American Journal of Medical Genetics 2:225-232 (1978)
Autosomal Dominant Fanconi Syndrome With Early Renal Failure Aaron L. Friedman, Carl W. Trygstad, and Russell W. Chesney Departments o f Pediatrics, University of Wisconsin Center for Health Sciences and Medical School, Madison (A.L. F., R. W. C.l;and Harbor General Hospital, Torrance, California (C.W. T.)
The “idiopathic” Fanconi syndrome occurs mostly sporadically, occasionally a s an iutosomal recessive trait. However, few instanccs o f autosomal dominant inheritance have been reported. We described a father and son with the Fanconi syndrome, ie, with renal glycosuria, generalized aminoaciduria, phosphaturia, metabolic acidosis, and bone disease. No other causes of the Fanconi syndrome were found. Bol h father and son developed end stage renal disease. Arninoaciduria in excess of that seen in renal insufficiency is shown by comparison with published data for amino acid excretion in uremia. Renal transplantation in the father has improved kidney function with no evidence of Fanconi syndrome. This family is unique in that there are no other reports of autosomal dominant Fanconi syndrome with progression to early renal failure. Key words: autosomal dominant, Fanconi syndrome, end stage renal failure
INTRODUCTION
The c’ombination of renal glycosuria, generalized aminoaciduria, phosphaturia, and osteomalacia defines the Fanconi syndrome [ 1 ] . Other findings include hypouricemia, hypokalemia, and hyperchloremic metabolic acidosis [ 11 . This syndrome m a y accompany a number of conditions of which cystinosis is the most common. In a small number of cases no ;ause can be found. These cases are said to have the “adult Fanconi syndrome”, coi-rectly termed the “idiopathic Fanconi syndrome ,” since children may also be affected. Fanconi syndrome occurs sporadically or as an autosomal recessive trait, but dominant transmission has been found in a few cases. We report a father and son with the idiopathic Fanconi syndrome, ie, with bone disease, excess urinary phosphate excretion, renal glucosuria, and aminoaciduria. Father and son developed early renal failure necessitating dialysis and transplantation in the father. Renal disease was present in other members of the father’s family, suggesting an autosomal dominant mode of transmission. licceived for publication January 5 , 1978; revision received April 20, 1978. Address reprint requests to Aaron L. Friedman, MD, School, 1300 Univ Ave, Madison, WI 53706.
Dept of Pediatrics, Univ of Wisconsin Medical
0148/7299/78/0203-0225$01.70 @ 1978 Alan R. Liss, h e
226
Friedman, Trygstad, and Chesney
CASE REPORTS Case 1
T.O., a male born in 1962 after an apparently normal pregnancy and delivery, was well until day 7 when persistent vomiting occurred after feeding. On day 19 he developed jerking movements on the left side of his body and was hospitalized. Results of serum chemical determinations included a BUN of 138 mg/dl, Na 142 mEq/L, C195 mEq/L, C02 23 mEq/L, K 7.1 mEq/L, Ca 6.9 mg/dl, PO4 15 mg/dl. His urine output was consistently 500-700 ml/day. After diet changes his BUN fell to 23 mg/dl, creatinine 2.0 mg/dl, Na 134 mEq/L, C1 100 mEq/L, K 2.0 mEq/L, PO4 4.8 mg/dl, and Ca 8.1 mg/dl. Sodium chloride and potassium acetate were added to his diet to overcome volume depletion and acidosis, resulting in improvement in serum potassium to 4.5 mEq/L, and C02 to 18.5 mEq/L. Seven hospitalizations were required in the first year of life because of vomiting and acidosis. In February 1965, T.O. was hospitalized because of poor growth and metabolic acidosis with serum chemical values of C02 14 mEq/L, C1 100 mEq/L, Na 144 mEq/L, and K 5.2 mEq/L. His serum phosphorus was 3.7 mg/dl and his tubular reabsorption of phosphate was 84%. His urine output ranged from 2 to 3 liters per day. He had 4' glucosuria and proteinuria (1.5 p / 2 4 hrs). Radiologic findings included metaphyseal fraying, coarse trabeculation, and marked demineralization. Further analysis of his urine showed generalized aminoaciduria (Table I). He was treated with sodium and potassium citrate, 50,000 units of vitamin D, and calcium gluconate.
TABLE I. Arninoaciduria - Excretion as Percent of Filtered Loads* ~
~~
Amino acid
Case I
Taurine Hydroxyproline Threonine Glutamine Proline Glycine Alanine Valine Methionine Isoleucine Leucine Tyrosine Phenylalanine Lysine Histidine Arginine
37 50 48 43 21 78 21 16.5 16 6 10 35 19.5
... ... ...
Case 2 18
... 99 61 36 76 52 43.5 68 44 65 148 92 53 99 14
Normalsa
< 12 < 3 < 5 < 12 < 3 < 25 < 5
< < < < < <
3L/day < 3%
...
2.8 mg/dl
14.4 mg/dl
> 3L/day
5.4 mg/dl
> 3L/day
...
generalized 9.3 mg/dl
100 mEq/L marked
4+ generalized 3.1 mg/dl 84.5% 14 mEq/L 5.3 mEq/L
2 Yr
13.5 mEq/L 4.3 mEq/L 8.2 mg/dl 103 mEq/L some improvement
1+
21 yr
7.5 p / 2 4 hr generalized 8.3 mg/dl 30% 23.5 mEq/L 4.1 mEq/L 6.8 mg/dl 101 mEq/L marked
22 yr
Case 2
TABLE 11. Evidence for Presence of the Fanconi Svndrome
3%
> 3L/day
3.8 mg/dl
13.5 mEq/L 3.5 mEq/L 4.9 mg/dl 109 mEq/L marked
...
1+-2+ generalized 6.2 mg/dl
8 yr
Case I
> 3L/day < 3%
7.7 mg/dl 115 mEq/L some improvement [PTH-660 ~ L E q / m l ] 6.5 mg/dl
up to 34 gm/24 hr generalized 3.0 mg/dl 5 0% 18 mEq/L 3.4 mEq/L
13 yr
5
a
0
w
h)
Autosomal Dominant Fanconi Syndrome
231
Recently, Smith et a1 [lo] reported a family with hypophosphotemia, renal glycosuria, proteinuria, generalized aminoaciduria, and bone disease possibly associated with diabetes mellitus. Symptoms developed during young adulthood, and in no case was there severe renal impairment. Ben Ishay et a1 [ 111 studied a woman with the Fanconi syndrome and relatives in three generations with generalized aminoaciduria; they emphasized a known finding in the Fanconi syndrome, hypouricemia. Early, severe kidney disease was not present. The kidney impairment we note may explain the lack of significant hypouricemia in our two patients. The familial tubulopathies reported by Illig and Prader [ 121 ,and Doolan et al [ 131 , involve a Fanconi-like syndrome; in both reports the patients had siblings with renal tubular abnormalities, but other generations were not involved. Niemann et a1 [ 141 reported four siblings with the idiopathic Fanconi syndrome; one of these developed glomerular insufficiency and died of uremia. Their mother had glycosuria and trace albuminuria. The authors postulated X-linked inheritance in this case. Burke et al [ 151 reported a family with nephrotic syndrome, nephrocalcinosis, and tubular dysfunction. That family was mainfested early in life with nephrotic syndrome, a condition not seen in our family. Two other findings reported by Burke and not seen in our cases are nephrocalcinosis and severe glomerular involvement on kidney biopsy. The variability in phenotypic expression in this family raises the question of whether we are dealing with more than one disorder. The Fanconi syndrome is a rare condition and the likelihood that the Fanconi syndrome and a second independent form of renal disease exist in the same family is very small. It is also possible for an autosomal dominant trait to exhibit a phenotypic spectrum ranging from severe (Case I), to intermediate (Case 2), to mild (other relatives) involvement. The finding of 14 apparently normal offspring and 10 apparently normal grandchildren from 3 affected family members (11-7, 11-8, and 11-10) is disturbing but may represent reduced penetrance or variable expressivity with some affected individuals not yet demonstrating disease. The aminoaciduria in our patients may be due to a decreased glomerular filtration rate. The aminoaciduria of uremia is probably related to elevated parathyroid hormone [ 151. In Case 2 elevated parathyroid hormone may have been present despite parathyroidectomy at the time amino acids were measured. However, by using published data for amino acid excretion in severe uremia [6], and comparing thesedata t o the amino acid excretion seen in Case 2, it is clear that a urinary amino acid leak existed in Case 2 far in excess of that expected on the basis of hyperparathyroidism alone (Fig 2). Table I and Figure 2 show excretion rates for certain amino acids at greater than 100% of the fdtered load. This finding suggests the secretion of amino acids, a phenomenon previously described by Scriver et al [ 161 . In conclusion, we think that the family we report represents a previously undescribed entity of dominantly inherited Fanconi syndrome with early renal failure.
ACKNOWLEDGMENTS
We acknowledge Dr Thomas Steele, Dr Weldon Shelp, and Dr Richard Rieselbach for performing many of the clearance studies in Case 2. The late Dr Harry A. Waisman carried out many of the early amino acid studies. We thank Dr John M. Opitz for advice and Ms Kathy Chenoweth-Corby for expert secretarial assistance. Supported in part by NIH grant AM19489.
232
F r i e d m a n , Trygstad, a n d Chesney
REFERENCES 1. Leaf A : The syndrome of osteomalacia, renal glycosuria, aminoaciduria, and increased phosphorus clearance (The Fanconi syndrome). In Stanbury JB, Wyngaarden JB, Frederickson DS (eds): “The Metabolic Basis of Inherited Disease.’’ New York: McGraw-Hill, (2):1205-1229, 1966. 2. Spackman DH, Stein WH, Moore S : Automatic recording apparatus for use in the chromatography of amino acids. Anal Chem 30:1190-1206, 1958. 3. Roe JH, Epstein JH, Goldstein NP: A photometric method for the determination of inulin in plasma and urine. J Biol Chem 178:839, 1949. 4. Arnaud CD, Tsao HS, Littledike T: Radioimmunoassay of human parathyroid hormone in serum. J Clin Invest 50:21-34, 197 1. 5. Soriano JF: Renal tubular reabsorption. In Barnett HH (ed):“Pediatrics.” New York: AppletonCentury Crofts (15):1315, 1972. 6. Gulyassy PF, Aviram A, Peters JH: Evaluation of amino acid and protein requirements in chronic uremia. Arch Intern Med 126:855-859, 1970. 7. Hunt DD, Stearns G, McKinley JB, Froning E, Hicks P, Bonfiglio M: Long term study of family with Fanconi syndrome without cystinosis (DeToni-Debre-Fanconi Syndrome). Am J Med 40: 492-510,1966. 8. Luder J, Sheldon WA: A familial tubular absorption defect of glucose and amino acids. Arch Dis Child 30:160-164, 1955. 9. Sheldon W, Luder J, Webb B : A familial tubular absorption defect of glucose and amino acids. Arch DisChild 36:90-95, 1961. 10. Smith R, Lindenbaum RH, Walton RJ: Hypophosphataemic osteomalacia and Fanconi syndrome of adult onset and dominant inheritance. Quart J Med 179:387-400, 1976. 11. Ben-Ishay D, Dreyfuss F, Ullmann TD: Fanconi syndrome with hypouricemia in an adult. Am J Med 311793-800,1961. 12. Illig von R, Prader A: Primare Tubulopathien. 11. Ein Fall von idiopathischem gluko-aminophosphat-Diabetes (DeToni-DebrePanconi Syndrom). Helvet Paediatr Acta 16:622-646, 1961. 13. Doolan PD, Morris MD, Harper HA: Aminoaciduria in an elderly man with the nephrotic syndrome and in a young man with a variant of the Fanconi syndrome. Ann Int Med 56:448-456, 1962. 14. Neimann N, Pierson M, Marchal C, Ranker G, Gregnou G: Nephrophatie familiale glomerulotubulaire avec syndrome d e DeToni-Debre-Fanconi. Arch Franc Pediatr 25 :43 -69, 1968. 15. Burke EC, Holley KE, Stickler GB: Familial nephrotic syndrome with nephrocalcenosis and tubular dysfunction. J Ped 82:202-206, 1973. 16. Scriver CR: Rickets and the pathogenesis of impaired tubular transport of phosphate and other solutes. Am J Med 57:43-49, 1974. 17. Scriver CR, Chesney RW, McInnes RR: Genetic aspects of renal tubular transport: diversity and topology of carriers. Kidney Int 9:149-171, 1976. 18. Scriver CR, Rosenberg LE: Distribution of amino acids in body fluids. “Amino Acid Metabolism and Its Disorders.” Philadelphia: WB Saunders (1):39-60, 1973.
Edited by John M. Opitz
Autosomal Dominant Fanconi Syndrome With Early Renal Failure Aaron L. Friedman, Carl W. Trygstad, and Russell W. Chesney Departments o f Pediatrics, University of Wisconsin Center for Health Sciences and Medical School, Madison (A.L. F., R. W. C.l;and Harbor General Hospital, Torrance, California (C.W. T.)
The “idiopathic” Fanconi syndrome occurs mostly sporadically, occasionally a s an iutosomal recessive trait. However, few instanccs o f autosomal dominant inheritance have been reported. We described a father and son with the Fanconi syndrome, ie, with renal glycosuria, generalized aminoaciduria, phosphaturia, metabolic acidosis, and bone disease. No other causes of the Fanconi syndrome were found. Bol h father and son developed end stage renal disease. Arninoaciduria in excess of that seen in renal insufficiency is shown by comparison with published data for amino acid excretion in uremia. Renal transplantation in the father has improved kidney function with no evidence of Fanconi syndrome. This family is unique in that there are no other reports of autosomal dominant Fanconi syndrome with progression to early renal failure. Key words: autosomal dominant, Fanconi syndrome, end stage renal failure
INTRODUCTION
The c’ombination of renal glycosuria, generalized aminoaciduria, phosphaturia, and osteomalacia defines the Fanconi syndrome [ 1 ] . Other findings include hypouricemia, hypokalemia, and hyperchloremic metabolic acidosis [ 11 . This syndrome m a y accompany a number of conditions of which cystinosis is the most common. In a small number of cases no ;ause can be found. These cases are said to have the “adult Fanconi syndrome”, coi-rectly termed the “idiopathic Fanconi syndrome ,” since children may also be affected. Fanconi syndrome occurs sporadically or as an autosomal recessive trait, but dominant transmission has been found in a few cases. We report a father and son with the idiopathic Fanconi syndrome, ie, with bone disease, excess urinary phosphate excretion, renal glucosuria, and aminoaciduria. Father and son developed early renal failure necessitating dialysis and transplantation in the father. Renal disease was present in other members of the father’s family, suggesting an autosomal dominant mode of transmission. licceived for publication January 5 , 1978; revision received April 20, 1978. Address reprint requests to Aaron L. Friedman, MD, School, 1300 Univ Ave, Madison, WI 53706.
Dept of Pediatrics, Univ of Wisconsin Medical
0148/7299/78/0203-0225$01.70 @ 1978 Alan R. Liss, h e
226
Friedman, Trygstad, and Chesney
CASE REPORTS Case 1
T.O., a male born in 1962 after an apparently normal pregnancy and delivery, was well until day 7 when persistent vomiting occurred after feeding. On day 19 he developed jerking movements on the left side of his body and was hospitalized. Results of serum chemical determinations included a BUN of 138 mg/dl, Na 142 mEq/L, C195 mEq/L, C02 23 mEq/L, K 7.1 mEq/L, Ca 6.9 mg/dl, PO4 15 mg/dl. His urine output was consistently 500-700 ml/day. After diet changes his BUN fell to 23 mg/dl, creatinine 2.0 mg/dl, Na 134 mEq/L, C1 100 mEq/L, K 2.0 mEq/L, PO4 4.8 mg/dl, and Ca 8.1 mg/dl. Sodium chloride and potassium acetate were added to his diet to overcome volume depletion and acidosis, resulting in improvement in serum potassium to 4.5 mEq/L, and C02 to 18.5 mEq/L. Seven hospitalizations were required in the first year of life because of vomiting and acidosis. In February 1965, T.O. was hospitalized because of poor growth and metabolic acidosis with serum chemical values of C02 14 mEq/L, C1 100 mEq/L, Na 144 mEq/L, and K 5.2 mEq/L. His serum phosphorus was 3.7 mg/dl and his tubular reabsorption of phosphate was 84%. His urine output ranged from 2 to 3 liters per day. He had 4' glucosuria and proteinuria (1.5 p / 2 4 hrs). Radiologic findings included metaphyseal fraying, coarse trabeculation, and marked demineralization. Further analysis of his urine showed generalized aminoaciduria (Table I). He was treated with sodium and potassium citrate, 50,000 units of vitamin D, and calcium gluconate.
TABLE I. Arninoaciduria - Excretion as Percent of Filtered Loads* ~
~~
Amino acid
Case I
Taurine Hydroxyproline Threonine Glutamine Proline Glycine Alanine Valine Methionine Isoleucine Leucine Tyrosine Phenylalanine Lysine Histidine Arginine
37 50 48 43 21 78 21 16.5 16 6 10 35 19.5
... ... ...
Case 2 18
... 99 61 36 76 52 43.5 68 44 65 148 92 53 99 14
Normalsa
< 12 < 3 < 5 < 12 < 3 < 25 < 5
< < < < < <
3L/day < 3%
...
2.8 mg/dl
14.4 mg/dl
> 3L/day
5.4 mg/dl
> 3L/day
...
generalized 9.3 mg/dl
100 mEq/L marked
4+ generalized 3.1 mg/dl 84.5% 14 mEq/L 5.3 mEq/L
2 Yr
13.5 mEq/L 4.3 mEq/L 8.2 mg/dl 103 mEq/L some improvement
1+
21 yr
7.5 p / 2 4 hr generalized 8.3 mg/dl 30% 23.5 mEq/L 4.1 mEq/L 6.8 mg/dl 101 mEq/L marked
22 yr
Case 2
TABLE 11. Evidence for Presence of the Fanconi Svndrome
3%
> 3L/day
3.8 mg/dl
13.5 mEq/L 3.5 mEq/L 4.9 mg/dl 109 mEq/L marked
...
1+-2+ generalized 6.2 mg/dl
8 yr
Case I
> 3L/day < 3%
7.7 mg/dl 115 mEq/L some improvement [PTH-660 ~ L E q / m l ] 6.5 mg/dl
up to 34 gm/24 hr generalized 3.0 mg/dl 5 0% 18 mEq/L 3.4 mEq/L
13 yr
5
a
0
w
h)
Autosomal Dominant Fanconi Syndrome
231
Recently, Smith et a1 [lo] reported a family with hypophosphotemia, renal glycosuria, proteinuria, generalized aminoaciduria, and bone disease possibly associated with diabetes mellitus. Symptoms developed during young adulthood, and in no case was there severe renal impairment. Ben Ishay et a1 [ 111 studied a woman with the Fanconi syndrome and relatives in three generations with generalized aminoaciduria; they emphasized a known finding in the Fanconi syndrome, hypouricemia. Early, severe kidney disease was not present. The kidney impairment we note may explain the lack of significant hypouricemia in our two patients. The familial tubulopathies reported by Illig and Prader [ 121 ,and Doolan et al [ 131 , involve a Fanconi-like syndrome; in both reports the patients had siblings with renal tubular abnormalities, but other generations were not involved. Niemann et a1 [ 141 reported four siblings with the idiopathic Fanconi syndrome; one of these developed glomerular insufficiency and died of uremia. Their mother had glycosuria and trace albuminuria. The authors postulated X-linked inheritance in this case. Burke et al [ 151 reported a family with nephrotic syndrome, nephrocalcinosis, and tubular dysfunction. That family was mainfested early in life with nephrotic syndrome, a condition not seen in our family. Two other findings reported by Burke and not seen in our cases are nephrocalcinosis and severe glomerular involvement on kidney biopsy. The variability in phenotypic expression in this family raises the question of whether we are dealing with more than one disorder. The Fanconi syndrome is a rare condition and the likelihood that the Fanconi syndrome and a second independent form of renal disease exist in the same family is very small. It is also possible for an autosomal dominant trait to exhibit a phenotypic spectrum ranging from severe (Case I), to intermediate (Case 2), to mild (other relatives) involvement. The finding of 14 apparently normal offspring and 10 apparently normal grandchildren from 3 affected family members (11-7, 11-8, and 11-10) is disturbing but may represent reduced penetrance or variable expressivity with some affected individuals not yet demonstrating disease. The aminoaciduria in our patients may be due to a decreased glomerular filtration rate. The aminoaciduria of uremia is probably related to elevated parathyroid hormone [ 151. In Case 2 elevated parathyroid hormone may have been present despite parathyroidectomy at the time amino acids were measured. However, by using published data for amino acid excretion in severe uremia [6], and comparing thesedata t o the amino acid excretion seen in Case 2, it is clear that a urinary amino acid leak existed in Case 2 far in excess of that expected on the basis of hyperparathyroidism alone (Fig 2). Table I and Figure 2 show excretion rates for certain amino acids at greater than 100% of the fdtered load. This finding suggests the secretion of amino acids, a phenomenon previously described by Scriver et al [ 161 . In conclusion, we think that the family we report represents a previously undescribed entity of dominantly inherited Fanconi syndrome with early renal failure.
ACKNOWLEDGMENTS
We acknowledge Dr Thomas Steele, Dr Weldon Shelp, and Dr Richard Rieselbach for performing many of the clearance studies in Case 2. The late Dr Harry A. Waisman carried out many of the early amino acid studies. We thank Dr John M. Opitz for advice and Ms Kathy Chenoweth-Corby for expert secretarial assistance. Supported in part by NIH grant AM19489.
232
F r i e d m a n , Trygstad, a n d Chesney
REFERENCES 1. Leaf A : The syndrome of osteomalacia, renal glycosuria, aminoaciduria, and increased phosphorus clearance (The Fanconi syndrome). In Stanbury JB, Wyngaarden JB, Frederickson DS (eds): “The Metabolic Basis of Inherited Disease.’’ New York: McGraw-Hill, (2):1205-1229, 1966. 2. Spackman DH, Stein WH, Moore S : Automatic recording apparatus for use in the chromatography of amino acids. Anal Chem 30:1190-1206, 1958. 3. Roe JH, Epstein JH, Goldstein NP: A photometric method for the determination of inulin in plasma and urine. J Biol Chem 178:839, 1949. 4. Arnaud CD, Tsao HS, Littledike T: Radioimmunoassay of human parathyroid hormone in serum. J Clin Invest 50:21-34, 197 1. 5. Soriano JF: Renal tubular reabsorption. In Barnett HH (ed):“Pediatrics.” New York: AppletonCentury Crofts (15):1315, 1972. 6. Gulyassy PF, Aviram A, Peters JH: Evaluation of amino acid and protein requirements in chronic uremia. Arch Intern Med 126:855-859, 1970. 7. Hunt DD, Stearns G, McKinley JB, Froning E, Hicks P, Bonfiglio M: Long term study of family with Fanconi syndrome without cystinosis (DeToni-Debre-Fanconi Syndrome). Am J Med 40: 492-510,1966. 8. Luder J, Sheldon WA: A familial tubular absorption defect of glucose and amino acids. Arch Dis Child 30:160-164, 1955. 9. Sheldon W, Luder J, Webb B : A familial tubular absorption defect of glucose and amino acids. Arch DisChild 36:90-95, 1961. 10. Smith R, Lindenbaum RH, Walton RJ: Hypophosphataemic osteomalacia and Fanconi syndrome of adult onset and dominant inheritance. Quart J Med 179:387-400, 1976. 11. Ben-Ishay D, Dreyfuss F, Ullmann TD: Fanconi syndrome with hypouricemia in an adult. Am J Med 311793-800,1961. 12. Illig von R, Prader A: Primare Tubulopathien. 11. Ein Fall von idiopathischem gluko-aminophosphat-Diabetes (DeToni-DebrePanconi Syndrom). Helvet Paediatr Acta 16:622-646, 1961. 13. Doolan PD, Morris MD, Harper HA: Aminoaciduria in an elderly man with the nephrotic syndrome and in a young man with a variant of the Fanconi syndrome. Ann Int Med 56:448-456, 1962. 14. Neimann N, Pierson M, Marchal C, Ranker G, Gregnou G: Nephrophatie familiale glomerulotubulaire avec syndrome d e DeToni-Debre-Fanconi. Arch Franc Pediatr 25 :43 -69, 1968. 15. Burke EC, Holley KE, Stickler GB: Familial nephrotic syndrome with nephrocalcenosis and tubular dysfunction. J Ped 82:202-206, 1973. 16. Scriver CR: Rickets and the pathogenesis of impaired tubular transport of phosphate and other solutes. Am J Med 57:43-49, 1974. 17. Scriver CR, Chesney RW, McInnes RR: Genetic aspects of renal tubular transport: diversity and topology of carriers. Kidney Int 9:149-171, 1976. 18. Scriver CR, Rosenberg LE: Distribution of amino acids in body fluids. “Amino Acid Metabolism and Its Disorders.” Philadelphia: WB Saunders (1):39-60, 1973.
Edited by John M. Opitz
