CLINICAL CONFERENCE Cystinosis By Norman Kretchmer, M.D. Department of Pediatrics, New York Hospital-Cornell Medical Center

DR. KRETCHMER: For many years pediatri figure for this laboratory is less than 0.1 gm/ cians have known a group of inherited diseases 12 hr); in a 12-hour specimen, erythrocytes 0; associated with specific biochemical defects. leukocytes 2,200,000 (normal for a female of Actually, these diseases were first compiled and this age), casts 50,000 (25,000 is normal in this demonstrated by Sir Archibald Garrod ap laboratory); the child also had glycosuria and proximately 50 years ago. The case we would the sugar was identified as glucose. like to present, one of cystinosis or cystine Chemical analyses of the blood: Urea-nitro storage disease, is an example of one of the so gen 30 to 45 mg/100 ml; carbon dioxide 22 called inborn errors of metabolism. rnM/l; sodium 138 mEq/l; potassium 2.7 to Patient B.F. was admitted to the New York 3.5 mEq/l; albumin 5.0 and globulin 2.5 gm/ Hospital with a chief complaint of growth re 100 ml; cholesterol 375 mg/100 ml; creatinine tardation. She was the product of a normal, 1.8 mg/100 ml (approximately twice normal); full-term, spontaneous delivery, and developed alkaline phosphatase 4.1 units (normal); cab well until 2 years of age when growth retarda cium 4.8 rnEq/l; and phosphorus 3.2 mEq/l. tion was noted. The urea clearance was 20% of normal for The child has photophobia and has always adults. The clearance of inulin was 12% of demonstrated polyunia. There has been no his normal for adults and the clearance of amino tory of convulsions. The patient has been fol nitrogen was 4 ml/min (normal clearance is bowed by a private physician for the past 2 1 to 2 ml/rnin). As the gbomerular filtration years. rate is one-fifth of the normal, the amino-mtro The members of the family are indicated in gen was cleared at approximately 20 to 30 Figure 1. There were three deaths, the maternal times the normal rate. father who died of diabetes mellitus compli Amino-nitrogen in the blood was 4 mg/100 cated with arteriosclerosis; and two siblings of ml (in our series the mean normal is 2.5 mg). the father, one who died of poliomyelitis and It is interesting that in at least 12 different de the other of pneumonia. terminations the concentration of amino-nitro The father and mother of the present patient gen in the urine ranged from 2 to 19 mg/kg! are living and well, one sibling died last year 24 hr with an average of 11 mg/kg/24 hr at the age of 7 years of cystine storage disease, (normal, 2 to 4 mg/kg/24 hr). and an elder male sibling of 11 years is alive By paper chromatography of the urine a and well. generalized increase in amino acids, except for The physical examination indicated a tern cystine, was demonstrated. In trvptophan load perature of 37.7°C, a pulse of 100, respira tests, no xanthurenic acid was formed. Four tions of 20, and a normal blood pressure. The per cent of a tyrosine load was excreted, patient is 92 cm tall and weighs 13.2 kg, and which is normal. Considering the clearance of is a small, doll-like, pale, co-operative, bright inulin, this child is clearing tyrosine about 5 girl. Also noted were the diminutive stature, to 10 times above normal. haziness of the corneas, photophobia and Together with Dr. Leon Hellman of the polyuria. The neurobogic examination was Sloan-Kettering Institute, tumrnover of plasma physiologic in all respects. protein was measured using C-14, and the half Laboratory examinations were as follows. life was found to be 15 days which is approxi Urine: Specific gravity 1.010 and pH 6.0; mately normal. protein excretion, 0.7 gm/12 hr (the normal Intracellular deposition of crystals resem

This Presentation was part of a Clinical Conference conducted under the Chairmanship of Dr. S. z. Levineat the NewYorkHospital,NewYorkCity, for the AnnualMeetingof theAcademy,October 11, 1956. 962

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bling cystine was found in the bone marrow. a chromosome within the nucleus. This gene Crystalline (leposits were seen in the cornea can act with or without other genes to produce by slit lamp. a protein which may be an enzyme and there (The patient,4@h:tyearsof age,waspre fore act as a catalyst. sented.) In order for the gene to produce a protein The major demonstrable physical feature such as an enzyme, other factors should be was the diminutive stature. considered. Precursor substances must be pres QUESTION:Canone see the crystalsin the ent and whether these precursor substances cornea without a slit lamp? are amino acids or peptides is not known. Dii. KHETCHMEH:Actually the crystals can Extraneous factors such as hormones, nutri l)e seen if the eves are viewed laterally with tion, or poisons may influence the formation an ophthalmoscope. A slit lamp is not required of the enzyme; either to increase or to de for this preliminary examination. crease the concentration or activity. The roentgenograms of the bones of this The enzyme or protein resulting from action child were negative. Should we see them? of the gene can either function in the intra t

t Fic. 1. Family of patient B.F. = cystine storage disease.

= death.

Dii. LEVINE: Do they show anything, Dr. cellular environment or may be dispersed in Baker? the blood stream in a form such as hemo Da. BAKER: Very minimal osteoporosis. globin, or any of the various proteins known Later on they will probably show the usual to be in the blood. These proteins are all related rachitic changes found in these patients. The to and are derived from action of the genes. roentgenograms are normal now. Normally, the enzyme would act on a sub Dii. LEvINE: What are these “¿usual―rachitic stance A (substrate) to convert it to a new changes? substance B (product). The resultant substance Dii. BAKEII: Typical rickets—swollen, cupped B can be metabolically'important or it may metaphyses amid a generalized loss of calcium be merely an inactive end product, an cx from the tubular bones. cretory product of metabolism. Now, one can DR. K1IETCHMER: We have presented a little postulate a situation wherein the gene does not girl who has a pronounced, inherited, bio act to produce the enzyme or where various chemical defect, the pathogenesis of which is environmental factors prevent the production unknown. Probably, a better understanding of of the enzyme. Thus, minimal amounts of this disease can be obtained if we discuss the product B result from A, and large amounts of mechanisms operating at the cellular level. A accumulate because a partial block exists. The gene or hereditary unit, is located on Substance A may be toxic to the individual as

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it accumulates, or new excretory products may Cystinosis, according to the prevalent con form from A. cept, results from a block in the most impor The development of the enzyme is important tant type of metabolism of amino acids, the in this mechanism, and we and others have incorporation of an amino acid into a protein. actually shown that enzymes do develop as the Cystinunia results from a block in the specific individual matures. In the premature infant, transfer of such amino acids as cvstine, lvsine, during the initial stages of formation of the and arginine. On the other hand, there is a enzyme p-h@droxyphenylpyruvate oxidase, sub block in the generalized transfer of all amino stance A or p-hydrox@phenybpyruvate accumu acids in hepatolenticular degeneration, or Wil lates and is excreted in the urine. son's disease. In this disease excretion of all In Figure 2 a few disorders associated with of the amino acids is increased in the urine. incomplete metabolism of amino acids are The problem with which we are concerned indicated. A similar chant could be constructed today is cystinosis. It is presuimed from the for the metabolism of lipids or carbohydrates. data which have so far been collected that the An amino acid can follow a variety of path primary block in metabolism is a block in pro ways to form final end products. The ultimate tein synthesis. Therefore, a group of definitive ______AMINOACID______

@ @1f .Cyst;nosis TUBULAR TRANSFER - Phenylpyruvic Ohgophrenia . (?)

Cystin- 4I @Ienticular urla \degeneration :Alcaptonuria Specific Transfer AMINO ACID ‘¿If PROTEIN

Generalized Transfer Co2 + H20+ NH2

Ftc. 2. Some disorders associated with incomplete metabolism of amino acids.

end products for an amino acid are carbon di clinical manifestations and chemical findings oxide, water and free amino groups; the latter are encountered in this child : There are cystine may be excreted in the form of urea. deposits in the reticuboendotheliab s@stem amid Another well-known metabolic pathway of in the cornea. These are associate(l with renal amino acids is synthesis into protein. A third insufficiency, h@perphosphaturia, hypokalemia pathway for amino acids such as the essential and a variety of other characteristics which are amino acids, is conversion to other amino acids. either directly due to the disease or result from Finally, in the total economy of the organism, the malignant character of the disease. the amino acids are reabsorbed from the The problem of the terminology in this dis glomerular filtrate back into the total organism ease has concerned many people; the disease via the renal tubule. has been known as the Fanconi syndrome, the Depending on the genes affected, we can Lignac-Fanconi syndrome, the Debré-DeToni expect different disorders to occur in the vari Fanconi syndrome. Probably the most correct ous pathways. An example of a deficiency in name, which is ignored, is the Abdenhalden the conversion of one amino acid to another Kaufman-Lignac syndrome. exists in phenylpyruvic oligophrenia. A de In cystine storage disease, it is not known ficiency in the complete catabolism of an amino whether the cystine deposits are actually the acid is prominent in alkaptonuria. result of the group of clinical findings or

Downloaded from www.aappublications.org/news by guest on October 1, 2021 AMERICAN ACADEMY OF PEDIATRICS —¿PROCEEDINGS 965 whether cvstine deposition produces the mani DR. KRETCHMER: This is a completely dif festations. Cystine is well known to be one of ferent disease from Lightwood's syndrome. the most insoluble of the amino acids and, These patients do not show nephrocalcinosis. therefore, it would have a tendency to precipi In fact, very often at necropsy of children who tate when present in high concentration. die early, the kidneys are completely normal; There are many workers who believe that deposition of stones or calcium is not seen as this disease is primanil@' a renal disease. This one would in idiopathic renal acidosis. conclusion is somewhat supported b@ the work QUESTION:Whatis the mechanismof the of Darmady. He showed that these children glycosuria? have a constriction of the neck of the proximal DR. KRETCHMER: That is a very difficult tubule. However, the physiologic importance question. The exact mechanism for glucose of this morphologic finding is vague. transport is unknown. It has been presumed The prognosis is poor for this child, and the through the @earsthat glucose is transported umsual cause of death in these children is renal through the aegis of phosphorylation, i.e., insufficienc@', of which rather severe ph@sio phosphate is bound to a glucose, and the glu logic evidence is present. cose then is able to enter the cell. This theory Present therapy in these disorders consists is slowly gaining disrepute. The question of of removal of the offending substrate. The the mechanism of the glycosuria can only be eventual treatment of these disorders of in answered indefinitely by indicating that there complete metabolism must, in general, be de is undoubtedly' a defect in the transport of rived from discovery of an alternate metabolic glucose in the renal tubule. pathway so that substances which accumulate QUESTION:Howare you treatingthis child? can be handled by other enzymes. As predicted DR. KRETCHMER: We are treating this child b@' Dr. Paumbing of the California Institute of primarily with potassium for the hypokalemia, Technology, treatment could also be accom and also with vitamins. This patient, in con plished by the replacement of the absent or trast to other children with cvstine storage defective enzyme or by inducing the individual disease, does not have the usual acidosis. to develop the enzyme normally. Therefore, we do not have to use alkalinizing QUESTION:Istheconcentrationofchobessolutions. She also does not have excessive terol usually elevated in the blood in this con phosphaturia, so that phosphate does not have dition? to he replaced. Dii. KRETCHMEII: It has been reported to Dn. LEvINE: Do you want to say anything be elevated in this condition. about the death of her brother? QUESTION:Istherean@'specialsignificance DR. KRETCHMER: The sibling of the patient to that? died of severe renal insufficiency and hyper Du. KRETCHMEH: So far no one has attached tension with congestive heart failure. At nec ami\' particular significance to the hypercholes ropsy his kidneys were small; histologically' terolemia, l)uit it has been found in at least 50% they showed hyalinized glomeruli and no of these patients. crystals were present. The kidneys did not QUESTION:Whatismeantbyturnoverofpro have the appearance of glomerubonephritis. tein? Crystals were found in the spleen, lymph Dn. KRETCHMER: The turnover of protein nodes, bone marrow and Kupfer cells. Dr. Jean in the plasma is an approximation referring to Oliver is dissecting the tubules in order to the average rate of the anabobism and catabo visualize any constriction in the neck of the bism of plasma proteins. This rate is usually proximal loop. given as the time required for half of the QUESTION:Wehave seen a family in which proteins to be built up and broken down. one child died very early, and a second died The proteins in this child are “¿turningover― within the first week of life, and a third de within 15 days. We thought that this might veboped a picture like the patient presented give information as to whether there was an here. There are two box's in this family, both anabolic or catabolic defect in cystine storage of whom are entirely normal. The three who disease. died were girls. QUESTION: At necropsy do these children DR. KRETCHMER: There is no indication of show nephrocalcinosis? sex linkage. This condition is apparently in

Downloaded from www.aappublications.org/news by guest on October 1, 2021 966 KRETCHMER —¿CYSTINOSIS herited through a recessive autosomal gene, in DR. KRETCHMER: No. These patients do not contrast to the Fanconi syndrome in the adult, have a peculiar odor, such as the musty odor where inheritance is probably through a domi observed in children with phenylpyruvic nant gene. There is no indication of sex bink oligophrenia. age, so far as I know. In the present family a QUESTION:What is the longestsurvival? boy and a girl were afflicted. DR. KRETCHMER: The most recent report QUESTION:Is it possibleto prepare a diet was a compilation of 14 cases by Bickel, and deficient in cystine, and would such a diet be the oldest child included was 10 years. The compatible with life? little boy, sibling of the present patient, was DR. KRETCHMER: That is a question that just past his seventh birthday. comes up quite often, especially in view of the QUESTION:The reasonI asked the question results obtained with a diet low in phenybala is because of a boy of about 12 years who nine in phenylpyruvic ohigophrenia. In answer was considered to be a diabetic, and at to the question, I think that a diet bow in necropsy we found a cystine-appearing ma cystine would not be completely compatible terial in the tubules of the kidneys and decal with life and growth. In addition, cysteine, cification of the bones. We wondered whether homocystine and methionine would have to this was an extremely rare example of cysti be removed from the diet of these children; nosis. at least one of these must be available to per This boy was not small for his age, but I mit life and protein synthesis. One would have was told that this was a characteristic case of to presume that cystine is the basic cause of DeToni-Fanconi's disease. all the difficulty, if treatment with a diet low DR. KRETCHMER: The terminology has in cystine was to be justified. created much confusion and apparently there QUESTION:Is thereany relationshipbetween was considerable discussion of it at the recent cvstinosis and cvstinunia, genetically? International Congress of Pediatrics. Cystine DR. KRETCHMER: No. Cystinuria also re storage disease should be designated the Ab suits from the action of a recessive gene, and derhalden-Kaufman-Lignac syndrome. The that is the reason it is included in Figure 2. Debré-DeToni-Fanconi syndrome is different; Cvstinuria is a disease of amino acid transfer the prominent signs are gbucosuria, amino in the renal tubules involving the transport of acidunia and rickets, but there are no deposits cystine, lysine, arginine, and ornithine. How of cystine crystals. ever, there is no genetic relationship between DR. LEvINE: Thus these are two different cystinuria and cystine storage disease. conditions which may' or may not be related, QtmsTIoN: Do these youngsters have a pe but they certainly present different clinical culiar odor to their bodies? pictures.

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