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Transcobalamin II deficiency(TCN2D)

MedGen UID:
137976
Concept ID:
C0342701
Disease or Syndrome
Synonyms: TC II DEFICIENCY; TCN2 DEFICIENCY; TCN2D; Transcolabamin II deficiency
SNOMED CT: TCN2 - Transcobalamin II deficiency (237934001); Transcobalamin II deficiency (237934001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): TCN2 (22q12.2)
 
Monarch Initiative: MONDO:0010149
OMIM®: 275350
Orphanet: ORPHA859

Definition

Transcobalamin II deficiency (TCN2D) is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities (summary by Haberle et al., 2009). Hall (1981) gave a clinically oriented review of congenital defects of vitamin B12 transport, and Frater-Schroder (1983) gave a genetically oriented review. [from OMIM]

Additional description

From MedlinePlus Genetics
Transcobalamin deficiency is a disorder that impairs the transport of cobalamin (also known as vitamin B12) within the body. Cobalamin is obtained from the diet; this vitamin is found in animal products such as meat, eggs, and shellfish. An inability to transport cobalamin within the body results in cells that lack cobalamin, which they need for many functions including cell growth and division (proliferation) and DNA production. The absence of cobalamin leads to impaired growth, a shortage of blood cells, and many other signs and symptoms that usually become apparent within the first weeks or months of life.

The first signs of transcobalamin deficiency are typically a failure to gain weight and grow at the expected rate (failure to thrive), vomiting, diarrhea, and open sores (ulcers) on the mucous membranes such as the lining inside the mouth. Neurological function is impaired in affected individuals, and they can experience progressive stiffness and weakness in their legs (paraparesis), muscle twitches (myoclonus), or intellectual disability.

People with transcobalamin deficiency often develop a blood disorder called megaloblastic anemia. Megaloblastic anemia results in a shortage of red blood cells, and the remaining red blood cells are abnormally large. Individuals with transcobalamin deficiency may also have a shortage of white blood cells (neutropenia), which can lead to reduced immune system function. Decreased cellular cobalamin can lead to a buildup of certain compounds in the body, resulting in metabolic conditions known as methylmalonic aciduria or homocystinuria.  https://medlineplus.gov/genetics/condition/transcobalamin-deficiency

Clinical features

From HPO
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
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.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
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).
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).
Megaloblastic bone marrow
MedGen UID:
68673
Concept ID:
C0238801
Laboratory or Test Result
Abnormal increased number of megaloblasts in the bone marrow.
Erythroid hypoplasia
MedGen UID:
488912
Concept ID:
C0542035
Disease or Syndrome
Decreased count of erythroid precursor cells, that is, erythroid lineage cells in the bone marrow.
Reticulocytopenia
MedGen UID:
167812
Concept ID:
C0858867
Finding
A reduced number of reticulocytes in the peripheral blood.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Decreased circulating IgA concentration
MedGen UID:
57934
Concept ID:
C0162538
Disease or Syndrome
Decreased levels of immunoglobulin A (IgA).
Decreased circulating total IgM
MedGen UID:
116095
Concept ID:
C0239989
Finding
An abnormally decreased level of immunoglobulin M (IgM) in blood.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Decreased circulating IgG concentration
MedGen UID:
1720114
Concept ID:
C5234937
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.
Hyperhomocystinemia
MedGen UID:
812677
Concept ID:
C3806347
Finding
An increased concentration of homocystine in the blood.
Abnormal circulating vitamin B12 concentration
MedGen UID:
866685
Concept ID:
C4021032
Finding
A deviation from the normal concentration of cobalamin (vitamin B12) in the blood. Vitamin B12 is one of the eight B vitamins.
Abnormal blood folate concentration
MedGen UID:
866690
Concept ID:
C4021037
Finding
Any deviation from the normal concentration of folate in the blood circulation.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVTranscobalamin II deficiency
Follow this link to review classifications for Transcobalamin II deficiency in Orphanet.

Professional guidelines

PubMed

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Recent clinical studies

Etiology

Verónica B, Crespo C, Lochner N, Rossetti E, Tagliavini C, Bouso C, Eiroa H
J Pediatr Endocrinol Metab 2024 Apr 25;37(4):380-386. Epub 2024 Mar 5 doi: 10.1515/jpem-2023-0577. PMID: 38436354
Ünal S, Karahan F, Arıkoğlu T, Akar A, Kuyucu S
Turk J Haematol 2019 Feb 7;36(1):37-42. Epub 2018 Sep 6 doi: 10.4274/tjh.galenos.2018.2018.0230. PMID: 30185401Free PMC Article
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Diagnosis

Kose E, Besci O, Gudeloglu E, Suncak S, Oymak Y, Ozen S, Isguder R
J Pediatr Endocrinol Metab 2020 Nov 26;33(11):1487-1499. doi: 10.1515/jpem-2020-0096. PMID: 32841161
Ünal S, Karahan F, Arıkoğlu T, Akar A, Kuyucu S
Turk J Haematol 2019 Feb 7;36(1):37-42. Epub 2018 Sep 6 doi: 10.4274/tjh.galenos.2018.2018.0230. PMID: 30185401Free PMC Article
Ratschmann R, Minkov M, Kis A, Hung C, Rupar T, Mühl A, Fowler B, Nexo E, Bodamer OA
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Rosenblatt DS, Cooper BA
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Therapy

Kose E, Besci O, Gudeloglu E, Suncak S, Oymak Y, Ozen S, Isguder R
J Pediatr Endocrinol Metab 2020 Nov 26;33(11):1487-1499. doi: 10.1515/jpem-2020-0096. PMID: 32841161
Chao MM, Illsinger S, Yoshimi A, Das AM, Kratz CP
Klin Padiatr 2017 Nov;229(6):355-357. Epub 2017 Nov 13 doi: 10.1055/s-0043-120266. PMID: 29132166
Ünal Ş, Rupar T, Yetgin S, Yaralı N, Dursun A, Gürsel T, Çetin M
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Kaikov Y, Wadsworth LD, Hall CA, Rogers PC
Eur J Pediatr 1991 Oct;150(12):841-3. doi: 10.1007/BF01955004. PMID: 1743216

Prognosis

Pongphitcha P, Sirachainan N, Khongkraparn A, Tim-Aroon T, Songdej D, Wattanasirichaigoon D
BMC Pediatr 2022 Apr 29;22(1):233. doi: 10.1186/s12887-022-03291-5. PMID: 35488219Free PMC Article
Ünal S, Karahan F, Arıkoğlu T, Akar A, Kuyucu S
Turk J Haematol 2019 Feb 7;36(1):37-42. Epub 2018 Sep 6 doi: 10.4274/tjh.galenos.2018.2018.0230. PMID: 30185401Free PMC Article
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Mol Genet Metab 2009 Nov;98(3):285-8. Epub 2009 Jun 6 doi: 10.1016/j.ymgme.2009.06.003. PMID: 19581117
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Clinical prediction guides

Pongphitcha P, Sirachainan N, Khongkraparn A, Tim-Aroon T, Songdej D, Wattanasirichaigoon D
BMC Pediatr 2022 Apr 29;22(1):233. doi: 10.1186/s12887-022-03291-5. PMID: 35488219Free PMC Article
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