Neurological outcome in adult patients with early-treated phenylketonuria

Pietz, Joachim; Dunckelmann, Robert; Rupp, André; Rating, D.; Meinck, H.-M.; Schmidt, H; Bremer, H. J.

doi:10.1007/s004310050945

Cited by 111 publications

(106 citation statements)

References 30 publications

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“…Untreated PAH deficiency is associated with intellectual disability; 64 however, with advances in NBS and treatment, untreated PAH deficiency is rare. Nonetheless, much data have been published indicating an inverse relationship between PHE levels and IQ.…”

Section: Acmg Practice Guidelines Neurocognitive and Psychological Oumentioning

confidence: 99%

“…Nonetheless, much data have been published indicating an inverse relationship between PHE levels and IQ. 64 IQ scores in individuals with PAH deficiency are principally related to age of the individual at the time of diet initiation and discontinuation. 65 Over the past half-century, IQ has served as one of the primary outcome variables for individuals with PAH deficiency, not only for monitoring cognitive development but also for assessing response to treatment.…”

Section: Acmg Practice Guidelines Neurocognitive and Psychological Oumentioning

confidence: 99%

“…These include consequences of a more rigid style of parenting, delayed autonomy for affected adults, and difficulties forming adult relationships. 64,90 Despite these concerns, early and continuously treated patients with PAH deficiency can have a normal health-related quality of life. 24 …”

Section: Psychological Issuesmentioning

confidence: 99%

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Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

523

443

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Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU) due to characteristic phenylketones accumulating in the urine of affected individuals, has a significant place in history as the first inborn error of metabolism identified through population-based screening, initiating a new era in the diagnosis and treatment of genetic disorders. PKU was first described in 1934 by the Norwegian physician Asbjörn Fölling, but it was not until the mid-1950s that a patient with PAH deficiency was treated with a low phenylalanine (PHE) diet. Although this first patient already had irreversible Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder.Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medica...

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Section: Acmg Practice Guidelines Neurocognitive and Psychological Oumentioning

confidence: 99%

Section: Acmg Practice Guidelines Neurocognitive and Psychological Oumentioning

confidence: 99%

See 1 more Smart Citation

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

523

443

View full text Add to dashboard Cite

show abstract

“…A number of studies suggest that these controlled patients still suffer some cognitive loss and clear neurologic stress (Diamond et al, 1997;Levy, 1999;Pietz et al, 1997Pietz et al, ,1998Pietz, 1998). Thus while dietary therapy for PKU can alleviate many of the most deleterious effects of the disease, it is not completely successful from a clinical standpoint.…”

Section: Introductionmentioning

confidence: 99%

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

et al. 2007

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Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah enu2 mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah enu2 mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah enu2 mice and corresponded to rapid reduction of serum Phe levels.

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“…In addition, increased tremor and decreased hand-wrist steadiness, finger-hand dexterity, and hand-wrist speed have been observed (Pietz et al, 1998).…”

mentioning

confidence: 99%

Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria.

et al. 2003

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This study examined motor control in 61 early and continuously treated patients with phenylketonuria (PKU) and 69 control participants, aged 7 to 14 years. The pursuit task demanded concurrent planning and execution of unpredictable movements, whereas the tracking task required a highly automated circular movement that could be planned in advance. PKU patients showed significantly poorer motor control in both tasks compared with control participants. Deficits were particularly observed for younger patients (age Ͻ 11 years). Differences between control participants and PKU patients were significantly greater in the pursuit task compared with the tracking task, indicating more serious deficits when a higher level of controlled processing is required. Correlations with historical phenylalanine levels indicated a later maturation of the level of control required by the pursuit task compared with the tracking task.

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Neurological outcome in adult patients with early-treated phenylketonuria

Cited by 111 publications

References 30 publications

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria.

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