Autosomal recessive methemoglobinemia

Autosomal recessive methemoglobinemia, also known as congenital methemoglobinemia or recessive hereditary methemoglobinemia, is an inherited blood disorder caused by a deficiency of the enzyme NADH-cytochrome b5 reductase (also called methemoglobin reductase or diaphorase I), encoded by the CYB5R3 gene. This enzyme is responsible for converting methemoglobin — a form of hemoglobin that cannot effectively carry oxygen — back to functional hemoglobin. When this enzyme is deficient, methemoglobin accumulates in the blood, reducing the oxygen-carrying capacity of red blood cells and leading to tissue hypoxia. There are two main types of this condition. Type I (also called erythrocyte type) is the milder form, in which the enzyme deficiency is limited to red blood cells. Patients with type I typically present with persistent cyanosis (a bluish discoloration of the skin, lips, and nail beds) from birth or early infancy but are otherwise generally healthy and have a normal life expectancy. Type II (also called generalized type) is a severe form in which the enzyme deficiency affects all body cells, including the brain. Type II presents with cyanosis along with severe neurological impairment, including intellectual disability, microcephaly, failure to thrive, movement disorders, and growth retardation. Type II is often fatal in early childhood. Treatment for type I primarily involves the use of methylene blue, which acts as an alternative electron carrier to reduce methemoglobin, and ascorbic acid (vitamin C), which can also help lower methemoglobin levels, though it is less effective. These treatments can improve cyanosis and cosmetic appearance in type I patients. Unfortunately, there is no effective treatment for the neurological manifestations of type II, and management remains largely supportive. Genetic counseling is recommended for affected families.

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