Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 29914000; ORPHA: 621;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q13.2 | Methemoglobinemia, type II | 250800 | Autosomal recessive | 3 | CYB5R3 | 613213 |
| 22q13.2 | Methemoglobinemia, type I | 250800 | Autosomal recessive | 3 | CYB5R3 | 613213 |
A number sign (#) is used with this entry because autosomal recessive methemoglobinemia due to deficiency of methemoglobin reductase is caused by homozygous or compound heterozygous mutation in the CYB5R3 gene (613213) on chromosome 22q13.
See also autosomal recessive methemoglobinemia type IV (250790), which is caused by mutation in the cytochrome b5 gene (CYB5A; 613218). Type III has been withdrawn (see below and Nagai et al., 1993).
Autosomal dominant methemoglobinemia, referred to as the 'M' type, is caused by variation in the hemoglobin A (HBA1; 141800) or hemoglobin B (HBB; 141900) genes; see 617973 and 617971, respectively.
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).
Gibson (1948) and Barcroft et al. (1945) correctly concluded that erythrocytes from affected individuals with methemoglobinemia were unable to reduce methemoglobin that is formed continuously at a normal rate under physiologic conditions. Gibson (1948) is credited with identifying this disorder as an enzymatic defect in a reductase (see HISTORY below). Increased circulating levels of methemoglobin, which is brown, give the skin a bluish color, which appears as cyanosis. In the normal state, about 1% of hemoglobin exists as methemoglobin; individuals become symptomatic when methemoglobin levels rise above 25% (Jaffe, 1986). Vascular collapse, coma, and death can occur when methemoglobin approaches 70% of total hemoglobin (review by Percy and Lappin, 2008).
Methemoglobinemia Type I
Tanishima et al. (1985) reported 2 Japanese brothers, born of consanguineous parents, with hereditary methemoglobinemia due to cytochrome b5 reductase deficiency. Katsube et al. (1991) provided follow-up of this family. The brothers, who were 24 and 26 years old, had moderate cyanosis without any evidence of neurologic involvement. Initial laboratory studies (Tanishima et al., 1985) showed lack of CYB5R3 enzyme activity in erythrocytes, leukocytes, and platelets. However, enzyme activity was not deficient in nonhematopoietic cells. Thus, the cases did not belong to either the classic erythrocytic or the generalized type, and was tentatively designated 'type III.' A study of relatives showed intermediate enzyme activity, consistent with heterozygosity. Tanishima et al. (1985) concluded that diagnosis by tissues other than blood cells may be important. Katsube et al. (1991) identified a homozygous mutation in the CYB5R3 gene (L149P; 613213.0003) in these patients. Further biochemical studies of these patients by Nagai et al. (1993) revealed that they did have residual enzyme activity in white blood cells, indicating that they actually had type I methemoglobinemia. As this was the only family reported with methemoglobinemia type III, that designation was shown not to exist.
Wu et al. (1998) reported a 3-year-old Chinese girl with type I methemoglobinemia. The patient was born after normal pregnancy and delivery. From the age of 1 month she appeared persistently cyanosed, but without mental or neurologic abnormalities, and her respiratory and cardiac functions were normal. The concentration of methemoglobin was 15%, and NADH-cytochrome b5R activity in erythrocytes was decreased. Her 5-year-old brother had the same symptoms, with 14.5% methemoglobin and decreased b5R activity. The unaffected parents had heterozygous levels of enzyme activity in red cells (about 65% of normal controls).
Methemoglobinemia Type II
Mental deficiency occurs only with the generalized enzyme-deficient form of the disorder, now known as type II (Hitzenberger, 1932; Worster-Drought et al., 1953; Jaffe, 1963).
Leroux et al. (1975) reported methemoglobinemia and mental retardation in patients with generalized deficiency of cytochrome b5 reductase. Lawson et al. (1977) also concluded that low leukocyte diaphorase correlates with mental retardation, a variable feature. The clinical picture in the neurologic form was reviewed by Jaffe and Hsieh (1971).
Shirabe et al. (1995) reported a girl, born of Italian second-cousin parents, with type II methemoglobinemia. She appeared cyanotic from the first days of life. In addition, the first months of life were characterized by feeding difficulties, failure to thrive, and psychomotor developmental delay. Therapy with ascorbate did not improve her neurologic condition. At 1 year of age, she had severe spastic and dystonic quadriparesis with hyperkinetic involuntary movements, severe microcephaly, and very simple and primitive reactions to environmental changes. A few months later, she developed generalized tonic seizures and myoclonic jerks that were not responsive to common antiepileptic drugs. At the age of 9 years, the patient was in a vegetative status. There was complete absence of immunologically detectable CYB5R3 enzyme in blood cells and skin fibroblasts. Cultured fibroblasts of the patient showed severely reduced NADH-dependent cytochrome c reductase, ferricyanide reductase, and semidehydroascorbate reductase activities.
Vieira et al. (1995) reported an Algerian patient with methemoglobinemia type II. The patient had profound mental retardation, microcephaly, and bilateral athetosis associated with cyanosis and absent CYB5R3 enzyme activities in erythrocytes, lymphocytes, and lymphoblastoid cell lines. Genetic analysis identified a homozygous nonsense mutation in the CYB5R3 gene (R219X; 613213.0007).
Owen et al. (1997) reported a 4-year-old boy with type II methemoglobinemia. He had dystonic athetoid cerebral palsy with mental retardation and microcephaly. He was found to have 60% methemoglobinemia that was persistent but responded to ascorbic acid treatment.
Aalfs et al. (2000) reported a child, born of healthy, unrelated Hindustani Suriname parents, with type II methemoglobinemia. She was born small for gestational age. Central cyanosis was noted shortly after birth. She had severe psychomotor retardation and microcephaly. Neurologic features included athetoid movements, generalized hypertonia, epilepsy, and a complete head lag. At 6 years of age, MRI of the brain demonstrated frontal and bitemporal cortical atrophy, cerebellar atrophy, retarded myelinization, and hypoplasia of the basal ganglia. There was almost no psychomotor development and she developed spastic tetraplegia with scoliosis. The patient died at the age of 8 years. Genetic analysis identified compound heterozygosity for 2 nonsense mutations in the CYB5R3 gene (Q77X; 613213.0014 and R160X; 613213.0015).
Enterogenous Methemoglobinemia
Neonates have only about 60% of normal adult levels of CYB5R3 and do not attain mature levels before 2 months of age (Wright et al., 1999). Low-birth-weight neonates have low levels of erythrocyte CYB5R3 (Miyazono et al., 1999). Thus, even infants without CYB5R3 mutations are at risk of developing methemoglobinemia if exposed to strong oxidizing agents, such as drugs.
Enterogenous methemoglobinemia might be confused with the genetic form. Rossi et al. (1966) described a patient with chronic methemoglobinemia for 14 years whose disorder was resolved by a course of neomycin.
Cohen et al. (1968) suggested that methemoglobinemia induced by malarial prophylaxis, such as chloroquine, primaquine and diamino-diphenylsulfone, could be an indication of the presence of the heterozygous state. In a historic article, Comly (1945) reported cyanosis in infants caused by nitrates in well water, which could easily be confused with cyanotic congenital heart disease and at times He could be fatal (Johnson et al., 1987). This continues to be a problem in rural areas. Presumably, an infant with methemoglobin reductase deficiency, and possibly even a heterozygote, would be unusually vulnerable.
Maran et al. (2005) reported 3 unrelated patients with acquired methemoglobinemia and no mutations in the CYB5R3 gene. One was an infant with age-related decreased CYB5R3 activity (60%) and 35% methemoglobin. The infant had 1 week of a diarrheal illness and required several administrations of methylene blue. Another patient developed methemoglobinemia upon exposure to lidocaine, and the third patient, who had 44% methemoglobin, had an unidentified toxin or infection.
West et al. (1967) provided electrophoretic evidence of anomalous enzyme structure of NADH diaphorase (the former name of CYB5R3; Percy and Lappin, 2008) in a case of methemoglobinemia. West et al. (1967) noted that electrophoretic variants of NADH diaphorase without methemoglobinemia have also been found, with a family pattern consistent with codominant inheritance.
By electrophoresis, Bloom and Zarkowsky (1969) described 3 varieties of the NADH diaphorase enzyme in patients with methemoglobinemia: total absence of detectable enzyme activity, decreased quantities of presumably normal enzyme, and decreased quantities of structurally variant enzyme. They added 2 new structural variants of NADH-methemoglobin reductase to the one originally described by Kaplan and Beutler (1967).
Prenatal Diagnosis
Kaftory et al. (1986) made the prenatal diagnosis of congenital methemoglobinemia with mental retardation by demonstration of an almost complete deficiency of cytochrome b5 reductase activity in cultured amniotic fluid cells.
Treatment with methylene blue (100-300 mg orally per day) or ascorbic acid (500 mg a day) is of cosmetic value (Waller, 1970). Methylene blue stimulates production of reduced NADPH through the pentose phosphate pathway in red blood cells (Percy and Lappin, 2008).
Karadsheh et al. (2001) reported a patient with coexisting glucose-6-phosphate deficiency (300908) and CYB5R3 deficiency. He developed metoclopramide-induced methemoglobinemia that did not respond to methylene blue treatment. This was because G6PD patients have blockage of the pentose phosphate pathway, which generates NADPH.
In a 3-year-old Chinese girl with type I methemoglobinemia, Wu et al. (1998) identified a homozygous mutation in the CYB5R3 gene (L73P; 613213.0013).
In an Italian girl with severe type II methemoglobinemia, Shirabe et al. (1995) identified a homozygous mutation in the CYB5R3 gene (613213.0005).
In a 4-year-old boy with type II methemoglobinemia, Owen et al. (1997) identified a homozygous splice site mutation in the CYB5R3 gene that resulted in the deletion of exon 6 (613213.0012).
Maran et al. (2005) reported 4 unrelated patients with recessive methemoglobinemia: 2 with type I and 2 with type II. Four different mutations in the CYB5R3 gene were identified (see, e.g., 613213.0008 and 613213.0012).
The enzymatic type of methemoglobinemia has unprecedentedly high frequency in the Athabaskan Indians (Eskimos) of Alaska (Scott, 1960; Scott et al., 1963). Balsamo et al. (1964) also observed CYB5R3 deficiency in Navajo Indians. Since the Navajo Indians and the Athabaskan Indians of Alaska are the same linguistic stock, the finding may illustrate the usefulness of rare recessive genes in tracing relationships of ethnic groups.
Following up on an observation of an unusually high proportion of Algerian subjects among patients with methemoglobinemia, Reghis et al. (1981) did a population survey of red cell cytochrome b5 reductase in 1,000 Algerian subjects. In 16, the activity of the enzyme was diminished by about 50%. The relatively high frequency of the deficiency allele was found in subjects of Kabyle origin.
Jaffe (1987) stated that the enzyme can be called cytochrome b5 reductase (dropping the NADH prefix) and the disorder can be called 'enzymopenic methemoglobinemia.'
Methemoglobinemia, although not usually considered an inborn error of metabolism in the strict garrodian sense, was the first hereditary trait in which a specific enzyme deficiency was identified (Gibson, 1948). (Type I glycogen storage disease (232200) is usually listed as the first disorder in which a specific enzymopathy was identified, by Cori and Cori, 1952).
Gibson (1993) gave a delightful account of his work on the enzyme defect in methemoglobinemia in Belfast, Northern Ireland. The patients he studied were 2 brothers, Russell and Fred Martin from Banbridge in Northern Ireland, in whom Dr. James Deeny, a local practitioner with early enthusiasm for ascorbic acid in the treatment of heart disease, had demonstrated the benefit of vitamin C (Deeny et al., 1943). The brothers had a blue appearance. When Russell was treated with vitamin C, he turned pink. Although Deeny assumed that he had corrected an underlying heart condition, cardiologists could find no cardiac abnormality in either brother. The physiologist Henry Barcroft carried out a detailed study of these cases during treatment and found raised levels of methemoglobin (Barcroft et al., 1945). Quentin Gibson (then of Queen's University, Belfast, Ireland) correctly identified the pathway involved in the reduction of methemoglobin in the family, thereby describing the first hereditary trait involving a specific enzyme deficiency (Gibson, 1948). See also the personal account of Gibson (2002).
Trost (1982) gave a popular account of the 'blue Fugates' of Kentucky and the studies of them by Cawein et al. (1964).
Early Reports of Possible Other Defects Causing Methemoglobinemia
Townes and Morrison (1962) reported biochemical studies of a variant of autosomal recessive methemoglobinemia. NADH-methemoglobin reductase (CYB5R3) activity of red cells was in the normal range and hemoglobin was apparently normal. Methemoglobin reduction in intact red cells was very low with glucose as the substrate, but normal with lactate. Intracellular glutathione was also low. Townes and Morrison (1962) postulated that the defect might be inadequate NADH formation resulting from decreased glutathione synthesis. However, this may have represented a basically different form of methemoglobinemia.
Muller et al. (1963) described 3 sibs with methemoglobinemia. Laboratory studies showed a deficient ability of erythrocytes to utilize glucose for methemoglobin reduction, but normal reduction of lactate. They suggested that their family had a hereditary deficiency of NADPH methaemoglobin reductase (CYB5R4; 608343). A deficiency of NADPH has never been reported.
Ozsoylu (1967) reported enzyme-deficiency methemoglobinemia in 3 generations and proposed dominant inheritance. However, consanguinity was present to account for a quasi-dominant pattern. The author thought this possibility was excluded by normal enzyme activity in individuals who would need to be heterozygotes to account for the pattern.
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Balsamo, P., Hardy, W. R., Scott, E. M. Hereditary methemoglobinemia due to diaphorase deficiency in Navajo Indians. J. Pediat. 65: 928-930, 1964. [PubMed: 14244100] [Full Text: https://doi.org/10.1016/s0022-3476(64)80017-2]
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