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Home , Aminoaciduria, Cystinosis, Cystinuria, Fanconi syndrome, Hartnup disease, Iminoglycinuria

ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 11, No. 3 Copyright © 1981, Institute for Clinical Science, Inc.

Inherited Disorders of Transport in Relation to the BRUCE A. BUEHLER, M.D.

Department of , University of Utah, Salt Lake City, UT 84132 and Utah State Training School, American Fork, UT 84003

ABSTRACT was first described in 1810. Since the initial description, a group of renal cellular transport deficit has been characterized. The study of genetic diseases that create a specific has expanded our knowledge of cellular structure, cellular transport, and intracellular concen­ tration gradients. A review of the theories and experimental data obtained through investigations of the renal aminoacidurias are presented.

Introduction wall with a “fluid motion.” Experiments In 1810, Wollaston15 noted urinary have partially confirmed this concept by stones in patients with renal that showing that some proteins are loosely appeared to be “flat hexagonal plates.” bonded to the external portion of the cell This initial description of cystinuria has wall (extrinsic proteins) while another led investigators to a partial understand­ group of proteins are integral to the cell ing of cellular amino acid transport mech­ wall (intrinsic proteins), requiring deter­ anisms and the discovery of other amino gent digestion of the membrane prior to acid transport disease. In order to under­ isolation.12 If this model is correct, it is stand better the observations of 170 years, likely that the intrinsic proteins are the it is useful to review the present theories sites of active amino acid transport against of structure, protein car­ an intracellular concentration gradient. rier moieties, and in Whatever the structure of the cell wall, biologic systems. experimental data strongly suggest that Singer and Nicolson13 are responsible amino acids enter the cell by active trans­ for our current models of cell membrane port. The concentration of amino acids in structure. They postulated that the cell extracellular fluid is lower than the intra­ membrane is a lipid bilayer with the hy­ cellular concentration. A simple passive drophilic end of the lipid molecule diffusion of amino acids across the cell oriented toward the extracellular space, membrane alone cannot explain the con­ and the hydrophobic end buried in the centration gradients. Our present under­ middle of the bilayer. They also en­ standing of sodium and potassium con­ visioned a protein moiety fitting through centrations in cells involves the presence the cell wall, interacting with the charged of an energy requiring “pump” to estab­ lipid molecules, and moving in the cell lish this gradient and the same process is 274 0091-7370/81/0500-0274 $00.90 © Institute for Clinical Science, Inc. INHERITED DISORDERS OF AMINO ACID TRANSPORT 275 required to explain amino acid movement TABLE I across the cell wall. This postulation is Amino Acid Transport supported by data which have shown the necessity for sodium ions to be available I ii IV Neutral Dibasic B-Amj.no during influx of amino acids into the cell Taurine cytoplasm.1 The exact energy source and Serine B-alanine Threonine B-isobutyric productive pathways have not yet been Cystine V identified. Xsoleucine III Acid Confirmation of cell membrane struc­ Imino Glutamic Aspartic ture and active transport mechanisms re­ mains to be accomplished, but the pres­ Asparagine ence of “carriers” for amino acid entrance in the cell is a well documented concept. “Permease,” “translocase,” and “pene­ trase” are some of the designations applied to amino acid carrier proteins, but the iso­ from the amino acid carriers. It has been lation and structural analysis of these demonstrated in patients with Hartnup’s moieties have eluded investigators. Proof disease (discussed later in this paper) that of their existence has come from indirect there is cellular loss of the influx carrier investigations using excess quantities of a for neutral amino acids but the same single amino acid with concommitant sat­ amino acids contained in dipeptides or uration of a specific carrier. When satura­ tripeptides are able to cross the cell mem­ tion occurs, there is a failure of cells to brane and enter the cell.5 This mecha­ absorb specific amino acids which share nism of oligopeptide transport prevents the same pathway. total intracellular depletion of single In table I are indicated the five amino amino acids in the absence of their acid specific transport pathways that have “carrier.” been demonstrated in vivo and in vitro. The concept of an energy requiring car­ These “carriers” were first elucidated in rier protein in the cell wall that is specific the control of influx of amino acids into for a group of amino acids explains the gastrointestinal and renal cells. Since observed aminoaciduria and poor gastro­ then the same “carriers” have been shown intestinal absorption encountered in cys- to operate for influx of amino acids into the tinuria. This concept is also useful in extracellular milieu.9 Therefore, satura­ explaining the complicated genetic pedi­ tion of a specific amino acid carrier can gree data which have emerged over the prevent absorption of extracellular amino past 170 years of observation. There are acids or prevent egress of intracellular patients who have large quantities of cys­ amino acids. tine in their and each patient’s kid­ Unfortunately, the presence of five ney biopsy shows impaired cystine up­ specific amino acid carriers does not ex­ take by renal cells. The parents of these plain all of the diseases characterized by children have approximately 50 percent of aminoaciduria. Some diseases only occur the normal ability to absorb cystine in in renal cells or gastrointestinal epi­ renal . This would appear to be a thelium while leukocytes may show no classical single , single loci, au­ abnormalities of transport.4 Possibly other tosomal recessive form of carrier protein systems exist in different cell lines or production with absence of activity in the there may be different gene repressor homozygote and 50 percent loss in the mechanisms within each system; obligate heterozygote. experimental data have not yet clarified this Regrettably, there are other patients discrepancy. It also appears that there is a who have slightly increased amounts of carrier for oligopeptides which is separate cystine in their urine, but have severe loss 276 BUEHLER of cystine uptake by gastrointestinal to infants. The newborn spills imino mucosal cells. These patients appear to acids, glycine, and the dibasic amino acids have an abnormal gene at a different site presumably owing to immaturity of carrier than the classical homozygote. The levels mechanisms. As much as 10 to 15 percent of urinary cystine are approximately one- of the filtered amino acid load is lost in the half the levels found in the classic urine until the kidney matures at three homozygote, while the levels of cystine months postpartum.9 A brief general de­ uptake at the may be scription of the separate aminoacidurias is one-half normal or virtually absent de­ useful in clarifying the concepts of amino pending on the patient. This suggests that acid transport discussed previously. some patients are heterozygotes at the gene locus for production of renal cell car­ Cystinuria rier protein and heterozygous or homozygous at a separate gene locus for The laboratory criteria for cystinuria are the production of the gastrointestinal cell increased quantities of cystine, lysine, ar­ carrier. Rosenberg has suggested that ginine, and ornithine in the urine. A sim­ these patients can be considered “double ple test for urinary cystine is the reaction heterozygotes” for the disease as com­ of cyanide-nitroprusside which gives a pared to the classic homozygote.7 This dark red color. The clinical features are hypothesis works well in explaining the cystine stones in the renal collecting sys­ three forms of cystinuria encountered tem, renal colic with , and pos­ clinically and also applies to the other de­ sibly renal insufficiency owing to stone scribed diseases of amino acid transport. formation. Intestinal absorption of lysine, Until there is isolation of the protein car­ arginine, cystine, and ornithine is de­ rier moiety, this explanation must remain creased. Stone formation appears to be hypothetical but its application is useful due to excess cystine in the urine while for purposes of genetic counselling. the other three amino acids do not cause clinical sequelae. Inheritance appears to Based on the previous observations and be autosomal recessive, occurring postulations, it is possible to identify a 1:16,000 live births. Treatment is to pre­ group of inherited aminoacidurias that vent stone formation by alkalinizing the can be considered abnormalities of amino urine or giving D- to bind acid cellular transport. These diseases are excess cystine. Surgical removal of the characterized by decreased cellular up­ renal calculi may be necessary. Finally, take of a group of amino acids or a single elevation of cystine in the urine, amino acid by the proximal tubular cells of the glomerular apparatus. Since absorp­ heterozygous or homozygous concen­ tion is decreased, the specific amino acids trations, appears to warrant therapy to cannot be returned to the blood by the prevent renal calculi formation. renal cells and these moieties are lost in the urine. In the normal individual, the Hypercystinuria kidney resorbs 93 to 100 percent of the This disease differs because lysine, ar­ amino acids filtered by the . In ginine, and ornithine are not elevated in the disorders of transport, only 50 percent the urine; only increased urinary cystine of certain amino acids are resorbed and is noted. There is limited clinical informa­ the other 50 percent are lost in the urine. tion available, but treatment of excess The amount of amino acid absorption by cystine excretion would appear to be ad­ gastrointestinal cells varies in these pa­ visable.2 The patients described in this tients, apparently dependent on a sepa­ pedigree also had hypocalcemia which rate gene loci. may have influenced cystine excretion. It must be noted that the values for kid­ This disease raises the speculation that ney resorption of amino acids do not apply cystine may have a separate carrier differ­ INHERITED DISORDERS OF AMINO ACID TRANSPORT 277 ent from the carrier involved in classic nithine without cystine, and normal cystinuria. serum amino acids. The clinical symptoms include , Hartnup’s Disease hepatomegaly, mental retardation, hyper­ ammonemia, and . Another The laboratory criteria for Hartnup’s phenotype without gastrointestinal disease are increased excretion of the symptoms has been described, and the pa­ neutral amino acids without dibasic tients have been asymptomatic.11 Treat­ amino acids or imino acids. The same ex­ ment in patients with gastrointestinal cess neutral amino acids are found in the symptoms include protein restriction and stool. The serum amino acids are meas­ arginine supplementation. Prognosis is ured as normal in spite of impaired intes­ good with treatment. The genetics of both tinal absorption. The excess of tryptophan types appears to be autosomal recessive in the stool creates excess bacterial caused with an unknown risk. tryptophan derivatives (indolacetyl glutamine and indoxyl sulfate) which are Dicarboxylic Aminoaciduria excreted in the urine. The clinical symptoms can mimic with skin Only two patients have been de­ photosensitivity, mild retardation and/or scribed.14 One patient was asymptomatic; psychiatric disorders, but the patients the other had mental retardation and may be asymptomatic. The disease occurs hypoglycemia. The laboratory criteria are in 1:16,000 live births. Treatment con­ increased glutamic and in sists of added nicotinic acid, a metabolite the urine. Owing to the limited number of of tryptophan, to prevent the pellagra-like cases, no conclusion can be derived. symptoms. The overall prognosis is excellent. Histidinuria

Iminoglycinuria (Joseph’s Syndrome) Two cases of mentally retarded males with elevated urinary histidine and nor­ The laboratory criteria for iminogly­ mal serum histidine have been de­ cinuria10 are increased urinary proline, scribed.8 Possibly a separate histidine car­ hydroxyproline, and glycine with normal rier deficiency is the cause. serum levels after six months of age. Prior to six months, all newborns exhibit these Lysenuria findings presumably due to immature car­ rier mechanisms. No clinical sequelae A single case is known with elevated have been noted. This disease is of inter­ urinary lysine only and decreased intesti­ est to the geneticist because some patients nal absorption. No conclusions can be have impaired gastrointestinal absorption drawn until further cases are found.6 and others are normal. It also appears that the renal heterozygote may excrete only TABLE II glycine and, in one pedigree by de Vries,3 the heterozygotes were mistakenly la­ Specific Aminoacidurias belled as a new syndrome called hyper- Hartnup's disease Neutral amino acids glycenuria. The incidence of homozy­ Cystinuria Cystine, lysine, gotes is approximately 1:20,000. No arginine, ornithine Dibasicaminoaciduria Lysine, ornithine, treatment is necessary. arginine Proline, glycine, hydroxyproline Dibasic Aminoaciduria Glucoglycinuria Glycine Hypercystinuria Cystine Histinuria Histidine The laboratory criteria are excretion of Lysinuria Lysine excess urinary lysine, arginine, and or­ 278 BUEHLER

TABLE III References

Generalized Aminoaciduria 1. B o n d y , P. K. and ROSENBERG, L. E.: Metabolic Control and Disease. Philadelphia, W. B. Saun­ ders Co., 1980, pp. 620-621. Environmental 2. B r o d e h l , J., G ellissen, K., and Kow- Heavy metals ^ ALEWSKO, S.: Isolated cystinuria in a family Chemicals: Nitrobenzene, lysoí&v aspirin, malic acid, expired with hypocalcemic tetany. Proceedings of the Vitamin B ^ ' C, D, deficiency Third International Congress on , Kwashiorkor Washington, 1966. 3. de Vries, A., Kochwa, S., L a z e b n ik , J., Hyperparathyroidism F r a n k , M., and D jaldetti, M.: Glycinuria, a hereditary disorder associated with nephro­ lithiasis. Amer. J. Med. 23:408-415, 1957. Genetic 4. G r o t h , U. and Rosenberg, L. E.: Transport of dibasic amino acids, cystine, and tryptophan by Hereditary fructose intolerance cultured fibroblasts: Absence of a defect Wilson's disease in cystinuria and . J. Clin. In­ Glycogen storage diseases vest. 51:2130-2142, 1972. Renal tubular 5. N av ab , F. and ASATOOR, A. M.: Studies on in­ Lowe's syndrome testinal absorption of amino acids and a dipep­ Idiopathic Fanconi's syndrome tide in a case of Hartnup disease. Gut 11:373- Busby syndrome 397, 1970. Luder-Sheldon syndrome 6. Omura, K., Yamanaka, N., Higami, S., M at- sauka, O., Fujimoto, A., Issik i, G., and T a d a , K.: Lysine syndrome: A new type of transport defect. Pediatrics 57:102-105, 1976. 7. ROSENBERG, L. E.: Cystinuria: Genetic hetero­ A summary of renal amino acid trans­ geneity and allelism. Science 154:1341-1343, port diseases is shown in table II. 1966. 8. S a b a te r , J., F e r r e , C., Puliol, M., and M ayo, A.: Histidinuria: Adrenal and intestinal his­ Generalized Aminoaciduria tidine transport deficiency found in two men­ tally retarded children. Clin. Genet. 9:117-124, A summary of the generalized amino­ 1976. acidurias is shown in table III. These dis­ 9. S c r iv e r , C. R. and BERGERON, M.: Amino acid eases do not fall under the description of transport in kidney. The use of to dis­ sect membrane and transepithelial transport. genetic absence or decrease in specific Heritable Disorders of Amino Acid Metabo­ amino acid carriers in the renal cell with lism. Nyham, W. L., ed. New York, John Wiley resultant specific aminoaciduria. Some and Sons, 1974, pp. 515-592. 10. S c r iv e r , C. R. and W ils o n , O. H.: Amino acid process, specific or idopathic, causes a transport: Evidence for genetic control of two generalized decrease in the absorption of types in human kidney. Science 155:1428- all amino acids by the glomerular ap­ 1430, 1967. 11. S im el, O., Perheentupa, J., R a p o la , J., Vis- paratus. These diseases have not been AKORPI, J., and E s k e lin , L.-E.: Lysinuric pro­ considered in this paper. tein intolerance. Amer. J. Med. 59:229-240, 1975. 12. SINGER, S. J.: Architecture and topography of Summary biologic membranes. Cell Membranes, Biochemistry, Cell Biology and Pathology. Transport of amino acids across the cell Weissman, G. and Claiborne, R., eds. New membrane is a specific process which ap­ York, Hospital Practice Press, 1975, pp. 35-44. 13. Singer, S. J. and N icolson, G. L.: The fluid pears to be mediated by several geneti­ mosiac model of the structure of cell mem­ cally determined carrier moieties. Gene­ branes. Science 175:720-731, 1972. tic modification or decreased production 14. S y n d e rm a n , S. E.: The amino acid require­ ments of the infant. Metabolic Control and Dis­ creates a group of diseases known as the ease. Bondy, P. K. and Rosenberg, L. E., eds. aminoacidurias. The investigation of Philadelphia, W. B. Saunders Co., 1980, pp. amino acid transport diseases may lead us 641-651. 15. W ollaston, W. H.: On cystic oxide, a new to a better understanding of renal and species of urinary calculus. Phil. Trans. Roy. gastrointestinal absorption mechanisms. Soc. 100:223-230, 1810.