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Deficiency of cytochrome-b5 reductase

MedGen UID:
75661
Concept ID:
C0268193
Disease or Syndrome
Synonyms: Diaphorase deficiency; Methemoglobinemia Due to Deficiency of Methemoglobin Reductase; METHEMOGLOBINEMIA, CONGENITAL, AUTOSOMAL RECESSIVE; NADH cytochrome B5 reductase deficiency; NADH diaphorase deficiency; NADH methemoglobin reductase deficiency
SNOMED CT: Deficiency of cytochrome-b>5< reductase (124184009); Congenital methemoglobinemia due to NADH-cytochrome b5 reductase 3 deficiency (767497003); Congenital NADH-methemoglobin reductase deficiency (767497003); Cytochrome b5 reductase deficiency (767497003); NADH-methemoglobin reductase deficiency (767497003); Chronic familial methemoglobin reductase deficiency (767497003); Autosomal recessive congenital methemoglobinemia (767497003)
 
Gene (location): CYB5R3 (22q13.2)
 
Monarch Initiative: MONDO:0009606
OMIM®: 250800

Definition

Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (review by Percy and Lappin, 2008). There are 2 types of methemoglobin reductase deficiency. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979). [from OMIM]

Clinical features

From HPO
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Opisthotonus
MedGen UID:
56246
Concept ID:
C0151818
Sign or Symptom
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
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.
Methemoglobinemia
MedGen UID:
6339
Concept ID:
C0025637
Disease or Syndrome
Abnormally increased levels of methemoglobin in the blood. In this form of hemoglobin, there is an oxidized ferric iron (Fe +3) rather than the reduced ferrous form (Fe 2+) that is normally found in hemoglobin. Methemoglobin has a reduced affinity for oxygen, resulting in a reduced ability to release oxygen to tissues.
Polycythemia
MedGen UID:
18552
Concept ID:
C0032461
Disease or Syndrome
Polycythemia is diagnosed if the red blood cell count, the hemoglobin level, and the red blood cell volume all exceed the upper limits of normal.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Exertional dyspnea
MedGen UID:
68549
Concept ID:
C0231807
Sign or Symptom
Perceived difficulty to breathe that occurs with exercise or exertion and improves with rest.
Decreased erythrocyte nicotinamide adenine dinucleotide-cytochrome b5 reductase activity
MedGen UID:
1053848
Concept ID:
CN376642
Finding
The activity of nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase in erythrocytes (red blood cells) is below the lower limit of normal.
Cyanosis
MedGen UID:
1189
Concept ID:
C0010520
Sign or Symptom
Bluish discoloration of the skin and mucosa due to poor circulation or inadequate oxygenation of arterial or capillary blood.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Esodeviation
MedGen UID:
1641033
Concept ID:
C4551734
Disease or Syndrome
A manifest or latent ocular deviation in which one or both eyes tends to deviate nasally.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Deficiency of cytochrome-b5 reductase in Orphanet.

Professional guidelines

PubMed

Sanpavat S, Nuchprayoon I, Kittikalayawong A, Ungbumnet W
J Med Assoc Thai 2001 Jun;84 Suppl 1:S91-8. PMID: 11529386
Hall AH, Kulig KW, Rumack BH
Med Toxicol 1986 Jul-Aug;1(4):253-60. doi: 10.1007/BF03259842. PMID: 3537620
Jaffé ER
Hosp Pract (Off Ed) 1985 Dec 15;20(12):92-6, 101-3, 108-10. doi: 10.1080/21548331.1985.11703207. PMID: 3934202

Recent clinical studies

Etiology

Kaftory A, Freundlich E, Manaster J, Shukri A, Hegesh E
Isr J Med Sci 1986 Nov;22(11):837-40. PMID: 3793441

Diagnosis

Ghotra S, Jangaard K, Pambrun C, Fernandez CV
BMJ Case Rep 2016 Mar 11;2016 doi: 10.1136/bcr-2016-214381. PMID: 26969357Free PMC Article
Percy MJ, Aslan D
J Clin Pathol 2008 Oct;61(10):1122-3. doi: 10.1136/jcp.2008.058701. PMID: 18820099
Kaftory A, Freundlich E, Manaster J, Shukri A, Hegesh E
Isr J Med Sci 1986 Nov;22(11):837-40. PMID: 3793441

Therapy

Hudspeth MP, Joseph S, Holden KR
J Child Neurol 2010 Jan;25(1):91-3. Epub 2009 May 26 doi: 10.1177/0883073809336136. PMID: 19471045
Percy MJ, Aslan D
J Clin Pathol 2008 Oct;61(10):1122-3. doi: 10.1136/jcp.2008.058701. PMID: 18820099

Prognosis

Jenkins MM, Prchal JT
Blood 1996 Apr 1;87(7):2993-9. PMID: 8639921

Clinical prediction guides

Jenkins MM, Prchal JT
Blood 1996 Apr 1;87(7):2993-9. PMID: 8639921
Hirono H
Lipids 1984 Jan;19(1):60-3. doi: 10.1007/BF02534610. PMID: 6708747
Hirono H
Lipids 1980 Apr;15(4):272-5. doi: 10.1007/BF02535839. PMID: 7374382

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