constitutional megaloblastic anemia with severe neurologic disease

Constitutional megaloblastic anemia with severe neurologic disease is a very rare inherited condition that affects blood formation and neurological function. It results from pathogenic variants in the DHFR gene, which is essential for folate metabolism. The disorder is inherited in an autosomal recessive pattern, meaning an individual must inherit two mutated copies of DHFR to be affected, and it is more commonly seen in families where parents share a common ancestor. Given its very rare prevalence, affecting fewer than 1 in 1,000,000 people, diagnosis and treatment require specialized evaluation and management.

The clinical presentation centers on both hematologic and neurological features. Characteristic laboratory findings include a consistently decreased cerebrospinal fluid concentration of 5-methyltetrahydrofolate and an increased mean corpuscular volume, both present in all affected individuals. In addition, some individuals experience megaloblastic anemia, elevated circulating lactate dehydrogenase levels, and absence seizures with eyelid myoclonia, although these features occur in a subset of cases. Not all individuals experience all features, and severity varies considerably.

The condition is caused by pathogenic variants in the DHFR gene, which codes for the enzyme dihydrofolate reductase. This enzyme plays a crucial role in folate metabolism, and its deficiency disrupts the production of DNA and other fundamental cellular processes, leading to abnormal blood cell development and neurological impairment. Inheritance is autosomal recessive, meaning two copies of the mutated gene are required to manifest the condition. It is more common when parents share a common ancestor, which increases the likelihood that both parents carry the same rare genetic variant. Genetic counseling is recommended for family planning and understanding recurrence risks.

Currently, management focuses on supportive care and symptom management as there are no specifically approved treatments for this condition. Treatment is tailored to the individual and typically involves a multidisciplinary team that may include specialists in neurology and hematology to address both neurological and hematologic manifestations. Regular surveillance is an essential part of long-term care, helping to identify potential complications early. Genetic counseling is also recommended so that patients and families can discuss treatment options and plan for future care.

The outlook for individuals with constitutional megaloblastic anemia with severe neurologic disease varies depending on symptom severity, age at diagnosis, and access to specialized care. With current standards of care, many individuals benefit from supportive management that improves quality of life, although the condition remains lifelong. Outcomes described in medical literature continue to evolve as standards of care improve, and the clinical course may range from periods of stability to later challenges in managing neurological or hematological complications. Families are encouraged to connect with specialists and genetic counselors to further explore care options and support networks.