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2842 Med Genet 1993; 30: 284-288 Phenylketonuria: variable phenotypic outcomes of the R261Q mutation and maternal PKU in J Med Genet: first published as 10.1136/jmg.30.4.284 on 1 April 1993. Downloaded from the offspring of a healthy homozygote Sandra Kleiman, Lina Vanagaite, Jeanna Bernstein, Gerard Schwartz, Nathan Brand, Avraham Elitzur, Savio L C Woo, Yosef Shiloh Abstract the synthesis or metabolism of its cofactor, Phenylketonuria (PKU) and benign tetrahydrobiopterine. HPA with phenylala- hyperphenylalaninaemia (HPA) result nine levels of 12 mmol/l or higher is usually from a variety of mutations in the gene expressed as the autosomal recessive disease for the hepatic enzyme phenylalanine phenylketonuria (PKU). PKU patients suffer hydroxylase. PKU has been found in the from severe mental retardation unless diag- Israeli population in two variants, classi- nosed soon after birth and treated with a low cal and atypical. The two are clinically phenylalanine diet throughout adolescence. indistinguishable and require treatment Phenylalanine levels of 0-24 to 1 1 mmol/l are with low phenylalanine diet to prevent usually regarded as benign HPA and are not mental retardation, but show differences considered an indication for dietary treatment. in serum phenylalanine levels and in The wide spectrum of HPAs has led to dif- tolerance to this amino acid. Maternal ferent designations for these conditions in dif- PKU is a syndrome of congenital anomal- ferent studies. ies and mental retardation that appears in In Israel, a pioneer in establishing a national offspring of PKU mothers as a result of screening programme for HPA,3 two variants fetal exposure to the high phenylalanine of PKU have been noted, which are clinically level in the maternal blood. We studied a indistinguishable in the untreated state: severe family in which two children with severe, classical PKU with serum phenylalanine levels classical PKU and their unaffected of 1-2 to 48 mmol/I on a normal diet and brother showed mild signs of maternal phenylalanine tolerance of 200 to 500 mg/day, PKU. Their mother had no clinical signs and atypical PKU with serum phenylalanine of of PKU, but the phenylalanine concentra- 1-2 to 2 4 mmol/I and a 500 to 1200 mg/day treatment is tion in her serum reached a level that tolerance. Less stringent dietary http://jmg.bmj.com/ usually characterises PKU patients. This required in atypical PKU. (Previous commu- woman represents a rare phenotype, nications referred to these variants of PKU as 'hidden' PKU 'North European' and 'Mediterranean',45 ref- Department of benign atypical PKU. Such Human Genetics, in women may lead to maternal PKU in lecting the lack of common nomenclature.) Sackler School of the offspring, similar to overt PKU. Benign HPA (also termed 'non-PKU HPA'4) Medicine, Tel Aviv Special attention should therefore be paid was classified in this population as 'high' or University, Ramat to women having children with any of the 'low', with serum phenylalanine levels of 0-6 to Aviv 69978, Israel. on September 25, 2021 by guest. Protected copyright. S Kleiman clinical hallmarks of maternal PKU, and 1-08 and 0-24 to 0-72 mmol/l and phenylal- L Vanagaite to children born to women known to have anine tolerance of 1100 to 1700 and 1500 to J Bernstein Y Shiloh benign HPA. The mother was also found 2000 mg/day, respectively. to be homozygous for a missense muta- HPA variability reflects a wide spectrum of Child Development tion at the phenylalanine hydroxylase mutations at the PAH locus that reduce the Institute, Sheba to different extents. Over 30 Medical Centre, Tel locus, R261Q, which does not abolish en- enzyme activity Hashomer, Israel. zymatic activity completely. In two other such mutations have been identified since the G Schwartz families, homozygosity for this mutation cloning of the PAH gene, and the correspond- N Brand resulted in atypical PKU in four children. ing enzymatic defects have been correlated A Elitzur This observation suggests that mutations with the clinical-biochemical phenotypes asso- Howard Hughes that do not completely destroy phenylala- ciated with these mutations.67 The search for Medical Institute, nine hydroxylase activity may exhibit new mutations and the finding of known muta- Department of Cell their Biology and Institute variable phenotypic expression which is tions in patients is facilitated by associ- of Molecular Genetics, unpredictable. Compound heterozygosity ation with specific haplotypes of restriction Baylor College of for R261Q and other mutations led in fragment length polymorphisms (RFLPs) in Medicine, Houston, the last 25 Texas 77030, USA. other patients either to classical PKU or the PAH gene."' During years, S L C Woo to mild benign HPA. routine screening of newborns for HPA and Genet dietary treatment of PKU patients throughout Correspondence to (J7 Med 1993;30:284-8) Dr Shiloh, Howard Hughes childhood has resulted in increasing numbers Medical Institute Research level above of such patients who grow up and lead normal Laboratories, University of A raised serum phenylalanine Michigan Medical Center, 0 12 mmol/l is defined as hyperphenylalani- lives as adults without dietary restrictions. MSRB II, Room 4570, 1150 from of This success has been overshadowed, how- W Medical Center Drive, naemia (HPA), and results impairment Ann Arbor, Michigan phenylalanine hydroxylation to tyrosine in the ever, by the recent emergence of a new syn- 48109-0650, USA. liver.'2 The defective enzyme in more than drome, maternal PKU, in women's children Received 5 August 1992. exposed in utero to high phenylalanine levels Revised version accepted 98% of cases is phenylalanine hydroxylase 13 October 1992. (PAH), and the rest are explained by defects in in their mother's blood. Maternal PKU is Phenylketonuria: variable phenotypic outcomes of the R261Q mutation and maternal PKU in the offspring of a healthy homozygote 285 characterised by low birth weight, microce- tion, are healthy, and have no history of PKU phaly, mental retardation, and a high risk of or any other metabolic or genetic disorder in cardiac anomalies.'2'3 It can be avoided by their families. Both in middle class grew up J Med Genet: first published as 10.1136/jmg.30.4.284 on 1 April 1993. Downloaded from reinstating the low phenylalanine diet before families with normal nutrition typical of this conception and throughout pregnancy.'4 The community. Physical examination showed all growing awareness of the consequences of three children to be microcephalic (head cir- HPA during pregnancy has directed attention cumference below the 2nd centile). The IQ of to females with benign HPA where high HPA the boy not affected with PKU (II-2) was 89, not sufficient to cause overt PKU in the while that of his parents was 100. Since these mother might nevertheless affect her fetus."-5'7 signs could be compatible with mild maternal Superti-Furga et all8 recently described a PKU, serum phenylalanine level was tested in family in which mild PKU in two sisters the mother and found to be 1-2 mmol-l. The resulted in maternal PKU in their offspring. high level was unusual, since most people with Both sisters were homozygous for a missense this degree of HPA are usually affected with mutation (R261Q) at codon 261 of the PAH PKU and show various degrees of mental gene, which does not totally abolish PAH retardation if not treated by diet. This woman enzymatic activity. was found, however, to be well adjusted We present here genetic and molecular ana- socially and works as a school teacher. Her lyses of a family in which PKU and maternal phenylalanine tolerance was 600 mg/day. We PKU coexist in the offspring. The molecular therefore assigned a specific phenotype to this basis for maternal PKU in this family is benign woman, benign atypical PKU. We concluded atypical PKU in the mother, who is homozy- that the signs of mild maternal PKU found in gous for the R261Q mutation. Other pheno- the children resulted from maternal HPA. types associated with this mutation in the Haplotype analysis showed the children Israeli population are presented. with classical PKU in this family to be com- pound heterozygotes with mutant haplotypes 1 and 4,20 while the mother was homozygous for Patients and families haplotype 1 (fig 1). The patients were tested Newborn screening in Israel and the criteria for the presence of the following mutations for classification of the different HPAs have previously found to be associated with haplo- been previously described.'-5 Psychological types 1 and 4 in other populations: R158Q, and developmental assessment of PKU R243ter, R252W, R261 Q, E280K, P281 L, patients is done on a yearly basis between the R408W, and Y414C.6921-25 Both patients were ages of 1 and 18 years using a variety of tests found to carry the missense mutation R261Q that examine IQ, motor-graphic ability, adap- on one of their PAH alleles. This mutation tation, educational achievement, and emotion- changes an arginine residue into glutamine at al development. The families investigated are codon 261 of the PAH results gene and in http://jmg.bmj.com/ part of a cohort of 110 Israeli families with residual enzyme activity of 30%.21-23 25 None of HPA that recently underwent genetic and mo- the other mutations was found in these lecular analysis (Kleiman et al, in preparation). patients. The presence of the R261Q mutation can be detected by PCR and subsequent Hinfl digestion. Further investigation of the segre- Methods gation of this mutation in the family showed, For the molecular analysis, construction of unexpectedly, that the mother was homozy- RFLP haplotypes at the PAH gene and detec- gous for this defect (fig 2). Direct sequencing on September 25, 2021 by guest.

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