Postgrad Med J: first published as 10.1136/pgmj.62.724.125 on 1 February 1986. Downloaded from Postgraduate Medical Journal (1986) 62, 125-129

Teratogenic inborn errors ofmetabolism

J.V. Leonard Department ofChildHealth, Institute ofChild Health (University ofLondon), 30 Guilford Street, London, WCJN IEH, UK.

Summary: Most children with inborn errors ofmetabolism are born healthy without malformations as the fetus is protected by the metabolic activity of the placenta. However, certain inborn errors of the fetus have teratogenic effects although the mechanisms responsible for the malformations are not generally understood. Inborn errors in the mother may also be teratogenic. The adverse effects of these may be reduced by improved metabolic control of the biochemical disorder.

Chromosomal disorders are responsible for many chromosomal disorder was suspected but the dysmorphic syndromes (De Grouchy & Turleau, karyotype was normal. Fortunately urine was ex- 1984) and, since the teratogenicity ofthalidomide was amined for'metabolic abnormalities and two unusual recognized, the potential toxicity to the fetus of drugs compounds were detected, 2-carboxypropyl con- given to the mother has also received much attention. jugates ofcysteine and cysteamine. These were shown Dysmorphic syndromes are now well described in to be derived from ethylacrylyl CoA that accumulated children whose mothers have taken hydantoins, meth- because ofan inborn error ofthe catabolism ofvaline. otrexate, alcohol, and warfarin (Shepard, 1983). Methylacrylyl CoA is a highly reactive compound

Many other drugs are under suspicion. forming conjugates spontaneously with compounds by copyright. By contrast, it has been standard teaching that containing free sulphydryl groups, and methylacrylate babies with inborn errors ofmetabolism are normally esters have been shown to be potent teratogens in rats formed and healthy at birth because the fetus is (Singh et al., 1972) causing skeletal abnormalities protected by the exchange ofnutrients and metabolites similar to those noted in the patient. Although free across the placenta. Only after birth does the disorder methylacrylyl CoA could not be detected and the become evident. However, this is not correct as inborn concentration of the conjugates was low, the quan- errors in the fetus and in the mother may be tities present in the tissues ofthe fetus were thought to teratogenic. have caused the malformations.

Multiple acyl CoA dehydrogenase deficiency http://pmj.bmj.com/ Inborn errors of the fetus In one of the early descriptions of multiple acyl CoA The fetus is only partially protected from the injurious dehydrogenase deficiency (also known as glutaric effects ofmany inborn errors by the placenta. In utero aciduria type II) the baby was noted to have dysmor- catabolic pathways are relatively inactive so that phic features including large head with bulging fontan- metabolites are likely to be formed only slowly, if at elle, low set ears, small palpebral fissures, short nose all. However, ifthey are formed, removal may be even with long philtrum, bilateral simian creases, dysplastic slower so that toxic metabolites accumulate. The nails and polycystic kidneys (Sweetman et al., 1980). on September 24, 2021 by guest. Protected rapidly growing tissues of the fetus are likely to be The patient developed a metabolic acidosis and hy- particularly vulnerable to any adverse effect of such poglycaemia, dying at the age of 24 hours. Numerous compounds. abnormal metabolites including glutaric, ethyl- malonic, isovaleric, isobutyric and several other dicar- 3-Hydroxyisobutyryl CoA deacylase deficiency boxylic acids were detected in the urine. Other patients with the same biochemical disorder have now been In 1982 Brown et al. reported a child who had died of described (Goodman & Frerman, 1984), some of multiple congenital abnormalities with abnormal whom have similar dysmorphic features (Goodman et facial features, tetralogy of Fallot, multiple vertebral al., 1983; Bohm et al., 1982). The disorder is caused by abnormalities and agenesis of the corpus collosum. A deficiency of several acyl CoA dehydrogenases (Leh- nert et al., 1982). The only biochemical difference Correspondence: J.V. Leonard, Ph.D., F.R.C.P. between the dvsmormhic and the non-dvsmormhic © The Fellowship of Postgraduate Medicine, 1986 Postgrad Med J: first published as 10.1136/pgmj.62.724.125 on 1 February 1986. Downloaded from 126 J.V. LEONARD patients is that sarcosine is present in the non-dysmor- secondary finding. Enzyme studies have been normal. phic patients but has not been found in the dysmorphic ones. However this is unlikely to be important (Good- The number ofinborn errors that cause dysmorphic man & Frerman, 1984). The organic acids appear to be syndromes is still very small and in only one inborn similar and no teratogenic compounds have been error has a compound been identified which could be identified. responsible for the malformation. However the princi- ple is established that inborn errors ofthe fetus can be Zellweger's syndrome responsible for dysmorphic changes and biochemical abnormalities should continue to be sought in dysmor- In 1964 Zellweger and his colleagues (Bowen et al., phic patients with autosomal recessive disorders. 1964) described the syndrome characterized by a However, the compounds responsible for the typical facial appearance with a tall forehead, slanting teratogenic effects may only be present at low concen- eyes, epicanthic folds and a large fontanelle in associa- tration and easily overlooked with the screening tion with marked , severe mental retarda- methods in current use, in contrast to many inborn tion, disturbed liver function and eye abnormalities. errors in which there is gross accumulation of Goldfischer et al. (1973) showed that metabolites. In Zellweger's syndrome there is failure of were not present in the liver ofthese patients and it has synthesis of , a major phospholipid now been shown that the membrane-bound enzymes component of cellular membranes as well as the normally present in the organelles are deficient (Wan- accumulation of other compounds. Thus in some ders et al., 1984). The typical biochemical consequen- disorders failure of synthesis could be responsible for ces are a severe deficiency of plasmalogens (Heymans malformations. et al., 1983), and accumulation ofvery long chain fatty acids (Brown et al., 1982), (Poulos et al., 1984), pipecolic acid (Govaerts et al., 1982), and Inborn errors of the mother abnormal C-27 bile acids (Mathis et al., 1980). Now that the biochemical basis of the disorder is clearer it An inborn error that causes only minor problems in has become apparent that there is wide phenotypic the adult may cause serious abnormalities in theby copyright. variation. Patients are probably always retarded and developing fetus. hypotonic but the dysmorphic features and the eye manifestations are varied (Govaerts et al., 1982). This Phenylketonuria has lead to the recognition that several other syn- dromes including infantile Refsum's (Poulos et Patients with phenylketonuria (PKU) have a de- al., 1984), neonatal (Brown et ficiency ofphenylalanine hydroxylase so that they are al., 1982), trihydrocoprostanic acidaemia (Parmentier unable to convert phenylalanine to tyrosine. Con- et al., 1979) are probably all variants ofthe Zellweger's sequently phenylalanine accumulates and tyrosine syndrome. So far the biochemical abnormalities in concentrations are reduced; indeed tyrosine becomes these disorders appear to be similar to those in an essential aminoacid. At birth, babies with PKU are http://pmj.bmj.com/ classical Zellweger's syndrome and at present there is normal. Without treatment the majority will become no explanation for the wide variation in expression. severely mentally retarded (Koch et al., 1974) but with The spectrum of peroxisomal disorders has been early diagnosis through neonatal screening and treat- extended still further as Heymans and his colleagues ment with a strict low phenylalanine diet, progress (1985) have shown that in rhizomelic chondrodys- during childhood is good with the mean IQ close to the plasia punctata peroxisomes are absent or abnormal population mean (MRC/DHSS Phenylketonuria morphologically with defective activity of certain Newsletter, 1980). The aim is to maintain the plasma peroxisomal enzymes. phenylalanine concentration between 100-500 JLmol/l on September 24, 2021 by guest. Protected but strict control is difficult to maintain and the diet is DOOR syndrome now usually relaxed during late childhood and adoles- cence. The plasma phenylalanine concentration is DOOR syndrome is an autosomal recessive disorder allowed to rise up to 1200 Lmol/l. Further relaxation that is characterized by deafness, nail dystrophy, of the diet is common so that by adult life patients are abnormal facies and mental retardation (Cantwell, often on a more or less normal diet with plasma 1975). The patients often have a severe seizure disor- phenylalanine concentrations in excess of 1500 pmol/l. der. Patton and his colleagues (1984) have recently The offspring of females whose phenylalanine con- described three patients with this disorder who ex- centrations are above 1200 ymol/l during the preg- creted a marked excess of 2-oxoglutarate in the urine. nancy have a high incidence of microcephaly and No other biochemical abnormalities have been found mental retardation (Lenke & Levy, 1980). Other and it is not yet known whether this is a primary or abnormalities include cardiac defects such as tetralogy Postgrad Med J: first published as 10.1136/pgmj.62.724.125 on 1 February 1986. Downloaded from TERATOGENIC INBORN ERRORS OF METABOLISM 127 of Fallot and ventricular septal defect, hypotonia and Harding et al. (1984) studied the brains of children a dysmorphic appearance similar to that of the fetal with OCTD and found evidence of abnormalities in alcohol syndrome (Lipson et al., 1981). The risk of the brain that were of prenatal origin. One boy who microcephaly and mental retardation at lower phen- died in the neonatal period and whose mother was an ylalanine concentrations is less but in one study, asymptomatic carrier had widespread histological even for those mothers whose highest recorded changes with poor myelination and marked spongy plasma phenylalanine concentration was between change in the deep white matter of the cerebral 180-600 Lmol/l, between 20-25% of the offspring hemispheres. Cerebellar heterotopias were also had mental retardation and microcephaly, a fourfold present. In a girl who died at the age of 13 months there increase above that expected (Lenke & Levy, 1980). was extensive brain destruction with good evidence This estimate is probably too high because of the that it had begun in utero. The mother had had severe method ofascertainment and in another study the risk hyperemesis throughout her pregnancy and during a of mental retardation and microcephaly when cord protein load she vomited. Despite this her plasma blood phenylalanine was less than 1100 lmol/l was ammonia rose to 102 gLmol/l. It was suggested that this low (Levy & Waisbren, 1983). The conclusion from carrier mother had had marked biochemical abnor- these apparently contradictory observations is most malities during her pregnancy that had initiated the probably that the risk to the fetus is directly related to brain damage in the fetus. the maternal phenylalanine concentrations, being very Ammonia is highly toxic to the brain and hyperam- high above 1200 gmol/l and decreasing, but not monaemia after birth often causes severe cerebral negligible, at lower phenylalanine levels. damage and death (Msall et al., 1984). However, Reintroducing the strict diet once pregnancy has ammonia is not the only potentially teratogenic factor. been confirmed does not prevent the abnormalities Arginine is not an essential aminoacid in normal (Lenke & Levy, 1980). In a number ofpregnancies diet individuals because it can be synthesized in the urea has been started before conception and in almost all cycle. In patients with inborn errors of this pathway, cases the outcome has been normal although not synthesis of arginine is reduced so it becomes an invariably so (R. Koch, personal communication). essential aminoacid (Brusilow, 1984). Deficiency may

The current practice is that if a mother is intending to develop during pregnancy with increased demands by copyright. have a child, she should go back on the diet before and may be a factor in prenatal damage. For these conception aiming to keep plasma phenylalanine reasons it has been recommended that the dietary concentrations below 500 tmol/l. intake of protein, plasma ammonia and aminoacids should be monitored during pregnancy of carrier Ornithine carbamoyl transferase deficiency females and, if any abnormality is detected, it should be corrected (Pembrey et al., 1985. Ornithine carbamoyl transferase deficiency (OCTD) is the most common ofthe inborn errors ofthe urea cycle Diabetes mellitus and is an X-linked disorder (Walser, 1983). Affected boys usually, but not invariably, have very low enzyme Although diabetes mellitus is not usually inherited in a http://pmj.bmj.com/ activity and present in the neonatal period with severe simple Mendelian fashion it is nevertheless a metabolic hyperammonaemia. By contrast the clinical expres- disorder with a genetic component. Infants ofmothers sion in females, even within one kindred, is very varied; with diabetes have an increased incidence of many some develop hyerammonaemia in childhood and congenital anomalies involving the cardiovascular and others have no symptoms at all. This marked variation skeletal system most commonly but also the genito- is a consequence of Lyonization, the process of urinary, gastro-intestinal and central nervous systems inactivation of one X chromosome in a cell at an early (Pedersen et al., 1964; Soler et al., 1976). The caudal stage in fetal development. The tissues, therefore, regression syndrome (Passarge & Lenz, 1966) and on September 24, 2021 by guest. Protected contain two populations of cells, each with one X related disorders such as femoral hypoplasia-unusual chromosome active. Since the process is random, the facies syndrome (Burn et al., 1984) may be the most composition of tissues will vary between individuals. specific although only a proportion of patients with In OCTD the patients' symptoms will depend on the these disorders are born to mothers with diabetes. relative proportion of the two populations of liver The risk of malformations is higher in those cells. Many females will have no symptoms but diabetics who have had the illness for longer and in nevertheless will be carriers and at risk ofhaving boys those with established vascular disease (Pedersen et with severe disease. Although the carriers may have al., 1964). Prediabetic women do not have any increase few clinical symptoms, their IQ may be lower than in risk so it is probable that it is the diabetes and not expected (Batshaw et al., 1980) and the disorder may other genetic factors that is responsible for the be responsible for abnormalities in the developing teratogenic effect (Bennett et al., 1979). Good control fetal brain. of the diabetes is thought to reduce the incidence of Postgrad Med J: first published as 10.1136/pgmj.62.724.125 on 1 February 1986. Downloaded from 128 J.V. LEONARD congenital anomalies in both man and experimental exposed to phenytoin but only one developed hydan- models (Baker et al., 1981; Miller et al., 1981). toin syndrome (Buehler, 1985). Enzyme studies showed that the activity of the epoxide hydralase was Although the precise mechanisms of the damage greatly reduced in the affected twin. Both twins were have not been elucidated in any of the maternal exposed to the same concentration of phenytoin but disorders, good metabolic control from conception because of the lower activity of the epoxide hydralase throughout the pregnancy will reduce significantly the in the affected fetus it was postulated that there was a risk to the fetus. greater accumulation ofthe oxide which was responsi- ble for the 'syndrome'. Interaction of drugs and enzyme variations Conclusions Both the therapeutic and toxic effects ofdrugs may be influenced by genetically determined variations in the Until recently inborn errors appeared to have little activity of enzymes responsible for drug metabolism. relevance to teratology but the disorders described The differences may also be one factor contributing to have altered this view. Compounds may be formed in the teratogenicity of some drugs as a reduction in the utero that are teratogenic and are not necessarily rate of some reactions could lead to the accumulation readily detectable with current screening methods. of toxic metabolites in utero. This may be extended since metabolites may be The risk of malformation in patients taking phen- formed (or not synthesized) at critical periods of ytoin and other hydantoins is between 7-15% (Han- development but the biochemical abnormality may be son et al., 1976; Shepard, 1983). These drugs are difficult to identify post-natally because of differences normally metabolized by the P450 system to form an in metabolic pathways. Thus many more recessive arene oxide which is then hydroxylated by epoxide dysmorphic syndromes may have a biochemical basis hydralase. If the activity of this enzyme is reduced the which has not yet been discovered because no simple epoxide would be liable to accumulate in tissues. The metabolic defect can be detected. intermediate oxide is a highly reactive compound that by copyright. will bind to cellular proteins and DNA thereby Acknowledgements becoming a potential teratogen. I would like to thank Drs M. Pembrey, M. Baraitser, Isabel In a recent remarkable case dizygotic twins were Smith, and M. Patton for their help and criticism.

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