Combined Immunodeficiency And Megaloblastic Anemia With Or Without Hyperhomocysteinemia

A number sign (#) is used with this entry because of evidence that combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (CIMAH) is caused by compound heterozygous mutation in the MTHFD1 gene (172460) on chromosome 14q23.

Description

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia is an inborn error of folate metabolism due to deficiency of methylenetetrahydrofolate dehydrogenase-1. Manifestations may include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, lymphopenia involving all subsets, and low T-cell receptor excision circles. Folinic acid supplementation is an effective treatment (summary by Ramakrishnan et al., 2016).

Clinical Features

Watkins et al. (2011) described a female infant, born to healthy nonconsanguineous parents of Ashkenazi Jewish and Russian descent, who presented at 2 months of age with febrile illness and pallor. She had megaloblastic anemia, atypical hemolytic uremic syndrome (HUS), and severe combined immunodeficiency. Serum cobalamin levels were within the reference range, but there was a consistent elevation of total homocysteine levels in blood. Studies on cultured fibroblasts revealed a selective decreased synthesis of methylcobalamin from labeled exogenous cyanocobalamin, suggestive of a disorder of homocysteine remethylation. Keller et al. (2013) provided additional information on this patient. Shortly after treatment for anemia and a urinary tract infection at age 2 months, she was found to have pancytopenia with elevated lactate dehydrogenase. Bronchoalveolar lavage showed evidence of Pneumocystis jiroveci, and she later developed a Candida albicans infection. Immunologic studies at age 3 months showed marked hypogammaglobulinemia and lymphopenia, with few T cells, B cells, or natural killer cells. Bone marrow biopsy showed giant bands and nuclear-cytoplasmic dyssynchrony, and peripheral blood smear showed hypersegmented neutrophils. There was no evidence of malignancy. Serum vitamin B12 and folate levels were normal, but homocysteine levels were elevated and methionine levels slightly low. The patient's neurologic phenotype included mild bilateral sensorineural hearing loss, symptomatic partial epilepsy that was refractory to multiple antiepileptic agents, and mild mental retardation. Brain MRI at age 11 months showed bilateral small hippocampi, which was unchanged on repeat study at 4 years of age. Cerebrospinal fluid amino acid and neurotransmitter profiles were normal at age 11 months.

Burda et al. (2015) reported 4 patients from 2 families with combined immunodeficiency and megaloblastic anemia. One patient (Patient 2) was an 18-month-old girl, born to nonconsanguineous French parents, who presented with asthenia, vomiting, and icteric skin. She had anemia characterized by schizocytosis and thrombopenia, indicating atypical hemolytic uremic syndrome, microangiopathy, retinopathy, and severe arterial hypertension. Bone marrow analysis revealed dyserythropoietic and megaloblastic anemia, leukopenia, and low haptoglobin. Serum cobalamin, transcobalamin, and unsaturated cobalamin binding capacity of total serum were normal, as was serum folate. However, both free and total carnitine were slightly decreased, and analysis of amino and organic acids revealed hyperhomocysteinemia, low-normal methionine, and normal methylmalonic acid. The patient responded slowly but completely with continued treatment with hydroxocobalamin, folinic acid, and betaine. At 6 years of age, her psychomotor development and a cerebral MRI were normal, but a previously diagnosed retinopathy had worsened and was unresponsive to treatment. Patient 3 was a 22-year-old woman from a nonconsanguineous family of Swedish origin who had been monitored closely from birth because of the medical history of her 2 older sibs. Hematologic investigations at day 4 of life showed macroblastic bone marrow with a slight megaloblastic appearance, consistent with cobalamin or folate deficiency, and marked anisocytosis. At 9 weeks of age, anemia and high MCV were noted, and she was diagnosed with thiamine-responsive megaloblastic anemia. At the age of 4 months, Hgb and MCV had normalized, and folic acid and cobalamin treatment was terminated. Bone marrow was then almost normalized with normoblastic erythropoiesis and normal myelopoiesis. At 7 months of age, she became anemic and developed a general inflammatory state. Autoantibodies with high titers against DNA and striated muscle appeared, and antinuclear antibodies were positive. Serum transaminases were only marginally elevated. Liver biopsy showed a low grade lymphohistiocytic inflammation in portal areas and in lobuli. Bone marrow showed macromegaloblastic anemia with anisocytosis and disturbed myelopoiesis. She did not show hyperhomocysteinemia. She was treated successfully with blood transfusions, gammaglobulin infusions, corticosteroids, cobalamin, and folic acid, with rapid response. She remained clinically well on folic acid supplementation. Her sibs remained well until age 6 weeks. Her sister (patient 4) developed moniliasis and presented at 9 weeks of age with anemia, vomiting, and labored breathing. Her brother (patient 5) presented with fever, lesions consistent with hand-foot-and-mouth disease, vomiting, and labored breathing. At age 9 weeks, he was found to have anemia, leukopenia, and thrombocytosis with extreme metabolic acidosis. Both died within hours.

Ramakrishnan et al. (2016) reported 2 brothers with combined immunodeficiency and megaloblastic anemia. One brother presented at age 4 months with clinical and immunologic features consistent with P. jirovecii pneumonia. Severe combined immunodeficiency was diagnosed on the basis of susceptibility to this pathogen and severe lymphopenia involving all lymphoid subsets. He remained free of significant infections on immunoglobulin replacement, prophylactic cotrimoxazole, and fluconazole. At 4 years of age, he presented with severe macrocytic anemia, which was confirmed to be megaloblastic on bone marrow examination. His younger brother was found to have severe lymphopenia and was treated prophylactically with cotrimoxazole and fluconazole. He responded to protein vaccines but not to conjugated polysaccharide vaccines. He developed septic arthritis at age 9 and subsequently had immunoglobulin replacement. On retrospective analysis, both brothers showed severe macrocytosis from infancy. Treatment with folinic acid completely cleared the anemia without further episodes and improved lymphocyte function and numbers.

Inheritance

Combined immunodeficiency and megaloblastic anemia is an autosomal recessive disorder (Watkins et al., 2011).

Clinical Management

The patient with CIMAH originally reported by Watkins et al. (2011) was treated with intramuscular hydroxocobalamin, oral folate, and betaine. Severe infections were treated and prevented with IVIG and prophylactic trimethoprim/sulfamethoxazole. Patients with CIMAH reported by Burda et al. (2015) and Ramakrishnan et al. (2016) were treated similarly and remained clinically well with folinic acid supplementation.

Molecular Genetics

In a child with combined immunodeficiency and megaloblastic anemia with hyperhomocysteinemia, Watkins et al. (2011) identified compound heterozygous mutations in the MTHFD1 gene (172460.0003-172460.0004).

In a French patient and 3 sibs in a Swedish family with CIMAH, Burda et al. (2015) identified compound heterozygous mutations in the MTHFD1 gene (172460.0005-172460.0008).

In 2 brothers with CIMAH, Ramakrishnan et al. (2016) identified compound heterozygous mutations in the MTHFD1 gene (172460.0009-172460.0010).