ABSTRACT
Folate and vitamin B(12) metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.
Subject(s)
DNA Mutational Analysis , Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics , Severe Combined Immunodeficiency/genetics , 3-Hydroxyacyl CoA Dehydrogenases/deficiency , 3-Hydroxyacyl CoA Dehydrogenases/genetics , Anemia, Megaloblastic/diagnosis , Anemia, Megaloblastic/drug therapy , Anemia, Megaloblastic/genetics , Bone Marrow Examination , Cardiomyopathies/diagnosis , Cardiomyopathies/drug therapy , Cardiomyopathies/genetics , Combined Modality Therapy , Drug Combinations , Drug Therapy, Combination , Exome/genetics , Female , Genetic Carrier Screening , Humans , Hydroxocobalamin/therapeutic use , Immunization, Passive , Infant , Infant, Newborn , Leukopenia/diagnosis , Leukopenia/drug therapy , Leukopenia/genetics , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/drug therapy , Lipid Metabolism, Inborn Errors/genetics , Minor Histocompatibility Antigens , Mitochondrial Myopathies , Mitochondrial Trifunctional Protein/deficiency , Nervous System Diseases , Opportunistic Infections/diagnosis , Opportunistic Infections/drug therapy , Opportunistic Infections/genetics , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/drug therapy , Peripheral Nervous System Diseases/genetics , Pneumonia, Pneumocystis/diagnosis , Pneumonia, Pneumocystis/drug therapy , Pneumonia, Pneumocystis/genetics , Retinitis Pigmentosa/diagnosis , Retinitis Pigmentosa/drug therapy , Retinitis Pigmentosa/genetics , Rhabdomyolysis , Sequence Analysis, DNA , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/drug therapy , Sulfadoxine/therapeutic use , Trimethoprim/therapeutic use , Vitamin B 12/therapeutic useABSTRACT
Growth retardation is common among children with epilepsy, and poor dietary intake may be one of the causes. The goal of this cross-sectional study was to compare the nutrient intake of children 1 to 8 years of age with intractable epilepsy to healthy children of the same age from the National Health and Nutrition Examination Survey 2001 to 2002 (N=1,718) and with the Dietary Reference Intakes. Children with intractable epilepsy were divided into two age groups: 1.0 to 3.9 and 4.0 to 8.9 years, to correspond with the Dietary Reference Intakes. Forty-three children with intractable epilepsy, mean age=4.7+/-2.2 years, had significantly lower intakes (P<0.05) of total energy; protein; carbohydrate; fat; dietary fiber; vitamins A, E, B-6, and B-12; riboflavin; niacin; folate; calcium; phosphorus; magnesium; zinc; copper; and selenium compared with healthy children. Thirty percent or more of the children with intractable epilepsy in both age groups had intakes below the Recommended Dietary Allowance or Adequate Intake for vitamins D, E, and K; folate; calcium; linoleic acid; and alpha-linolenic acid. Health care professionals caring for children with intractable epilepsy should be aware of this pattern of decreased nutrient intake and educate families to provide an adequate diet and/or consider vitamin/mineral supplementation.
Subject(s)
Child Nutrition Disorders/etiology , Child Nutritional Physiological Phenomena/physiology , Energy Intake/physiology , Epilepsy/physiopathology , Nutrition Surveys , Case-Control Studies , Child , Child Nutrition Disorders/epidemiology , Child, Preschool , Dietary Carbohydrates/administration & dosage , Dietary Fats/administration & dosage , Dietary Proteins/administration & dosage , Female , Humans , Infant , Male , Minerals/administration & dosage , Nutrition Policy , Nutritional Requirements , Vitamins/administration & dosageABSTRACT
PURPOSE: The aim of this study was to describe vitamin D status in children with intractable epilepsy prescribed newer antiepileptic drugs (AEDs) before initiation of and during 15-month treatment with the ketogenic diet (KD). METHODS: Serum vitamin D (25-OHD and 1,25-OHD) and parathyroid hormone (PTH) were assessed in prepubertal children with intractable epilepsy before initiation of and during KD therapy. Three-day weighed dietary records including KD and vitamin and mineral supplementation were obtained at baseline and at 1 month. RESULTS: Forty-five children (aged 5.1 +/- 2.7 years) were enrolled. Before KD therapy, 4% had deficient and 51% had insufficient serum 25-OHD levels. Vitamin D intake was less than recommended in 47%. Adequate vitamin D intake, fewer AEDs, and generalized seizures were associated with higher serum 25-OHD levels (p < 0.01). After 3 months on the KD, 25-OHD levels increased (p < 0.001), and PTH declined (p < 0.001). Over the next 12-month period, 25-OHD levels steadily declined (p < 0.001), and PTH did not significantly change. CONCLUSIONS: Children with intractable epilepsy treated with newer AEDs had poor vitamin D status. Their status improved over the first 3 months of KD therapy with vitamin D supplementation and slowly declined thereafter.
Subject(s)
Anticonvulsants/adverse effects , Dietary Fats/administration & dosage , Epilepsy/blood , Epilepsy/diet therapy , Nutritional Status , Vitamin D Deficiency/blood , Vitamin D/blood , 25-Hydroxyvitamin D 2/blood , 25-Hydroxyvitamin D 2/deficiency , Adolescent , Child , Child, Preschool , Dietary Fats/metabolism , Dietary Supplements , Epilepsy/drug therapy , Female , Humans , Infant , Ketosis/metabolism , Longitudinal Studies , Male , Parathyroid Hormone/blood , Seasons , Vitamin D Deficiency/chemically inducedABSTRACT
OBJECTIVE: The concept of "rational polypharmacy" has been associated with anticonvulsant management for decades, but the term has not been applied to nonpharmacologic therapies. METHODS: We conducted a multicenter, retrospective study of children who received concurrent diet (ketogenic or modified Atkins) and vagus nerve stimulation (VNS) treatment for medically intractable epilepsy. RESULTS: Thirty children in total from six epilepsy centers were treated over a 6-yr period. The median age at the initiation of combination therapy was 10 yr (range, 4-24 yr). Sixteen (53%) received dietary therapy followed by VNS; no differences were noted between centers. After 3 months, 21 (70%) had seizure reduced by >50% over the previous single nonpharmacologic treatment, of whom 13 (62%) had improvement within the first month. A 5-min VNS off-time correlated with >90% seizure reduction (p = 0.02). The median duration of nonpharmacologic polytherapy was 12 months (range, 0.5-96 months); 17 (57%) remain on dual therapy at this time. No side effects were noted. Most patients who discontinued combination therapy did so because of a lack of efficacy rather than restrictiveness. CONCLUSIONS: In this small group, the combined use of diet and VNS appeared synergistic and yielded rapid benefits. It may be more effective with longer VNS off-times. Further prospective studies of this combination in refractory pediatric epilepsy are needed to help guide optimal use.
Subject(s)
Dietary Fats/administration & dosage , Dietary Fats/metabolism , Electric Stimulation Therapy/methods , Epilepsy/diet therapy , Epilepsy/therapy , Ketosis/metabolism , Vagus Nerve/physiology , Adolescent , Adult , Child , Child, Preschool , Combined Modality Therapy , Diet, Carbohydrate-Restricted , Epilepsy/metabolism , Evaluation Studies as Topic , Female , Humans , Longitudinal Studies , Male , Retrospective Studies , Treatment OutcomeABSTRACT
PURPOSE: The ketogenic diet (KD) is an efficacious treatment for intractable epilepsy, associated with infrequent side effects. The KD is known to be deficient in most vitamins and minerals and may be deficient in trace minerals. We report biochemical selenium deficiency in nine patients on the KD, including one who developed cardiomyopathy. METHODS: A whole-blood selenium level was obtained on the symptomatic patient after noting the patient's poor appearance on physical examination. Children already treated and children beginning the KD were then evaluated prospectively for selenium status by measuring whole-blood or serum selenium as part of routine laboratory evaluation every 3 months. RESULTS: The index case had no detectable whole-blood selenium. Cardiac physical examination and ECG were normal, but the echocardiogram revealed cardiomyopathy. Thirty-nine additional children had the selenium status evaluated. Eight had selenium levels below the normal range (six initially, and two developed low selenium levels on serial testing). They were referred for cardiology evaluations, which were normal. Selenium supplementation improved levels in all children. Low levels were seen in some children after only a few months of treatment. CONCLUSIONS: The nutrient adequacy of the currently used KD has not been fully evaluated. The nutrient content of KD with usual supplements may not meet Recommended Dietary Allowances (RDA) for selenium and may not provide other trace minerals in adequate amounts. At our center, selenium deficiency was found in 20% of the patients evaluated. Screening for selenium deficiency is suggested if the patient KD regimen does not meet > or =75% of the RDA or if the child is symptomatic. Nutrient supplementation should provide adequate trace elements for children treated with the KD. The KD requires close monitoring of the overall nutritional status.