Metabolic Mistakes

For many physicians the inborn errors of metabolism represent a somewhat esoteric group, unlikely to be encountered in clinical practice. Many more diseases have been added to the list of “inborn errors” in the last few years and these diseases can no longer be considered as rareties.


METABOLIC MISTAKES
For many physicians the inborn errors of metabolism represent a somewhat esoteric group, unlikely to be encountered in clinical practice. M any more diseases have been added to the list of " inborn errors" in the last few years and these diseases can no longer be considered as rareties.
T h e concept of " inborn errors of metabolism" was introduced by Sir Archibald Garrod in 1908, when he suggested that four metabolic disorders : albinism alcaphenuria cystinuria pentosuria had certain features in common.
These features were four in number.
1. T h e onset of symptoms or signs could be traced to the first few weeks of life.
2. A familial tendency was noted in many cases.
3. These diseases were relatively benign in nature. 4. In many cases the disease showed itself in the progeny of consanguineous marriages.
Before consideration of the clinical aspects of some of these diseases it is valuable to discuss the genetic principles involved in inheritance of disease and its expression within individuals.
Classically genetic defects arc transmitted by one of three modes of inherit ance.
In dominant inheritance most of the individuals affected are heterozygous for the abnormality. Occasionally however, two affected individuals will mate and produce an offspring who is homozygous for the trait concerned. Such an individual usually has a more severe form of the disease than either of his affected parents.
A recessive gene will only be expressed in individuals who arc homozygous for the condition.
As a general rule the following findings suggest a recessive mode of inherit ance.
1. T h e great majority of the affected persons arc the offspring of parents who arc normal in outward appearance.
2. T h e condition tends to affect the siblings in a family, but does not usually affect parents or offspring unless there is intermarriage between close blood relatives.
3. There is an undue proportion of consanguineous marriages among the parents of affected persons. Thus consanguinity occurs in about 80 per cent, of the parents of phenyl-ketonuries, which is considerably higher than the one per cent, seen in the population as a whole.
T h e classical exam ple of a condition transm itted by sex-linked inheritance is that of haem ophilia. Since haem ophilia is a recessive trait the offspring, if fem ale will show no clinical disease, but can transm it the abnorm ality to her m ale offspring who will display all the stigmata of the disease.

I.
It should be emphasised that genetic conditions are seldom completely " dom inant" or com pletely " recessive" . T h is is best illustrated by the following e xa m p les:- In hereditary spherocytosis the heterozygote has anaemia, spherocytosis, in creased red cell fragility and all the characteristics of the clinical disease. The hom ozygote with the two abnormal genes (aa) occurs rarely, but upon investi gation of such an individual, his condition is little different from that of the heterozygote -except that the haem olytic process may be a little more severe. Y et, although clinically similar, the genetic make-up is quite different and the condition is regarded as being transmitted as a " dom inant" .
In sickle cell anaemia the heterozygote (Ss) has about 40 per cent Ilb S + 60 per cent H bA in the blood. T h is places it as intermediate between the affected homozygote (ss) and the normal (SS). Such conditions may be re garded as being neither com pletely dom inant nor com pletely recessive.
Finally in 0 ketonuria the heterozygote Pp is almost normal in every way. Such patients may have some difficulty in handling large amounts of 0 alanine as compared with the normal individual (PP).
T h u s genetic conditions only appear to be dom inant or recessive, depending upon how well one can distinguish between the heterozygote and the normal and the heterozygote and the homozygote with two abnormal genes. II. W h ile genes are regularly transmitted they are not always expressed in an individual. T hus in some conditions an abnormal trait may " skip" a gener ation, and only careful study will show some m inor degree of the abnormality in the " skipped" generation. III. A trait which is truly inherited need not necessarily be present at birth but may appear later in life (despite G arrod's original com m ents upon the nature of inborn errors). T h e most tragic example of such a disease is pro bably that of H untingdon's chorea in which the individual develops marked mental deterioration with involuntary m ovem ents etc. at the age of 30 -40 years.

E X P R E S S IO N O F T H E IN B O R N E R R O R S O F M E T A B O L I S M
It is not possible to discuss here the mechanism of protein synthesis and gene reproduction. Let us consider, however, a known example of the primary effect of a gene upon a specific molecule within the body.
T h is may be illustrated by considering sickle-cell anaemia. As mentioned earlier it is known that in this disease two forms of haemoglobin are present in the blood of affected individuals -Ilb A + Ilb S . N ow the exact gene responsible for the presence of Ilb S cannot be identified as yet.
However, on analysis of the globulin moiety of both Ilb A + Ilb S it can be shown that there is a difference of one amino acid only, i.e.
Ilb A -Hist -V al -Leu -Leu -T h re -Pro -G lu -G lu Ilb S -Hist -V al -Leu -Leu -T h re -Pro -V al -Glu T his simple difference has far reaching effects on the I.E .P . and hence the solubility of Ilb S is much less than the solubility of Ilb A , with the resultant tendency to haemolysis of red cells containing Ilb S and the stigmata of sickle-cell anaemia.
So far only protein molecules appear to be involved in the primary gene effects of the hereditary disorders.
It is convenient now to classify inborn errors as to the way in which they express disturbances in protein molecules. T hree main types may be dis tinguished according to Hsia.
1. Disturbances in the structure of the protein molecules whereby there appears to be a change in the actual shape or arrangement of the molecules themselves.
2. Disturbances of synthesis of the protein molecule whereby an enzyme is not properly made, or may be entirely absent.
3. Disturbances in the function of the protein molecule, where an enzyme is either absent or not functioning properly.
It is obvious that any classification is highly tentative and until we have more information regarding the " gene effect'' then no definite and accurate classification will be possible. Space allows only of the description of a few of these diseases and we may now consider some of those disturbances due to enzyme defects or malfunction.
These represent for most of us the " classical" inborn errors of metabolism and best known among these are the defects in the metabolic pathways of the aromatic amino-acids.
T h e normal pathways of phenyl-alanine and tyrosine metabolism arc shown in Fig. 1 and the site of enzyme defects by Roman numerals.
I. 0 ketonuria is a hereditary condition, characterised by mental retardation and the presence of phenyl-pyruvic acid in the urine. Nearly 400 cases have been reported since the first cases were described by Foiling in 1934.
Clinically, the children found to be suffering from this disorder arc noted for their unusually attractive features in infancy. Unlike many mental defec tives they show only a slight reduction in stature and head size. M any of the children have blonde h air, blue eyes and a fair skin. A few show a tendency towards developing eczema.
Neurologically 110 change in muscle here can be demonstrated, but there is an accenuation of both the deep and superficial tendon reflexes. T h e majority of patients have an I.Q . of 30 or less.

P A T H O G E N E S IS
As indicated 0 alanine is normally converted to tyrosine by the enzyme 0 alanine hydroxylase.
M itom a et al. have shown that two protein fractions are involved in this reaction; a labile fraction I, which is present only in the liver; and a more stable fraction II, which is present also in the kidney and heart. T h e system requires D P N H and the overall reaction appears to occur in one step with no intermediates.
Recent studies have shown that in 0 ketonuria fraction II is present in the tissues in normal amounts and that the disease occurs because of a deficiency of fraction I in this enzyme system. An excessive accumulation of 0 alanine in the blood and C S F thus results. This has three effects.
1. Excess 0 alanine is converted by a transaminase to 0 pyruvic acid which is converted to 0 acetic acid 0 lactic acid 0 actclyl glutamine and excreted in the urine.
2. The excess 0 alanine also inhibits the normal pathways of tyrosine meta bolism. There is a fall in melanin production, and this is responsible for the light pigment in the skin and hair of such patients. There is also a disturbance in adrenaline production, since 0 ketonuries have unusually low blood adrenaline levels.
3. T h e amino acid excess may also be responsible in some way for the C N S damage, which is characterised by mental retardation, epileptic seizures and abnormal E .E .G . changes.
Diagnosis can now be established early in life by the simple screening procedure using phenistix (effectively, acidified ferric chloride).
Treatm ent is based upon a diet free of 0 alanine consisting of a protein hydrolysate.
Associated with 0 ketonuria as a disorder of the aromatic aminoacids is tyrosinosis, first described in 1932 by M edes.
In the patient described, there was a continuous excretion of P-O II-0 pyruvic acid, but no other clinical signs. Recently, Felix and his co-workers have made similar observations on two patients with liver disease. T h e mode of trans mission of tyrosinosis is completely unknown and the disease itself is extremely rare. In 26,000 reducing urines tested not one gave a positive reaction to M illon's test.
Tyrosinosis appears to be due to a congenital absence of the liver enzyme P -O II-0 pyruvic oxidase, which requires glutathione and either vitamin C or dichloro-phenol-indophcnol as cofactors. If the protein intake increases or dietary tryosine is increased the amount of P-O II 0 pyruvate in the urine will increase. T h e following substances also appear in the urine. Tyrosine 0 lactic acid 3.4 D .O .P .A . On the other hand if hom ogentisic acid is fed to the patient P -O II-0 pyruvate docs not appear in the urine i.e. the block is at site II in Fig. (i).
N o treatment is required for this condition. T h e third condition associated with the aromatic amino-acids is that of Alcaptonuria, which is characterised by the excretion of homogentisic acid in the urine.
Apart from the discolouration of the urine, there are no clinical mani festations until the second or third decade, when ochronosis begins to appear. T his consists of ochrc-like pigments in various parts of the body.
T h e deposits are particularly prominent in the sclera on cither side of the corneal limbus, in the ears and nasal cartilages, and in the superficial tendons of the hand.
By the time such patients reach middle age they usually complain of pain and stiffness in the large joints, owing to a deforming arthritis. X-ray examin ation shows the presence of thin, densely calcified intervertebral discs.

Fragment
In most cases alcaptonuria is transmitted as an autosomal recessive trait, but in some instances it appears to be transmitted as a simple dominant. In these families the affected individuals must be regarded as heterozygous for the condition.
It would thus appear that there are two types of alcaptonuria, which arc not related to each other. As yet it is not known whether the two types are alleles or at different loci on the same chromosome.
As the feeding of hom ogentistic acid to alcaptonurics results in almost quantitative recovery of that substance from the urine, it is postulated that the block exists as shown at site III in Fig (j). This has recently been con firmed in a patient with alcaptonuria.
T h e treatment of this condition is confined to the symptomatic treatment of the arthritis.
Albinism, as the name implies, is characterised by a complete abscnce of pigment in the skin, eyes and hair. T he pupils appear to be red and the iris is pink or bluish from reflected light.
Astigmatism Photophobia (are present in varying degrees) Nystagmus T he hair is fine and white or very pale yellow in colour. T h e condition is transmitted as a simple recessive, as is shown by the fact that 20 -30 per cent, result from marriages between cousins.
T h e pathogenesis of albinism appears to be due to the absence of the enzyme tyrosinase from the melanocytes of the skin. Clinical examination is usually sufficient for diagnosis and treatment consists of prevention of exposure to sunlight and proper protection of the eyes by dark glasses.
T h e classification of diseases used in this artcile was taken from " Inborn errors of metabolism'' by H sia published by Year Book Medical Publishers Inc. MEDICAL a n d DENTAL DEFENCE UNION OF SCOTLAND LTD.
Benefits Offered by the Union : Defence of claims for alleged negligence in professional work, including unlim ited indem nity and costs. Defence of claims against a principal in respect of acts by an assistant or locum. Advice on difficulties arising out of professional practice.