Brain MRI changes in phenylketonuria: Associations with dietary status

Abstract

Following the introduction 30 years ago of neonatal screening and early dietary treatment for phenylketonuria there has been a dramatic decrease in the severity of neurological dysfunction associated with this disorder. However, there is evidence that subtle neurological impairment remains common in early treated subjects and in the last 3 years there have been a number of reports of overt neurological impairment with white matter abnormalities on MRI. The frequency of white matter changes in phenylketonuria, and the relation of these changes to dietary management, have remained unclear. The present study examines MRI findings in 34 subjects aged 8-33 years. Twenty-five subjects had been detected by routine neonatal screening and nine had been missed in the screening programme. At the time of the investigation 16 of the early treated and two of the late treated subjects were still receiving a diet low in phenylalanine. All but two of the 34 subjects showed abnormalities on MRI. In the early diagnosed group it could be shown that the severity of MRI changes (graded 1-5) was significantly and independently associated with phenylalanine concentrations at the time of investigation and the time since dietary treatment had been withdrawn. These data are consistent with studies in animals showing that hyperphenylalaninaemia increases myelin turnover in a dose dependent manner. It is suggested that the effects of phenylalanine on myelin pose a lifelong hazard to the nervous system.

Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria

“…Of 19 studies reporting neurologic symptoms, the 10 reporting prevalence of both epilepsy/seizures and tremors were included in the MA (Campistol et al, 2012;Crowley, Koch, Fishler, Wenz, & Ireland, 1990;González et al, 2011;Leuzzi, Bianchi, Tosetti, Carducci, & Antonozzi, 2000;Leuzzi, Trasimeni, Gualdi, & Antonozzi, 1995;McDonnell, Esmonde, Hadden, & Morrow, 1998;Pfaendner et al, 2005;Pitt & Danks, 1991;Schuett et al, 1985;Thompson et al, 1993). Table 3 presents MA results that show higher than expected prevalence estimates for neuropsychiatric symptoms in adults with PKU (based on clinical observation) when compared with prevalence estimates (based on a structured diagnostic interview) established by the U.S. National Comorbidity Survey Replication (Kessler, Chiu, Demler, & Walters, 2005).…”

Phenylalanine requirement in children with classical PKU determined by indicator amino acid oxidation

“…Sixty four mg.kg".daym' represents the lysine requirements suggested by FAONHO (1 985) for children 2 yean old and is higher that the requirement suggested for boys 10-1 2 yean old for whom requirements is defined as 4440 mg. kg" .dayW' . Because normal daily dietary lysine intake of these subjeds varied between 59 …”

Long-Term Enzymatic and Phenotypic Correction in the Phenylketonuria Mouse Model by Adeno-Associated Virus Vector-Mediated Gene Transfer

“…Nevertheless, the range remained below the level (Ͻ900 M) recommended to prevent brain damage (25). When AAV vector stably transduced hepatocytes in experimental animals, nonintegrated extrachromosomal genomes were reported to be the major form of recombinant AAV in the liver and to be the primary source of recombinant AAV-based gene expression (26,27).…”