What are the other Names for this Condition? (Also known as/Synonyms)

• Autosomal Recessive Methemoglobinemia
• Congenital Methemoglobinemia
• HM (Hereditary Methemoglobinemia)

What is Hereditary Methemoglobinemia? (Definition/Background Information)

• Hereditary Methemoglobinemia (HM) is a rare red cell disorder classified principally into two clinical phenotypes - autosomal recessive congenital (or hereditary) methemoglobinemia types I and II (RCM 1 and 2)
  • In RCM type 1, cyanosis from birth is the only symptom. It is well-tolerated and is associated with mild complaints of headaches, fatigue and shortness of breath upon exertion. It is caused by mutations of the CYB5R3 gene encoding the NADH-cytochrome b5 reductase (Cb5R) and Cb5R deficiency is limited to the erythrocytes
  • RCM type 2, with global loss of Cb5R function, is much more severe; the cyanosis is accompanied by neurological dysfunction (with intellectual deficit, microcephaly, growth retardation, opisthotonus, strabismus and hypertonia), which usually becomes evident during the first four months of life
• The treatment of Hereditary Methemoglobinemia revolves around administration of methylene blue and/or ascorbic acid. However, these treatments have no effect on the neurological dysfunction in RCM type 2

(Source: Hereditary Methemoglobinemia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Hereditary Methemoglobinemia? (Age and Sex Distribution)

• Hereditary Methemoglobinemia is a rare congenital disorder. The presentation of symptoms may occur at birth or in infancy
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Hereditary Methemoglobinemia? (Predisposing Factors)

• A positive family history may be an important risk factor, since Hereditary Methemoglobinemia is inherited
• Currently, no other risk factors have been clearly identified for this disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Hereditary Methemoglobinemia? (Etiology)

Hereditary Methemoglobinemia is caused by mutations in the CYB5R3 gene, which codes for the enzyme NADH-cytochrome b5 reductase.

• In general, type 1 RCM is generally associated with missense mutations
• However, RCM type 2 is more commonly associated with truncating mutations, splicing errors, or mutations that lead to disruption of the active site
• Both types are inherited in an autosomal recessive manner

Autosomal recessive mode of inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Hereditary Methemoglobinemia?

The signs and symptoms of Hereditary Methemoglobinemia vary between types 1 and 2, and from one individual to another.

The signs and symptoms of Hereditary Methemoglobinemia type 1 include:

• Cyanosis at birth
• Headache
• Fatigue
• Labored breathing with physical exertion

The signs and symptoms of Hereditary Methemoglobinemia type 2 include:

• Cyanosis at birth
• Muscle spasms (opisthotonus, in which the head, neck and spine arch back unnaturally)
• Strabismus (poor muscle control in eyes, leading to cross-eyes)
• Growth retardation
• Microcephaly
• Intellectual deficiency

How is Hereditary Methemoglobinemia Diagnosed?

Hereditary Methemoglobinemia is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary
• Molecular genetic testing to check for or confirm causative gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Hereditary Methemoglobinemia?

The complications of Hereditary Methemoglobinemia are more common in type 2 (although physical limitations may occur in type 1 as well) and may include:

• Inability to perform strenuous physical activities
• Problems with movement 
• Cerebral palsy
• Severe intellectual deficiency
• Epilepsy

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Hereditary Methemoglobinemia Treated?

There is no cure for Hereditary Methemoglobinemia, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. The treatment may include:

• Administration of ascorbic acid for mild cases of cyanosis
• Administration of ascorbic acid and methylene blue for severe cases of cyanosis

The neurological signs and symptoms of RCM type 2 are not alleviated by the above treatments.

How can Hereditary Methemoglobinemia be Prevented?

Currently, Hereditary Methemoglobinemia may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Hereditary Methemoglobinemia? (Outcomes/Resolutions)

• The prognosis of Hereditary Methemoglobinemia is dependent upon the severity of the signs and symptoms and associated complications, if any
• The prognosis of RCM type 2 is more guarded, owing to the neurological signs and symptoms
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Hereditary Methemoglobinemia:

• Two additional forms of RCM have also been reported. RCM type 3 was the term used to define a phenotype with cyanosis, but without neurological abnormalities in which Cb5R deficiency was identified in leucocytes and platelets as well as erythrocytes
• RCM type 4 is a very rare disease associated with chronic cyanosis caused by mutations in the CYB5A gene encoding cytochrome b5

(Source: Hereditary Methemoglobinemia ; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/