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A patient with carnitine-acylcarnitine translocase deficiency with a mild phenotype
CLINICAL AND LABORATORY OBSERVATIONS
A
A patient with carnitine-acylcarnitine translocase deficiency with a mild phenotype
A. A. M. Morris, PhD, MRCP, S. E. Olpin, PhD, M. Brivet, PhD, D. M. Turnbull, MD, PhD, R. A. K. Jones, MD, FRCP, and J. V. Leonard, PhD, FRCP Carnitine-acylcarnitine translocase deficiency, a rare β-oxidation defect, is manifest in most cases by cardiomyopathy and death in early childhood. We report an affected patient, 3 years of age, who has had no serious complications. The residual enzyme activity in fibroblasts was higher than in previously reported patients, which may explain the benign clinical course. (J Pediatr 1998;132:514-6)
Long-chain fatty acids destined for β-oxidation enter mitochondria bound to carnitine. Before entering mitochondria, acyl groups are transferred from coenzyme A to carnitine by carnitine palmitoyltransferase I. Carnitine-acylcarnitine translocase catalyzes the movement of acylcarnitines across the inner mitochondrial membrane in exchange for free carnitine. After entering the mitochondria, acyl groups are transferred back to coenzyme A by CPT II. Most published cases of carnitine-acylcarnitine translocase deficiency have had a severe clinical phenotype, with cardiomyopathy and death in early childFrom the Institute of Child Health, London, United Kingdom; Sheffield Children’s Hospital, Sheffield, United Kingdom; Laboratoire de Biochimie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France; Division of Clinical Neuroscience, University of Newcastle, Newcastle upon Tyne, United Kingdom; and Wexham Park Hospital, Slough, United Kingdom. Submitted for publication Dec. 20, 1996; accepted July 23, 1997. Reprint requests: A. A. M. Morris, PhD, MRCP, Department of Child Health, Royal Victoria Infirmary, Queen Victoria Rd., Newcastle upon Tyne, NE1 4LP, U.K. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/85008
514
hood.1-6 We report a family with two affected children, one of whom is in good health at 3 years of age. Carnitine-acylcarnitine translocase deficiency is not inevitably associated with a worse prognosis than other defects of long-chain fatty acid oxidation.
CASE REPORT Our patients were the sixth and seventh children of first-cousin Pakistani parents; four older children are healthy, but a fifth died at 3 months of age. The sixth child (birth weight, 3.05 kg) had respiratory distress and seizures at 48 hours of age, with an undetectable blood glucose concentration. Initially, his condition improved with intravenous administration of glucose and ventilation, but later the same day he had ventricular tachycardia and seizures, despite normal blood glucose levels, and died. Autopsy revealed severe steatosis of the myocardium, liver (panlobular), and renal tubules (proximal more than distal). Mild fatty change and reduced glycogen content was found in muscle. Urine organic acid analysis showed an excess of lactate, dicarboxylic,
and hydroxydicarboxylic acids with no ketones. The seventh child (birth weight, 2.9 kg) was admitted electively to the neonatal unit and breast fed every 3 hours; this child was also given supplements of formula milk through a nasogastric tube. At 14 days, blood spot acylcarnitine analysis by electron-spray tandem mass spectrometry showed low acetylcarnitine with elevated long-chain species (palmitoylcarnitine, 8.85 µmol/L; normal, <4.82 µmol/L; courtesy of D. S. Millington). Plasma
See editorial, p. 384. carnitine concentrations were low (free, <1.0 µmol/L; normal, 22 to 50 µmol/L; total, 13.0 µmol/L; normal, 26 to 62 µmol/L). The infant therefore received a medium-chain triglyceride–based formula (Monogen, Scientific Hospital Supplies International Ltd.). CPT
Carnitine palmitoyltransferase
When 4 months old, the patient underwent a diagnostic fast for 7.5 hours, at which point he became drowsy. No hypoglycemia was present; however, from 6 hours onward, the plasma free fatty acid concentration rose rapidly, reaching 3.33 mmol/L after 7.5 hours without any rise in ketone bodies (3-hydroxybutyrate concentration 0.04 mmol/L). Urine organic acid analysis showed grossly increased se-
THE JOURNAL OF PEDIATRICS Volume 132, Number 3, Part 1 bacate, suberate, and adipate, with moderately increased C8:1, C10:1, 3-hydroxyC10:0, and 3-hydroxy-C10:1 dicarboxylic acids. The overnight feeding interval was gradually increased to 5 hours, and lowfat solids were introduced, with walnut oil for essential fatty acids. Frequent drinks of glucose polymer were given whenever the patient was unwell, with hospital admissions if he fed poorly. Despite this, at 12 months of age he had a brief hypoglycemic seizure (blood glucose, <0.5 mmol/L). From 2 years of age, uncooked cornstarch was added to the nighttime feeding; and at 2 years 9 months, the effect of this on subsequent fasting was monitored. Even after 9 hours of fasting, the blood glucose was 5.3 mmol/L (96 mg/dl), the plasma free fatty acid concentration had only risen to 0.12 mmol/L, and tandem mass spectrometry showed normal longchain acylcarnitine concentrations in the blood. Plasma carnitine levels were found to have risen from their neonatal values even without supplementation (free carnitine, 6 µmol/L; total, 20.0 µmol/L). Currently, at 3 years of age, the patient is growing and developing normally with no abnormal findings on examination. Results of echocardiography and electrocardiography have been consistently normal. The result of electromyography of the tibialis anterior is normal, but the deltoid shows some low-amplitude, short-duration units, as well as normal motor units. Plasma creatine kinase is marginally elevated (152 U/L; normal, <120 U/L).
METHODS Fibroblasts were cultured from the seventh child. β-Oxidation flux in fibroblasts was measured as previously described using tritiated myristate and palmitate.2 Published techniques were used for measurement of CPT I and II activities,7 cellular carnitine uptake,8 and carnitineacylcarnitine translocase, carnitine acetyltransferase, and the pyruvate oxidase system.2
RESULTS β-Oxidation fluxes from myristate and palmitate were markedly reduced (Table),
MORRIS
ET AL.
Table. β-Oxidation flux and enzyme activities in fibroblasts from our patient, control subjects, and six previous cases, all of whom died by 24 months of age
Flux from [9,10-3H]myristate† Flux from [9,10-3H]palmitate† Translocase activity‡
Patient
Control subjects
Previous cases*
0.72, 0.87
8.04 ± 1.74 (n = 25) (5.45-11.30) 9.39 ± 1.70 (n = 25) (6.75-13.40) 1.47 ± 0.20 (n = 15) (0.93-2.00)
0.32 ± 0.10 (n = 4) (0.26-0.46) 0.30 ± 0.14 (n = 6) (0.08-0.51) Undetectable (n = 6)
0.88, 0.97 0.04, 0.03
Values for control subjects and previous cases are mean ± SD, with ranges shown in parentheses. *Previous cases of carnitine-acylcarnitine translocase deficiency analyzed in the same laboratory (References 2 to 4 and three unpublished cases). †Values are expressed as nanomoles of 3H O released per hour per milligram of protein. 2 ‡Values are expressed as nanomoles per minute per milligram of protein.
suggesting a defect of carnitine-acylcarnitine translocase, CPT I or II, or the plasma membrane carnitine transporter. Fibroblast uptake of L-methyl-[3H]carnitine was normal, as were the activities of CPT I and II, pyruvate oxidase, and carnitine acetyltransferase (data not shown). In contrast, carnitine-acylcarnitine translocase activity was only 3.0% to 6.8% of control values (Table).
DISCUSSION There have been seven previous reports of carnitine-acylcarnitine translocase deficiency.1-6,9 All patients were seen within 2 days of birth with hypoglycemia, hyperammonemia, or sudden death. Five patients had cardiomyopathy, two had transient heart block, and one had ventricular tachycardia at the time of presentation. Most patients died before 3 months of age; the oldest two died at 24 and 37 months, respectively, with skeletal myopathy and cardiomyopathy. Our surviving patient has a milder phenotype, with fasting intolerance as the main problem. At 3 years of age, he has no evidence of cardiomyopathy and no clinical evidence of myopathy, although electromyography and plasma creatine kinase levels show minor abnormalities. One other patient with a mild phenotype has been reported, although follow-up was only until 5 months of age.9 The phenotypes seem to correlate with residual enzyme activity. In our patient and that of Dionisi-Vici et al.9 carnitine-acylcarnitine translocase activity
was approximately 5% of control values, whereas in more severely affected patients, activity was generally undetectable. β-Oxidation flux values were also higher for our patient than for patients with more severe phenotypes (Table).2-4 Comparison of our two affected siblings suggests that the degree of neonatal lipolysis is another important determinant of the clinical outcome. The improved fasting tolerance, blood acylcarnitine profiles, and plasma carnitine levels all indicate greater stability now than in infancy. Nevertheless, experience with other defects of long-chain β-oxidation shows that even mildly affected patients can have late complications such as rhabdomyolysis.
REFERENCES 1. Stanley CA, Hale DE, Berry GT, Deleeuw S, Boxer J, Bonnefont JP. A deficiency of carnitine-acylcarnitine translocase in the inner mitochondrial membrane [brief report]. N Engl J Med 1992;327:19-23. 2. Pande SV, Brivet M, Slama A, Demaugre F, Aufrant C, Saudubray JM. Carnitine-acylcarnitine translocase deficiency with severe hypoglycemia and auriculoventricular block: translocase assay in permeabilized fibroblasts. J Clin Invest 1993;91:1247-52. 3. Ogier de Baulney H, Slama A, Touati G, Turnbull D, Pourfarzam M, Brivet M. Neonatal hyperammonaemia caused by a defect of carnitine-acylcarnitine translocase. J Pediatr 1995;127:723-8. 4. Niezen-Koning KE, van Spronsen FJ, Ijlst L, et al. A patient with a lethal cardiomyopathy and a carnitine-acylcarnitine translocase deficiency. J Inherit Metab Dis 1995; 18:230-2.
515
DELLERT
ET AL.
5. Brivet M, Slama A, Millington DS, et al. Retrospective diagnosis of carnitine-acylcarnitine translocase deficiency by acylcarnitine analysis in the proband Guthrie card and enzymatic studies in the parents. J Inherit Metab Dis 1996;19:181-4. 6. Chalmers RA, Stanley CA, English N, Wigglesworth JS. Mitochondrial carnitineacylcarnitine translocase deficiency present-
THE JOURNAL
ing as sudden neonatal death. J Pediatr 1997;131:220-5. 7. Schaefer J, Jackson S, Taroni F, Swift P, Turnbull DM. Characterisation of carnitine palmitoyltransferases in patients with a carnitine palmitoyltransferase deficiency: implications for diagnosis and therapy. J Neurol Neurosurg Psychiatry 1997;62:169-76. 8. Treem WR, Stanley CA, Finegold DN, Hale
PEDIATRICS MARCH 1998
OF
DE, Coates PM. Primary carnitine deficiency due to failure of carnitine transport in kidney, muscle and fibroblasts. N Engl J Med 1988;319:1331-5. 9. Dionisi-Vici C, Garavaglia B, Bartuli A, et al. Carnitine acylcarnitine translocase deficiency: benign course without cardiac involvement [abstract]. Pediatr Res 1995; 37:147A.
B
Bone mineral content in children with short bowel
syndrome after discontinuation of parenteral nutrition Susan F. Dellert, MD, Michael K. Farrell, MD, Bonny L. Specker, PhD, and James E. Heubi, MD
To determine whether children with short bowel syndrome had evidence of metabolic bone disease, total body bone mineral content was measured by dual-energy x-ray absorptiometry in 18 patients and 36 age-, sex-, and race-matched control subjects. Children with short bowel syndrome had decreased bone mineral content compared with control subjects; however, it was not significant when adjusted for differences in weight and height. Whether these children will have normal bone accretion throughout puberty is not known. (J Pediatr 1998;132:516-9)
Metabolic bone disease has been described in children and adults receiving prolonged parenteral nutrition. The etiology is not well understood, and it is not clear whether bone mass improves once parenteral nutrition has been discontinued.1-4 The purpose of this study was to determine whether children with short From the Division of Pediatric Gastroenterology and Nutrition, Pediatric Bone Research Center, Children’s Hospital Research Foundation, Cincinnati, Ohio. Supported in part by U.S. Public Health Service Grant no. M01 RR08084 from the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health. Submitted for publication Feb. 21, 1996; accepted June 6, 1997. Reprint requests: James E. Heubi, MD, General Clinical Research Center, Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/83971
516
bowel syndrome, who no longer require parenteral nutrition, have decreased bone mass. We hypothesized that children with SBS receiving enteral alimentation would have decreased total body bone mineral content when compared with healthy age-, sex-, and racematched children. We also hypothesized that the decrease in BMC would be secondary to reduced calcium absorption, as evidenced by high serum 1,25-dihydroxy vitamin D and normal serum 25hydroxy vitamin D levels.
METHODS Subjects Subjects were identified from the medical records of the Children’s Hospital Medical Center, Cincinnati, Ohio, from 1984 to 1994. Children who had a history
of intestinal resection, omphalocele, or gastroschisis and required parenteral nutrition for at least 1 month, but were cur-
See editorial, p. 386. rently receiving full enteral nutrition, were recruited for the study. Exclusion criteria included long-term corticosteroid use beyond the neonatal period, hepatobiliary disease, cystic fibrosis, or kidney disease.
BMC 25-OHD 1,25-(OH)2D RDA SBS
Bone mineral content 25-Hydroxy vitamin D 1,25-Dihydroxy vitamin D Recommended daily allowance Short bowel syndrome
Data Collection and Analytic Methods Total body BMC was measuredby dual-energy x-ray absorptiometry with the Hologic QDR-2000 scanner (Hologic, Inc., Waltham, Mass.) with either pediatric or adult software. Normative data for total body BMC in children were not available; therefore, comparisons were made with two control subjects per patient (matched by age, sex, and race). The matching was performed to account for differences in BMC seen in childhood.5,6
A
A patient with carnitine-acylcarnitine translocase deficiency with a mild phenotype
A. A. M. Morris, PhD, MRCP, S. E. Olpin, PhD, M. Brivet, PhD, D. M. Turnbull, MD, PhD, R. A. K. Jones, MD, FRCP, and J. V. Leonard, PhD, FRCP Carnitine-acylcarnitine translocase deficiency, a rare β-oxidation defect, is manifest in most cases by cardiomyopathy and death in early childhood. We report an affected patient, 3 years of age, who has had no serious complications. The residual enzyme activity in fibroblasts was higher than in previously reported patients, which may explain the benign clinical course. (J Pediatr 1998;132:514-6)
Long-chain fatty acids destined for β-oxidation enter mitochondria bound to carnitine. Before entering mitochondria, acyl groups are transferred from coenzyme A to carnitine by carnitine palmitoyltransferase I. Carnitine-acylcarnitine translocase catalyzes the movement of acylcarnitines across the inner mitochondrial membrane in exchange for free carnitine. After entering the mitochondria, acyl groups are transferred back to coenzyme A by CPT II. Most published cases of carnitine-acylcarnitine translocase deficiency have had a severe clinical phenotype, with cardiomyopathy and death in early childFrom the Institute of Child Health, London, United Kingdom; Sheffield Children’s Hospital, Sheffield, United Kingdom; Laboratoire de Biochimie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France; Division of Clinical Neuroscience, University of Newcastle, Newcastle upon Tyne, United Kingdom; and Wexham Park Hospital, Slough, United Kingdom. Submitted for publication Dec. 20, 1996; accepted July 23, 1997. Reprint requests: A. A. M. Morris, PhD, MRCP, Department of Child Health, Royal Victoria Infirmary, Queen Victoria Rd., Newcastle upon Tyne, NE1 4LP, U.K. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/85008
514
hood.1-6 We report a family with two affected children, one of whom is in good health at 3 years of age. Carnitine-acylcarnitine translocase deficiency is not inevitably associated with a worse prognosis than other defects of long-chain fatty acid oxidation.
CASE REPORT Our patients were the sixth and seventh children of first-cousin Pakistani parents; four older children are healthy, but a fifth died at 3 months of age. The sixth child (birth weight, 3.05 kg) had respiratory distress and seizures at 48 hours of age, with an undetectable blood glucose concentration. Initially, his condition improved with intravenous administration of glucose and ventilation, but later the same day he had ventricular tachycardia and seizures, despite normal blood glucose levels, and died. Autopsy revealed severe steatosis of the myocardium, liver (panlobular), and renal tubules (proximal more than distal). Mild fatty change and reduced glycogen content was found in muscle. Urine organic acid analysis showed an excess of lactate, dicarboxylic,
and hydroxydicarboxylic acids with no ketones. The seventh child (birth weight, 2.9 kg) was admitted electively to the neonatal unit and breast fed every 3 hours; this child was also given supplements of formula milk through a nasogastric tube. At 14 days, blood spot acylcarnitine analysis by electron-spray tandem mass spectrometry showed low acetylcarnitine with elevated long-chain species (palmitoylcarnitine, 8.85 µmol/L; normal, <4.82 µmol/L; courtesy of D. S. Millington). Plasma
See editorial, p. 384. carnitine concentrations were low (free, <1.0 µmol/L; normal, 22 to 50 µmol/L; total, 13.0 µmol/L; normal, 26 to 62 µmol/L). The infant therefore received a medium-chain triglyceride–based formula (Monogen, Scientific Hospital Supplies International Ltd.). CPT
Carnitine palmitoyltransferase
When 4 months old, the patient underwent a diagnostic fast for 7.5 hours, at which point he became drowsy. No hypoglycemia was present; however, from 6 hours onward, the plasma free fatty acid concentration rose rapidly, reaching 3.33 mmol/L after 7.5 hours without any rise in ketone bodies (3-hydroxybutyrate concentration 0.04 mmol/L). Urine organic acid analysis showed grossly increased se-
THE JOURNAL OF PEDIATRICS Volume 132, Number 3, Part 1 bacate, suberate, and adipate, with moderately increased C8:1, C10:1, 3-hydroxyC10:0, and 3-hydroxy-C10:1 dicarboxylic acids. The overnight feeding interval was gradually increased to 5 hours, and lowfat solids were introduced, with walnut oil for essential fatty acids. Frequent drinks of glucose polymer were given whenever the patient was unwell, with hospital admissions if he fed poorly. Despite this, at 12 months of age he had a brief hypoglycemic seizure (blood glucose, <0.5 mmol/L). From 2 years of age, uncooked cornstarch was added to the nighttime feeding; and at 2 years 9 months, the effect of this on subsequent fasting was monitored. Even after 9 hours of fasting, the blood glucose was 5.3 mmol/L (96 mg/dl), the plasma free fatty acid concentration had only risen to 0.12 mmol/L, and tandem mass spectrometry showed normal longchain acylcarnitine concentrations in the blood. Plasma carnitine levels were found to have risen from their neonatal values even without supplementation (free carnitine, 6 µmol/L; total, 20.0 µmol/L). Currently, at 3 years of age, the patient is growing and developing normally with no abnormal findings on examination. Results of echocardiography and electrocardiography have been consistently normal. The result of electromyography of the tibialis anterior is normal, but the deltoid shows some low-amplitude, short-duration units, as well as normal motor units. Plasma creatine kinase is marginally elevated (152 U/L; normal, <120 U/L).
METHODS Fibroblasts were cultured from the seventh child. β-Oxidation flux in fibroblasts was measured as previously described using tritiated myristate and palmitate.2 Published techniques were used for measurement of CPT I and II activities,7 cellular carnitine uptake,8 and carnitineacylcarnitine translocase, carnitine acetyltransferase, and the pyruvate oxidase system.2
RESULTS β-Oxidation fluxes from myristate and palmitate were markedly reduced (Table),
MORRIS
ET AL.
Table. β-Oxidation flux and enzyme activities in fibroblasts from our patient, control subjects, and six previous cases, all of whom died by 24 months of age
Flux from [9,10-3H]myristate† Flux from [9,10-3H]palmitate† Translocase activity‡
Patient
Control subjects
Previous cases*
0.72, 0.87
8.04 ± 1.74 (n = 25) (5.45-11.30) 9.39 ± 1.70 (n = 25) (6.75-13.40) 1.47 ± 0.20 (n = 15) (0.93-2.00)
0.32 ± 0.10 (n = 4) (0.26-0.46) 0.30 ± 0.14 (n = 6) (0.08-0.51) Undetectable (n = 6)
0.88, 0.97 0.04, 0.03
Values for control subjects and previous cases are mean ± SD, with ranges shown in parentheses. *Previous cases of carnitine-acylcarnitine translocase deficiency analyzed in the same laboratory (References 2 to 4 and three unpublished cases). †Values are expressed as nanomoles of 3H O released per hour per milligram of protein. 2 ‡Values are expressed as nanomoles per minute per milligram of protein.
suggesting a defect of carnitine-acylcarnitine translocase, CPT I or II, or the plasma membrane carnitine transporter. Fibroblast uptake of L-methyl-[3H]carnitine was normal, as were the activities of CPT I and II, pyruvate oxidase, and carnitine acetyltransferase (data not shown). In contrast, carnitine-acylcarnitine translocase activity was only 3.0% to 6.8% of control values (Table).
DISCUSSION There have been seven previous reports of carnitine-acylcarnitine translocase deficiency.1-6,9 All patients were seen within 2 days of birth with hypoglycemia, hyperammonemia, or sudden death. Five patients had cardiomyopathy, two had transient heart block, and one had ventricular tachycardia at the time of presentation. Most patients died before 3 months of age; the oldest two died at 24 and 37 months, respectively, with skeletal myopathy and cardiomyopathy. Our surviving patient has a milder phenotype, with fasting intolerance as the main problem. At 3 years of age, he has no evidence of cardiomyopathy and no clinical evidence of myopathy, although electromyography and plasma creatine kinase levels show minor abnormalities. One other patient with a mild phenotype has been reported, although follow-up was only until 5 months of age.9 The phenotypes seem to correlate with residual enzyme activity. In our patient and that of Dionisi-Vici et al.9 carnitine-acylcarnitine translocase activity
was approximately 5% of control values, whereas in more severely affected patients, activity was generally undetectable. β-Oxidation flux values were also higher for our patient than for patients with more severe phenotypes (Table).2-4 Comparison of our two affected siblings suggests that the degree of neonatal lipolysis is another important determinant of the clinical outcome. The improved fasting tolerance, blood acylcarnitine profiles, and plasma carnitine levels all indicate greater stability now than in infancy. Nevertheless, experience with other defects of long-chain β-oxidation shows that even mildly affected patients can have late complications such as rhabdomyolysis.
REFERENCES 1. Stanley CA, Hale DE, Berry GT, Deleeuw S, Boxer J, Bonnefont JP. A deficiency of carnitine-acylcarnitine translocase in the inner mitochondrial membrane [brief report]. N Engl J Med 1992;327:19-23. 2. Pande SV, Brivet M, Slama A, Demaugre F, Aufrant C, Saudubray JM. Carnitine-acylcarnitine translocase deficiency with severe hypoglycemia and auriculoventricular block: translocase assay in permeabilized fibroblasts. J Clin Invest 1993;91:1247-52. 3. Ogier de Baulney H, Slama A, Touati G, Turnbull D, Pourfarzam M, Brivet M. Neonatal hyperammonaemia caused by a defect of carnitine-acylcarnitine translocase. J Pediatr 1995;127:723-8. 4. Niezen-Koning KE, van Spronsen FJ, Ijlst L, et al. A patient with a lethal cardiomyopathy and a carnitine-acylcarnitine translocase deficiency. J Inherit Metab Dis 1995; 18:230-2.
515
DELLERT
ET AL.
5. Brivet M, Slama A, Millington DS, et al. Retrospective diagnosis of carnitine-acylcarnitine translocase deficiency by acylcarnitine analysis in the proband Guthrie card and enzymatic studies in the parents. J Inherit Metab Dis 1996;19:181-4. 6. Chalmers RA, Stanley CA, English N, Wigglesworth JS. Mitochondrial carnitineacylcarnitine translocase deficiency present-
THE JOURNAL
ing as sudden neonatal death. J Pediatr 1997;131:220-5. 7. Schaefer J, Jackson S, Taroni F, Swift P, Turnbull DM. Characterisation of carnitine palmitoyltransferases in patients with a carnitine palmitoyltransferase deficiency: implications for diagnosis and therapy. J Neurol Neurosurg Psychiatry 1997;62:169-76. 8. Treem WR, Stanley CA, Finegold DN, Hale
PEDIATRICS MARCH 1998
OF
DE, Coates PM. Primary carnitine deficiency due to failure of carnitine transport in kidney, muscle and fibroblasts. N Engl J Med 1988;319:1331-5. 9. Dionisi-Vici C, Garavaglia B, Bartuli A, et al. Carnitine acylcarnitine translocase deficiency: benign course without cardiac involvement [abstract]. Pediatr Res 1995; 37:147A.
B
Bone mineral content in children with short bowel
syndrome after discontinuation of parenteral nutrition Susan F. Dellert, MD, Michael K. Farrell, MD, Bonny L. Specker, PhD, and James E. Heubi, MD
To determine whether children with short bowel syndrome had evidence of metabolic bone disease, total body bone mineral content was measured by dual-energy x-ray absorptiometry in 18 patients and 36 age-, sex-, and race-matched control subjects. Children with short bowel syndrome had decreased bone mineral content compared with control subjects; however, it was not significant when adjusted for differences in weight and height. Whether these children will have normal bone accretion throughout puberty is not known. (J Pediatr 1998;132:516-9)
Metabolic bone disease has been described in children and adults receiving prolonged parenteral nutrition. The etiology is not well understood, and it is not clear whether bone mass improves once parenteral nutrition has been discontinued.1-4 The purpose of this study was to determine whether children with short From the Division of Pediatric Gastroenterology and Nutrition, Pediatric Bone Research Center, Children’s Hospital Research Foundation, Cincinnati, Ohio. Supported in part by U.S. Public Health Service Grant no. M01 RR08084 from the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health. Submitted for publication Feb. 21, 1996; accepted June 6, 1997. Reprint requests: James E. Heubi, MD, General Clinical Research Center, Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/83971
516
bowel syndrome, who no longer require parenteral nutrition, have decreased bone mass. We hypothesized that children with SBS receiving enteral alimentation would have decreased total body bone mineral content when compared with healthy age-, sex-, and racematched children. We also hypothesized that the decrease in BMC would be secondary to reduced calcium absorption, as evidenced by high serum 1,25-dihydroxy vitamin D and normal serum 25hydroxy vitamin D levels.
METHODS Subjects Subjects were identified from the medical records of the Children’s Hospital Medical Center, Cincinnati, Ohio, from 1984 to 1994. Children who had a history
of intestinal resection, omphalocele, or gastroschisis and required parenteral nutrition for at least 1 month, but were cur-
See editorial, p. 386. rently receiving full enteral nutrition, were recruited for the study. Exclusion criteria included long-term corticosteroid use beyond the neonatal period, hepatobiliary disease, cystic fibrosis, or kidney disease.
BMC 25-OHD 1,25-(OH)2D RDA SBS
Bone mineral content 25-Hydroxy vitamin D 1,25-Dihydroxy vitamin D Recommended daily allowance Short bowel syndrome
Data Collection and Analytic Methods Total body BMC was measuredby dual-energy x-ray absorptiometry with the Hologic QDR-2000 scanner (Hologic, Inc., Waltham, Mass.) with either pediatric or adult software. Normative data for total body BMC in children were not available; therefore, comparisons were made with two control subjects per patient (matched by age, sex, and race). The matching was performed to account for differences in BMC seen in childhood.5,6