways interact at a central step where 5-methyltetrahydrofolate donates its methyl group to homocysteine to produce methionine and tetrahydrofolate. Methyl cobalamin and folate interact at this critical step. Both nutrients have a crucial role in DNA synthesis and in delivering S-adenosylmethionine, the universal methyl donor. Severe and mild inherited disorders in folate and cobalamin pathways have been described. The two groups of disorders share some similarities, but differ in the molecular mechanism, metabolic dysregulation, and disease management. This review summarizes selected disorders, including rare and common mutations that affect folate and cobalamin absorption, transport, or dependent enzymes. When the mutations are discovered early enough, many of the described disorders are easily treatable by B vitamin supplementation, which often prevents or reverses the manifestation of the disease. Therefore, the screening for mutations is recommended and should be carried out as early as possible: after occurrence of the first symptoms or when a certain constellations of the folate and cobalamin related markers are measured, such as elevated homocysteine and/or methylmalonic acid.

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Section: Cerebral Folate Deficiencymentioning

confidence: 71%

Section: Cerebral Folate Deficiencymentioning

confidence: 99%

Section: Cerebral Folate Deficiencymentioning

confidence: 99%

Section: Inherited Disorders Of Folate Metabolism and Transportmentioning

confidence: 99%

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Genetic defects in folate and cobalamin pathways affecting the brain

Kirsch

Herrmann

Obeid

2012

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…Two protein-coding mutations in DHFR have also been described. Patients homozygous for the Leu80Phe mutation (15) had megaloblastic anemia and/or pancytopenia and cerebral folate and BH4 deficiencies, while patients homozygous for the Asp153Val mutation (16) had megaloblastic anemia and mild learning disabilities.…”

mentioning

confidence: 99%

Arrested Hematopoiesis and Vascular Relaxation Defects in Mice with a Mutation in Dhfr

Thoms

Knezevic

Liu

et al. 2016

Molecular and Cellular Biology

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f Dihydrofolate reductase (DHFR) is a critical enzyme in the folate metabolism pathway and also plays a role in regulating nitric oxide (NO) signaling in endothelial cells. Although both coding and noncoding mutations with phenotypic effects have been identified in the human DHFR gene, no mouse model is currently available to study the consequences of perturbing DHFR in vivo. In order to identify genes involved in definitive hematopoiesis, we performed a forward genetic screen and produced a mouse line, here referred to as Orana, with a point mutation in the Dhfr locus leading to a Thr136Ala substitution in the DHFR protein. Homozygote Orana mice initiate definitive hematopoiesis, but expansion of progenitors in the fetal liver is compromised, and the animals die between embryonic day 13.5 (E13.5) and E14.5. Heterozygote Orana mice survive to adulthood but have tissue-specific alterations in folate abundance and distribution, perturbed stress erythropoiesis, and impaired endothelium-dependent relaxation of the aorta consistent with the role of DHFR in regulating NO signaling. Orana mice provide insight into the dual roles of DHFR and are a useful model for investigating the role of environmental and dietary factors in the context of vascular defects caused by altered NO signaling.

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Treatable Inborn Errors of Metabolism Causing Intellectual Disability: A Review and Diagnostic Approach

Karnebeek

Stöckler

2014

Encyclopedia of Life Sciences

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Intellectual disability (ID) is a devastating condition, affecting between 2% and 3% of children and adults globally. Early recognition of underlying conditions associated with ID that are amenable to treatment can dramatically improve health outcomes and decrease burdens to patients, families and society. However, current recommendations to investigate genetic causes of ID are based on frequencies of single conditions and diagnostic yields, rather than availability of causal therapy. Inborn errors of metabolism (IEM) constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available. Our systematic literature review identified 81 IEMs which present with ID as a prominent feature and are amenable to causal therapy. Therapeutic modalities were also identified and prioritised. The evidence created by our research has been translated into a two‐tiered diagnostic protocol currently implemented in our institution, the BC Children's Hospital. The first tier of this protocol includes easily available biochemical group tests, with the potential to identify 65% of the currently known treatable IDs. This first tier can be applied by community paediatricians and specialists in all patients presenting with global developmental delay/ID without referral to a specialised centre. The second tier includes specific tests, which should be ordered based on the differential diagnosis, established by physicians experienced with rare treatable IDs. A digital tool (an App www.treatable‐id.org ) supports the protocol, and serves as information portal for all users, ranging from students to specialists. Key Concepts: Inborn errors of metabolisms (IEMs) constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available. Early recognition of IEMs allows for timely initiation of treatment to prevent or minimise brain damage. Early recognition and treatment of IEMs is crucial for improving health outcomes and reducing disease burden for affected individuals, their families and societies. A total of 81 treatable IEM presenting with intellectual disability as a major feature were identified in the systematic review. Sixty‐two percent of IDs can be reliably detected through a panel of readily available metabolic screening tests on blood and urine. The remainder of treatable IDs is diagnosed via disease‐specific tests. A protocol indicating metabolic group tests capturing 65% of treatable IDs enables community‐based paediatricians and other specialists to perform the first tier diagnostic work‐up of treatable Ids. Normal newborn screening results in a patient with ID of unknown origin should not reassure the clinician that treatable metabolic disorders have been ruled out, as the patient might not have been screened for a particular disease or at all. Therapeutic modalities are accessible and most with acceptable side effects. The development of the treatable ID App capitalises on new digital and social media to raise awareness for rare treatable diseases and increase the likelihood of early diagnosis in children with ID of unknown origin.

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Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency

Cited by 94 publications

References 36 publications

Genetic defects in folate and cobalamin pathways affecting the brain

Genetic defects in folate and cobalamin pathways affecting the brain

Arrested Hematopoiesis and Vascular Relaxation Defects in Mice with a Mutation in Dhfr

Treatable Inborn Errors of Metabolism Causing Intellectual Disability: A Review and Diagnostic Approach

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