PKU and COVID19: How the pandemic changed metabolic control

Abstract

Background:
COVID19 pandemic urged the need to take severe measures for reducing the epidemic spread. Lockdowns were imposed throughout countries and even Inborn errors of metabolism (IEMs) affected patients had to face it and adapt, with management strategies changes coming along. Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism causing, when not treated, blood Phe increases and consequent central nervous system (CNS) damage. Dietary intervention is the main recognized treatment and must be maintained long-life, however adherence is often suboptimal in adulthood. Aim of this study was to evaluate whether and how the pandemic had impacted PKUs metabolic control and what factors may have played a role as potential modifiers.

Methods:
Patients ≥4 yo and in follow-up at our Metabolic Clinic were enrolled in this study, divided into subgroups according to age (GROUP A < 12 yo; GROUP B ≥ 12 yo). Videoconsults were conducted on a minimum monthly basis and collected DBS were studied and compared to previous year same time-period in order to evaluate possible changes.

Results:
39% of patients (n = 121) increased the number of performed DBS. "Non-compliant" patients were reduced (11-3%) with a - 14% of patients with mean Phe levels >600 umol/l and a - 8% of patients with 100% DBS above same level. GROUP A maintained substantially unchanged metabolic control among two analyzed time-periods. On the contrary, GROUP B demonstrated significant reductions in mean blood Phe concentrations (p < 0.0001) during the pandemic (mean 454 umol/l, SD ± 252, vs. 556.4 umol/l, SD ± 301).

Discussion:
COVID19 pandemic strongly impacted people's life with lifestyle habits changing consistently. PKU patients had to adapt their dietary restrictions to the new environment they were exposed to and, if younger patients could have been less exposed (meals strictly according to diet plan independently from setting), adolescent and adults strongly reflected the obligation to stay home by showing better metabolic control. Multiple factors could have played a role in that and the availability of teleconsultancy may have contributed allowing easier connections, but our data demonstrate how the pandemic and the environment can strongly impact PKUs adherence to treatment and how removing distance barriers can ameliorate and optimize metabolic compliance.

Full text

Since January 2020 Elsevier has created a COVID-19 resource centre with
free information in English and Mandarin on the novel coronavirus COVID-
19. The COVID-19 resource centre is hosted on Elsevier Connect, the
company's public news and information website.
Elsevier hereby grants permission to make all its COVID-19-related
research that is available on the COVID-19 resource centre - including this
research content - immediately available in PubMed Central and other
publicly funded repositories, such as the WHO COVID database with rights
for unrestricted research re-use and analyses in any form or by any means
with acknowledgement of the original source. These permissions are
granted for free by Elsevier for as long as the COVID-19 resource centre
remains active.

Molecular Genetics and Metabolism Reports 27 (2021) 100759
Available online 23 April 2021
2214-4269/© 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
PKU and COVID19: How the pandemic changed metabolic control
Valentina Rovelli
*
, Juri Zuvadelli, Vittoria Ercoli, Chiara Montanari, Sabrina Paci,
Alice Re Dionigi, Andrea Scopari, Elisabetta Salvatici, Graziella Cefalo, Giuseppe Banderali
Inborn Errors of Metabolism Unit, Clinical Department of Pediatrics, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Italy
ARTICLE INFO
Keywords:
COVID-19
PKU
Diet
Adherence
Metabolic control
Lockdown
ABSTRACT
Background: COVID19 pandemic urged the need to take severe measures for reducing the epidemic spread.
Lockdowns were imposed throughout countries and even Inborn errors of metabolism (IEMs) affected patients
had to face it and adapt, with management strategies changes coming along. Phenylketonuria (PKU) is an inborn
error of phenylalanine (Phe) metabolism causing, when not treated, blood Phe increases and consequent central
nervous system (CNS) damage. Dietary intervention is the main recognized treatment and must be maintained
long-life, however adherence is often suboptimal in adulthood. Aim of this study was to evaluate whether and
how the pandemic had impacted PKUs metabolic control and what factors may have played a role as potential
modiers.
Methods: Patients ≥4 yo and in follow-up at our Metabolic Clinic were enrolled in this study, divided into
subgroups according to age (GROUP A <12 yo; GROUP B ≥12 yo). Videoconsults were conducted on a min-
imum monthly basis and collected DBS were studied and compared to previous year same time-period in order to
evaluate possible changes.
Results: 39% of patients (n =121) increased the number of performed DBS. “Non-compliant” patients were
reduced (11–3%) with a −14% of patients with mean Phe levels >600 umol/l and a −8% of patients with 100%
DBS above same level. GROUP A maintained substantially unchanged metabolic control among two analyzed
time-periods. On the contrary, GROUP B demonstrated signicant reductions in mean blood Phe concentrations
(p <0.0001) during the pandemic (mean 454 umol/l, SD ±252, vs. 556.4 umol/l, SD ±301).
Discussion: COVID19 pandemic strongly impacted people’s life with lifestyle habits changing consistently. PKU
patients had to adapt their dietary restrictions to the new environment they were exposed to and, if younger
patients could have been less exposed (meals strictly according to diet plan independently from setting),
adolescent and adults strongly reected the obligation to stay home by showing better metabolic control.
Multiple factors could have played a role in that and the availability of teleconsultancy may have contributed
allowing easier connections, but our data demonstrate how the pandemic and the environment can strongly
impact PKUs adherence to treatment and how removing distance barriers can ameliorate and optimize metabolic
compliance.
1. Introduction
Phenylketonuria (PKU; OMIM 261600) is an inborn error of meta-
bolism caused by mutations in the PAH gene, coding for the liver
enzyme phenylalanine hydroxylase (PAH, EC 1.14.16.1) and normally
converting the aminoacid phenylalanine (Phe) into tyrosine (Tyr) [1].
Absence or decrease in PAH activity results in increased blood Phe
concentrations, or its metabolites, with consequent toxic levels reaching
mainly the CNS. Left untreated, symptoms can develop shortly after
birth and include neurological impairment with possible psychomotor
delay, seizures, autism and behavioral disorders. Mainstay treatment to
date is a lifelong dietary intervention which can guarantee normal
growth and neurodevelopment. Diet consists in the use of low protein
foods, amino acid substitutes and micronutrient supplements. Palat-
ability, exibility and ease of use are primarily important to ensure
patients’ compliance to prescriptions [2].
Abbreviations: PKU, Phenylketonuria; PAH, phenylalanine hydroxylase; Phe, phenylalanine; DBS, Dried Blood Spot; Tyrosine, (Tyr); CNS, Central Nervous System;
LD, Lockdown; IEM, Inborn errors of metabolism; MAM-2019, March–April-May 2019; MAM-2020, March–April-May 2020..
* Corresponding author.
E-mail address: valentina.rovelli@asst-santipaolocarlo.it (V. Rovelli).
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism Reports
journal homepage: www.elsevier.com/locate/ymgmr
https://doi.org/10.1016/j.ymgmr.2021.100759
Received 12 April 2021; Accepted 13 April 2021

Molecular Genetics and Metabolism Reports 27 (2021) 100759
2
Recently the world had to face the COVID19 pandemic and many
countries announced quarantine measures (“lockdown”, LD) shortly
after rst reported cases. Italy was the rst western country to deal with
the spreading of the disease and imposing LD in order to delay and avoid
community transmission, thus sudden lifestyle changes were under-
taken. People had to cope and adapt switching to spending most of their
time at home, moving from one place to another only for emergency
reasons or work, working remotely and, more importantly, cooking
themselves instead of consuming prepared meals in restaurants, pubs or
canteens. All gathering places were also closed and younger people (e.g.
students normally eating in the school-cafeteria), got back to eat at
home.
Patients affected by IEMs did not differ and had to face LD measures
the same way, switching their “managing the diet” habits from a known
and usual setting to a total new one within just some days. Clinical
monitors and health supervisors had to adapt too in order to encounter
new needs, and “telehealth” became the main tool doing so assuring the
need of care besides the pandemic spread.
PKU is a chronic disease mainly affecting nutritional life aspects, thus
can be used as a procient IEM example to reect possible LD’s induced
changes in IEM affected patients’ life. Accordingly, aim of this study was
to evaluate whether and how PKU patients’ metabolic control may have
changed during the pandemic.
2. Aims of the study
Aim of this study was to analyze and identify possible signicant
changes in blood Phe concentrations and in monitoring frequencies
(number of DBS made) during lockdown (2020) compared to same time-
period during the previous year (2019).
3. Patients and methods
Patients affected by PKU (conrmed by molecular analysis)
requiring dietary intervention and in follow up at our Metabolic Clinic
(San Paolo Hospital, ASST Santi Paolo e Carlo, University of Milan, Italy)
were enrolled in this study and subjected to videoconsults on at least a
monthly basis. Study population was divided into subgroups with
regards to age: GROUP A, age 4–12 yo (“pediatric population”) and
GROUP B ≥12 yo (“adolescent and adult population”). Patients <4 yo
were excluded due to dietary restrictions expected to be strictly
observed independently from environment. We identied as “lost at
follow up” all patients who, before lockdown period, weren’t getting
back to clinic for at least 2 consecutive years as suggested by literature
[3]. As rst lockdown in Italy began at the end of February 2020 and
nished at the end of May 2020, study periods were identied as
March–April-May 2019 (MAM-2019) and March–April-May 2020
(MAM-2020). As dried blood spots (DBS) have been proven to be a
powerful sampling method to monitor PKUs metabolic control (in this
study identied by mean of blood Phe values during analyzed time pe-
riods), they were reviewed and analyzed considering both monitoring
frequencies and single obtained Phe value results [4]. Patients with less
than 1 DBS performed per month were excluded due to possible related
bias, as suggested by literature. All analyzed DBS were collected during
the morning after overnight fasting, as suggested by current guidelines
[5]. Metabolic control was considered “insufcient” for identied Phe
levels above set “safe ranges” depending on age (>360 umol/L if age
<12 yo and >600 umol/L for age ≥12 yo) and patients consequently
identied as “non-compliant” for Phe levels >1000 umol/l. Pregnancy
and Kuvan treatment starting along analyzed time periods were
considered as exclusion criteria due to possible related bias.
4. Statistical analysis
Data were analyzed category related. Wilcoxon paired sample t-test
was used to compare sets of data acquired from patients during MAM
2019 and MAM 2020; condence intervals (95% CIs) were used to
examine differences in blood Phe concentrations between the two
identied time periods. For normal distribution of individual charac-
teristics, Pearson’s correlations were used for comparison; in other cases
Spearman’s correlations were used. Data were analyzed using SPSS
version 26.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were
expressed as mean (standard deviation, SD) and median (min-max).
Signicant values were considered for p < 0.05.
5. Results
5.1. Demographics
A total of 310 PKU patients in actual follow up at our Clinic were
screened and reviewed for enrollment purposes. Among those, 192 pa-
tients were considered eligible for this study as meeting all inclusion
criteria (n =192, sample size). Mean identied age for study population
was 21.9 y.o. (age range 4–65 yo). Gender resulted equally distributed
among GROUP B and nearly equally distributed among GROUP A
[Table 1].
5.2. Monitoring frequencies
Follow up visits didn’t differ as much in numerical terms comparing
2019–2020 (+2.9% in 2020). Major change was, during 2020, how
they’ve been done: only 9% of visits were performed in person while in
91% they were done remotely.
In terms of blood monitoring frequencies, a total number of 1068 dB
were received by our Clinic during MAM 2020, vs 1131 during MAM
2019 (−5.9%). 39% of patients (n =121) increased the number of
performed DBS, moving from at least 1 dB to a maximum of 5 per month.
Among those who increased monitoring frequencies, 85% (n =103)
were adolescents and adults thus frequency increase was more evident
among older population (Fig. 1).
Furthermore we could observe 37 patients (12%) who weren’t per-
forming any DBS in MAM 2019 and started doing so in MAM 2020 (at
least one DBS per month).
5.3. Metabolic control
Metabolic control did not differ signicantly among pediatric pop-
ulation (GROUP A) during MAM 2019 vs MAM 2020. On the contrary,
adolescent and adult population (GROUP B) demonstrated a signicant
improvement in metabolic control showing reduced Phe values during
MAM 2020 compared to MAM 2019, as shown in Table 2.
An increase in the percentage of patients with mean Phe blood
concentrations below the upper recommended threshold could also be
observed analyzing both age groups, as shown in Fig. 2.
5.4. Patients’ stories
- PATIENT 1: M., 19 yo male PKU, lost at follow-up, no DBS sent to our
Centre since 2017. Last Phe value at plasma aminoacids prole =
1680 umol/L (year 2017). At the beginning of MAM 2020 M. could
be recalled offering telehealth services and advised to get back to the
Table 1
PKU sample demographic characteristics.
Demographics (n =192)
GROUP A (n =51) GROUP B (n =141)
Age (y)
Mean (SD) 8.4 (±2.0) 26.8 (±11.7)
Median (min-max) 9.1 (4–11) 24.0 (12–65)
Gender (n)
M/F 31/20 70/71
V. Rovelli et al.

Molecular Genetics and Metabolism Reports 27 (2021) 100759
3
Centre for monitoring purposes. He thus performed a preliminary
DBS which demonstrated non-compliant Phe levels (1613 umol/L).
Strict diet was restarted and M. was compliant to follow new dietary
recommendations. At the end of April 2020, DBS showed mean blood
Phe levels of 244 umol/L, meaning excellent metabolic control. Such
results are still conrmed at present.
- PATIENT 2: S., 30 yo male PKU, poor cognition of being PKU thus
non-compliant to recommendations and difcult to identify in terms
of Phe tolerance. During MAM 2019 he had sent to our Clinic just n.2
dB. After recall he could be again involved in adherence and began to
be interested and participating. During MAM 2020 n.13 dB were
received (4.33 dB/month) and tolerance could be again identied
thus dietary intervention could be optimize.
- PATIENT 3: G., 22 years old female PKU, developmentally delayed
for a genetic condition, showing insufcient metabolic control since
accepted on a daily basis in a controlled community where
consuming meals. During MAM 2019, her mean blood Phe levels
were 649.2 ±243.3 umol/L (min: 303 umol/L; max: 998 umol/L).
After LD measures enforcement, G. couldn’t attend her habitual
community and was obliged to get back at home with her parents
that were asked again to take care of the diet. Average metabolic
control during MAM 2020 changed strongly: her Phe levels drop
down to 289.5 ±182.2 3 umol/L (min:74 umol/L; max: 571 umol/
L).
6. Discussion
Transition from childhood to adulthood can be demanding. Studies
suggest that children are more independent with their food choices as
they become adolescents, thus more likely to be inuenced by peers and
less likely to choose healthy foods among others [6]. Same scenario can
be expected among IEMs affected patients, among whom PKUs can best
represent the scenario of a strongly recommended dietary intervention,
challenging since the very beginning of life and more and more so every
other year. PKUs are known to experience difculties when dealing with
social environments to which they can be exposed (i.e. social life, job
activities, etc.) and consequent insufcient metabolic control is often
describe. This may also be linked to an altered perception and awareness
Fig. 1. Percentages of patients changing monitoring frequencies among two analyzed time periods (MAM 2019 vs. MAM 2020) (a), also divided per age (b).
Table 2
Metabolic control expressed by mean of Phe levels assessed with DBS among two
analyzed time periods (MAM 2020 vs MAM 2019).
Blood Phe values (umol/l)
MAM 2019 MAM 2020 p
GROUP A
Mean (SD) 315.4 (114) 309.2 (134) 0.717
Median (min-max) 311.5 (85–586) 287.8 (86–645)
GROUP B
Mean (SD) 556.4 (301) 454 (252) 0.000*
Median (min-max) 478 (113–1612) 409 (35–1525)
*
Signicant values were considered for p <0.05.
Fig. 2. Changes in blood Phe values according to age, comparing MAM 2019
vs. MAM 2020 time-period. * =statistically signicant (p values <0.05); ** =
statistically signicant (p values <0.01).
“Non-compliant” patients were also reduced (lowering from 11% to 3%) with
also a nding of −14% of patients with mean Phe levels >600 umol/l and a −
8% of patients with 100% DBS above same level (results shown in Fig. 3).
Fig. 3. Variations between percentages of PKU non-compliant patients during
MAM 2019 vs MAM 2020.
No signicant differences could be observed on a gender basis.
V. Rovelli et al.

Molecular Genetics and Metabolism Reports 27 (2021) 100759
4
of the disease: about 40% of PKUs do not consider PKU as a disease and
consequently don’t fully understand the importance of the dietary
intervention [7].
COVID-19 world pandemic imposed a new set of challenges for IEMs
affected patients and PKU population can represent a valuable example
of that. During the pandemic, patients were asked to stay home and
avoid contact with other people, thus severe repercussions on both food
access and utilization were evident with direct effects on lifestyle habits,
including changes in social environments and physical activity patterns
to which they were exposed. Efforts to keep choosing healthy dietary
habits and maintain adherence to treatment had to be made, same for
clinical monitors and health providers that had to adapt trying to nd
new ways for improving metabolic outcomes besides social distancing.
The use of “telehealth” was one of the most important improvements
and adaptation to that, with virtual care becoming a consistent part of
clinical care [8,9]. Our study investigated how all that can have possibly
affected PKU patients, analyzing possible changes in metabolic control
and monitoring frequencies over same time-periods (2020 vs. 2019).
Differences could be found and were mostly evident for adolescent and
adult population. If among child population (GROUP A) metabolic
control did not differ signicantly during MAM 2019 vs MAM 2020,
adolescent and adult patients (GROUP B) demonstrated a signicant
decrease in blood Phe concentrations with signicant improvements in
metabolic control (556.4 ±301 umol/l in MAM 2019 vs. 454 ±252
umol/l in MAM 2020). This may have been related to the different social
and familiar context: younger patients maybe already used to be
“controlled” and kept on track by parents, while adolescent and adult
patients are more used to managing diet alone thus are more prone to
change lifestyle habits when pushed to. Moreover, even if a slight
decrease in the total number of performed DBS could be observed among
two analyzed time periods, a total of 121 (39%) patients increased the
number of DBS performed, maybe reecting an improvement in illness
awareness and the will to improve dietary adherence (Fig. 1). We found
this evidence relatively uncommon considering how we are normally
used to read in literature about adolescent and adult patients demon-
strating poor dietary adherence with increasing age [10–12]. Our results
could demonstrate instead how adolescent and adult patients, if exposed
to a more favorable social environment with less external inuences, can
concentrate more on diet and signicantly improve metabolic control
reducing out of range Phe-values.
Being exposed not to strangers but only to familiar/parents, having
more spare time to spend cooking and to advocate to improve adherence
to the regular consumption of aminoacids substitutes played a major
role in that and can thus be identied as main modiers optimizing
compliance, as already previously suggested by literature [13]. Also, as
follow up visits didn’t differ as much in terms of numbers comparing
2019–2020 (+2.9% in 2020), these results add support to the fact that it
wasn’t the changes in clinical management that changed metabolic
control of our patients, but themselves.
Psychological issues and potential QoL/neurological changes
weren’t assessed in this study as not considered rst aims of evaluation
and this can be a limit to fully determine how the pandemic affected PKU
patients’ lives. Even if strongly impacting lives, lockdown may have
created the ideal situation to encourage PKU patients to take care of
themselves, pushing them to adapt the diet/supplements to their lives
and not only the other way round. This could be furthermore demon-
strated with the evidence of reducing percentages of non-compliant
patients, both considering having Phe values >600 umol/l and >1000
umol/l, and for the nding of increasing monitoring frequency over
MAM 2020.
On the healthcare providers perspective, we strongly believe that the
empowerment of interventions that can promote access to care and
assistance services (such as “telehealth”) played a major role in that.
Such assumption is even more supported considering that associations
between higher stafng intensity and improvements in patient’s
adherence to clinics’ recommendations have been already described in
literature [14]. As we strongly used telehealth services during MAM
2020, we speculate that this was denitely linked to the better outcomes
observed.
7. Conclusion
The world scenario in which we have recently found ourselves
operating as health care providers has strongly impacted on standard
clinical practice as well as, on the other hand, on people suffering from
chronic diseases and in need of follow up and treatment. Emerged data
from this study can demonstrate how much the social context to which
this type of patients are normally exposed to can have a strong inuence
on the ability to keep metabolic control on track, but how much this can
actually also lead to positive outcomes, obtaining a signicant
improvement in metabolic trends when correctly assessed and
addressed. PKU population represent an excellent example of how this
can be possible. Our results highlight positive and statistically signi-
cant changes in metabolic control and monitoring frequencies in the
population of adolescent and adult PKU during lockdown, thus strongly
suggest keeping implementations made during lockdown even on the
long term, in order to be able to enhance as much as possible the positive
effects achieved and continue to reach patients more effectively and
more quickly, facilitating them in their treatment processes and in the
possibility of receiving assistance regardless of their geographical loca-
tion and/or possibilities related to the social context to which they are
exposed to.
Acknowledgements
This research did not receive any specic grant from funding
agencies in the public, commercial, or not-for-prot sectors.
References
[1] OMIM® and Online Mendelian Inheritance in Man, OMIM Entry – # 261600 –
PHENYLKETONURIA; PKU, in: PHENYLKETONURIA; PKU, 2020.
[2] A. MacDonald, Diet and compliance in phenylketonuria, Eur. J. Pediatr. Suppl. 159
(2) (2000) 136–141, https://doi.org/10.1007/pl00014375.
[3] J. Beazer, J. Breck, C. Eggerding, P. Gordon, S. Hacker, A. Thompson, Strategies to
engage lost to follow-up patients with phenylketonuria in the United States: best
practice recommendations, Mol. Genet. Metab. Rep. 23 (January) (2020), https://
doi.org/10.1016/j.ymgmr.2020.100571, p. 100571.
[4] K. Li, J.C. Naviaux, J.M. Monk, L. Wang, R.K. Naviaux, Improved dried blood spot-
based metabolomics: a targeted, broad-spectrum, single-injection method,
Metabolites 10 (3) (2020), https://doi.org/10.3390/metabo10030082.
[5] A.M.J. Van Wegberg, et al., The complete European guidelines on phenylketonuria:
diagnosis and treatment, Orphanet J. Rare Dis. 12 (1) (2017) 1–56, https://doi.
org/10.1186/s13023-017-0685-2.
[6] M. Seymour, S.L. Hoerr, Y. Li Huang, Inappropriate dieting behaviors and related
lifestyle factors in young adults: are college students different? J. Nutr. Educ.
Behav. 29 (1) (1997) 21–26, https://doi.org/10.1016/s0022-3182(97)70142-0.
[7] C. Cazzorla, et al., Living with phenylketonuria in adulthood: the PKU ATTITUDE
study, Mol. Genet. Metab. Rep. (2018), https://doi.org/10.1016/j.
ymgmr.2018.06.007.
[8] M.A. Kadir, Role of telemedicine in healthcare during COVID-19 pandemic in
developing countries, Telehealth Med. Today (2020) 1–5, https://doi.org/
10.30953/tmt.v5.187.
[9] D. Golinelli, E. Boetto, G. Carullo, A.G. Nuzzolese, M.P. Landini, M.P. Fantini, How
the COVID-19 pandemic is favoring the adoption of digital technologies in
healthcare: a literature review, medRxiv (2020), https://doi.org/10.1101/
2020.04.26.20080341, pp. 0–2.
[10] J.H. Walter, et al., How practical are recommendations for dietary control in
phenylketonuria? Lancet 360 (9326) (2002) 55–57, https://doi.org/10.1016/
S0140-6736(02)09334-0.
[11] J.H. Walter, F.J. White, Blood phenylalanine control in adolescents with
phenylketonuria, Int. J. Adolesc. Med. Health 16 (1) (2004) 41–45, https://doi.
org/10.1515/IJAMH.2004.16.1.41.
[12] M.R. Crone, F.J. Spronsen, K. Oudshoorn, J. Bekhof, G. van Rijn, P.H. Verkerk,
Behavioural factors related to metabolic control in patients with phenylketonuria,
V. Rovelli et al.

Molecular Genetics and Metabolism Reports 27 (2021) 100759
5
J. Inherit. Metab. Dis. 28 (5) (2005) 627–637, https://doi.org/10.1007/s10545-
005-0014-0.
[13] L. Borghi, C. Moreschi, A. Toscano, P. Comber, E. Vegni, The PKU & ME study: a
qualitative exploration, through co-creative sessions, of attitudes and experience of
the disease among adults with phenylketonuria in Italy, Mol. Genet. Metab.
Reports 23 (January) (2020), https://doi.org/10.1016/j.ymgmr.2020.100585, p.
100585.
[14] E.R. Jurecki, et al., Adherence to clinic recommendations among patients with
phenylketonuria in the United States, Mol. Genet. Metab. 120 (3) (2017) 190–197,
https://doi.org/10.1016/j.ymgme.2017.01.001.
V. Rovelli et al.