- Email: [email protected]
Early onset of essential fatty acid deficiency in patents with cystic fibrosis receiving a semisynthetic diet
958
Clinical and laboratory observations
disordered functioning of individuals with PKU has been debated 9,~0and should continue to be investigated. Without a matched control group, it is difficult to determine whether the women were affected by PKU or hyperphenylalaninemia in relatively subtle ways. It is possible that they would have been more intelligent, better educated, more financially stable, and emotionally more secure if they were biochemically normal. Nevertheless, these results are potentially useful because they might provide a basis for comparison with adults who have nonclassic PKU and who received dietary treatment after newborn screening identification. It is unlikely that there will be another opportunity to study a cohort of adults with untreated atypical PKU. As a group the women adequately performed life's tasks and were making suitable adjustments in their roles as mothers, wives, and members of their communities.
REFERENCES 1. Jervis GA: The clinical picture. In Lyman FL, editor: Phenylketonuria. Springfield, IlL, I963, Charles C Thomas, p 52. 2. Partington MW: Long-term studies of untreated phenylketonuria. II. The plasma phenylalanine level. Neuropadiatrie 9:255, 1978.
The Journal of Pediatrics December I984
3. Hsia DY-Y, O'Flynn ME, Berman JL: Atypical phenylketonuria with borderline or normal intelligence. Am J Dis Child 116:143, 1968. 4. Perry TL, Hansen S, Tisehler B, Richards FM, Sokol M: Unrecognized adult phenylketonuria: Implications for obstetrics and psychiatry. N Engl J Med 289:395, 1973. 5. Levy HL, Waisbren SE: Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. N Engl J Med 309:1269, 1983. 6. Nie NH, Hull CH, Jenkins JG, Steinbrenner K, Bent DH: Statistical package for the social sciences. New York, 1975, McGraw-Hill. 7. Hull CH, Nie NH: SPSS Update: New procedures and facilities for releases 7 and 8. New York, 1979, McGrawHill. 8. Hollingshead AB, Redlich FC: Two-factor index of social position. Unpublished manuscript, Yale University, 1957. (Available from AB Hollingshead, New Haven, Conn.) 9. Bessman SP, Williamson ML, Koch R: Diet, genetics, and mental retardation interaction between phenylketonuric heterozygous mother and fetus to produce nonspecificdiminution of IQ: Evidencein support of the justification hypothesis. Proc Natl Acad Sci USA 75:1562, 1978. 10. Scriver CR, Cole DEC, Houghton SA, Levy HL, Granier A, Laberge C: Cord-bloodtyrosine levelsin the full-term phenylketonuric fetus and the "justification hypothesis." Proc Natl Acad Sci USA 77:6175, 1980.
Early onset of essential fatty acid deficiency in patients with cystic fibrosis receiving a semisynthetic diet Howard G. Parsons, M.D., Gillian Shillabeer, M.Sc., and Alfred W. Rademaker, Ph.D. Calgary, Alberta, Canada
PATIENTS WITH CYSTIC FIBROSIS frequently have malnutrition and growth failure. ~ Improved growth has been reported using semisynthetic diets 2.3; the rationale to give predigested nutrients was to circumvent the digestive
From the Gastrointestinal Research Unit, University of Calgary. Supported by a grant from the Alberta Children's Hospital Research Foundation and the Alberta Heritage Foundation for Medical Research. Submitted for publication Feb. 16, 1984; accepted June 8, 1984. Reprint requests: Howard G. Parsons, M.D., Department of Pediatrics, Division of Gastroenterology and Nutrition, 3330 Hospital Drive N.W., Calgary, Alia., Canada T2N 4NI.
abnormalities found in 85% of patients with CF. In several instances this resulted in the semisynthetic diet being administered without supplemental pancreatic enzymes, a prerequisite for vegetable oil hydrolysis and essential fatty acid absorption.2'3 The potential detrimental effect on C~ EDTA EFA
Cystic fibrosis Ethylenediametetraacetic acid Essential fatty acids
EFA status has not been examined in short-term studies. Many investigators have documented a high incidence of EFA deficiency in patients with CF receiving their regular diet. ~ Because the semisynthetic diet is used to correct nutrient deficiencies, it is important that the EFA status in
Volume 105 Number 6
patients with C F receiving a semisynthetic diet without pancreatic enzymes be determined. We evaluated early plasma phosphatidylcholine fatty acid changes in patients with CF who received as their sole nutrient source a semisynthetic diet low in E F A and without pancreatic enzyme supplementation. METHODS The study group consisted of three patients with C F and pancreatic exocrine deficiency given a semisynthetic diet (Vivonex, Norton-Eaton) by continuous nasogastric drip for 14 days. The fat content of standard Vivonex is 1.3% of total calories as safflower oil. Their weight and triceps, biceps, subscapular, and suprailiac skinfold measurements were done by standard techniques? Body fat was determined from the measurement of skinfold thickness? No pancreatic enzymes or other nutrient supplementations were provided and routine management, other than diet, was not altered. Blood samples were collected in EDTA at 0, 7, and 14 days of therapy, and the plasma was collected and stored at - 7 0 ~ C until analyzed for fatty acid profiles. Patients 1 and 3 were again assessed at 28 days, 2 weeks after returning to their regular diet and pancreatic enzyme supplementation. A 25-year-old woman in good health and with no known disease served as a control and ingested a standard North American diet; plasma was collected at similar time intervals and handled identically to that of the patients with CF. Plasma lipids were extracted in chloroform-methanol (2:1) 6 and separated into individual phospholipids by thin-layer chromatography. 7,8 The fatty acids of the isota.ted phospatidylcholine were determined by gas-liquid chromatography from methyl esters. Gas chromatography analysis was performed on a Hewlett-Packard model 5840 equipped with an SP-2100 capillary column. A mixture of methyl esters of fatty acids (Applied Sciences Laboratories, State College, Pa.) of known compbsition was used as a reference standard for identification. The retention time of 9,12,15-eicosatrienoic acid was established by using plasma from weanling rats that receive~l a fat-free diet for 4 weeks. Peak area was calculated by chromatographlinked integrator. The relative percentage of each fatty acid in the total fatty acids was determined on a weight percent basis using pentadecanoic acid as an internal standard and are presented as the mean percent _+ SE. Comparison of four control measures with the single measurement at time 0 in three patients was done by using a two-tailed t test for a priori contrasts with unequal sample size per group. A level <0.5 (P < 0.05) was considered to be statistically significant. Differences over time for the three patients were analyzed using two-way
Clinical and laboratory observations
959
Table. Patient characteristics Patient
On entry to study Age (yr) Weight (percentile) During study kCal/day consumed AWeight (kg) 2xBody fat (kg)
17.6 <3 4060.0 +2.9 +2.31
2
3
17.0 3
21.9 <3
2520.0 +2.0 +1.65
3247.0 +2.9 +2.3
analysis of variance. If the t test was statistically significant (P < 0.05), the Duncan standardized range text 9 was used to determine which times were different. Essential fatty acid deficiency was defined as decreased linoleic and arachidonic acids; increased palmitic, palmitoleic, and oleic acids; the appearance of 9,12,15-eicosatrienoic acid (triene); and a triene/tetraene (arachidonic acid) ratio >0.2? 0 RESULTS On entry into the study each patient was at or below the 3rd percentile for weight. Over the 14 days of treatment the mean weight gain was 2.6 kg, with 80% (2.1 kg) of the weight gain resulting from increased body fat (Table). Even before the semisynthetic diet was initiated, the fatty acid composition of plasma phosphatidylcholine of the patients with C F differed from the control values. Phosphatidylcholine contained less linoleic acid (16.07 _+ 1.07 vs 21.0 + 0.74) and increased palmitoleic (3.03 + 0.22 vs 1.60 ___ 0.50). From days 0 to 7 of Vivonex therapy there was a decrease in linoleic acid, from 16.07% + 1.70% to 7.30% _+ 1.50%, with an increase in palmitoleic acid from 3.03% _+ 0.25% to 4.50% _+ 0.38% and oleic acid from 18.07% _+ 1.48% to 25.73% ___ 2.01%. The changes in linoleic, palmitoteic, and oleic acids persisted from days 7 to 14 (Figure). From days 0 to 14 there was also a decrease in arachidonic acid from 11.03% _+ 1.08% to 7.80% _+ 0.60% ( P < 0 . 1 0 ) . The 9,12,15-eicosatrienoic acid was increased from 7 to 14 days and 0 to 14 days. Two weeks after cessation of Vivonex therapy, and with a regular diet, the fatty acid changes, although still abnormal, were less marked than while receiving Vivonex. There was a large increase in linoleic acid (P < 0.05), whereas patmitoleate and oleate decreased (P < 0.10). During the semisynthetic diet the 20:3,w9/20:4,w6 ratio rose from 0.08 _+ 0.50 to 0.19 _+ 9.04 by day 7, and further increased to 0.36 ___0.17 by day 14. After 14 days of a conventional diet and pancreatic enzyme replacemen(, the 20:3,w9/20:4,o~6 returned to the normal range (0,1 _+ 0.05).
960
Clinical and laboratory observations
The Journal of Pediatrics December 1984
35
30
[ ] pre-vivonex "~. uJ
[ ] 7 days vivonex [ ] 14 days vivonex
25
[ ] 28 days (14 days post-vivonex) 20
*
~
+
~e 10
Palmitoleate
Stearate
Oleate
Linoleate
Eicosatrienoate
Arachidonate
Figure. Plasma phosphatidylcholine fatty acid profiles (mean % _+ SE) before, during, and after Vivonex therapy in patients with cystic fibrosis. P < 0.05. * 0 to 7, 0 to 14 days; ** 7 to 14 days; + 14 to 28 days.
DISCUSSION At the time of entry into the study our patients with cystic fibrosis were similar to those reported by others. Reduced tissue levels of linoleie acid were associated with increased palmitoleic acid. These fatty acid changes are characteristic of E F A deficieneyJ ~ Another measurement of E F A status is the trienetetraene ratio. An increase in the ratio of 20:3,~o9/20:4,w6 suggests an increase in the production of the oleic acid metabolite 9,12,15-eicosatrienoic acid, as a consequence of decreased dietary linoleate or its conversion to its major metabolite, arachidonate. A ra~io >0.2 is considered abnormal. Our patients did not have increased levels of 9,12,15-eicosatrienoic nor an elevated 20:3,w9/20:4,~o6 ratio at the time of entry into the study, a finding similar to other reports. The arachidonic acid content appears to reflect the length of time E F A deficiency has existed. The semisynthetic diet in our patients increased the severity of the E F A deficiency by day 7. By day 14 the increased E F A deficiency persisted and the 20:3,w9/ 20:4,w6 ratio had become abnormal. The arachidonic acid content of phosphatidylcholine slowly decreased. By day 14 of the diet the decrease approached significance (P > 0.05 to <0.10). Under short-term conditions (0 to 28 days) there are two requirements for the development of E F A deficiency: a fat-free diet and a continuous infusion of carbohydrate, which prevents the mobilization of the large linoleate stores in adipose tissue." Once a eucaloric intake is met by
continuous administration of carbohydrate, increased insulin secretion inhibits the mobilization of lipid from tissue fat. The high-energy intake in our patients was provided in a manner that not only prevented lipolysis but favored lipogenesis. In fact, in our patients body fat composition increased by 1.65 to 2.3 kg during the 14 days of therapy. Therefore, to prevent an aggravation of the E F A deficiency in our patients, the diet had to contain adequate E F A in an absorbable form. Safflower oil in standard Vivonex provides 1.3% of total calories. Linoleic acid constitutes 78% of the fatty acid composition in safflower oils; no other E F A are present. Therefore, approximately 1% of the total calories of Vivonex is present as EFA. Biochemically, the requirement for EFA is met with an intake >_ 1% of total energy; however, allowing for individual differences, the recommended daily allowance gas been set at a minimum of 3% of total energy) ~ Even if it is assumed that enough E F A were present in the diet to meet the patient's needs, our patients would not have received 1% of their total energy as EFA; the EFA in the form of triacylglycerides would not be absorbed without adequate exocrine function for lipolysis. Even with enzyme replacement, the coefficient of absorption in CF is only approximately 80% (normal, >93%). In summary, our patients with C F had E F A deficiency at the time of entry into the study. This was heightened at 7 days by providing, without supplemental pancreatic enzymes, a semisynthetic diet low in EFA, high in energy,
Volume 105 Number 6
and given continuously. Thus, semisynthetic diets low in E F A should not be the sole source of fat in a host with a compromised ability to a b s o r b fat for even as short a time as 1 week.
REFERENCES
1. Chase HP, Long MA, Levin MH: Cystic fibrosis and malnutrition. J PEDIATR 95:337, 1979. 2. Allan JD, Mason A, Moss AD: Nutritional supplementation in treatment of cystic fibrosis of the pancreas. Am J Dis Child 125:22, 1973. 3. Berry HK, Kellogg FW, Hunt MM, Ingberg RL, Richter L, Gutjahr C: Dietary supplement and nutrition in children with cystic fibrosis. Am J Dis Child 129:165, 1974. 4. Jelliffe DB: The assessment of the nutritional status of community: With special reference to field surveys in developing regions of the world, Geneva, 1966, WHO Monograph Series No. 53.
Clinical and laboratory observations
96I
5. Darnin JVGA, Rahaman MM: The assessment of the amount of fat in'the human body from measurements of skinfold thickness. Br J Nutr 21:681, 1967. 6. Folch J, Lees M, Sloane-Stanley GA: A simple method of isolation and purification of total lipids from animal tissues. J BiN Chem 226:497, 1959. 7. Skipski V, Good J J, Barclay M, Reggio RB: Quantitative analysis of simple lipid classes by thin-layer chromatography. Biochem Biophys 152:10, 1968. 8. Skipski VP, Peterson RF, Bai'clay M: Quantitative analysis of phospholipids by thin-layer chromatography. Bioehem J 90:374, 1964. 9. Snedcor GW, Cochran WG: Statistical methods, ed 7. Ames, Iowa, Iowa State University Press, 1980. 10. Joint FAO/WHO Ad Hoc Expert Committee on Dietary Fats and Oils in Human Nutrition, Rome, FAO Food and Nutrition Paper No. 3. 11. Wene JD, Connor WE, Den Besten L: The development of essential fatty acid deficiency in healthy men, fed fat-free diets intravenously and orally. J Clin Invest 56:127, 1975.
Episodic weakness in pyruvate decarboxylase deficiency O w e n B. E v a n s , M . D . Jackson, Mississippi
PYRUVATE DECARBOXYLASE DEFICIENCY is a progressive neurologic disease with variable symptoms and signs, usually ataxia, weakness of ocular motility, a n d peripheral nerve disease.~ M a n y patients also have episodes of acute weakness a n d worsening ataxia? -4 A l t h o u g h the underlying e n z y m e deficiency has been d o c u m e n t e d , t h e cause for the relapsing course has not been determined. The results of a n investigation into the m e c h a n i s m of a n acute exacerbation in a patient with P D C deficiency are reported here. CASE REPORT This 15-year-old boy was a term product of an uncomplicated pregnancy, labor, and delivery and was bor n to unrelated parents. Early development was delayed, and at age 6 years the parents sought medical attention because of his difficulty in walking; ataxic cerebral palsy was diagnosed. Symptoms progressed, and at age 10 years he was nonambulatory and dysarthric and receiving
From the Department of Pediatrics, University Medical Center. Supported in part by a grant from the Muscular Dystrophy Association. Submitted for publication Jan. 30, 1984; accepted June 29, 1984. Reprint requests: Evans, University Medical Center, Department of Pediatrics, Jackson Mississippi 39216.
special education. Over the ensuing 5 years his symptoms worsened and he developed increasing weakness. There have been several episodes of severe weakness and ataxia; recovery from these episodes has been incomplete. The patient was hospitalized at age 15 years with acute weakness after a mild gastrointestinal illness with diarrhea and fever. One day prior to admission his truncal and limb ataxia became worse, and on the day of admission he became severely weak and had difficulty in swallowing. Examination at admission showed marked growth failure. The patient was alert and respon-
ATP DCA LAD PDC PDH
Adenosine tri!bhosphate Dichloroacetate Lipoamide dehydrogenase Pyruvate decarboxylase Pyruvate dehydrogenase
sive, but his behavior suggested moderate retardation. Extraocular motility was impaired, particularly laterally. Pupillary responses were normal, and a fundoscopic examination showed unremarkable findings. Visual acuity and hearing were normal. There was bilateral facial, palatal, and tongue weakness. The voice was nasal. The deep-tendon reflexes were absent;'~and there was no response to plantar stimulation. There was moderate muscle atrophy and severe weakness, both proximally and distally; the patient was unable to lift his head or extremities from the bed. There was
Clinical and laboratory observations
disordered functioning of individuals with PKU has been debated 9,~0and should continue to be investigated. Without a matched control group, it is difficult to determine whether the women were affected by PKU or hyperphenylalaninemia in relatively subtle ways. It is possible that they would have been more intelligent, better educated, more financially stable, and emotionally more secure if they were biochemically normal. Nevertheless, these results are potentially useful because they might provide a basis for comparison with adults who have nonclassic PKU and who received dietary treatment after newborn screening identification. It is unlikely that there will be another opportunity to study a cohort of adults with untreated atypical PKU. As a group the women adequately performed life's tasks and were making suitable adjustments in their roles as mothers, wives, and members of their communities.
REFERENCES 1. Jervis GA: The clinical picture. In Lyman FL, editor: Phenylketonuria. Springfield, IlL, I963, Charles C Thomas, p 52. 2. Partington MW: Long-term studies of untreated phenylketonuria. II. The plasma phenylalanine level. Neuropadiatrie 9:255, 1978.
The Journal of Pediatrics December I984
3. Hsia DY-Y, O'Flynn ME, Berman JL: Atypical phenylketonuria with borderline or normal intelligence. Am J Dis Child 116:143, 1968. 4. Perry TL, Hansen S, Tisehler B, Richards FM, Sokol M: Unrecognized adult phenylketonuria: Implications for obstetrics and psychiatry. N Engl J Med 289:395, 1973. 5. Levy HL, Waisbren SE: Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. N Engl J Med 309:1269, 1983. 6. Nie NH, Hull CH, Jenkins JG, Steinbrenner K, Bent DH: Statistical package for the social sciences. New York, 1975, McGraw-Hill. 7. Hull CH, Nie NH: SPSS Update: New procedures and facilities for releases 7 and 8. New York, 1979, McGrawHill. 8. Hollingshead AB, Redlich FC: Two-factor index of social position. Unpublished manuscript, Yale University, 1957. (Available from AB Hollingshead, New Haven, Conn.) 9. Bessman SP, Williamson ML, Koch R: Diet, genetics, and mental retardation interaction between phenylketonuric heterozygous mother and fetus to produce nonspecificdiminution of IQ: Evidencein support of the justification hypothesis. Proc Natl Acad Sci USA 75:1562, 1978. 10. Scriver CR, Cole DEC, Houghton SA, Levy HL, Granier A, Laberge C: Cord-bloodtyrosine levelsin the full-term phenylketonuric fetus and the "justification hypothesis." Proc Natl Acad Sci USA 77:6175, 1980.
Early onset of essential fatty acid deficiency in patients with cystic fibrosis receiving a semisynthetic diet Howard G. Parsons, M.D., Gillian Shillabeer, M.Sc., and Alfred W. Rademaker, Ph.D. Calgary, Alberta, Canada
PATIENTS WITH CYSTIC FIBROSIS frequently have malnutrition and growth failure. ~ Improved growth has been reported using semisynthetic diets 2.3; the rationale to give predigested nutrients was to circumvent the digestive
From the Gastrointestinal Research Unit, University of Calgary. Supported by a grant from the Alberta Children's Hospital Research Foundation and the Alberta Heritage Foundation for Medical Research. Submitted for publication Feb. 16, 1984; accepted June 8, 1984. Reprint requests: Howard G. Parsons, M.D., Department of Pediatrics, Division of Gastroenterology and Nutrition, 3330 Hospital Drive N.W., Calgary, Alia., Canada T2N 4NI.
abnormalities found in 85% of patients with CF. In several instances this resulted in the semisynthetic diet being administered without supplemental pancreatic enzymes, a prerequisite for vegetable oil hydrolysis and essential fatty acid absorption.2'3 The potential detrimental effect on C~ EDTA EFA
Cystic fibrosis Ethylenediametetraacetic acid Essential fatty acids
EFA status has not been examined in short-term studies. Many investigators have documented a high incidence of EFA deficiency in patients with CF receiving their regular diet. ~ Because the semisynthetic diet is used to correct nutrient deficiencies, it is important that the EFA status in
Volume 105 Number 6
patients with C F receiving a semisynthetic diet without pancreatic enzymes be determined. We evaluated early plasma phosphatidylcholine fatty acid changes in patients with CF who received as their sole nutrient source a semisynthetic diet low in E F A and without pancreatic enzyme supplementation. METHODS The study group consisted of three patients with C F and pancreatic exocrine deficiency given a semisynthetic diet (Vivonex, Norton-Eaton) by continuous nasogastric drip for 14 days. The fat content of standard Vivonex is 1.3% of total calories as safflower oil. Their weight and triceps, biceps, subscapular, and suprailiac skinfold measurements were done by standard techniques? Body fat was determined from the measurement of skinfold thickness? No pancreatic enzymes or other nutrient supplementations were provided and routine management, other than diet, was not altered. Blood samples were collected in EDTA at 0, 7, and 14 days of therapy, and the plasma was collected and stored at - 7 0 ~ C until analyzed for fatty acid profiles. Patients 1 and 3 were again assessed at 28 days, 2 weeks after returning to their regular diet and pancreatic enzyme supplementation. A 25-year-old woman in good health and with no known disease served as a control and ingested a standard North American diet; plasma was collected at similar time intervals and handled identically to that of the patients with CF. Plasma lipids were extracted in chloroform-methanol (2:1) 6 and separated into individual phospholipids by thin-layer chromatography. 7,8 The fatty acids of the isota.ted phospatidylcholine were determined by gas-liquid chromatography from methyl esters. Gas chromatography analysis was performed on a Hewlett-Packard model 5840 equipped with an SP-2100 capillary column. A mixture of methyl esters of fatty acids (Applied Sciences Laboratories, State College, Pa.) of known compbsition was used as a reference standard for identification. The retention time of 9,12,15-eicosatrienoic acid was established by using plasma from weanling rats that receive~l a fat-free diet for 4 weeks. Peak area was calculated by chromatographlinked integrator. The relative percentage of each fatty acid in the total fatty acids was determined on a weight percent basis using pentadecanoic acid as an internal standard and are presented as the mean percent _+ SE. Comparison of four control measures with the single measurement at time 0 in three patients was done by using a two-tailed t test for a priori contrasts with unequal sample size per group. A level <0.5 (P < 0.05) was considered to be statistically significant. Differences over time for the three patients were analyzed using two-way
Clinical and laboratory observations
959
Table. Patient characteristics Patient
On entry to study Age (yr) Weight (percentile) During study kCal/day consumed AWeight (kg) 2xBody fat (kg)
17.6 <3 4060.0 +2.9 +2.31
2
3
17.0 3
21.9 <3
2520.0 +2.0 +1.65
3247.0 +2.9 +2.3
analysis of variance. If the t test was statistically significant (P < 0.05), the Duncan standardized range text 9 was used to determine which times were different. Essential fatty acid deficiency was defined as decreased linoleic and arachidonic acids; increased palmitic, palmitoleic, and oleic acids; the appearance of 9,12,15-eicosatrienoic acid (triene); and a triene/tetraene (arachidonic acid) ratio >0.2? 0 RESULTS On entry into the study each patient was at or below the 3rd percentile for weight. Over the 14 days of treatment the mean weight gain was 2.6 kg, with 80% (2.1 kg) of the weight gain resulting from increased body fat (Table). Even before the semisynthetic diet was initiated, the fatty acid composition of plasma phosphatidylcholine of the patients with C F differed from the control values. Phosphatidylcholine contained less linoleic acid (16.07 _+ 1.07 vs 21.0 + 0.74) and increased palmitoleic (3.03 + 0.22 vs 1.60 ___ 0.50). From days 0 to 7 of Vivonex therapy there was a decrease in linoleic acid, from 16.07% + 1.70% to 7.30% _+ 1.50%, with an increase in palmitoleic acid from 3.03% _+ 0.25% to 4.50% _+ 0.38% and oleic acid from 18.07% _+ 1.48% to 25.73% ___ 2.01%. The changes in linoleic, palmitoteic, and oleic acids persisted from days 7 to 14 (Figure). From days 0 to 14 there was also a decrease in arachidonic acid from 11.03% _+ 1.08% to 7.80% _+ 0.60% ( P < 0 . 1 0 ) . The 9,12,15-eicosatrienoic acid was increased from 7 to 14 days and 0 to 14 days. Two weeks after cessation of Vivonex therapy, and with a regular diet, the fatty acid changes, although still abnormal, were less marked than while receiving Vivonex. There was a large increase in linoleic acid (P < 0.05), whereas patmitoleate and oleate decreased (P < 0.10). During the semisynthetic diet the 20:3,w9/20:4,w6 ratio rose from 0.08 _+ 0.50 to 0.19 _+ 9.04 by day 7, and further increased to 0.36 ___0.17 by day 14. After 14 days of a conventional diet and pancreatic enzyme replacemen(, the 20:3,w9/20:4,o~6 returned to the normal range (0,1 _+ 0.05).
960
Clinical and laboratory observations
The Journal of Pediatrics December 1984
35
30
[ ] pre-vivonex "~. uJ
[ ] 7 days vivonex [ ] 14 days vivonex
25
[ ] 28 days (14 days post-vivonex) 20
*
~
+
~e 10
Palmitoleate
Stearate
Oleate
Linoleate
Eicosatrienoate
Arachidonate
Figure. Plasma phosphatidylcholine fatty acid profiles (mean % _+ SE) before, during, and after Vivonex therapy in patients with cystic fibrosis. P < 0.05. * 0 to 7, 0 to 14 days; ** 7 to 14 days; + 14 to 28 days.
DISCUSSION At the time of entry into the study our patients with cystic fibrosis were similar to those reported by others. Reduced tissue levels of linoleie acid were associated with increased palmitoleic acid. These fatty acid changes are characteristic of E F A deficieneyJ ~ Another measurement of E F A status is the trienetetraene ratio. An increase in the ratio of 20:3,~o9/20:4,w6 suggests an increase in the production of the oleic acid metabolite 9,12,15-eicosatrienoic acid, as a consequence of decreased dietary linoleate or its conversion to its major metabolite, arachidonate. A ra~io >0.2 is considered abnormal. Our patients did not have increased levels of 9,12,15-eicosatrienoic nor an elevated 20:3,w9/20:4,~o6 ratio at the time of entry into the study, a finding similar to other reports. The arachidonic acid content appears to reflect the length of time E F A deficiency has existed. The semisynthetic diet in our patients increased the severity of the E F A deficiency by day 7. By day 14 the increased E F A deficiency persisted and the 20:3,w9/ 20:4,w6 ratio had become abnormal. The arachidonic acid content of phosphatidylcholine slowly decreased. By day 14 of the diet the decrease approached significance (P > 0.05 to <0.10). Under short-term conditions (0 to 28 days) there are two requirements for the development of E F A deficiency: a fat-free diet and a continuous infusion of carbohydrate, which prevents the mobilization of the large linoleate stores in adipose tissue." Once a eucaloric intake is met by
continuous administration of carbohydrate, increased insulin secretion inhibits the mobilization of lipid from tissue fat. The high-energy intake in our patients was provided in a manner that not only prevented lipolysis but favored lipogenesis. In fact, in our patients body fat composition increased by 1.65 to 2.3 kg during the 14 days of therapy. Therefore, to prevent an aggravation of the E F A deficiency in our patients, the diet had to contain adequate E F A in an absorbable form. Safflower oil in standard Vivonex provides 1.3% of total calories. Linoleic acid constitutes 78% of the fatty acid composition in safflower oils; no other E F A are present. Therefore, approximately 1% of the total calories of Vivonex is present as EFA. Biochemically, the requirement for EFA is met with an intake >_ 1% of total energy; however, allowing for individual differences, the recommended daily allowance gas been set at a minimum of 3% of total energy) ~ Even if it is assumed that enough E F A were present in the diet to meet the patient's needs, our patients would not have received 1% of their total energy as EFA; the EFA in the form of triacylglycerides would not be absorbed without adequate exocrine function for lipolysis. Even with enzyme replacement, the coefficient of absorption in CF is only approximately 80% (normal, >93%). In summary, our patients with C F had E F A deficiency at the time of entry into the study. This was heightened at 7 days by providing, without supplemental pancreatic enzymes, a semisynthetic diet low in EFA, high in energy,
Volume 105 Number 6
and given continuously. Thus, semisynthetic diets low in E F A should not be the sole source of fat in a host with a compromised ability to a b s o r b fat for even as short a time as 1 week.
REFERENCES
1. Chase HP, Long MA, Levin MH: Cystic fibrosis and malnutrition. J PEDIATR 95:337, 1979. 2. Allan JD, Mason A, Moss AD: Nutritional supplementation in treatment of cystic fibrosis of the pancreas. Am J Dis Child 125:22, 1973. 3. Berry HK, Kellogg FW, Hunt MM, Ingberg RL, Richter L, Gutjahr C: Dietary supplement and nutrition in children with cystic fibrosis. Am J Dis Child 129:165, 1974. 4. Jelliffe DB: The assessment of the nutritional status of community: With special reference to field surveys in developing regions of the world, Geneva, 1966, WHO Monograph Series No. 53.
Clinical and laboratory observations
96I
5. Darnin JVGA, Rahaman MM: The assessment of the amount of fat in'the human body from measurements of skinfold thickness. Br J Nutr 21:681, 1967. 6. Folch J, Lees M, Sloane-Stanley GA: A simple method of isolation and purification of total lipids from animal tissues. J BiN Chem 226:497, 1959. 7. Skipski V, Good J J, Barclay M, Reggio RB: Quantitative analysis of simple lipid classes by thin-layer chromatography. Biochem Biophys 152:10, 1968. 8. Skipski VP, Peterson RF, Bai'clay M: Quantitative analysis of phospholipids by thin-layer chromatography. Bioehem J 90:374, 1964. 9. Snedcor GW, Cochran WG: Statistical methods, ed 7. Ames, Iowa, Iowa State University Press, 1980. 10. Joint FAO/WHO Ad Hoc Expert Committee on Dietary Fats and Oils in Human Nutrition, Rome, FAO Food and Nutrition Paper No. 3. 11. Wene JD, Connor WE, Den Besten L: The development of essential fatty acid deficiency in healthy men, fed fat-free diets intravenously and orally. J Clin Invest 56:127, 1975.
Episodic weakness in pyruvate decarboxylase deficiency O w e n B. E v a n s , M . D . Jackson, Mississippi
PYRUVATE DECARBOXYLASE DEFICIENCY is a progressive neurologic disease with variable symptoms and signs, usually ataxia, weakness of ocular motility, a n d peripheral nerve disease.~ M a n y patients also have episodes of acute weakness a n d worsening ataxia? -4 A l t h o u g h the underlying e n z y m e deficiency has been d o c u m e n t e d , t h e cause for the relapsing course has not been determined. The results of a n investigation into the m e c h a n i s m of a n acute exacerbation in a patient with P D C deficiency are reported here. CASE REPORT This 15-year-old boy was a term product of an uncomplicated pregnancy, labor, and delivery and was bor n to unrelated parents. Early development was delayed, and at age 6 years the parents sought medical attention because of his difficulty in walking; ataxic cerebral palsy was diagnosed. Symptoms progressed, and at age 10 years he was nonambulatory and dysarthric and receiving
From the Department of Pediatrics, University Medical Center. Supported in part by a grant from the Muscular Dystrophy Association. Submitted for publication Jan. 30, 1984; accepted June 29, 1984. Reprint requests: Evans, University Medical Center, Department of Pediatrics, Jackson Mississippi 39216.
special education. Over the ensuing 5 years his symptoms worsened and he developed increasing weakness. There have been several episodes of severe weakness and ataxia; recovery from these episodes has been incomplete. The patient was hospitalized at age 15 years with acute weakness after a mild gastrointestinal illness with diarrhea and fever. One day prior to admission his truncal and limb ataxia became worse, and on the day of admission he became severely weak and had difficulty in swallowing. Examination at admission showed marked growth failure. The patient was alert and respon-
ATP DCA LAD PDC PDH
Adenosine tri!bhosphate Dichloroacetate Lipoamide dehydrogenase Pyruvate decarboxylase Pyruvate dehydrogenase
sive, but his behavior suggested moderate retardation. Extraocular motility was impaired, particularly laterally. Pupillary responses were normal, and a fundoscopic examination showed unremarkable findings. Visual acuity and hearing were normal. There was bilateral facial, palatal, and tongue weakness. The voice was nasal. The deep-tendon reflexes were absent;'~and there was no response to plantar stimulation. There was moderate muscle atrophy and severe weakness, both proximally and distally; the patient was unable to lift his head or extremities from the bed. There was