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Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia(CIMAH)

MedGen UID:
1615364
Concept ID:
C4540434
Disease or Syndrome
Synonyms: COMBINED IMMUNODEFICIENCY AND MEGALOBLASTIC ANEMIA; METHYLENETETRAHYDROFOLATE DEHYDROGENASE 1 DEFICIENCY
 
Gene (location): MTHFD1 (14q23.3)
 
Monarch Initiative: MONDO:0060611
OMIM®: 617780

Definition

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia is an inborn error of folate metabolism due to deficiency of methylenetetrahydrofolate dehydrogenase-1. Manifestations may include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, lymphopenia involving all subsets, and low T-cell receptor excision circles. Folinic acid supplementation is an effective treatment (summary by Ramakrishnan et al., 2016). [from OMIM]

Clinical features

From HPO
Asthenia
MedGen UID:
2107
Concept ID:
C0004093
Sign or Symptom
A state characterized by a feeling of weakness and loss of strength leading to a generalized weakness of the body.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hypoplastic hippocampus
MedGen UID:
1388294
Concept ID:
C4476822
Congenital Abnormality
Underdevelopment of the hippocampus.
Macrocytic anemia
MedGen UID:
1920
Concept ID:
C0002886
Disease or Syndrome
A type of anemia characterized by increased size of erythrocytes with increased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin (MCH).
Megaloblastic anemia
MedGen UID:
1527
Concept ID:
C0002888
Disease or Syndrome
Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Anemia of inadequate production
MedGen UID:
95937
Concept ID:
C0392708
Pathologic Function
A kind of anemia characterized by inadequate production of erythrocytes.
Thrombocytosis
MedGen UID:
163397
Concept ID:
C0836924
Disease or Syndrome
Increased numbers of platelets in the peripheral blood.
Infective arthritis
MedGen UID:
13918
Concept ID:
C0003869
Disease or Syndrome
The inflammation of one or more joints caused by any infectious pathogen within the joint space. Symptoms include pain, stiffness, and decreased range of motion in the affected joint.
Recurrent pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Autoimmunity
MedGen UID:
2136
Concept ID:
C0004368
Pathologic Function
The occurrence of an immune reaction against the organism's own cells or tissues.
Eczematoid dermatitis
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Severe combined immunodeficiency disease
MedGen UID:
88328
Concept ID:
C0085110
Disease or Syndrome
A type of primary immune deficiency that is characterized by a more severe defect in both the T- and B-lymphocyte systems.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Hypersegmentation of neutrophil nuclei
MedGen UID:
870828
Concept ID:
C4025288
Finding
An excessive division of the lobes of the nucleus of a neutrophil.
Decreased circulating antibody concentration
MedGen UID:
892481
Concept ID:
C4048270
Finding
An abnormally decreased level of immunoglobulin in blood.
Hyperhomocystinemia
MedGen UID:
812677
Concept ID:
C3806347
Finding
An increased concentration of homocystine in the blood.
Decreased circulating methylcobalamin concentration
MedGen UID:
867371
Concept ID:
C4021736
Finding
The concentration of methylcobalamin in the blood circulation is below the lower limit of normal. Methylcobalamin is a form of vitamin B12.
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.

Professional guidelines

PubMed

Wong A, Galiabovitch E, Bhagwat K
ANZ J Surg 2019 Apr;89(4):303-308. Epub 2018 Jul 5 doi: 10.1111/ans.14713. PMID: 29974615
Langan RC, Goodbred AJ
Am Fam Physician 2017 Sep 15;96(6):384-389. PMID: 28925645
Levin BL, Varga E
J Genet Couns 2016 Oct;25(5):901-11. Epub 2016 Apr 30 doi: 10.1007/s10897-016-9956-7. PMID: 27130656

Recent clinical studies

Therapy

Gu J, Lei C, Zhang M
BMC Ophthalmol 2023 Oct 13;23(1):413. doi: 10.1186/s12886-023-03149-z. PMID: 37833663Free PMC Article
Guéant JL, Guéant-Rodriguez RM, Oussalah A, Zuily S, Rosenberg I
Thromb Haemost 2023 Mar;123(3):270-282. Epub 2022 Sep 28 doi: 10.1055/a-1952-1946. PMID: 36170884
Wu HHL, Wang AY
Vitam Horm 2022;119:325-353. Epub 2022 Feb 25 doi: 10.1016/bs.vh.2022.01.011. PMID: 35337625
Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B
J Neurol Neurosurg Psychiatry 2020 Nov;91(11):1201-1209. Epub 2020 Jul 20 doi: 10.1136/jnnp-2019-321913. PMID: 32690803Free PMC Article
Zaric BL, Obradovic M, Bajic V, Haidara MA, Jovanovic M, Isenovic ER
Curr Med Chem 2019;26(16):2948-2961. doi: 10.2174/0929867325666180313105949. PMID: 29532755

Prognosis

Guéant JL, Guéant-Rodriguez RM, Oussalah A, Zuily S, Rosenberg I
Thromb Haemost 2023 Mar;123(3):270-282. Epub 2022 Sep 28 doi: 10.1055/a-1952-1946. PMID: 36170884
Wu HHL, Wang AY
Vitam Horm 2022;119:325-353. Epub 2022 Feb 25 doi: 10.1016/bs.vh.2022.01.011. PMID: 35337625
Katsiki N, Perez-Martinez P, Mikhailidis DP
Curr Pharm Des 2017;23(22):3224-3232. doi: 10.2174/1381612823666170317124913. PMID: 28317478
Smulders YM, Blom HJ
J Inherit Metab Dis 2011 Feb;34(1):93-9. Epub 2010 Jun 22 doi: 10.1007/s10545-010-9151-1. PMID: 20567905Free PMC Article
Herrmann W
Clin Lab 2006;52(7-8):367-74. PMID: 16955635

Clinical prediction guides

Gu J, Lei C, Zhang M
BMC Ophthalmol 2023 Oct 13;23(1):413. doi: 10.1186/s12886-023-03149-z. PMID: 37833663Free PMC Article
Guéant JL, Guéant-Rodriguez RM, Oussalah A, Zuily S, Rosenberg I
Thromb Haemost 2023 Mar;123(3):270-282. Epub 2022 Sep 28 doi: 10.1055/a-1952-1946. PMID: 36170884
Wu HHL, Wang AY
Vitam Horm 2022;119:325-353. Epub 2022 Feb 25 doi: 10.1016/bs.vh.2022.01.011. PMID: 35337625
Katsiki N, Perez-Martinez P, Mikhailidis DP
Curr Pharm Des 2017;23(22):3224-3232. doi: 10.2174/1381612823666170317124913. PMID: 28317478
Smulders YM, Blom HJ
J Inherit Metab Dis 2011 Feb;34(1):93-9. Epub 2010 Jun 22 doi: 10.1007/s10545-010-9151-1. PMID: 20567905Free PMC Article

Recent systematic reviews

Wen Y, He H, Zhao K
J Assist Reprod Genet 2023 Jul;40(7):1533-1558. Epub 2023 May 30 doi: 10.1007/s10815-023-02823-x. PMID: 37248348Free PMC Article
Rao RV, Subramaniam KG, Gregory J, Bredesen AL, Coward C, Okada S, Kelly L, Bredesen DE
Int J Mol Sci 2023 Jan 14;24(2) doi: 10.3390/ijms24021659. PMID: 36675177Free PMC Article
Boelens Keun JT, Arnoldussen IA, Vriend C, van de Rest O
Adv Nutr 2021 Dec 1;12(6):2265-2287. doi: 10.1093/advances/nmab060. PMID: 34113965Free PMC Article
Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B
J Neurol Neurosurg Psychiatry 2020 Nov;91(11):1201-1209. Epub 2020 Jul 20 doi: 10.1136/jnnp-2019-321913. PMID: 32690803Free PMC Article
Morris AA, Kožich V, Santra S, Andria G, Ben-Omran TI, Chakrapani AB, Crushell E, Henderson MJ, Hochuli M, Huemer M, Janssen MC, Maillot F, Mayne PD, McNulty J, Morrison TM, Ogier H, O'Sullivan S, Pavlíková M, de Almeida IT, Terry A, Yap S, Blom HJ, Chapman KA
J Inherit Metab Dis 2017 Jan;40(1):49-74. Epub 2016 Oct 24 doi: 10.1007/s10545-016-9979-0. PMID: 27778219Free PMC Article

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