J. Inher. Metab. Dis. 15 (1992) 261-268 © SSIEM and KluwerAcademicPublishers. Printed in the Netherlands
Decreased Selenium Intake and Low Plasma Selenium Concentrations Leading to Clinical Symptoms in a Child with Propionic Acidaemia S. YANNICELLII, K. M. HAMBIDGE2 and M. F. PICCIANO3 1Department of Pediatrics, Division of Genetics and Inherited Metabolic Diseases Clinic, The Children's Hospital, Box B-153, 1056 East 19th Avenue, Denver, Colorado, USA; aDepartment of Pediatrics, The Children's Hospital, Denver, Colorado, USA; 3pennsylvania State University, Nutrition Department, University Park, Pennsylvania, USA
Summary: A child with biotin-non-responsive propionic acidaemia treated with a propiogenic amino acid-restricted diet presented with an elevated blood mean corpuscular volume (MCV) of 93.1 r, indicative of macrocytosis, and unusual hair texture with hypopigmentation. Plasma selenium concentration at this time was subnormal (45.9/~g/L), and calculated dietary selenium intake was 4.7 #g/day. After 4 months of selenium supplementation (50 pg/day) plasma selenium concentration normalized (97.7/~g/L) in conjunction with a reduced MCV (84.0fl) and a dramatic improvement in hair growth, colour and length. Two additional periods off and on selenium supplementation, of varying time intervals, resulted in similar clinical changes. We conclude that these clinical changes were due to a deficient intake of dietary selenium.
Propionic acidaemia (McKusick 23200) is an inherited defect in the enzyme propionylCoA carboxylase (EC 4.1.1.41). The disorder is manifested by the decreased ability to metabolize propiogenic amino acids (isoleucine, methionine, threonine, valine), the side-chain of cholesterol and odd-chained fatty acids. The cornerstone of treatment involves a propiogenic amino acid-restricted diet utilizing special medical foods with restricted intake of whole protein sources. Decreased intakes and low plasma concentrations of selenium in children with inborn errors of metabolism have been documented previously (Lombeck and Bremer 1977; Acosta et al 1987; Gropper et al 1988). The dependence on chemically defined formulae to meet the majority of these patients' protein requirements may result in inadequate intakes and greater requirements of trace elements (Acosta et al 1987; Gropper et at 1988). Children with phenylketonuria (PKU) and maple syrup urine disease (MSUD) have shown an improvement in their selenium status after selenium supplementation (Lombeck et al 1980; Steiner et al 1982).
MS received 3.6.91 Accepted 9.12.91 261
262
Yannicelti et al.
Selenium, an essential trace element in humans, is necessary for the activity of glutathione peroxidase, the enzyme involved with the degradation of hydrogen peroxide and other organic hydroperoxides. Absence of selenium results in the inactivation of glutathian peroxidase, causing free-radical formation which can damage cell membranes (Brown et aI 1986). Selenium deficiency in humans has been identified in individuals receiving long-term total parenteral nutrition (TPN), and in patients with kwashiorkor, Keshan disease and Kaschin-Beck disease (Mathias and Jackson 1982; Kien and Ganthe'r 1983; Brown et al 1986; Diplock 1987). Deficiency has been associated with cardiomyopathy, muscle pain, arrhythmias and whitening of nail beds (Kien and Ganther 1983; Brown et al 1986). Vinton et al (1987) reported a child receiving long-term TPN who developed erythrocyte macrocytosis, and hair and skin depigmentation as a manifestation of selenium deficiency. This patient responded to intravenous selenium supplementation (2/~g kg- 1 day- 1) with a reversal in hair and skin hypopigmentation, and normalization of MCV. CASE REPORT
The patient (A.P.) is a 5.5-year-old female with propionic acidaemia treated since infancy with a propiogenic amino acid-restricted diet. She has a history of chronic anorexia and is dependent on gastrostomy feedings of special medical foods (OS 1, Protein-Free Diet Powder (Product 80056), Mead Johnson Nutritionals, Evansville, IN, USA) and natural protein sources (Enfamil with Iron®, Mead Johnson Nutritionals) to meet her nutritional requirements. Frequent recurrent illnesses and acidotic episodes resulting in cessation of feedings for short periods of time place the patient at risk of nutrient deficiencies. At 3 years of age, A.P. presented with sparse scalp hair, 0.5 cm in length from crown to mid-occiput with significant distal lengthening to 7.6-10.2cm and darker coloration (Figure 1). Hair was coarse and brittle with a significant degree of hair loss. Plasma selenium concentration at this time was significantly depressed (Table 1). Quantitation of glutathione peroxidase activity was not performed at time of presentation. Intakes of total protein (25.5g/day) and energy (1150kcal/day) were within recommended guidelines for treatment (Elsas and Acosta 1988). Whole protein fraction provided 1.0g kg -1 day -1. Anthropometric measures and biochemical parameters measuring visceral and somatic protein stores were within normal limits. Plasma zinc, copper, iron, cobalamin, and folate were all within the normal range for age. Vitamin E was analysed because of its close relationship with selenium as an antioxidant (Lipson et al 1988). Vitamin E (6 and ~) was not significantly changed throughout the study, and the ratio of plasma vitamin E to total tipid remained within normal limits. A review of A.P?s dietary regimen revealed a very low daily intake of selenium (4.7 ~tg/day), 24% of the age-specific Recommended Dietary Allowance (Food and Nutrition Board 1989). Therefore, selenium deficiency was suspected. The selenium intake was calculated from the nutrient composition of dietary products and special medical foods from the manufacturer's data. The prescribed medical foods were not supplemented with selenium. J. Inher. Metab. Dis. 15 (1992)
Selenium and Propionic Acidaemia
263
Figure 1 Initial presentation, before selenium supplementation Table 1 Plasma selenium, plasma glutathione peroxidase and mean corpuscular volume (MCV) in A.P. prior to and during periods on and off selenium supplementation Period 1
Biochemical parameters Plasma selenium (pg/L) Plasma glutathione peroxidase Total (U/L)" Se-dependent MCV (fl)
At presentation
2
3
45.9
97.7
69.7
190.5
ND
257,7 218.6 84.0
ND
107.7 43.4 86.2
93,1
4
5
On Off On Off On selenium selenium selenium selenium selenium
97.1
57.1
168.8 162.4 92.0
134.33
226.7 165.6 87.4
21 unit is defined as 1#mol of the NADPH oxidized per minute
J. Inher. Metab. Dis, 15 (1992)
264
Yannicelli et al.
METHODS
Selenium supplementation (selenious acid) of 50#g/day (4.5 #g kg-1 day-1) was initiated. Selenious acid was used as the source of selenium because it was the form most readily available. Nutrition support during the entire study was kept constant. Protein (total and whole) and energy intake and medications were adjusted for weight. These changes were very minor throughout the study. Plasma selenium concentrations were determined using a gas chromatograph equipped with an electron-capture detector (Model 5890A, Hewlett Packard) (McCarthy et al t981). All assays included National Bureau of Standards (NBS) bovine liver ( # 1577a) and non-fat bovine milk powder (#1349). Reproducibility and reliability of the plasma selenium analysis was within 5%. An internal control of pooled human plasma was stored with other haemotological samples and analysed with each assay to ensure adequacy of storage methods, which proved acceptable. Selenium-dependent glutathione peroxidase activity was measured in plasma using a modification of the coupled assay described by Paglia and Valentine (1967) with hydrogen peroxide as substrate. Total plasma glutathione peroxidase was measured in plasma samples using the same method with tertiary-butyl hydroperoxide as substrate. RESULTS After 4 months of supplementation, the MCV and plasma selenium were normalized (Table I, period 1) and hair showed a dramatic improvement. Hair became darker in colour and thicker, and assumed normal length and distribution. Coarseness was still evident (Figure 2). To substantiate our initial findings, selenium supplementation was discontinued after parental consent. Within 6 months, sparse hypopigmented hair was apparent and macrocytosis developed. Plasma selenium concentration was subnormal (Table 1, period 2) but not as depleted as at presentation. Additional phases off and on selenium supplementation (periods 3, 4 and 5, Table 1), each approximately 6 months in duration, were implemented, with improvement while on selenium and worsening when off selenium supplementation. Although plasma selenium concentration during each 'off supplementation period never returned to the low concentration found initially, the clinical and biochemical changes were still evident (Table 1, Figure 1). Despite the decreases in plasma selenium, the total and selenium-dependent glutathione peroxidase activities were not significantly altered during each phase of the study. Analysis of celt haemolysis did not reveal increased lysis during a period off selenium supplementation, and no clinical evidence of cardiomyopathy or muscle weakness occurred. DISCUSSION Clinical signs of selenium depletion have not been reported in patients with inborn errors of metabolism, although researchers have found low plasma selenium concentrations in children with PKU and MSUD (Lombeck et al 1978; Rottoli et al J. Inher, Metab. Dis, 15 (1992)
Selenium and Propionic Acidaemia
265
Fignre 2 After the first trial of selenium supplementation 1985; Acosta et al 1987; Gropper et al 1988; Lipson et al 1988; Reilly et al 1990). Greeves and colleagues (1990) suggested a possible role of selenium deficiency in a 9-month-old infant treated for PKU who presented with cardiac dysrhythmia. Several factors that affect trace element status may be responsible for depressed plasma selenium concentrations in these children. These factors include the physical characteristics and chemical composition of the diet, infections and diseases (Milner 1990). Lombeck and colleagues (1984) and Gropper and colleagues (1988) report lower intakes of dietary selenium in children with inborn errors of metabolism compared to normal children. Nine children with PKU had a median intake of 6.9 #g/day in comparison to 33.5klg/day in healthy infants and children (Lombeck et al 1984). A.P.'s daily intake of 4.7 #g selenium was significantly lower than the recommendation of 20 pg/day for 4-6-year-old children (Food and Nutrition Board 1989; Litov and Combs 1991), and is comparable to intakes of children in China with Keshan disease. Children with inborn errors of metabolism consuming special medical foods may have increased requirements for selenium (Acosta et al 1987). This may be due to the chemical composition of the elemental diet. Children with propionic acidaemia are J. Inher. Metab. Dis. 15 (i992)
266
Yannicelli et aI.
usually limited to consuming only simple carbohydrates and restricted quantities of vegetables, fruits and cereals, which are poorer sources of selenium compared to meats, seafood and dairy products (Morris and Levander 1970; Pennington et al 1986). Therefore, the total amount of selenium consumed and the question of selenium bioavailabitity must be considered for children with propionic acidaemia. Selenium deficiency has been described in patients on long-term TPN (Kien and Gunther 1983; Brown et al 1986; Vinton et al 1987) who were receiving no selenium. Vinton et al (I987) improved clinical status in their patient after supplementation of intravenous selenium increased serum selenium from a mean concentration of 38 _+ 11/~g/L to 81 #g/L. The initial value closely correlates with A.P.'s initial plasma selenium concentration of 45.9#g/L Normal plasma selenium for adults ranges between 90 and 165 #g/L (Thompson and Robinson 1980). Human milk-fed infants have mean plasma selenium values of 60-80 pg/L, and formula-fed infants have a mean value of 30-50/~g/L (Smith et al 1988). Thus, A.P.'s initial value was tow owing to a very low intake of selenium. Increases in plasma selenium levels are not always associated with a concurrent rise in glutathione peroxidase activity (Lipson et al 1988). Therefore, the percentage of tissue selenium associated with glutathione peroxidase activity may fluctuate (Whanger and Butler 1988). Plasma selenium concentrations alone are considered the most practical indicator of an individual's selenium status (Litov and Combs 1991). Although A.P.'s glutathione peroxidase activity did not significantly change, decreases in activity have been described in treated children with PKU (Lombeck et al 1978; Steiner et al 1982). Researchers have speculated that depressed selenium stores may not affect an individual's overall health status unless accompanied by other factors such as stress and infection (Diplock 1987). An insult to the body may be the factor that places the selenium-deprived individual over the clinical threshold. Children with propionic acidaemia often suffer intermittent infectious illness with acidosis, and are predisposed to frequent infections (Stork et al t986). During times of intermittent illness with acidosis, infants and children are often removed from their usual diet regimen and placed on either intravenous and/or oral glucose solutions, thereby further compromising selenium intake. It may be beneficial for metabolic clinicians to consider the selenium status of children with inborn errors of metabolism who are dependent on medical foods for adequate nutritional status. This is especially important for the child who is anorexic and/or gastrostomy-dependent. ACKNOWLEDGEMENT This report was supported by grant MCJ000252, USDHHS Bureau of Maternal and Child Health, and grant (RR-69) from the General Clinical Research Centers Program, NIH, Rockville, MD, USA.
J. Inher. Metab. Dis. 15 (1992)
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267
REFERENCES
Acosta PB, Gropper SS, Clarke-Scheehan N et al (1987) Trace element status of PKU children ingesting an elemental diet. J Parenter Enteral Nutr 11 287-292 Brown MR, Cohen HJ, Lyons JM et al (t986) Proximal muscle weakness and selenium deficiency associated with long-term parenteral nutrition. Am J Clin Nutr 43:549-554 Diptock AT (1987) Trace elements in human health with special reference to selenium Am J CIin Nutr 45:1313-1322 Elsas LJ, Acosta PB (1988) Nutrition support of inherited metabolic diseases. In Shills ME, Young VR eds. Modern Nutrition in Health and Disease. Philadelphia: Lea & Febiger, 13371379 Food and Nutrition Board, National Research Council (1989) Recommended Dietary Allowances, 10th edn. Washington, DC: National Academy Press Greeves LG, Carson DL, Craig BG, McMaster D (1990) Potentially life-threatening cardiac dysrhythmia in a child with selenium deficiency and phenylketonuria. Acta Paediatr Scand 79:1259-1262 Gropper SS, Acosta PB, Clarke-Sheehan N, Wenz E, Koch R (1988) Trace element status of children with PKU and normal children. J Am Diet Assoc 88:459-465 Kien CL, Ganther HE (1983) Manifestations of chronic selenium deficiency in a child receiving total parenteral nutrition. Am J Clin Nutr 37:319-328 Lipson A, Masters H, O'Halloran M, Thompson S, Coveney J, Yu J (1988). The selenium status of children with phenylketonuria: Results of selenium supplementation. Aust Paediatr 24:128-131 Litov RE, Combs GF (1991) Selenium in pediatric nutrition. Pediatrics 87:339-351 Lombeck I, Bremer HJ (1977) Primary and secondary disturbances in trace element metabolism connected with genetic metabolic disorders. Nutr Metab 21:49-64 Lombeck I, Kasperek K, Harbiseh HD et al (1978). The selenium state of children, II. Selenium content of serum, whole blood, hair and the activity of erythrocyte glutathione peroxidase in dietetically treated patients with phenylketonuria and maple syrup urine disease. Eur J Pediatr 128:2t3-223 Lombeck I, Kasperek K, Bachmann D, Feinendegen LE, Bremer HJ (1980). Selenium requirements in patients with inborn errors of amino acid metabolism and selenium deficiency. Eur J Pediatr 134:65-68 Lombeck I, Ebert KH, Kasperek K, Feinendegen LE, Bremer HJ (t984) Selenium intake of infants and young children, healthy children and dietetically treated patients with phenylketonuria. Eur J Pediatr 143:99-102 Mathias PM, Jackson AA (1982) Selenium deficiency in Kwashiokor. Lancet 1:1312-1313 McCarthy TP, Brodie B, Milner JA, Bevill RF (1981) Improved method for selenium determination in biological samples by gas chromatography. J Chromatogr 225:9-16 Milner JA (1990) Trace minerals in the nutrition of children. J Pediatr 117:S147-155 Morris VC, Levander OA (1970) Selenium content of foods. J Nutr 100:1383-1388 Paglia DL, Valentine WN (1967). Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab CIin Med 70:158-169 Pennington JAT, Young BE, Wilson DB, Johnson RD, Vanderveen JE (1986) Mineral content of foods and total diets: The Selected Minerals in Foods Survey, 1982 to 1984. J Am Diet Assoc 86:876-891 Reilly C, Barrett JE, Patterson CM, Tinggi U, Latham SL, Marrinan A (1990) Trace element nutrition status and dietary intake of children with phenylketonuria. Am J Clin Nutr 52: 159-165 Rottoli A, Lista G, Zecchini G, Butte C, Longhi R (1985) Plasma selenium levels in treated phenylketonuric patients. J Inher Metab Dis 8 (suppI 2): 127-128 Smith AM, Picciano MF, Milner JA, Hatch, TF (1988) Influence of feeding regimens on selenium concentrations and gtutathioue peroxidase activities in plasma and erythrocytes. J Trace Elements Exp Med I: 209-216
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Steiner G, Menzel H, Lombeck I, Ohnesorge FK, Bremer HJ (1982) Plasma glutathione peroxidase after selenium supplementation in patients with a reduced selenium state. Eur J Pediatr 138:138-140 Stork LC, Ambruso DR, Wallner SF et al (1986) Pancytopenia in propionic acidemia: Hematologic evaluation and studies of hematopoiesis in vitro. Pediatr Res 20:783-788 Thompson CD, Robinson MF (1980) Selenium in human health and disease with emphasis on those aspects peculiar to New Zealand. Am J Clin Nutr 33:303-323 Vinton NE, Dahlstrom KA, Stobel CT, Ament ME (1987) Macrocytosis and pseudoalbinism: Manifestations of selenium deficiency. J Pediatr 111:711-717 Whanger PD, Butler JA (1988) Effects of various dietary levels of selenium as selenite or selenomethionine on tissue selenium levels and glutathione peroxidase activity in rats. J Nutr 118:846-852
SOCIETY FOR THE STUDY OF INBORN ERRORS OF METABOLISM The SSIEM was founded in 1963 by a small group in the North of England but now has more than 70% of its members outside the UK. The aim of the Society is to promote the exchange of ideas between professional workers in different disciplines who are interested in inherited metabolic disorders. This aim is pursued in scientific meetings and publications. The Society holds an annual symposium concentrating on different topics each year with facilities for poster presentations. There is always a clinical aspect as well as a laboratory component. The meeting is organized so that there is ample time for informal discussion; this feature has allowed the formation of a network of contacts throughout the world. The international and multidisciplinary approach is also reflected in the Journal of Inherited Metabolic Disease. If you are interested in joining the SSIEM then contact the Treasurer: Dr. D. Isherwood, Department of Clinical Biochemistry, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, L12 2AP, UK. The current subscription is £30 per year payable January 1st each year. This subscription includes the 6 issues of the Journal of Inherited Metabolic Disease as well as the regular circulation of a newsletter.
J: lnher. Metab. Dis. 15 (1992)
Decreased Selenium Intake and Low Plasma Selenium Concentrations Leading to Clinical Symptoms in a Child with Propionic Acidaemia S. YANNICELLII, K. M. HAMBIDGE2 and M. F. PICCIANO3 1Department of Pediatrics, Division of Genetics and Inherited Metabolic Diseases Clinic, The Children's Hospital, Box B-153, 1056 East 19th Avenue, Denver, Colorado, USA; aDepartment of Pediatrics, The Children's Hospital, Denver, Colorado, USA; 3pennsylvania State University, Nutrition Department, University Park, Pennsylvania, USA
Summary: A child with biotin-non-responsive propionic acidaemia treated with a propiogenic amino acid-restricted diet presented with an elevated blood mean corpuscular volume (MCV) of 93.1 r, indicative of macrocytosis, and unusual hair texture with hypopigmentation. Plasma selenium concentration at this time was subnormal (45.9/~g/L), and calculated dietary selenium intake was 4.7 #g/day. After 4 months of selenium supplementation (50 pg/day) plasma selenium concentration normalized (97.7/~g/L) in conjunction with a reduced MCV (84.0fl) and a dramatic improvement in hair growth, colour and length. Two additional periods off and on selenium supplementation, of varying time intervals, resulted in similar clinical changes. We conclude that these clinical changes were due to a deficient intake of dietary selenium.
Propionic acidaemia (McKusick 23200) is an inherited defect in the enzyme propionylCoA carboxylase (EC 4.1.1.41). The disorder is manifested by the decreased ability to metabolize propiogenic amino acids (isoleucine, methionine, threonine, valine), the side-chain of cholesterol and odd-chained fatty acids. The cornerstone of treatment involves a propiogenic amino acid-restricted diet utilizing special medical foods with restricted intake of whole protein sources. Decreased intakes and low plasma concentrations of selenium in children with inborn errors of metabolism have been documented previously (Lombeck and Bremer 1977; Acosta et al 1987; Gropper et al 1988). The dependence on chemically defined formulae to meet the majority of these patients' protein requirements may result in inadequate intakes and greater requirements of trace elements (Acosta et al 1987; Gropper et at 1988). Children with phenylketonuria (PKU) and maple syrup urine disease (MSUD) have shown an improvement in their selenium status after selenium supplementation (Lombeck et al 1980; Steiner et al 1982).
MS received 3.6.91 Accepted 9.12.91 261
262
Yannicelti et al.
Selenium, an essential trace element in humans, is necessary for the activity of glutathione peroxidase, the enzyme involved with the degradation of hydrogen peroxide and other organic hydroperoxides. Absence of selenium results in the inactivation of glutathian peroxidase, causing free-radical formation which can damage cell membranes (Brown et aI 1986). Selenium deficiency in humans has been identified in individuals receiving long-term total parenteral nutrition (TPN), and in patients with kwashiorkor, Keshan disease and Kaschin-Beck disease (Mathias and Jackson 1982; Kien and Ganthe'r 1983; Brown et al 1986; Diplock 1987). Deficiency has been associated with cardiomyopathy, muscle pain, arrhythmias and whitening of nail beds (Kien and Ganther 1983; Brown et al 1986). Vinton et al (1987) reported a child receiving long-term TPN who developed erythrocyte macrocytosis, and hair and skin depigmentation as a manifestation of selenium deficiency. This patient responded to intravenous selenium supplementation (2/~g kg- 1 day- 1) with a reversal in hair and skin hypopigmentation, and normalization of MCV. CASE REPORT
The patient (A.P.) is a 5.5-year-old female with propionic acidaemia treated since infancy with a propiogenic amino acid-restricted diet. She has a history of chronic anorexia and is dependent on gastrostomy feedings of special medical foods (OS 1, Protein-Free Diet Powder (Product 80056), Mead Johnson Nutritionals, Evansville, IN, USA) and natural protein sources (Enfamil with Iron®, Mead Johnson Nutritionals) to meet her nutritional requirements. Frequent recurrent illnesses and acidotic episodes resulting in cessation of feedings for short periods of time place the patient at risk of nutrient deficiencies. At 3 years of age, A.P. presented with sparse scalp hair, 0.5 cm in length from crown to mid-occiput with significant distal lengthening to 7.6-10.2cm and darker coloration (Figure 1). Hair was coarse and brittle with a significant degree of hair loss. Plasma selenium concentration at this time was significantly depressed (Table 1). Quantitation of glutathione peroxidase activity was not performed at time of presentation. Intakes of total protein (25.5g/day) and energy (1150kcal/day) were within recommended guidelines for treatment (Elsas and Acosta 1988). Whole protein fraction provided 1.0g kg -1 day -1. Anthropometric measures and biochemical parameters measuring visceral and somatic protein stores were within normal limits. Plasma zinc, copper, iron, cobalamin, and folate were all within the normal range for age. Vitamin E was analysed because of its close relationship with selenium as an antioxidant (Lipson et al 1988). Vitamin E (6 and ~) was not significantly changed throughout the study, and the ratio of plasma vitamin E to total tipid remained within normal limits. A review of A.P?s dietary regimen revealed a very low daily intake of selenium (4.7 ~tg/day), 24% of the age-specific Recommended Dietary Allowance (Food and Nutrition Board 1989). Therefore, selenium deficiency was suspected. The selenium intake was calculated from the nutrient composition of dietary products and special medical foods from the manufacturer's data. The prescribed medical foods were not supplemented with selenium. J. Inher. Metab. Dis. 15 (1992)
Selenium and Propionic Acidaemia
263
Figure 1 Initial presentation, before selenium supplementation Table 1 Plasma selenium, plasma glutathione peroxidase and mean corpuscular volume (MCV) in A.P. prior to and during periods on and off selenium supplementation Period 1
Biochemical parameters Plasma selenium (pg/L) Plasma glutathione peroxidase Total (U/L)" Se-dependent MCV (fl)
At presentation
2
3
45.9
97.7
69.7
190.5
ND
257,7 218.6 84.0
ND
107.7 43.4 86.2
93,1
4
5
On Off On Off On selenium selenium selenium selenium selenium
97.1
57.1
168.8 162.4 92.0
134.33
226.7 165.6 87.4
21 unit is defined as 1#mol of the NADPH oxidized per minute
J. Inher. Metab. Dis, 15 (1992)
264
Yannicelli et al.
METHODS
Selenium supplementation (selenious acid) of 50#g/day (4.5 #g kg-1 day-1) was initiated. Selenious acid was used as the source of selenium because it was the form most readily available. Nutrition support during the entire study was kept constant. Protein (total and whole) and energy intake and medications were adjusted for weight. These changes were very minor throughout the study. Plasma selenium concentrations were determined using a gas chromatograph equipped with an electron-capture detector (Model 5890A, Hewlett Packard) (McCarthy et al t981). All assays included National Bureau of Standards (NBS) bovine liver ( # 1577a) and non-fat bovine milk powder (#1349). Reproducibility and reliability of the plasma selenium analysis was within 5%. An internal control of pooled human plasma was stored with other haemotological samples and analysed with each assay to ensure adequacy of storage methods, which proved acceptable. Selenium-dependent glutathione peroxidase activity was measured in plasma using a modification of the coupled assay described by Paglia and Valentine (1967) with hydrogen peroxide as substrate. Total plasma glutathione peroxidase was measured in plasma samples using the same method with tertiary-butyl hydroperoxide as substrate. RESULTS After 4 months of supplementation, the MCV and plasma selenium were normalized (Table I, period 1) and hair showed a dramatic improvement. Hair became darker in colour and thicker, and assumed normal length and distribution. Coarseness was still evident (Figure 2). To substantiate our initial findings, selenium supplementation was discontinued after parental consent. Within 6 months, sparse hypopigmented hair was apparent and macrocytosis developed. Plasma selenium concentration was subnormal (Table 1, period 2) but not as depleted as at presentation. Additional phases off and on selenium supplementation (periods 3, 4 and 5, Table 1), each approximately 6 months in duration, were implemented, with improvement while on selenium and worsening when off selenium supplementation. Although plasma selenium concentration during each 'off supplementation period never returned to the low concentration found initially, the clinical and biochemical changes were still evident (Table 1, Figure 1). Despite the decreases in plasma selenium, the total and selenium-dependent glutathione peroxidase activities were not significantly altered during each phase of the study. Analysis of celt haemolysis did not reveal increased lysis during a period off selenium supplementation, and no clinical evidence of cardiomyopathy or muscle weakness occurred. DISCUSSION Clinical signs of selenium depletion have not been reported in patients with inborn errors of metabolism, although researchers have found low plasma selenium concentrations in children with PKU and MSUD (Lombeck et al 1978; Rottoli et al J. Inher, Metab. Dis, 15 (1992)
Selenium and Propionic Acidaemia
265
Fignre 2 After the first trial of selenium supplementation 1985; Acosta et al 1987; Gropper et al 1988; Lipson et al 1988; Reilly et al 1990). Greeves and colleagues (1990) suggested a possible role of selenium deficiency in a 9-month-old infant treated for PKU who presented with cardiac dysrhythmia. Several factors that affect trace element status may be responsible for depressed plasma selenium concentrations in these children. These factors include the physical characteristics and chemical composition of the diet, infections and diseases (Milner 1990). Lombeck and colleagues (1984) and Gropper and colleagues (1988) report lower intakes of dietary selenium in children with inborn errors of metabolism compared to normal children. Nine children with PKU had a median intake of 6.9 #g/day in comparison to 33.5klg/day in healthy infants and children (Lombeck et al 1984). A.P.'s daily intake of 4.7 #g selenium was significantly lower than the recommendation of 20 pg/day for 4-6-year-old children (Food and Nutrition Board 1989; Litov and Combs 1991), and is comparable to intakes of children in China with Keshan disease. Children with inborn errors of metabolism consuming special medical foods may have increased requirements for selenium (Acosta et al 1987). This may be due to the chemical composition of the elemental diet. Children with propionic acidaemia are J. Inher. Metab. Dis. 15 (i992)
266
Yannicelli et aI.
usually limited to consuming only simple carbohydrates and restricted quantities of vegetables, fruits and cereals, which are poorer sources of selenium compared to meats, seafood and dairy products (Morris and Levander 1970; Pennington et al 1986). Therefore, the total amount of selenium consumed and the question of selenium bioavailabitity must be considered for children with propionic acidaemia. Selenium deficiency has been described in patients on long-term TPN (Kien and Gunther 1983; Brown et al 1986; Vinton et al 1987) who were receiving no selenium. Vinton et al (I987) improved clinical status in their patient after supplementation of intravenous selenium increased serum selenium from a mean concentration of 38 _+ 11/~g/L to 81 #g/L. The initial value closely correlates with A.P.'s initial plasma selenium concentration of 45.9#g/L Normal plasma selenium for adults ranges between 90 and 165 #g/L (Thompson and Robinson 1980). Human milk-fed infants have mean plasma selenium values of 60-80 pg/L, and formula-fed infants have a mean value of 30-50/~g/L (Smith et al 1988). Thus, A.P.'s initial value was tow owing to a very low intake of selenium. Increases in plasma selenium levels are not always associated with a concurrent rise in glutathione peroxidase activity (Lipson et al 1988). Therefore, the percentage of tissue selenium associated with glutathione peroxidase activity may fluctuate (Whanger and Butler 1988). Plasma selenium concentrations alone are considered the most practical indicator of an individual's selenium status (Litov and Combs 1991). Although A.P.'s glutathione peroxidase activity did not significantly change, decreases in activity have been described in treated children with PKU (Lombeck et al 1978; Steiner et al 1982). Researchers have speculated that depressed selenium stores may not affect an individual's overall health status unless accompanied by other factors such as stress and infection (Diplock 1987). An insult to the body may be the factor that places the selenium-deprived individual over the clinical threshold. Children with propionic acidaemia often suffer intermittent infectious illness with acidosis, and are predisposed to frequent infections (Stork et al t986). During times of intermittent illness with acidosis, infants and children are often removed from their usual diet regimen and placed on either intravenous and/or oral glucose solutions, thereby further compromising selenium intake. It may be beneficial for metabolic clinicians to consider the selenium status of children with inborn errors of metabolism who are dependent on medical foods for adequate nutritional status. This is especially important for the child who is anorexic and/or gastrostomy-dependent. ACKNOWLEDGEMENT This report was supported by grant MCJ000252, USDHHS Bureau of Maternal and Child Health, and grant (RR-69) from the General Clinical Research Centers Program, NIH, Rockville, MD, USA.
J. Inher. Metab. Dis. 15 (1992)
Selenium and Propionic Acidaemia
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REFERENCES
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SOCIETY FOR THE STUDY OF INBORN ERRORS OF METABOLISM The SSIEM was founded in 1963 by a small group in the North of England but now has more than 70% of its members outside the UK. The aim of the Society is to promote the exchange of ideas between professional workers in different disciplines who are interested in inherited metabolic disorders. This aim is pursued in scientific meetings and publications. The Society holds an annual symposium concentrating on different topics each year with facilities for poster presentations. There is always a clinical aspect as well as a laboratory component. The meeting is organized so that there is ample time for informal discussion; this feature has allowed the formation of a network of contacts throughout the world. The international and multidisciplinary approach is also reflected in the Journal of Inherited Metabolic Disease. If you are interested in joining the SSIEM then contact the Treasurer: Dr. D. Isherwood, Department of Clinical Biochemistry, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, L12 2AP, UK. The current subscription is £30 per year payable January 1st each year. This subscription includes the 6 issues of the Journal of Inherited Metabolic Disease as well as the regular circulation of a newsletter.
J: lnher. Metab. Dis. 15 (1992)
