Abstract
Summary Background: Phenylketonuria (PKU) is a metabolic disorder caused by phenylalanine hydroxylase gene (PAH) mutations. If left untreated, PKU patients develop severe mental retardation potentially due to neurodegeneration. This is the first study that investigates presence of mitochondrial DNA variants in PKU patients, m.10398A, reportedly associated with neurodegenerative diseases and m.10410T. Methods: We analyzed 64 PKU patients and 50 healthy controls from Serbian population. PKU patients were categorized into groups according to time of diagnosis and compliance to low-phenylalanine diet. The IQ was determined according to age-appropriate scales. Results: We detected m.10398A and m.10410T variants by direct sequencing. Frequency of m.10398A was similar in patients and healthy controls (82.81% and 82.00% respectively) suggesting their identical ethnic background. No variation was detected for m.10410. In group with late diagnosis and poorly controlled diet, no statistically significant difference in average IQ was found between patients with m.10398A and m.10398G. The same was shown for PKU patients with higher IQ, diagnosed at neonatal screening and treated with low-phenylalanine diet. However, when patients carrying p.L48S, a PAH mutation with inconsistent effect, were excluded from the study, presence of m.10398A variant was associated with lower IQ. Conclusions: This study emphasizes the importance of neonatal screening and good control of low-phenylalanine diet in PKU patients. Statistical analysis did not indicate clear impact of mitochondrial DNA variant m.10398A on IQ of PKU patients, except when PAH genotype was also considered. Studies in larger cohorts will elucidate the association between PAH gene mutations, mitochondrial DNA variants and complex PKU cognitive phenotype.
Highlights
Phenylketonuria (PKU, MIM#261600) is an inborn error of metabolism caused by a deficiency of the hepatic enzyme, phenylalanine hydroxylase (PAH), due to mutations in the PAH gene [1]
Studies in larger cohorts will elucidate the association between PAH gene mutations, mitochondrial DNA variants and complex PKU cognitive phenotype
The m.10398A variant was uniformly distributed among PKU patients and the control group, we further analyzed the distribution of the m.10398A variant within the four different groups of patients (DBNS+low Phe diet treatment (LPD), diagnosed by neonatal screening (DBNS)+PCD, late diagnosis (LD)+LPD and LD+PCD) (Table I)
Summary
Phenylketonuria (PKU, MIM#261600) is an inborn error of metabolism caused by a deficiency of the hepatic enzyme, phenylalanine hydroxylase (PAH), due to mutations in the PAH gene [1]. Even in well treated PKU patients, intelligence quotient (IQ) is several points lower than in healthy controls, and neurophysiological and neuropsychological impairments develop [2,3]. To this day, the exact pathophysiologic mechanism by which PKU results in cognitive dysfunction remains unclear. Inconsistencies between the PAH genotype and the PKU metabolic phenotype (level of Phe in serum) have been reported. These inconsistencies shifted a paradigm of PKU as a simple Mendelian disorder toward the understanding of a more complex disease phenotype [5,6]. One of many examples for genotype-phenotype inconsistency is the most frequent mutation in Serbian population, p.L48S [7, 8]
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