Hardo Lilleväli "Hyperphenylalaninaemias and neurophysiological disorders associated with the condition“

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View all other units

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Date:

12.05.2020 - 15:00

On 12 May at 15:00 Hardo Lilleväli will defend his doctoral thesis via Teams "Hyperphenylalaninaemias and neurophysiological disorders associated with the condition“.

Supervisors:
Professor Katrin Õunap (MD, PhD, University of Tartu, Faculty of Medicine, Institute of Clinical Medicine, Department of Clinical Genetics)
Kersti Lilleväli (PhD, University of Tartu, Faculty of Medicine, Institute of Biomedicine and Translational Medicine, Department of Physiology).

Opponent:
Professor Johannes Zschocke (MD, PhD, Chair of Human Genetics, Medical University Innsbruck, Austria).

Summary
Phenylketonuria (PKU) is an inherited metabolic disorder, wherein phenylalanine (Phe) excess in dietary protein is not metabolised due to deficiency in phenylalanine hydroxylase (PAH). High levels of Phe and its metabolites cause mental and physical disabilities. These can be avoided by early low-protein dietary treatment with Phe-free protein substitution. Thus, rapid detection of the disorder is of utmost importance. The incidence of PKU in Estonia is 1 in 6700 newborns. In Estonia, newborns are screened for PKU since 1993.

In our study, 17 pathogenic variants in PAH gene were found. High genetic homogeneity of Estonian 94 PKU patients was revealed: 80.4% of the affected alleles carry variation p.Arg408Trp. This homogeneity is reflected in phenotype: 87% of the patients have classical PKU with low Phe tolerance. Pedigrees of many Estonian PKU patients can be traced to South or South-East Estonia. The incidence and allelic distribution of PKU is similar among ethnic groups in Estonia.

The diet of Estonian PKU patients can be traced by the records of blood analyses in the electronic laboratory system of Tartu University Hospital. In early childhood, most of the families manage to keep Phe levels in recommended range. In elementary school, the median results of more than half of the patients’ analyses exceed the recommended level. In adolescence, the situation improves and remains similar in adulthood. The tendency has been observed also in other countries.

Disorders of Phe degradation may be caused also by lack of PAH cofactor tetrahydrobiopterin (BH4). The disorders of BH4 are rare, usually more complicated, and more difficult to treat. In 1991, a child with a disorder in BH4 regeneration (DHPR deficiency) was born, but neither cytogenetic methods, nor Sanger sequencing could find the molecular cause. By genome sequencing, an inversion of 9.1 Mb was revealed, which interrupts the gene coding DHPR. So large pathogenic structural variant in genome has not been reported.

Location:

Via Teams

Event category:

Defence

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Hardo Lilleväli "Hyperphenylalaninaemias and neurophysiological disorders associated with the condition“

September