- Email: [email protected]
Neonatal Vitamin B12 Deficiency Secondary to Maternal Subclinical Pernicious Anemia: Identification by Expanded Newborn Screening
Neonatal Vitamin B12 Deficiency Secondary to Maternal Subclinical Pernicious Anemia: Identification by Expanded Newborn Screening MICHAEL MARBLE, MD, SARA COPELAND, MD, NASHAT KHANFAR, MD,
AND
DAVID S. ROSENBLATT, MD
A neonate with elevated propionylcarnitine on the newborn screen was found to have methylmalonic acidemia due to vitamin B12 deficiency. The mother was also vitamin B12-deficient. This case illustrates the utility of expanded newborn screening for detection of vitamin B12 deficiency, allowing prompt treatment and prevention of potential sequelae. (J Pediatr 2008;152:731-3)
itamin B12 (cobalamin) is produced by microorganisms and found in fish, meat, and dairy products but not in fruits and vegetables. In the gut, vitamin B12 binds to intrinsic factor. The vitamin B12–intrinsic factor complex binds to a receptor in the distal small bowel (cubam), and the vitamin passes through the enterocyte and enters the portal circulation. Intracellular vitamin B12 metabolism is compartmentalized. In mitochondria, vitamin B12 is converted to adenosylcobalamin, the cofactor for methylmalonyl CoA mutase, a key enzyme in methylmalonic acid metabolism. In the cytoplasm, vitamin B12 is converted to methylcobalamin, the cofactor for methionine synthase, which catalyzes the methylation of homocysteine to generate methionine. Methylmalonic acidemia is genetically heterogeneous. Causes include primary deficiency of methylmalonyl CoA mutase, defects in intracellular cobalamin metabolism, and vitamin B12 absorption defects. Methylmalonic acidemia also results from nutritional vitamin B12 deficiency, which in neonates is usually due to maternal B12 deficiency.1 Based on acylcarnitine analysis in blood spots, tandem mass spectrometry (MS/MS) has enabled expansion of newborn screening (NBS) to include organic acidemias, including methylmalonic acidemia.2,3 Propionylcarnitine is the major marker for detection of methylmalonic acidemia. We report a patient with elevated propionylcarnitine who was found to have vitamin B12 deficiency secondary to maternal deficiency.
V
REPORT OF A CASE The proband, a full-term female with a birth weight of 3205 g, was referred for metabolic evaluation due to elevated propionylcarnitine on the expanded NBS (age 70 hours). Her methylmalonylcarnitine level was normal. These findings and those of subsequent metabolic evaluation are summarized in Table. At age 8 days, urine organic acid analysis showed a significantly elevated methylmalonic acid (MMA) level, mildly elevated plasma homocysteine level, and normal plasma methionine and carnitine levels and plasma acylcarnitine profile. At age 14 days, urine MMA was still elevated, and serum vitamin B12 level was low. At this time, maternal vitamin B12 level was measured and found to be low despite From the Department of Pediatrics, Division the mother’s regular consumption of meat, fish, and dairy. Further maternal evaluation of Clinical Genetics, Louisiana State University revealed low serum iron and ferritin levels, low-normal mean corpuscular volume, and the Health Sciences Center, Children’s Hospital of New Orleans, New Orleans, LA (M.M.); presence of parietal cell antibodies (Table). We concluded that the infant’s positive NBS Division of Medical Genetics, University of most likely resulted from vitamin B12 deficiency secondary to maternal deficiency. Studies Iowa Children’s Hospital, Iowa City, IA (S.C.); on cultured fibroblasts to rule out the less likely possibility of an inborn error of cobalamin Progressive Pediatrics, Monroe, LA (N.K.); and Departments of Human Genetics, Medmetabolism were subsequently performed and found to be normal. icine and Pediatrics, McGill University, MonDaily intramuscular injections of 1 mg hydroxycobalamin (OHCbl) corrected the treal, Quebec, Canada (D.R). infant’s vitamin B12 deficiency and homocysteinemia. The urine organic acid profile Submitted for publication Aug 1, 2007; last revision received Dec 27, 2007; accepted normalized. The injections were gradually reduced to weekly doses, then biweekly doses, Jan 18, 2008. and finally stopped by age 6 months. Plasma homocysteine and serum vitamin B12 levels Reprint requests: Michael Marble, MD, 200 remained normal. Random urine MMA measurements during and after the course of Henry Clay Avenue, New Orleans, LA 70118. E-mail: [email protected]. OHCbl treatment were minimally above reference range, most recently 4.2 g/mg MMA MS/MS
Methylmalonic acid Tandem mass spectrometry
NBS
Newborn screening, OHCbl, Hydroxycobalamin
0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.01.023
731
Table. Diagnostic laboratory data on the proband and mother Infant age 70 hours
Infant age 8 days
Infant age 14 days
Maternal laboratory values
NBS (MS/MS): Propionylcarnitine (C3): 11.6 mol (⬍ 8.00 mol) Methylmalonylcarnitine (C4-DC): 0.07 mol (⬍ 1.00 mol) Propionylcarnitine/acetylcarnitine (C3/C2): 0.480 (⬍ 0.500) Urine organic acids: MMA: 206 g/mg creatinine (⬍ 3.6 g/mg creatinine) Plasma homocysteine: 14 mol (⬍ 9 mol) Plasma methionine: 22 mol (10 to 60 mol) Plasma acylcarnitine profile (MS/MS): normal Urine organic acids: MMA 128 g/mg creatinine (⬍ 3.6 g/mg creatinine) Plasma methionine: 32 mol (10 to 60 mol) Serum vitamin B12: 125 pg/mL (188 to 1059 pg/mL) Serum vitamin B12: 105.7 pg/mL (188 to 1059 pg/mL) Serum iron: 26.6 g/dL (35 to 150 g/dL) Serum ferritin: 21 ng/mL (30 to 180 ng/mL) Hemoglobin: 13.1 g/dL Hematocrit: 39.1% Mean corpuscular volume: 82.4 fl (80 to 97 fl) Parietal cell antibodies: positive Gastric biopsy: severe chronic atrophic gastritis with early intestinal metaplasia
creatinine (reference range, ⬍ 3.6 g/mg). These minimal elevations are of no apparent metabolic significance and may be secondary to intestinal bacterial metabolism. Growth variables remained normal on breast milk and infant formula.
DISCUSSION Vitamin B12 deficiency in infants is usually caused by maternal deficiency due to strict vegetarian diet or pernicious anemia. Untreated infants are at risk for failure to thrive, hematologic problems, and irreversible neurodevelopmental consequences.4-8 Clinical presentation often occurs at age 4 to 8 months.8 Detection by NBS has been reported in several neonates whose mothers had vitamin B12 deficiency.2,9,10 The maternal deficiency was due to gastric bypass surgery in 1 case9 and to vegetarian diet in 2 other cases in which the cause was mentioned.10 Although megaloblastic anemia was not detected in our patient’s mother, her low serum vitamin B12 level and the presence of parietal cell antibodies were consistent with subclinical pernicious anemia. Eventually, she underwent a gastric biopsy, which demonstrated severe chronic atrophic gastritis. Measurement of maternal MMA level could have provided a functional indication of her intracellular cobalamin status; however, this was not performed before initiation of cobalamin therapy. MMA measurement is an established diagnostic tool for vitamin B12 deficiency.11 732
Marble et al
Although our early impression was that the infant’s positive NBS was secondary to maternal subclinical pernicious anemia, there was a significant delay (11 months) before the mother underwent gastric biopsy to confirm atrophic gastritis. The remote possibility of a heritable cobalamin defect remained a consideration for the infant. Therefore, the treatment strategy was to correct the vitamin B12 deficiency using OHCbl, which would also be effective for defects in cobalamin metabolism.12 The OHCbl injections were continued, at reduced intervals, until the completion of fibroblast metabolic studies. After cessation of vitamin supplementation, the infant’s metabolic variables and growth rate remained normal, and the vitamin B12 deficiency did not recur. An alternative to this approach, after correcting vitamin B12 levels, would be to monitor clinical and laboratory status without further vitamin supplementation. The proportion of neonates with vitamin B12 deficiency detected by expanded NBS is unknown. A study of adult patients with low serum vitamin B12 levels found a correlation between propionylcarnitine level and plasma MMA level in patients with markedly elevated MMA;13 however, the correlation was weak in those patients with lesser elevations of MMA. In 35% of the subjects, MMA was not elevated, and in these subjects the upper limit of propionylcarnitine concentration did not exceed that of controls.13 Although our patient’s propionylcarnitine level was elevated on the NBS, the confirmatory acylcarnitine profile at age 8 days was normal despite elevated urine MMA. Because the plasma acylcarnitine profile is the methodology used to confirm results of the filter paper NBS, the use of either a repeat filter paper NBS test or only the plasma acylcarnitine profile could have led to a false-negative result. Therefore, urine organic acid analysis is critical for metabolic evaluation of newborns with elevated propionylcarnitine level on the NBS. Our findings suggest that all neonates who demonstrate an elevated propionylcarnitine level on the NBS and are subsequently found to have an elevated MMA level should be evaluated for vitamin B12 deficiency, as should their mothers.
REFERENCES 1. Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol 1999;36:19-34. 2. Naylor EW, Chase DH. Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. J Child Neurol 1999;14(Suppl 1): S4-8. 3. Dionisi-Vici C, Deodato F, Roschinger W, Rhead W. Wilcken B. “Classical” organic acidurias, propionic aciduria, methylmalonic aciduria, and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis 2006;29:383-9. 4. Danielsson L, Enocksson E, Hagenfeldt L, Rasmussen EB, Tillberg E. Failure to thrive due to subclinical maternal pernicious anemia. Acta Paediatr Scand 1988;77:310-1. 5. Kuhne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr 1991;150:205-8. 6. Weiss R, Fogelman Y, Bennett M. Severe vitamin B12 deficiency in an infant associated with a maternal deficiency and a strict vegetarian diet. J Pediatr Hematol Oncol 2004;26:270-1. 7. Codazzi D, Sala F, Parini R, Langer M. Coma and respiratory failure in a child with severe vitamin B12 deficiency. Pediatr Crit Care Med 2005;6:483-5. 8. Korenke GC, Hunneman DH. Eber S, Hanefeld F. Severe encephalopathy with epilepsy in an infant caused by subclinical maternal pernicious anaemia: case report and review of the literature. Eur J Pediatr 2004;163:196-201.
The Journal of Pediatrics • May 2008
9. Campbell CD, Ganesh J, Ficicoglu C. Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency. Haematologica 2005;90(12 Suppl):ECR 45. 10. Wiley V, Carpenter K, Wilcken B. Newborn screening with tandem mass spectrometry: 12 months experience in NSW Australia. Acta Paediatr Suppl 1999;432:48-51. 11. Holleland G, Schneede J, Ueland PM, Lund PC, Refsum H, Sandberg S. Cobalamin deficiency in general practice: assessment of the diagnostic utility and
cost– benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin Chem 1999;45:189-98. 12. Andersson HC, Shapira E. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (CblC). J Pediatr 1998;132:121-4. 13. Kushnir MM, Shushan B, Roberts WL, Pasquali M. Serum acylcarnitines and vitamin B12 deficiency. Clin Chem 2002;48:1126-8.
50 years ago in The Journal of Pediatrics MANAGEMENT
OF BRONCHIAL ASTHMA IN CHILDREN
Unger L, Wolf AA, Johnson JH, Unger DL. J Pediatr 1958;52:539-46
In the 1940s, “bronchial asthma” was equated with an allergic condition. Unger et al emphasized that a delay in allergy surveys, including skin tests, was apt to be followed by chronic asthma with emphysema and chest deformation. Consequently, skin tests should be conducted in all cases of “bronchial asthma.” Following strict precautions and protocols, the skin tests performed in their institute included all possible inhalant materials and foods. The results guided subsequent asthma management. The standard therapy for bronchial asthma in the 1940s included specific, symptomatic, and preventive measures. Specific therapy included avoidance of causative allergens, including inhalant materials and foods, with or without hyposensitization. Hyposensitization involved repeated injections of increasing amounts of extracts of important unavoidable allergens given over extended periods. Symptomatic therapy consisted mainly of subcutaneous injections of epinephrine or rectal aminophylline. Corticosteroids were thought to temporarily eliminate the asthmatic symptoms as they occurred, without curing asthma. Preventive therapy was instituted when allergic parents planned for pregnancy. Home environment adjustments, careful new food trials, occupational planning, and allergy surveys were thought to be effective in preventing the onset of severe asthma in children. The definition and management of asthma have evolved substantially over the past 50 years with increasing knowledge of its pathophysiologic changes. Currently, asthma is classified as a chronic hyperresponsive inflammatory disorder,1 and it is no longer termed “bronchial asthma.” Asthma is a clinical diagnosis,2 and various investigations can help confirm the diagnosis. These include measurements of lung function (especially reversibility and variability), airway hyperresponsiveness,3 airway inflammation (eg, sputum eosinophils or neutrophils,4 exhaled NO,5 or CO6), and allergic status by skin testing and specific IgE. Skin tests with all possible inhalant materials and foods are no longer in favor. Avoiding the risk factors that cause asthma symptoms is advised. Asthma medications include stepwise “controller” medications (with glucocorticosteroids as the cornerstone7) and “reliever” medications. Inhalation agents are preferred. Specific immunotherapy, such as hyposensitization or anti-IgE, should be considered only after the patient fails to respond to strict environmental avoidance and pharmacologic intervention, such as inhaled steroids.8,9 Bronchodilators10 and systemic glucocorticosteroid11 are used for acute exacerbations. Epinephrine injections are reserved only for anaphylaxis or angioedema. Over the past 50 years, asthma has increasingly become a major cause of chronic morbidity and mortality. It is hoped that continued advances in treatment can someday bring asthma under control. Annie Fok Oi Ling, MRCPCH Department of Paediatrics Prince of Wales Hospital Shatin, Hong Kong
REFERENCES
10.1016/j.jpeds.2007.11.029
1. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001;344:350-62. 2. Levy ML, Fletcher M, Price DB, Hausen T, Halbert RJ, Yawn BP. International Primary Care Respiratory Group Guidelines: diagnosis of respiratory diseases in primary care. Prim Care Respir J 2006;15:20-34. 3. Cockcroft DW, Murdock KY, Berscheid BA, Gore BP. Sensitivity and specificity of histamine PC20 determination in a random selection of young college students. J Allergy Clin Immunol 1992;89(1 Pt 1):23-30. 4. Pizzichini MM, Papov TA, Efthimiadis A, Hussack P, Evans S, Pizzichini E, et al. Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med 1996;154(4 Pt 1):866-9. 5. Kharitonov S, Alving K, Barnes PJ. Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur Respir J 1997;10:1683-93. 6. Horvath I, Barnes PJ. Exhaled monoxides in asymptomatic atopic subjects. Clin Exp Allergy 1999;29:1276-80. 7. Juniper EF, Kline PF, Vanzieleghem MA, Ramsdale EH, O’Byrne P, Hargreave FE. Effect of long-term treatment with an inhaled corticosteroid on airway responsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142:832-6. 8. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003:CD001186. 9. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. Ann Allergy Asthma Immunol 1998;81(5 Pt 1):401-5. 10. Reisner C, Kotch A, Dworkin G. Continuous versus frequent intermittent nebulization of albuterol in acute asthma: a randomized, prospective study. Ann Allergy Asthma Immunol 1995;75:41-7. 11. Manser R, Reid D, Abramson M. Corticosteroids for acute severe asthma in hospitalized patients. Cochrane Database Syst Rev 2000;2.
Neonatal Vitamin B12 Deficiency Secondary to Maternal Subclinical Pernicious Anemia: Identification by Expanded Newborn Screening
733
AND
DAVID S. ROSENBLATT, MD
A neonate with elevated propionylcarnitine on the newborn screen was found to have methylmalonic acidemia due to vitamin B12 deficiency. The mother was also vitamin B12-deficient. This case illustrates the utility of expanded newborn screening for detection of vitamin B12 deficiency, allowing prompt treatment and prevention of potential sequelae. (J Pediatr 2008;152:731-3)
itamin B12 (cobalamin) is produced by microorganisms and found in fish, meat, and dairy products but not in fruits and vegetables. In the gut, vitamin B12 binds to intrinsic factor. The vitamin B12–intrinsic factor complex binds to a receptor in the distal small bowel (cubam), and the vitamin passes through the enterocyte and enters the portal circulation. Intracellular vitamin B12 metabolism is compartmentalized. In mitochondria, vitamin B12 is converted to adenosylcobalamin, the cofactor for methylmalonyl CoA mutase, a key enzyme in methylmalonic acid metabolism. In the cytoplasm, vitamin B12 is converted to methylcobalamin, the cofactor for methionine synthase, which catalyzes the methylation of homocysteine to generate methionine. Methylmalonic acidemia is genetically heterogeneous. Causes include primary deficiency of methylmalonyl CoA mutase, defects in intracellular cobalamin metabolism, and vitamin B12 absorption defects. Methylmalonic acidemia also results from nutritional vitamin B12 deficiency, which in neonates is usually due to maternal B12 deficiency.1 Based on acylcarnitine analysis in blood spots, tandem mass spectrometry (MS/MS) has enabled expansion of newborn screening (NBS) to include organic acidemias, including methylmalonic acidemia.2,3 Propionylcarnitine is the major marker for detection of methylmalonic acidemia. We report a patient with elevated propionylcarnitine who was found to have vitamin B12 deficiency secondary to maternal deficiency.
V
REPORT OF A CASE The proband, a full-term female with a birth weight of 3205 g, was referred for metabolic evaluation due to elevated propionylcarnitine on the expanded NBS (age 70 hours). Her methylmalonylcarnitine level was normal. These findings and those of subsequent metabolic evaluation are summarized in Table. At age 8 days, urine organic acid analysis showed a significantly elevated methylmalonic acid (MMA) level, mildly elevated plasma homocysteine level, and normal plasma methionine and carnitine levels and plasma acylcarnitine profile. At age 14 days, urine MMA was still elevated, and serum vitamin B12 level was low. At this time, maternal vitamin B12 level was measured and found to be low despite From the Department of Pediatrics, Division the mother’s regular consumption of meat, fish, and dairy. Further maternal evaluation of Clinical Genetics, Louisiana State University revealed low serum iron and ferritin levels, low-normal mean corpuscular volume, and the Health Sciences Center, Children’s Hospital of New Orleans, New Orleans, LA (M.M.); presence of parietal cell antibodies (Table). We concluded that the infant’s positive NBS Division of Medical Genetics, University of most likely resulted from vitamin B12 deficiency secondary to maternal deficiency. Studies Iowa Children’s Hospital, Iowa City, IA (S.C.); on cultured fibroblasts to rule out the less likely possibility of an inborn error of cobalamin Progressive Pediatrics, Monroe, LA (N.K.); and Departments of Human Genetics, Medmetabolism were subsequently performed and found to be normal. icine and Pediatrics, McGill University, MonDaily intramuscular injections of 1 mg hydroxycobalamin (OHCbl) corrected the treal, Quebec, Canada (D.R). infant’s vitamin B12 deficiency and homocysteinemia. The urine organic acid profile Submitted for publication Aug 1, 2007; last revision received Dec 27, 2007; accepted normalized. The injections were gradually reduced to weekly doses, then biweekly doses, Jan 18, 2008. and finally stopped by age 6 months. Plasma homocysteine and serum vitamin B12 levels Reprint requests: Michael Marble, MD, 200 remained normal. Random urine MMA measurements during and after the course of Henry Clay Avenue, New Orleans, LA 70118. E-mail: [email protected]. OHCbl treatment were minimally above reference range, most recently 4.2 g/mg MMA MS/MS
Methylmalonic acid Tandem mass spectrometry
NBS
Newborn screening, OHCbl, Hydroxycobalamin
0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.01.023
731
Table. Diagnostic laboratory data on the proband and mother Infant age 70 hours
Infant age 8 days
Infant age 14 days
Maternal laboratory values
NBS (MS/MS): Propionylcarnitine (C3): 11.6 mol (⬍ 8.00 mol) Methylmalonylcarnitine (C4-DC): 0.07 mol (⬍ 1.00 mol) Propionylcarnitine/acetylcarnitine (C3/C2): 0.480 (⬍ 0.500) Urine organic acids: MMA: 206 g/mg creatinine (⬍ 3.6 g/mg creatinine) Plasma homocysteine: 14 mol (⬍ 9 mol) Plasma methionine: 22 mol (10 to 60 mol) Plasma acylcarnitine profile (MS/MS): normal Urine organic acids: MMA 128 g/mg creatinine (⬍ 3.6 g/mg creatinine) Plasma methionine: 32 mol (10 to 60 mol) Serum vitamin B12: 125 pg/mL (188 to 1059 pg/mL) Serum vitamin B12: 105.7 pg/mL (188 to 1059 pg/mL) Serum iron: 26.6 g/dL (35 to 150 g/dL) Serum ferritin: 21 ng/mL (30 to 180 ng/mL) Hemoglobin: 13.1 g/dL Hematocrit: 39.1% Mean corpuscular volume: 82.4 fl (80 to 97 fl) Parietal cell antibodies: positive Gastric biopsy: severe chronic atrophic gastritis with early intestinal metaplasia
creatinine (reference range, ⬍ 3.6 g/mg). These minimal elevations are of no apparent metabolic significance and may be secondary to intestinal bacterial metabolism. Growth variables remained normal on breast milk and infant formula.
DISCUSSION Vitamin B12 deficiency in infants is usually caused by maternal deficiency due to strict vegetarian diet or pernicious anemia. Untreated infants are at risk for failure to thrive, hematologic problems, and irreversible neurodevelopmental consequences.4-8 Clinical presentation often occurs at age 4 to 8 months.8 Detection by NBS has been reported in several neonates whose mothers had vitamin B12 deficiency.2,9,10 The maternal deficiency was due to gastric bypass surgery in 1 case9 and to vegetarian diet in 2 other cases in which the cause was mentioned.10 Although megaloblastic anemia was not detected in our patient’s mother, her low serum vitamin B12 level and the presence of parietal cell antibodies were consistent with subclinical pernicious anemia. Eventually, she underwent a gastric biopsy, which demonstrated severe chronic atrophic gastritis. Measurement of maternal MMA level could have provided a functional indication of her intracellular cobalamin status; however, this was not performed before initiation of cobalamin therapy. MMA measurement is an established diagnostic tool for vitamin B12 deficiency.11 732
Marble et al
Although our early impression was that the infant’s positive NBS was secondary to maternal subclinical pernicious anemia, there was a significant delay (11 months) before the mother underwent gastric biopsy to confirm atrophic gastritis. The remote possibility of a heritable cobalamin defect remained a consideration for the infant. Therefore, the treatment strategy was to correct the vitamin B12 deficiency using OHCbl, which would also be effective for defects in cobalamin metabolism.12 The OHCbl injections were continued, at reduced intervals, until the completion of fibroblast metabolic studies. After cessation of vitamin supplementation, the infant’s metabolic variables and growth rate remained normal, and the vitamin B12 deficiency did not recur. An alternative to this approach, after correcting vitamin B12 levels, would be to monitor clinical and laboratory status without further vitamin supplementation. The proportion of neonates with vitamin B12 deficiency detected by expanded NBS is unknown. A study of adult patients with low serum vitamin B12 levels found a correlation between propionylcarnitine level and plasma MMA level in patients with markedly elevated MMA;13 however, the correlation was weak in those patients with lesser elevations of MMA. In 35% of the subjects, MMA was not elevated, and in these subjects the upper limit of propionylcarnitine concentration did not exceed that of controls.13 Although our patient’s propionylcarnitine level was elevated on the NBS, the confirmatory acylcarnitine profile at age 8 days was normal despite elevated urine MMA. Because the plasma acylcarnitine profile is the methodology used to confirm results of the filter paper NBS, the use of either a repeat filter paper NBS test or only the plasma acylcarnitine profile could have led to a false-negative result. Therefore, urine organic acid analysis is critical for metabolic evaluation of newborns with elevated propionylcarnitine level on the NBS. Our findings suggest that all neonates who demonstrate an elevated propionylcarnitine level on the NBS and are subsequently found to have an elevated MMA level should be evaluated for vitamin B12 deficiency, as should their mothers.
REFERENCES 1. Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol 1999;36:19-34. 2. Naylor EW, Chase DH. Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. J Child Neurol 1999;14(Suppl 1): S4-8. 3. Dionisi-Vici C, Deodato F, Roschinger W, Rhead W. Wilcken B. “Classical” organic acidurias, propionic aciduria, methylmalonic aciduria, and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis 2006;29:383-9. 4. Danielsson L, Enocksson E, Hagenfeldt L, Rasmussen EB, Tillberg E. Failure to thrive due to subclinical maternal pernicious anemia. Acta Paediatr Scand 1988;77:310-1. 5. Kuhne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr 1991;150:205-8. 6. Weiss R, Fogelman Y, Bennett M. Severe vitamin B12 deficiency in an infant associated with a maternal deficiency and a strict vegetarian diet. J Pediatr Hematol Oncol 2004;26:270-1. 7. Codazzi D, Sala F, Parini R, Langer M. Coma and respiratory failure in a child with severe vitamin B12 deficiency. Pediatr Crit Care Med 2005;6:483-5. 8. Korenke GC, Hunneman DH. Eber S, Hanefeld F. Severe encephalopathy with epilepsy in an infant caused by subclinical maternal pernicious anaemia: case report and review of the literature. Eur J Pediatr 2004;163:196-201.
The Journal of Pediatrics • May 2008
9. Campbell CD, Ganesh J, Ficicoglu C. Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency. Haematologica 2005;90(12 Suppl):ECR 45. 10. Wiley V, Carpenter K, Wilcken B. Newborn screening with tandem mass spectrometry: 12 months experience in NSW Australia. Acta Paediatr Suppl 1999;432:48-51. 11. Holleland G, Schneede J, Ueland PM, Lund PC, Refsum H, Sandberg S. Cobalamin deficiency in general practice: assessment of the diagnostic utility and
cost– benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin Chem 1999;45:189-98. 12. Andersson HC, Shapira E. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (CblC). J Pediatr 1998;132:121-4. 13. Kushnir MM, Shushan B, Roberts WL, Pasquali M. Serum acylcarnitines and vitamin B12 deficiency. Clin Chem 2002;48:1126-8.
50 years ago in The Journal of Pediatrics MANAGEMENT
OF BRONCHIAL ASTHMA IN CHILDREN
Unger L, Wolf AA, Johnson JH, Unger DL. J Pediatr 1958;52:539-46
In the 1940s, “bronchial asthma” was equated with an allergic condition. Unger et al emphasized that a delay in allergy surveys, including skin tests, was apt to be followed by chronic asthma with emphysema and chest deformation. Consequently, skin tests should be conducted in all cases of “bronchial asthma.” Following strict precautions and protocols, the skin tests performed in their institute included all possible inhalant materials and foods. The results guided subsequent asthma management. The standard therapy for bronchial asthma in the 1940s included specific, symptomatic, and preventive measures. Specific therapy included avoidance of causative allergens, including inhalant materials and foods, with or without hyposensitization. Hyposensitization involved repeated injections of increasing amounts of extracts of important unavoidable allergens given over extended periods. Symptomatic therapy consisted mainly of subcutaneous injections of epinephrine or rectal aminophylline. Corticosteroids were thought to temporarily eliminate the asthmatic symptoms as they occurred, without curing asthma. Preventive therapy was instituted when allergic parents planned for pregnancy. Home environment adjustments, careful new food trials, occupational planning, and allergy surveys were thought to be effective in preventing the onset of severe asthma in children. The definition and management of asthma have evolved substantially over the past 50 years with increasing knowledge of its pathophysiologic changes. Currently, asthma is classified as a chronic hyperresponsive inflammatory disorder,1 and it is no longer termed “bronchial asthma.” Asthma is a clinical diagnosis,2 and various investigations can help confirm the diagnosis. These include measurements of lung function (especially reversibility and variability), airway hyperresponsiveness,3 airway inflammation (eg, sputum eosinophils or neutrophils,4 exhaled NO,5 or CO6), and allergic status by skin testing and specific IgE. Skin tests with all possible inhalant materials and foods are no longer in favor. Avoiding the risk factors that cause asthma symptoms is advised. Asthma medications include stepwise “controller” medications (with glucocorticosteroids as the cornerstone7) and “reliever” medications. Inhalation agents are preferred. Specific immunotherapy, such as hyposensitization or anti-IgE, should be considered only after the patient fails to respond to strict environmental avoidance and pharmacologic intervention, such as inhaled steroids.8,9 Bronchodilators10 and systemic glucocorticosteroid11 are used for acute exacerbations. Epinephrine injections are reserved only for anaphylaxis or angioedema. Over the past 50 years, asthma has increasingly become a major cause of chronic morbidity and mortality. It is hoped that continued advances in treatment can someday bring asthma under control. Annie Fok Oi Ling, MRCPCH Department of Paediatrics Prince of Wales Hospital Shatin, Hong Kong
REFERENCES
10.1016/j.jpeds.2007.11.029
1. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001;344:350-62. 2. Levy ML, Fletcher M, Price DB, Hausen T, Halbert RJ, Yawn BP. International Primary Care Respiratory Group Guidelines: diagnosis of respiratory diseases in primary care. Prim Care Respir J 2006;15:20-34. 3. Cockcroft DW, Murdock KY, Berscheid BA, Gore BP. Sensitivity and specificity of histamine PC20 determination in a random selection of young college students. J Allergy Clin Immunol 1992;89(1 Pt 1):23-30. 4. Pizzichini MM, Papov TA, Efthimiadis A, Hussack P, Evans S, Pizzichini E, et al. Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med 1996;154(4 Pt 1):866-9. 5. Kharitonov S, Alving K, Barnes PJ. Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur Respir J 1997;10:1683-93. 6. Horvath I, Barnes PJ. Exhaled monoxides in asymptomatic atopic subjects. Clin Exp Allergy 1999;29:1276-80. 7. Juniper EF, Kline PF, Vanzieleghem MA, Ramsdale EH, O’Byrne P, Hargreave FE. Effect of long-term treatment with an inhaled corticosteroid on airway responsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142:832-6. 8. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003:CD001186. 9. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. Ann Allergy Asthma Immunol 1998;81(5 Pt 1):401-5. 10. Reisner C, Kotch A, Dworkin G. Continuous versus frequent intermittent nebulization of albuterol in acute asthma: a randomized, prospective study. Ann Allergy Asthma Immunol 1995;75:41-7. 11. Manser R, Reid D, Abramson M. Corticosteroids for acute severe asthma in hospitalized patients. Cochrane Database Syst Rev 2000;2.
Neonatal Vitamin B12 Deficiency Secondary to Maternal Subclinical Pernicious Anemia: Identification by Expanded Newborn Screening
733