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

Figures & data

Table 1. Studies assessing effects of reducing blood Phe for ≥3 weeks in adults with PKU and neuropsychiatric symptoms.

First Author, Year, [Reference]	N	Population and Treatment	Blood Phe (µmol/L) Mean ± SD (range)	Effects on Low-Phe Diet
Blinded Cross-over Studies
Lee et al. (2009)	17	Late-treated, off-diet, intellectual disability, severe challenging behavior	off diet: 1570 ± 222	“Challenging behaviors” varied with individual but included aggression, agitation, self-injury, and screaming. No significant changes in frequency of challenging behaviors from participant diaries or in Aberrant Behavior Checklist, but 76% of caregivers gave positive comments on behavior during low-Phe diet
		Returned to low-Phe diet for 24 weeks	on diet: 553 ± 158
Marholin et al. (1978)	5	Late/untreated–treated, off diet, intellectual disability, severe challenging behavior	off diet: 2119–2906	“Challenging behaviors” varied with individual but included aggression, self-injury, and stereotyped behavior. Few significant desirable behavior changes occurred in 4 adults in which proper methodological controls were employed. Tremor and stereotypy were ameliorated in 2 of 5 adults.
		Returned to low-Phe diet for 8 weeks	on diet: 180–600
ten Hoedt et al. (2011)	9	Early and continuous treatment	on diet: 709 ± 332	Self-reported mood states were significantly less favorable (Profile of Mood States, p = 0.017) during Phe loading
		4-week Phe load	Phe load: 1259 ± 332
Interventional Studies (Single Cohorts)
Bik-Multanowski et al. (2008)	13	Early-treated, off-diet, psychiatric distress	off diet: 1160 (780–1620)	While on diet, 77% (10/13) showed significant improvement in Psychological Well Being Index, particularly in domains of anxiety and depression
		Returned to low-Phe diet for 3 months	on diet: 180–600
M. C. Brown and Guest (1999)	8	Untreated, intellectual disability, severe challenging behaviors	off diet: 1614 ± 355	“Challenging behaviors” varied with individual but included aggression, screaming, self-injury, and stubbornness. Caregiver diaries reported 59% reduction in frequency of negative behaviors. Significant reduction in medication use and hospitalization for asthma and respiratory tract infection.
		Introduced to low-Phe diet for 12 months	on diet: 617 ± 139
Finkelson et al. (2001)	21	Early-treated, off-diet, then returned to diet as adults	not reported	While on diet, 86% (18/21) reported improvement in symptoms (mood lability, energy level, concentration, obesity)
Fitzgerald et al. (2000)	5	Untreated, intellectual disability, severe challenging behaviors	off diet: 1676 (1535–1880)	“Challenging behaviors” varied with individual but included aggression, agitation, screaming, hyperactivity, and self-injury. Caregivers reported improved communication skills, alertness and attention while on diet and 4 of 5 participants showed marked reduction in challenging behaviors (aggression, hyperactivity, agitation).
		Introduced to low-Phe diet for 12 months	on diet: 479 (401–640)
Gassió et al. (2003)	15	Early/late-treated, off-diet, then returned to low-Phe diet for 12 months	on diet: 717 (330–1342)	While on diet, 40% reported improved health, 53% were calmer and less easily upset, 40% were more alert/better able to maintain attention, and 29% were less impulsive/aggressive
Schuett et al. (1985)	72	Early-treated, off-diet, then returned to low-Phe diet for ~10 months	not reported	While on diet, 58% showed positive changes in behavior, 78% showed marked decrease in hyperactivity, 83% showed loss of moodiness
Yannicelli and Ryan (1995)	88	Untreated, intellectual disability	off diet: 1659 (1000–2330)	Within 3 to 8 weeks of introducing low-Phe diet, 46% showed improved behavior, including reductions in degree of irritability (67%), attention to task (59%), hyperactivity (51%), aggressive behavior (46%), moodiness (46%), and incidence of neurologic symptoms (26%). Reduction in use of psychotropic medications was reported in 40% of those who showed improved behavior.
		Introduced to low-Phe diet for ≥ 2 months	on diet: 617 (182–1495)

Table 2. Studies assessing effects of blood Phe on executive function in adults with PKU.

First Author, Year, [Reference]	N	Population and Treatment	Blood Phe (µmol/L) Mean ± SD (range)	Results in Low Blood Phe vs. High Blood Phe Cohorts
Intervention Studies (Single Cohort)
Lou et al. (1987)	9	Early- (5) and late-treated (4), off diet	1477 (980–2050)	6 of 7 participants with abnormally long continuous visual reaction times on regular diet showed improved reaction times on low-Phe diet (means: 34.6 vs. 31.6 1/100 sec)
		After 3 weeks on low-Phe diet	758 (456–1052)
Pietz et al. (1993)	5	Early-treated, off diet	1600 (1290–2130)	On low-Phe diet, participants showed improved scores for attention (Dot Pattern Exercise: 8.8 vs. 11.7) and cognitive flexibility (Color Pattern Exercise)
		After 4 weeks on low-Phe diet	753 (515–1023)
Schmidt et al. (1994)	14	Early-treated, off diet	1332 (569–1949)	On low-Phe diet, participants showed significantly improved scores for attention (Dot Pattern Exercise: 8.1 vs. 10.1, p < 0.001)
		After 4 weeks on low-Phe diet	636 (121–1017)
ten Hoedt et al. (2011)	9	Early and continuous treatment	on diet: 709 ± 332	Phe loading resulted in a significant larger fluctuation in tempo during sustained attention (p = 0.029), but had no significant effect on other measures (Amsterdam Neuropsychological Tasks)
		4-Week Phe load	Phe load: 1259 ± 332
Studies Comparing Cohorts with Low and High Blood Phe
Bik-Multanowski et al. (2011)	22	Early-treated	≤720	Low Phe cohort showed improved scores for working memory (Spatial Span: −1.09 SD vs. −2.92 SD), attention (Rapid Visual Info: −1.59 SD vs. −2.49 SD), and inhibitory control (Stop Signal accuracy: 0.68 vs. 0.60)
	27	Early-treated	>720
Brumm et al. (2004)	11	Early-treated	<1000	When comparing low vs. high Phe cohorts the following reached or neared statistical significance: Attention (CPT Omission Errors 49.7 vs 65.5 and CPT response rate 57.8 vs. 37.3), language function (BNT 40.8 vs 13.1, COWAT 22.7 vs. 5.3, Animal Naming Test 21.9 vs. 16.9, PPVT-R 67.5 vs. 39.9, WAIS-R Vocabulary 67.3 vs. 47.7), psychomotor speed (WAIS-R Digit Symbol 68.8 vs. 48.7).
	13	Early-treated	>1000
Burgard et al. (1997)	8	Early, continuously treated	870 (569–1150)	Low Phe cohort showed significantly improved scores for attention (Dot Pattern Exercise: 8.7 vs. 10.2)
	8	Early-treated, off diet	1350 (1029–1876)
Channon et al. (2007)	25	Early, continuously treated	759 (221–1233)	Low Phe cohort showed significantly improved scores for working memory (2-back [% accuracy]: 88.9 vs. 84.6, p < 0.01) and attention (0-back [% accuracy]: 98.8 vs. 97.1, p < 0.01), but not cognitive flexibility (Object Alteration [% correct trials]: 66.5 vs. 60.2). Low Phe cohort results were mixed for inhibitory control, with significantly better results for speed (Flanker [speed]: 0.45 vs. 49, .47 vs. .52; p < 0.01) but deficits in accuracy (Flanker [% accuracy]: 99.4 vs. 98.0)
	25	early-treated, off diet	1286 (990–1651)
Dawson et al. (2011)	21	Early, continuously treated	640 ± 103	Low Phe cohort showed improved scores for reaction time (saccadic latency: 6.0 vs. 5.6). Reaction times for low Phe cohort did not differ from unaffected controls (p = 0.82), while those for high Phe cohort were significantly worse (p = 0.02)
	56	Early-treated, off diet	1461 ± 185

Table 3. Meta-analyses of reported neuropsychiatric complications and executive function deficits in adults with PKU.

	Number of Study Arms	Number of PKU Participants Tested
Psychiatric Symptoms			Symptom Prevalence (95% CI)
Inattention
Overall	5	805	49% (26%–73%)
Early-treated PKU	2	586	20% (17%–23%)
Late/untreated PKU	3	219	68% (54%–81%)
Hyperactivity
Overall	8	945	20% (14%–28%)
Early-treated PKU	6	745	16% (12%–22%)
Late/untreated PKU	2	200	34% (20%–51%)
Anxiety
Overall	8	889	22% (11%–36%)
Early-treated PKU	5	670	8% (6%–11%)
Late/untreated PKU	3	219	49% (26%–72%)
Depression
Overall	8	889	18% (8%–31%)
Early-treated PKU	6	689	12% (5%–22%)
Late/untreated PKU	2	200	35% (16%–58%)
Neurologic Symptoms			Symptom Prevalence (95% CI)
Epilepsy/seizures
Overall	14	1,028	10% (5%–17%)
Early-treated PKU	7	745	3% (1%–5%)
Late/untreated PKU	7	283	21% (17%–26%)
Tremors
Overall	14	1,028	29% (16%–44%)
Early-treated PKU	7	745	18% (9%–29%)
Late/untreated PKU	7	283	40% (17%–65%)
Executive Function Deficits (Early-treated PKU only)			Effect Size: Standardized Mean Difference (95% CI) [p-value]
Working memory	5	112	0.08 (−0.45 to +0.61) [p = 0.77]
Attention	11	252	0.74 (0.55 to 0.93) [p < 0.0001]
Cognitive flexibility	7	157	0.43 (0.12 to 0.74) [p = 0.006]
Inhibitory control	6	119	0.41 (0.005 to 0.81) [p = 0.047]

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