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IRIS COLOUR IN PHENYLKETONURIA

BY J. M. BERG AND J. STERN Fountain Hospital, London

Many observers have noted the relative lack of pigmentation which is considered to be a striking feature of phenylketonuria (Knox & Hsia, 1957; Wright & Tarjan, 1957). Colour dilution of the hair of phenylketonurics has been shown to be statistically significant (Cowie & Penrose, 1951), but we have found no record of an objective comparative study of phenylketonuric iris colour. Furthermore, the genetic and neurogenic control of pigmentation in the iris differs from that in the hair (Lerner, 1955). We therefore record some observations on iris colour in phenylketonurics.

MATERIAL AND METHOD

The iris colours of twenty-six phenylketonurics (thirteen of each sex) from the Fountain Hospital, ranging in age from 1 year 2 months to 27 years 11 months, were compared with those of fifty-two non-phenyketonuric mental defectives from the same hospital. For each phenylketonuric, two non-phenylketonuric controls of the same sex and age (to within 2 months) were selected from the patients’ register. All the patients were on a similar diet. As there were no Jewish, African or Asian patients amongst the phenylketonurics, such patients were not included in the control group.

In addition, the iris colours of twenty-three unaffected sibs were examined. These sibs were members of eleven families containing phenylketonurics.

Iris colours were assessed as described by Berg (1958) with the ‘Martin Augen-Farben Tafel’, consisting of sixteen glass eyes ranging from dark brown to light blue and labelled one to sixteen respectively. A detailed description of the Martin scale is given by Grieve & Morant (1 946).

RESULTS AND DISCUSSION

Comparison of the iris colours of the phenylketonurics and controls is shown in Table 1. Using the xa test in the form of a 2 x 3 contingency table, it is found that the iris colours of the phenylketonurics differ significantly from those of the controls. It should be noted, however, that over 25 % of the phenylketonurics’ iris colours fall outside the ‘light ’ range, while nearly 50 % of the controls fall within this range.

Analysis of the data in terms of the revised Martin scale advocated by Grieve & Morant (1946), in which the eyes are divided into three groups (numbers < 8, 8-11 and 13, 12 and l&l6), reveals an equally significant difference between the phenylketonurics and controls. The distribution of iris colours in our fifty-two controls resembled that recorded by these authors (Grieve & Morant, 1946, Tables 3 and 4) for 875 chiefly British people, when analysed on the revised scale by a 2 x 3 contingency table (xa= 0.0408, I” 0.98).

Table 2 shows that a statistically significant dilution of iris colour occum in phenylketonurics compared with their unaffected sibs, 9 (75 %) of the phenylketonurics compared with 6 (26 %) of the sibs falling within the ’light’ mnge ( D . F . = ~ , xa=5.84, Pc0.02). In two instances (Families nos. 1 and a), however, there was no dilution. The case of Family no. 1 waa parti- cularly striking as both unaffected sibs had lighter iris colours than the patient. The difference

J. M. BERG AND J. STERN 37 1

was sufficiently marked to be obvious even without the aid of the Martin scale. This effect could not be attributed to age differences, aa the mean age of the unaffected sibs was close to that of the patient.

Table 2 also shows that the I.Q.’S of phenylketonurics are unrelated to the iris colour differ- ences between them and their unaffected sibs.

Though iris colour of the phenylketonurics, as 8 group, is significhntly lighter than that of the controls and unaffected sibs, dilution in individual cases is apparently offset by other factors involved in the pigmentation of the iris. Iris colour per se is thus an unreliable diagnostic criterion in this disease.

Iris colour

Martin scale reading

Table 1. Irir, colour distribution of twenty-six phenylketonurics and jifty-two controls

‘ Dark ’ 1 ‘Medium’ ‘Light’ Total

1 2 3 4 5 I 6 7 8 9 1 0 1 1 1 ~ 1 3 1 4 1 5 1 6

No. of phenylketonurics No. of controls

Total

0 0 0 0 1 3 1 0 0 o 2 2 I 8 5 3 26 0 2 1 6 6 1 x 1 1 5 4 4 6 6 4 4 52

1+15=16 6+ 13’ 19 I9 + 24= 43 78

Table 2 . Iris colours of twelve phenylketonurics and twenty-three unaffected sibs

Family no.

I

2

3

4

5

6 7

8

9

I 0

XI

V.

Phenylketonurica Unaffected sibs Iris colour dif- ference (phenyl

ketonurica minw mean of

uneffected)

-4 26 8 F. V.6 6 a 31 X I M.

b 17 9 F.

4} +8 14 9 F. V . 2 I 2 a 18 I I F.

b 10 7 M. 4 a 24 2 M.

c 13 5 M. 6 a 5 6 M.

Age Iris Age Iris colour sex colour 6 & sex

y. m. y. m. I.Q.

___-

I 0 1°)

16 11 M. v . 7 14 b 13 5 M. ;} +7%

:;} - 1

17 9 M. V . 5 I3 b 10 8 M. ::} +3*

a 6 5 F. V. 15 I4 b 7 9 F. S.B.46 14 b 3 7 F-

G O 7 F. I4

16 6 F. V. 7 16 13 7 F. 5 3 5 M. v . 4 5 9 o F. 4 + I

+ 34 I 2

+I1

9 8 M. M.P.35 15 a I I 4 F. b 6 o M.

a 10 8 M.

0 6 8 M. 6

4 b 3 11 F.

a 12 7 M.

+2

+8 4}

8 7 M. V. 12 6 a 7 7 M-

4 6 F. V. 14 12 I 2 F. 4

6 2 F. S.B.33 15 b I0 0 F. ;) +6.) c 6 2 M. 13

S.B. = Stanford Binet Scale. M.P. = Memill Palmer Scale. =Vineland Social Maturity Soale.

372 I R I S COLOUR I N PHENYLKETONURIA

Melanin, the principal pigment responsible for iris colour (Cowan, 1956; Lerner, 1955), is a product of tyrosine metabolism. In phenylketonuria, the primary metabolic error is the deficient hydroxylation of phenylalanine to tyrosine, the conversion being only about 10 % of normal (Udenfriend, 1953). Nevertheless, a well-balanced diet contains enough tyrosine to preclude a primary deficiency. Melanin production, however, depends not only on the avail- ability of tyrosine, but also on the effective concentration of the enzyme tyrosinase and perhaps other enzymes, and their inhibitors, in the chain leading to melanin (Lerner, 1956).

The primary error in phenylketonuria leads to distortion of the metabolism of other aromatic amino-acids and the accumulation of a number of abnormal metabolites (Knox & Hsia, 1957). Phenylalanine, the serum concentration of which is raised in phenylketonuria, itself com- petitively inhibits mushroom tyrosinase (Dancis & Balis, 1955). Furthermore, it has been found that darkening of hair occurs in phenylketonuric children on a phenylalanine-free diet (Woolf, GriBths & Moncrieff, 1955). It therefore appears reasonable to attribute the observed dis- tribution of iris colour to varying degrees of inhibition of pigment formation by one or more of the abnormal metabolites formed in phenylketonuria.

SUMMARY The iris colours of twenty-six phenylketonurics at the Fountain Hospital were compared with those of a matched group of fifty-two non-phenylketonurics from the same hospital, by means of the ‘Martin Augen-Farben Tafel’.

A similar comparison was made of twelve of these phenylketonurics, from eleven families, and twenty-three of their unaffected sibs.

Iris colour of the phenylketonurics was found to be significantly lighter than that of the controls and unaffected sibs, although exceptions were noted in individual cases.

The observed dilution is tentatively attributed to inhibition of pigment formation by the abnormal metabolites formed in phenylketonuria.

We are greatly indebted to Dr. B. H. Kirman and Prof. L. S. Penrose for stimulating dis- cussions and helpful comments. We also wish to thank Miss M. F. Craib and Miss M. A. Kerry for their most valuable help in contacting the sibs of patients. The Intelligence Test results were made available through the courtesy of the Psychology Department, Fountain Hospital.

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GRIEVE, J. & MORANT, G. M. (1946). Records of eye colours for British populations and a description of a

KNOX, W. E. & HSIA, D. Y. Y. (1957). Pathogenic problems in phenylketonuria. Amer. J . Med. 22, 687. LERNER, A. B. (1955). Melanin pigmentation. Amer. J . Med. 19, 902. UDENFRIEND, S. (1953). The hydroxylation of phenylalanine and rtntipyrine in phenylpyruvic oligophrenia.

WOOLF, L. I., GRIFFITHS, R. & MONCRIEFF, A. (1955). Treatment of phenylketonuria with a diet low in

WRIGHT, S. W. & TARJAN, G. (1957). Phenylketonuria. Amer. J . Dis. Child. 93, 405.

pyruvic oligophrenia. Pediatrics, 15, 63.

new eye-colour scale. Ann. Eugen., L a d . , 13, 161.

J . Biol. Chem. 203, 961.

phenylalanine. Brit. Med. J . 2, 57.