Phenylketonuria

Prognosis and complications
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By Cary O Harding MD

Prognosis in untreated phenylketonuria is poor, although 2% to 5% of untreated children will have normal intelligence. In treated individuals with phenylketonuria, prognosis is usually good, with normal intelligence. Individuals with phenylketonuria who maintain strict adherence to the diet have the best outcomes; most of those who discontinue the diet will exhibit a decline in IQ scores (Holtzman et al 1986; Ris et al 1994). The severity of decrease in IQ score correlates with the duration off of the diet and the age when the diet was discontinued, with the poorest performance occurring in children who discontinued the diet before 6 years of age.

However, even children treated early and who successfully maintain their plasma phenylalanine concentrations within the targeted treatment range will likely exhibit mild executive impairment (Diamond et al 1997; Leuzzi et al 2004). This topic has recently been the subject of intense research by multiple investigators seeking to define the cause(s) and to find a remedy for these issues; these ongoing efforts have recently been summarized in a series of review articles (White et al 2010). Seemingly minor fluctuations in plasma phenylalanine concentrations in well-controlled individuals can interfere with neuropsychological function; younger children are especially sensitive to this effect (Huijbregts et al 2002). Even mild elevations of plasma phenylalanine concentrations chronically above the recommended treatment range may have detrimental effects on cognition (Diamond 1994). Some functions (cognitive flexibility, attention, and complex problem solving) have a strong negative correlation with elevated plasma phenylalanine concentrations at the time of testing (Ris et al 1994). One theory is that there is dysfunction of prefrontal cortex, possibly due to dopamine depletion (Diamond et al 1997).

When assessed by their teachers, children with phenylketonuria are more likely to be rated as having more deviant behavior (mannerisms, anxiety, hyperactivity, and less social) than unaffected individuals, but are not rated as more aggressive or disobedient (Smith et al 1988). Children with phenylketonuria are more likely to be treated with stimulant medications than unaffected individuals (Arnold et al 2004). Adolescents and adults with phenylketonuria show more depression, dependency, low frustration tolerance, and low self-esteem, and are prone to social withdrawal (Weglage et al 1992; Waisbren and Zaff 1994). The incidence of these abnormalities correlates with duration of poor dietary compliance, but the symptoms often respond to renewed dietary phenylalanine restriction (Waisbren and Zaff 1994). Formal screening for psychiatric symptoms in adults with PKU reveals a high and previously under appreciated incidence of psychosis, paranoid ideation, obsessive-compulsive disorder, depression, and anxiety; both acute and chronic elevations of blood phenylalanine concentration are correlated with the occurrence of psychiatric symptoms (Bilder et al 2013). Individuals diagnosed and treated late (older than 3 months old), treated adults who have had difficulty with diet adherence, and even untreated adults with cognitive abnormalities who were born prior to the advent of newborn screening may significantly benefit from the favorable behavioral effects of a low-phenylalanine diet (Gassio et al 2003). It is clear that, even in well-controlled individuals, there are neuropsychological effects of elevated brain phenylalanine concentrations.

Neurologic deterioration, such as spasticity and cognitive decline, has been reported in some individuals. Minor neurologic abnormalities, such as tremors and fine motor difficulties, can be seen in fairly well controlled individuals with phenylketonuria; however, significant neurologic deterioration has only been reported in those with probable late treatment or with IQs of less than 80. This has not been seen in individuals treated early, except due to a concomitant vitamin B12 deficiency (Brenton and Pietz 2000).

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
References cited
Contributors