What is the pattern of inheritance of methemoglobinemia (methemoglobinopathy)?

From the Guidelines

Methemoglobinemia typically exhibits an autosomal recessive or autosomal dominant pattern of inheritance, depending on the underlying cause, with autosomal recessive inheritance seen in NADH-cytochrome reductase deficiency and autosomal dominant inheritance in cases of alpha, beta, and gamma globin mutations causing HbM. This means that the risk of passing the condition to offspring varies based on the specific genetic mutation responsible for the methemoglobinemia. According to 1, NADH-cytochrome reductase deficiency, which leads to methemoglobinemia, is inherited in an autosomal recessive fashion, suggesting that there may be no family history unless the patient is from a small community or their parents are closely related. On the other hand, alpha, beta, and gamma globin mutations resulting in HbM typically follow an autosomal dominant inheritance pattern, but many cases are due to de novo mutational events, which can complicate the prediction of inheritance patterns.

Key points to consider in the inheritance pattern of methemoglobinemia include:

• The specific genetic cause of the methemoglobinemia, as different mutations can lead to different patterns of inheritance
• The presence of a known family history, which can indicate autosomal dominant inheritance but may be absent in autosomal recessive cases or those resulting from de novo mutations
• The importance of genetic counseling for affected individuals planning to have children, given the potential risk of transmission to offspring, as highlighted in the context of methemoglobinemia diagnosis and treatment recommendations by 1.

In clinical practice, understanding the pattern of inheritance is crucial for providing accurate genetic counseling and for the management of methemoglobinemia, considering the potential for variable expression and penetrance of the condition, as well as the possibility of associated symptoms such as cognitive impairment, growth retardation, microcephaly, and dystonia in more severe forms like methemoglobinemia type II, as noted in 1.

From the Research

Pattern of Inheritance of Methemoglobinemia

• Methemoglobinemia can be inherited in an autosomal recessive pattern, with two main phenotypes: type I and type II 2.
• In type I, the enzyme deficiency is restricted to erythrocytes, usually discovered in infancy but not exclusively 2.
• In type II, the CYB5R deficiency is generalized and affects all cells, leading to an early onset 2.
• The disease can also be caused by genetic mutations affecting globin chains, resulting in M hemoglobins (M Hbs) 2, 3.
• Methemoglobinemia can be congenital or acquired, with acquired causes including oxidizing drugs or chemicals 2, 3, 4.
• The pattern of inheritance is related to the CYB5R3 gene, with mutations in this gene leading to autosomal recessive congenital methemoglobinemia 2.
• Some cases of methemoglobinemia may not be discovered until adulthood, as illustrated by a case study of a patient from Bahrain who exhibited an unknown dyspnea at the age of 37 years without trigger events or oxidizing products 2.

Key Factors Influencing the Pattern of Inheritance

• Genetic mutations in the CYB5R3 gene or globin chains can lead to methemoglobinemia 2, 3.
• The severity of the disease depends on the type of mutation and the level of enzyme deficiency 2, 3.
• Acquired causes of methemoglobinemia, such as oxidizing drugs or chemicals, can also play a role in the development of the disease 2, 3, 4.