The mutations and VNTRs in the phenylalanine hydroxylase gene of phenylketonuria in St Petersburg

Abstract

This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S‐adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and c.257A>G; p.Asp86Gly. Clinically, the major abnormalities in addition to fetal hydrops (very likely due to impaired synthetic liver function) were severe hypotonia/myopathy, feeding problems, and respiratory failure. Metabolic abnormalities included elevated plasma S‐adenosylhomocysteine, S‐adenosylmethionine, and methionine, with hypoalbuminemia, coagulopathies, and serum transaminase elevation. The older sister died at age 25 days, but the definitive diagnosis was made only retrospectively. The underlying genetic abnormality was diagnosed in the second sister, but treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days. These cases extend the experience with AHCY deficiency in humans, based until now on only the four patients previously identified, and suggest that the deficiency in question may be a cause of fetal hydrops and developmental abnormalities of the brain.

Phenylketonuria mutations in Europe

“…Relative R408W-H2 frequencies of up to 84% were found in the Baltic states [Lillevali et al, 1996;Kasnauskiene et al, 2003;Pronina et al, 2003]. There are incomplete data sets for the European part of Russia and other states of the former Soviet Union [Charikova et al, 1993;Baranovskaya et al, 1996]; recent data from the Ukraine have been published in abstract format [Nechyporenko and Livshits, 2002]. Apart from a high frequency of R408W-H2, PKU is quite heterogeneous in the Czech Republic [Kozak et al, 1997].…”

Hyperphenylalaninaemias in Estonia: Genotype–Phenotype Correlation and Comparative Overview of the Patient Cohort Before and After Nation-Wide Neonatal Screening

“…We present an updated cohort and data about the genotypic and phenotypic distribution of Estonian PKU patients. The relative frequency (80%) of the major p.Arg408Trp variation has remained among the highest across populations, with the most similar prevalence in our mainland neighbour Latvia, followed by Lithuania: 76% and 73.5%, respectively (Kasnauskiene et al 2003;Pronina et al 2003), gradually decreasing southward -62% in Poland, 42% in the Czech Republic (Reblova et al 2013), 23-27% in Germany (Aulehla-Scholz andHeilbronner 2003), and westward -14-19% in Sweden (Ohlsson et al 2016), being also very high (71%) in North-Western direction, the St. Petersburg region (Baranovskaya et al 1996). The exceptionally high prevalence (84%) of this variation reported two decades ago could be considered a result of insufficient diagnostic capabilities in the past, leaving milder HPA cases out of the reach of paediatricians and clinical geneticists.…”

Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness.

“…The reason for this discrepancy was probably a low number of patients with PKU who were genotyped and, on the other hand, a selective genotyping which was performed to detect the most common mutations only. In fact, when analyzing the published data on prevalence of "BH4-responsive" variants (Zschocke, 2003), their actual percentage in Poland resembles the one in other countries of Eastern Europe, including Czech Republic, Slovakia, Bulgaria, Lithuania as well as, probably, Ukraine and the European part of Russia, where only screening for specific mutations was performed (Zschocke, 2003;Kozak et al, 1997;Kadasi et al, 1995;Kalaydjieva, 1993;Kasnauskiene, 2003;Nechiporenko & Lalivshits, 2000;Baranovskaya et al, 1996;Charikova, 1993). All these countries represent together a population of approx.…”