combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia is a multi-system condition that affects both the immune and hematologic systems, as well as the central nervous system. It is associated with pathogenic variants in the MTHFD1 gene, which plays a critical role in folate metabolism. The condition is characterized by severe immunodeficiency, megaloblastic anemia, and neurological findings such as mild intellectual disability and seizures, and it is typically identified in early childhood. This condition is very rare, affecting fewer than 1 in 1 million people.

Individuals with this condition typically present with a constellation of findings affecting several organ systems. The immune system is markedly impaired, with decreased total lymphocyte count and decreased circulating immunoglobulin concentration, leading to severe combined immunodeficiency. Hematologic abnormalities include megaloblastic anemia, pancytopenia, and hypersegmentation of neutrophil nuclei, accompanied by increased lactate dehydrogenase levels. Neurologically, affected individuals often experience mild intellectual disability, seizures, and structural brain changes such as a hypoplastic hippocampus. Not all individuals experience all features, and severity varies considerably.

This condition is caused by pathogenic variants in the MTHFD1 gene. The MTHFD1 gene is important for folate metabolism, and disruptions in its function can affect multiple systems including immune regulation, blood cell production, and neurological development. It is inherited in an autosomal recessive manner, which means that an affected individual has inherited two copies of the altered gene, one from each parent. This condition is more common when parents share a common ancestor, and genetic counseling is recommended to help families understand the implications for family planning and carrier testing.

Currently, management focuses on supportive care and symptom management tailored to the individual’s needs, as there are no FDA-approved treatments specifically linked to this condition. Treatment typically involves a multidisciplinary team that addresses immune dysfunction, hematologic abnormalities, and neurological symptoms. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Patients should discuss treatment options with their healthcare team, and genetic counseling is recommended for families to understand available supportive strategies and implications for future family planning.

Outcomes for individuals with this condition vary depending on symptom severity, age at diagnosis, and access to specialized care. The overall course is variable; some individuals may experience stabilization of symptoms while others face challenges related to immune and neurological function. With current standards of care, many individuals benefit from tailored supportive management and ongoing surveillance. Outcomes described in medical literature continue to evolve as standards of care improve, and families are encouraged to connect with specialists, such as genetic counselors, for ongoing guidance and support.

Clinical trials are underway exploring new treatment approaches for this condition. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility, as ongoing research continues to investigate potential therapies.