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Clinical

and Metabolic

Abnormalities

in a Boy

with

Dietary

Deficiency

of Biotin

Lawrence Sweetman, PhD, Linda Surh, Herman Baker, PhD,

Raymond M. Peterson, MD, and William L. Nyhan, MD, PhD

From the Department of Pediatrics, University of California, San Diego, La Jolla; The

Regional Center for the Mentally Retarded, San Diego, California; and College of

Medicine and Dentistry of New Jersey, East Orange

ABSTRACT. Dietary deficiency ofbiotin was documented in an 1 1-year-old retarded boy as a consequence of a dietary prescription containing raw eggs. Clinical

mani-festations were alopecia totalis and an erythematous, exfoliative dermatosis. Metabolic characteristics included increased excretion of3-methylcrotonylglycine,

3-hydrox-yisovaleric acid, 3-hydroxypropionic acid, methylcitric

acid, and lactic acid, as well as a propensity for the development of ketosis. The activities of propionyl coen-zyme A carboxylase and 3-methyicrotonyl coenzyme A carboxylase in extracts of leukocytes were deficient. Treatment with biotin and the removal of raw eggs, which contain the biotin-binding protein, avidin, from the diet led to the reversal of all of the clinical and metabolic

manifestations observed. Pediatrics 68:553-558, 1981; biotin deficiency, carboxylases, organic aciduria.

Biotin is an essential component of human nutri-tion that is required for the function of a number of carboxylase enzymes. 3-Methylcrotonyl-coenzyme

A (CoA) carboxylase (EC 6.4.1.4) is essential for the catabolism of leucine, propionyl-CoA carboxylase (EC 6.4.1.3) is essential for the catabolism of isoleu-cine, threonine, valine, and methionine, and pyruvic

acid carboxylase (EC 6.4.1.1) is concerned with

gluconeogensis and the regulation of carbohydrate metabolism. Consequently a deficiency of biotin would be expected to have widespread metabolic effects. In fact experience with heritable abnormal-ities in this system, known now as multiple

carbox-ylase deficiency, is of overwhelming illness often

fatal in early life (references 1 to 5; L. Sweetman et al, unpublished data, 1978). These patients can be successfully treated with 10 mg or more of biotin

Received for publication Aug 12, 1980; accepted Jan 14, 1981. Reprint requests to (L.S.) Department of Pediatrics, M-009, University of California, San Diego, La Jolla, CA 92093.

PEDIATRICS (ISSN 0031 4005). Copyright © 1981 by the

American Academy of Pediatrics.

daily. Fortunately, biotin is widely abundant in

foods and is produced as well by intestinal bacteria so that its deficiency is rare.

Symptomatic deficiency of biotin is difficult to produce in experimental animals and has been seen in man only under specialized circumstances. Avi-din, a protein present in raw egg white, binds biotin so effectively that it is not absorbed from the intes-tine and the quantity is more than sufficient to bind all of the biotin in the egg yolks.6

It is the purpose of this report to describe an 11-year-old boy with clinical deficiency of biotin in-duced by the daily ingestion of raw eggs. Biotin

deficiency in a child has been described only once

previously, in a brief report.7 We found that its metabolic consequences, not previously described, were similar to those observed in multiple carbox-ylase deficiency.3’5’8

CASE REPORT

I.R. was an 1 1-year-old mentally retarded boy who was

referred because of the development of alopecia totalis

and a generalized erythematous, scaly eruption most prominent on the face. He was the 4 lb 11 oz, 17/4 in product of an eight-month pregnancy of a 29-year-old mother. There was no parental consanguinity. Slow de-velopment was apparent by 6 months of age. He sat at age 3 years and walked at age 6 years. He had no speech, and his IQ was estimated at 30. He was difficult to feed and grew poorly.

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#{149}1”

0

b 4

Physical examination revealed a retarded white boy

with a striking bright red eruption that gave his face a masklike appearance (Fig 1). There was complete alope-cia. He had no eyebrows, eyelashes, or lanugo hair on his head. The skin in the involved areas was thickened and

scaling or crusted. On the face there were fissures in the rash, but there was no weeping. The rash extended over

the auricles and into the canals of the ears. A relation to minor trauma was evident in an area of eruption at the neck where a soft T-shirt rubbed the skin. There was an ulcerated area over a contact point with a shoe. In general, extensor surfaces were involved, as well as the hands and

feet. He also had a thick, red, apparently tender, tongue. He appeared to be about the size of a 5-year-old, with height 43 uui, weight 20 kg, and head circumference 48.5 cm, all below 2 SD from the mean. The testes were undescended bilaterally. Deep tendon reflexes were brisk. The hemoglobin level was 16.7 gm/100 ml and hema-tocrit (Hct) 48%. The concentration of cholesterol was

175 mg/100 ml. Electrolyte concentrations were normal,

as were glucose, lactate, and pyruvate concentrations. A thorough evaluation of the diet following the discov-ery of the organic aciduria revealed that a nutritional supplement, which contained 26 oz of full-strength Simi-lac, 1 to 2 oz of Wesson oil, and two raw eggs, had been prescribed by a dietitian approximately five years previ-ously. This had gradually become his total caloric intake, and he ingested approximately 32 oz/day. He also drank

some water.

METHODS

Nonvolatile organic acids in urine were analyzed qualitatively and quantitatively by liquid partition chromatography followed by gas chromatography and analyzed qualitatively by gas chromatography-mass spectrometry as described previously.9 Con-centrations of amino acids were determined

quan-Fig 1. Appearance of patient before treatment with

bio-tin, illustrating alopecia and dermatosis.

titatively using ion exchange chromatography.’#{176}

Concentrations of biotin were determined in a

bioassay employing Ochromonas

Leukocytes were isolated from heparinized pe-ripheral blood by centrifugation for ten minutes at 450

x

g, collection of the buffy coat, lysis of eryth-rocytes by treating with 2 ml of 0.75% NH4C1 in 0.05

M tris(hydroxymethyl)aminomethane (Tris) HC1,

pH 7.6, for five minutes at room temperature and

centrifuging for ten minutes at 450 x g, repeating this lysis step, then washing the leukocyte pellet by

suspending in 0.9% NaC1 0.02 M Tris HC1 pH 8.2

and centrifuging for five minutes at 450 x g. The

leukocytes were lysed by freezing and thawing fol-lowed by the addition of 0.1 ml of 1% Triton

X-100.

After suspension, the mixture was centrifuged for five minutes at 450 x g, and 20 .d of the supernatant fluid was assayed for the carboxylases as reported by Gravel et al,’2 with either 2.5 mM propionyl-CoA or 3-methylcrotonyl-CoA as substrate.

RESULTS

The pattern of excretion of organic acids

(mea-sured in micromoles per milligram of creatinine) in the urine after an oral dose of leucine (100 mg/kg) is as follows: 3-hydroxybutyric acid, 245.9; 3-meth-ylcrotonylglycine, 0.095; methylcitric acid, 0.123; 3-hydroxyisovaleric acid, 7.67; lactic acid, 6.38; 2-hy-droxybutyric acid, 0.380. In addition to the 12-hour collection obtained in the Clinical Research Center,

two other samples, which had been collected ten

days and 43 days previously, were analyzed. The

significantly elevated excretions of 3-methylcroto-nylglycine and 3-hydroxyisovaleric acid suggested a deficiency of 3-methylcrotonyl-CoA carboxylase. The elevated excretions of 3-hydroxypropionic acid and methylcitric acid suggested a deficiency of

pro-pionyl-CoA carboxylase. Both enzymes require

bio-tin and the metabolic evidence for deficiencies in their activities suggested either a metabolic defect of biotin metabolism or a dietary deficiency of

bio-tin. The former appeared unlikely because of the

normal organic acid levels in the urine from three

years previously. The latter was consistent with the discovery of the unusual diet which contained raw eggs.

At the time of the two urine collections shortly

before admission, the patient had no ketonuria. On

admission he had acute otitis media and a staphy-lococcal infection, a temperature of 39.4 C and a

leukocyte count of 30,000/cu mm. He was ketotic;

concomitant with the elevated excretion of

3-hy-droxybutyric acid, excretion of citric acid and

3-methylcrotonylglycine was decreased. Although the

excretion of methylcitric acid is often decreased

(3)

did not occur in this instance. In contrast the excre-tion of 3-hydroxypropionic acid and that of lactic acid were highest in the sample containing a large amount of 3-hydroxybutyric acid.

Following the administration of an oral load of L-leucine there was a massive increase in the excre-tion of 3-hydroxybutyrate in the first 12 hours. There was concomitant reduction in the excretion of 3-methyicrotonyiglycine and of methylcitric acid, but the excretion of 3-hydroxyisovalenc acid and lactic acid increased. 2-Hydroxybutyrate appeared in the urine. Following the administration of 100 mg/kg of L-isoleucine there was a similar increase in the excretion of 3-hydroxybutyric acid to 250.2

tmo1e/mg of creatinine, and 0.824 tmole/mg of

creatinine of 2-hydroxybutyric acid was found in

the urine. The excretion of 3-methylcrotonylglycine

and 3-hydroxyisovaleric acid, as well as that of citric and methylcitric acids decreased, but the excretion

of 3-hydroxypropionic acid and lactic acid

in-creased.

The concentrations of amino acids in the blood were within normal limits before biotin treatment was initiated. However, the concentrations of gly-cine and alanine at 2.1 and 2.3 mg/100 ml, respec-tively, were probably relatively high as compared with quite low levels of most of the amino acids. For instance the concentrations of phenylalanine, serine, and lysine were 0.59, 0.93, and 1.14 mg/100 ml, respectively. These observations would be con-sistent with a protein-deficient diet, along with al-tered metabolism of pyruvic acid and the dimin-ished cleavage of glycine seen in disorders of organic acid metabolism.

Base line studies were conducted while the pa-tient was receiving a diet identical with that he had

received at home. Following their completion the

diet was changed, in that the eggs were cooked. In addition the child was given 1 mg of biotin each day. This was given intravenously during the first two days in the hospital, and orally thereafter. Within two days of the initiation of therapy, the excretion of all of the organic acids had returned to

normal except that of 3-hydroxyisovaleric acid, and

that had returned to normal by six days of therapy (Table 1).

The concomitant clinical change was dramatic. The skin of the face and other areas of dermatosis

began to improve within two days and the

improve-ment was progressive. There was hair growth within two weeks, and within a month he had an apprecia-ble crop of hair. The diet was adjusted appropri-ately for age, even though the patient continued to

refuse anything but a liquid formulation. His skin

and hair have remained normal over a

1#{189}-year-period of observation.

The activity of propionyl-CoA carboxylase in the

patient was 1.5 pmole/min/mg ofprotein (2% of the

normal value of 86), and the activity of

3-methyl-crotonyl-CoA carboxylase was 0.8 pmole/min/mg

of protein (normal 7.7). Incubation of the blood of the patient with biotin, 0.4 mg/mI, for 2.5 hours led to a 2.6-fold increase in the activity of

propionyl-CoA carboxylase in the leukocytes. This enzyme

from a control individual increased only 0.3-fold under the same conditions. This suggests that in-active propionyl-CoA carboxylase was converted to

active holopropionyl-CoA carboxylase in the

leu-kocytes of the patient when incubated with biotin.

The course of activity of propionyl-CoA

carbox-ylase on treatment with biotin and removal of avi-din from the diet is shown in Fig 2. Treatment was

begun on day 2 in hospital, and the increase in

activity was linear after day 4. Activity was normal by day 8. By this time the activity was 81 pmoles/

min/mg of protein (normal 74 to 101).

Data on the activity of propionyl-CoA and

3-methylcrotonyl-CoA carboxylases in extracts of

cul-tured fibroblasts are shown in Table 2. The values for each were normal. In contrast are the data for a patient with multiple carboxylase deficiency in

whom the defect appears to be in the activity of

holocarboxylase synthetase.’3

The concentrations of biotin in the plasma are shown in Table 3. The value obtained in the patient was approximately half of the lowest value obtained in three control subjects. It was also substantially below the normal range of 200 to 500 pg/mI

gener-TABLE 1. Excretion of Orga nic Acids (jt mol/mg of Cr eatinine) i n Urine 3-Methyl- crotonyl-glycine 3-Hydroxy-isovaleric Acid Lactic Acid 3-Hydroxy-propionic Acid Methyl-citric Acid 3-Hydroxy-butyric Acid Citric + Isocitric Acid

3 years earlier 43 days earlier 10 days earlier Admission

1 mg of biotin/day 36-48 hr 1 mg of biotin/day 6 days 1 mg of biotin/day 38 days

<0.01 0.301 1.633 0.117 <0.01 <0.01 <0.01 0.860 7.201 6.523 4.315 2.216 0.112 0.150 2.594 0.679 0.832 2.336 0.853 0.866 2.888 <0.01 0.292 0.115 0.535 <0.01 <0.01 0.092 <0.01 0.329 0.491 0.353 <0.01 <0.01 <0.01 21.10 1.62 0.062 19.37 11.59 0.211 113.24 4.03 4.47 4.34 1.04 1.48 1.96 2.88

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8

U

0

.2

0’

.0

.; C

0 0

ci.

Fig 2. Activity of propionyl-CoA carboxylase in mixed leukocyte extracts and response to treatment with biotin and elimination of avidin by cooking eggs in diet. Normal propionyl-CoA carboxylase activity is 7 to 9 pmole/min/ ml of blood.

2 4

DAYS

6 8

TABLE 2. Carboxylase Activities in Fibroblasts

Media Propionyl- 3-Methyl- No. of

Biotin CoA crotonyl- Assays

(big/liter) (nmole/hr/ CoA mg protein) (nmole/hr/

mg protein)

Patient 5

55

43.8 41.6

18.8 16.0

4

4

Normal subject* 5

55

37.3 ± 6.2 43.4 ± 7.8

16.6 ± 1.9 16.5 ± 2.5

Holocarboxylase synthetase deficiency 5

55

0.08 20.0

0.01 2.8

3 3

* Values are means ± SDfor fibroblasts from three normal individuals; each was assayed

three to five times.

ally given for unselected populations. Furthermore,

a sample of plasma obtained from the patient 2#{189} years earlier was analyzed and found to contain 542

pg/mi. The deficiency of biotin in the patient was

shown even more clearly in the data on the urine. The value obtained in the patient was approxi-mately 40 times less than the control mean. Fur-thermore, analysis of a sample of urine obtained

from the patient three years previously revealed

13.7 ng/mg of creatimne, a normal value. In this study lower values were obtained in the urine of a series of six newborn infants in whom the mean was

17.8 and the range 4.3 to 29.4 ng/mg of creatinine.

Following treatment with biotin the values obtained in the patient were very high. The concentrations

in the plasma ranged from 738 to 6,860 pg/mi and

that of the urine from 523 to 1,862 ng/mg of

creat-inine. Thus, it is apparent that even 1 mg/day is a

pharmacologic dose.

DISCUSSION

The most obvious clinical manifestations of a

deficiency of biotin are the effects on the skin and hair. In our patient the eruption of the face was grotesquely impressive; it was a brilliant red, thick-ened, scaly, and fissured. It was associated with alopecia totalis and glossitis. A fine, scaly dermatitis

and alopecia that rendered him almost bald was

also observed in the only other child in whom

deficiency of biotin has been reported.7 A desqua-mating dermatosis was also described in four adult

human volunteers in whom biotin deficiency was

induced by the feeding of egg white.4 These individ-uals also developed glossitis, anorexia, nausea, and an active distaste for the diet. Behavioral

manifes-tations observed included depression,

hallucina-tions, somnolence, and a panic state. In a 62-year-old cirrhotic woman in whom biotin deficiency was inadvertently produced by a physician’s

prescrip-tion of a diet containing six raw eggs and 2 qt of

skim milk daily, the skin was dry and scaly.’5 More

TABLE 3. Carboxylase Activities in Fibroblasts

Media

Biotin (pg/liter)

Propionyl-CoA

(nmole/hr/mg protein)

3-Methylcro-tonyl-CoA (nmole/hr/mg

No. of

Assays

protein)

Patient 5

55

43.8 41.6

18.8 16.0

4 4

Normal subject 5

55

32.6 70.0

9.4 20.0

5 2

Holocarboxylase synthetase 5 0.08 0.01 3

(5)

prominent symptoms were a sore, reddened tongue, red oral mucosa, and fissured lips. Her anorexia was such that she stopped eating other foods but con-tinued to take the prescribed mixture.

A scaling, red dermatitis has also been character-istically observed in infants with multiple

carbox-ylase deficiency,13’5 an inborn error of metabolism in which the activities of the biotin-requiring car-boxylases for 3-methylcrotonyl-CoA,

propionyl-CoA, and pyruvic acid are all deficient.’’8 Varying degrees of alopecia, including alopecia totalis, have been observed in these infants. Two general pat-terns of disease have been delineated, an early infantile form in which generalized cutaneous erup-tion has been associated with acute overwhelming, often lethal acidotic illness (references 1, 5, and 8;

L. Sweetman et al, unpublished data, 1978). Among

these patients the skin lesions have been described as resembling ichthyosis or seborrheic dermatitis. Patients with a later infantile form had a pattern of skin eruption that has been diagnosed as acroder-matitis enteropathica.33”T In these patients the

der-matosis disappears with therapy with 10 mg of

biotin/day or more. It is of interest that our patient

with biotin deficiency had earlier been given a

diagnosis of acrodermatitis enteropathica by a

der-matologist; an extended period of treatment with zinc was without benefit.

Hypercholesterolemia was observed in a 5-year-old boy with biotin deficiency reported by Scott7; the boy had been tube-fed a mixture containing six raw eggs daily while ill with bulbospinal poliomy-elitis. Hypercholesterolemia was also reported in

the four volunteers studied by Sydenstricker et al.’4 The serum concentration of cholesterol was normal in our patient and in the cirrhotic woman reported by Baugh et al.’5 These differences probably rep-resent dietary differences in the various mixtures

consumed, but the hypercholesterolemia could be

reversed by treatment with biotin and removal of

egg white, without changes in the diet.7

The metabolic response to a deficiency of biotin is represented in our patient by the abnormal pat-tern of excretion of organic acids. It was this that led us to the diagnosis. The sequence of events was such that the pattern of excretion ofurinary organic acids suggested deficient activity of biotin-requiring

enzymes. A short time later this was documented

in leukocytes, but in our study, inasmuch as this pattern can also result from dietary deficiency, ex-ploration of the diet was undertaken and uncovered the extraordinary diet our patient was receiving.

This led to the protocol of further study and to

successful therapy.

Defective catabolism of leucine was indicated by

the excretion of 3-methylcrotonylglycine and

3-hy-droxyisovaleric acid. The excretion of the latter was

considerably greater than that of any of the other specific metabolites. Excretion of 3-hydroxyisova-leric acid in the urine has also been reported in rats made deficient in biotin by feeding a diet high in

avidin.’9 Defective catabolism of isoleucine and

va-line was indicated by the excretion of

3-hydroxy-propiomc acid and 3-methylcitric acid. Defective

metabolism of pyruvic acid, as represented in the

excretion of lactic acid, was the least prominent. In

fact, it was within normal limits, except in the

presence of ketosis and large amounts of 3-hydrox-ybutyric acid in the urine, reflecting the variety of metabolic pathways open to accumulating pyruvic acid.

The most prominent effect ofloading with leucine or isoleucine in the presence of deficiency of biotin was the induction of massive ketosis and the excre-tion of massive amounts of 3-hydroxybutyric acid. The effects of ketosis in decreasing the excretion of citric acid, methylcitric acid, and 3-methylcroto-nylglycine is of more general interest. These

obser-vations could have relevance to the diagnosis of

inborn errors of the metabolism of propionate or

multiple carboxylase deficiency which may mani-fest itself with massive ketosis, particularly at times of infection. Thus the nature of the diagnosis may be obscured at just the time it is most important to make it. The excretion of 3-hydroxyisovaleric acid is a more reliable and constant indicator of disor-dered metabolism of leucine, but of course it will not distinguish a defect in 3-methylcrotonyl-CoA

carboxylase, which should respond to biotin, from isovaleric acidemia, which will not. The excretion of 2-hydroxybutyric acid appeared clearly to be a consequence of the excretion of large amounts of 3-hydroxybutyric acid or events leading to its genesis.

2-Hydroxybutyric aciduria has been observed in

propionic acidemia under conditions that

accom-pany elevated concentrations oflactic acid (S. Wad-man, personal communication, 1979).

The deficient activity of propionyl-CoA and

3-methylcrotonyl-CoA carboxylases was shown in

ex-tracts of mixed leukocytes. Treatment with biotin returned carboxylase activity to normal, consistent with the changes in the excretion of the organic acids. Deficiency of biotin was documented by anal-ysis of the concentrations of biotin in the blood and

urine. The absence of an inborn error of the metab-olism or the transport of biotin was indicated by the prompt and lasting response to treatment with 1 mg of biotin per day. It was documented by the normal activity of the carboxylases in extracts of cultured fibroblasts and by analysis of the content of biotin in samples of plasma and urine (which had been obtained from the patient some years earlier

and kept frozen), in which the concentrations of

(6)

It is of interest that the deficiency of biotin in our patient, and in two other documented cases,7”5 re-sulted from the well intended prescription of a diet designed to increase the intake of protein. There is a popular misconception that raw eggs are nutri-tionally superior to cooked ones; this notion may have gained popularity during the wide success of the movie “Rocky.” Physicians as well as dietitians

may be unaware of the deleterious effects of the

prolonged ingestion of raw eggs. Members of each group have been responsible for the prescriptions in our patient and others.’5 Exfoliative dermatitis and biotin deficiency have also been reported in a man who chose for himself a diet largely composed of raw eggs in wine.20

In at least two patients with heritable multiple carboxylase deficiency, altered immune responses,

especially to Candida have been observed.3 Our

patient had a history of previous cutaneous

candi-diasis. Thus, unusual susceptibility to infection, at least with Candida, could be an additional hazard for the patient with a deficiency of biotin.

ACKNOWLEDGMENTS

This work was supported in part by US Public Health Service grant HD04608 from the National Institute of

Child Health and Human Development, and

Umver-sity of California, San Diego General Clinical Research Center grant RR-00827 from the Division of Research Resources, National Institutes of Health, Bethesda, MD; and grant 04007 from the Health Services Administration, Department ofHealth, Education and Welfare, Rockville, MD.

We thank Ms Janette Holm for her technical

assist-ance.

REFERENCES

1. Gompertz D, Draffan GH, Watts JL, et al: Biotin-responsive f-methylcrotonylglycinuria. Lancet 2:22, 1971

2. Roth K, Cohn R, Yandrasitz J, et al: Beta-methylcrotonic aciduria associated with lactic acidosis. J Pediatr 88:229,

1976

3. Cowan JM, Packman 5, Wara DW, et al: Multiple biotin-dependent carboxylase deficiencies associated with defects in T-cell and B-cell immunity. Lancet 2:115, 1979 4. Charles BM, Hosking G, Green A, et a!: Biotin-responsive

alopecia and developmental regression. Lancet 2:118, 1979

5. Lehnert W, Niederhoff H, Junker A, Saule H, et a!: A case of biotin-responsive 3-methylcrotonylglycin- and 3-hydrox-yisovaleric aciduria. Eur J Pediatr 132:107, 1979

6. Gyorgy P, Rose CS, Eakin RE, et a!: Egg white injury as result of nonabsorption or inactivation of biotin. Science 93: 477, 1941

7. Scott D: Clinical biotin deficiency (“egg white injury”): Re-port of a case with some remarks on serum cholesterol. Acta Med Scand 162:69, 1958

8. Sweetman L, Bates SP, Hull D, et al: Propionyl-CoA car-boxylase deficiency in a patient with biotin-responsive 3-methylcrotonylglycinuria. Pediatr Res 11:1144, 1977

9. Sweetman L: Liquid partition chromatography and gas chro-matography-mass spectrometry in identification of acid me-tabolites of amino acids, in Nyhan WL (ed): Heritable Dir-orders ofAmino Acid Metabolism. New York, John Wiley & Sons, 1974, p 730

10. Spackman DH, Stein WH, and Moore 5: Automatic

record-ing apparatus for use in the chromatography of amino acids.

Anal Chem 30:1190, 1958

11. Baker H, Frank 0, Matovitch VB, et a!:A new assay method for biotin in blood, serum, urine, and tissue. Anal Biochem 3:31, 1962

12. Gravel RA, Lam KF, Scully KJ, et al: Genetic

complemen-tation of propionyl-CoA carboxylase deficiency in cultured

human fibroblasts. Am J Hum Genet 29:378, 1977

13. Weyler W, Sweetman L, Maggio DC et al: Deficiency of propionyl-CoA carboxylase in a patient with methylcrotonyl-glycinuria. Clin Chim Acta 76:321, 1977

14. Sydenstricker VP, Singal SA, Briggs AP, et al: Observations

on the “egg white injury” in man, and its cure with a biotin concentrate. JAMA 118:1199, 1942

15. Baugh CM, Malone JH, Butterworth CE Jr: Human biotin deficiency: A case history of biotin deficiency induced by raw egg consumption in a cirrhotic patient. Am J Clin Nutr 21: 173, 1968

16. Saunders M, Sweetman L, Robinson B, et al: Biotin-response

organic aciduria: Multiple carboxylase defects and

comple-mentation studies with propionicacidemia in cultured

fibro-blasts. J Clin Invest 64:1695, 1979

17. Thoene J, Sweetman L, Yoshino M: Biotin-responsive

mul-tiple carboxylase deficiency. Am J Hum Genet 31:64A, 1979 18. WolfB, Hsia YE, Boychuk R, et al: In vivo enzyme activation

by biotin of multiple carboxylase deficiency in a neonate.

Pediatr Res 14:529, 1980

19. Tanaka K, Isselbacher KJ: Experimental /3-hydroxyisoval-eric aciduria induced by biotin deficiency. Lancet 2:930, 1970 20. Williams RH: Clinical biotin deficiency. N Engi J Med 228:

(7)

1981;68;553

Pediatrics

Nyhan

Lawrence Sweetman, Linda Surh, Herman Baker, Raymond M. Peterson and William L.

Clinical and Metabolic Abnormalities in a Boy with Dietary Deficiency of Biotin

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(8)

1981;68;553

Pediatrics

Nyhan

Lawrence Sweetman, Linda Surh, Herman Baker, Raymond M. Peterson and William L.

Clinical and Metabolic Abnormalities in a Boy with Dietary Deficiency of Biotin

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