Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: PAH
• Condition: Phenylketonuria (PKU)
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• PAH ⇔ 0009861 (phenylketonuria): Definitive Actionability

Actionability Rationale

Definitive actionability was the consensus but it was also recognized that actionability decreases as severity of disease and age at diagnosis increase. Actionability for this condition is expected to be lower when ascertained outside of the newborn time period or with non-classic phenotypes. We acknowledge that opportunistic genomic screening cannot replace biochemical newborn screening for this condition.

Final Consensus Scores

Gene Condition Pairs: PAH ⇔ 0009861 (OMIM:261600)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
PAH deficiency-related morbidity from elevated blood phenylalanine levels / Evaluation and management by specialists to achieve target phenylalanine levels with dietary and/or pharmacologic therapies	2	3A	3A	2	10AA

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU), has considerable geographic variation. Two recent meta-analyses (k=45 and 46 studies) of the birth prevalence of PAH deficiency, based mostly on newborn screening (NBS) program data, reported a global birth prevalence of 6/100,000 births (ranging from 0.3-38/100,000 births in different regions). For the severe “classic” form of PAH deficiency, exact prevalence is not known but is estimated to be about 1/15,000 births. Prevalence information on other forms (e.g., mild PAH deficiency, hyperphenylalaninemia) was not identified. [1, 2, 3]

Clinical Features

Clinical features of PAH deficiency include intellectual disability, developmental delay, stunted growth, microcephaly, epilepsy, musty body odor, decreased skin and hair pigmentation, eczema, behavior problems (hyperactivity), psychiatric symptoms, motor disturbances, and emotional and attention deficit disorders. Individuals also have decreased myelin formation and decreased dopamine, norepinephrine, and serotonin production, as well as structural anomalies and other pathologies in the brain.
PAH deficiency presents a spectrum of severity based on the degree of elevated phenylalanine (Phe). Timing, duration, and intensity of exposure to high Phe levels in childhood and adolescence determine the severity of symptoms and long-term brain effects experienced by people with PAH deficiency. The most severe individuals were historically referred to as “classic PKU”. (NOTE: This report will refer to them as “severe”.) Individuals with a milder presentation and Phe concentrations consistently above 120 μmol/L but lower than 1,200 μmol/L on an unrestricted diet may be referred to as having hyperphenylalaninemia (HPA).
Without dietary restriction of Phe, most children with severe PAH deficiency develop profound and irreversible intellectual disability. Individuals with HPA are at a much lower risk for cognitive and neuropsychological impairment in the absence of treatment.
Phe is a potent teratogen, and elevated blood Phe levels in a pregnant person can result in a teratogenic syndrome in the fetus, even if the fetus does not have PAH deficiency. Poorly controlled disease during pregnancy can lead to microcephaly, poor fetal growth, birth defects (e.g., congenital heart defects, craniofacial abnormalities), intellectual disability, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders in the child. When treatment is adhered to, the chances of a good outcome are comparable to the general population. [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20]

Natural History

Infants with PAH deficiency show no physical signs at birth. Almost all individuals are diagnosed by newborn screening and treated immediately, resulting in essentially normal development, although neuropsychological deficits and psychiatric, behavioral, and social issues can occur. In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe, and can lead to neurological damage and intellectual disability if left untreated. Problems can emerge later in life including exaggerated deep tendon reflexes, tremor, paraplegia or hemiplegia, and osteopenia. In cases of severe PAH deficiency, late diagnosed individuals present mostly with signs of severe progressive developmental delay. Some individuals not diagnosed until adulthood present with neurological complications without severe neurocognitive impairment. Untreated individuals develop profound, permanent intellectual impairment and deterioration of cognitive performance and motor skills. In treated individuals, clinical signs vary based on treatment and diet compliance.
Adults with severe PAH deficiency who had good control of Phe levels neonatally and during childhood typically have normal intelligence but may develop mild degrees of intellectual deficit. However, over time, neuropsychiatric issues may manifest in treatment-adherent adults. In general, individuals with milder PAH pathogenic variants have better response to the adjunct pharmacologic therapy sapropterin.
Historically, children diagnosed with PAH deficiency were allowed to relax the dietary restriction of Phe in adolescence. However, it has been demonstrated that increased Phe levels in adulthood have been associated with development of significant adverse psychiatric and neurocognitive problems, including anxiety, depression, phobias, panic attacks, deficits in executive functioning, decreases in intelligence quotient (IQ), reduced attention span, slow information-processing abilities, and slow motor reaction time. These adults may also develop vision loss, minor neurologic abnormalities such as tremor and brisk reflexes and, in some cases, more severe neurologic dysfunction such as paralysis. [4, 5, 6, 10, 11, 13, 14, 15, 16, 17]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed ACT sheets to help clinical decision-making following newborn screening (https://www.acmg.net/PDFLibrary/Phenylalanine.pdf) and for care of adults with the condition (https://www.acmg.net//PDFLibrary/Adult-PKU.pdf). [21, 22, 23]

There are several evidence-based management guidelines for PAH deficiency. The guidelines are nuanced and not replicated in their entirety here. [4, 6, 12, 14, 15, 17, 18, 24, 25, 26]

To establish the extent of disease and needs in an individual diagnosed with PAH deficiency, the following are recommended:
•Referral to a specialized metabolic center or access to specialized care
•Analysis of blood Phe, Phe:Tyr (tyrosine) ratio, and other amino acids (AAs)
•A 24–48-hour tetrahydrobiopterin (BH4) loading test should be performed to determine responsiveness to sapropterin, except in those whose genotype is known to be non-responsive (i.e., 2 “null” alleles). (Tier 2) [4, 14, 15, 16, 18, 24]

A multidisciplinary team experienced in the treatment of PAH deficiency is needed for appropriate management of individuals of all ages. The team should include, at a minimum, an experienced metabolic dietitian, a metabolic physician (one pediatrician for care of infants and children and one physician specific for young adult/adult care), and psychologist. Consider a neuropsychologist/psychiatrist, social worker, nurse or nurse practitioner, diet technician or nutritionist team, and clinic coordinator. Management should be life-long, systematic, and ideally in specialized metabolic centers. (Tier 2) [4, 12, 14, 15, 18, 26]

Regular professional health support is needed throughout life to encourage healthy feeding behaviors and cultivate positive eating attitudes, with a positive acceptance of a low phenylalanine diet. (Tier 1) [14]

DIETARY MANAGEMENT RECOMMENDATIONS

The mainstay of treatment is dietary therapy with restriction of dietary Phe intake, which results in decreased blood Phe levels. This consists of a combination of reducing natural/intact protein consumption according to individual Phe tolerance, prescribing low-protein and Phe-free medical foods, and/or supplementation with Phe-free AAs to improve nutrition and prevent nutritional deficiencies. The initiation of dietary therapy depends on the Phe levels and should start immediately after diagnosis, when indicated. Two pharmacologic therapies (sapropterin and pegvaliase) have been approved and may reduce or eliminate the need for dietary restriction in some individuals. Any combination of therapies that facilitate improvement in Phe levels for a given individual is appropriate. Therapies should be individualized and, in children, is based on age and accounts for size and growth rate. All individuals should be encouraged to follow treatment recommendations (dietary therapy, and/or pharmacotherapies) throughout their lives. (Tier 2) [4, 6, 12, 14, 15, 18, 25, 26]

Age-specific levels at which blood Phe should be maintained differ by geographic area and guideline. Based on conclusive evidence, all guidelines agree that target Phe levels should be 120–360 μmol/L for individuals up to the age of 12 years. (Tier 1) [14]

However, guidelines differ for older individuals. Some guidelines recommend 120–360 μmol/L as the target Phe level for all individuals of any age, while other guidelines recommend that target Phe levels be between 120–600 μmol/L for those 12 years and older. All guidelines agree that untreated individuals with blood Phe level ≥360 μmol/L are recommended to initiate treatment. Treatment of Phe levels between 120-360 μmol/L is not recommended, although a threshold for the adverse effects of mildly elevated blood Phe has not been proven. However, infants diagnosed with PAH deficiency that have blood Phe levels between 120-360 μmol/L should be followed for the first 1-2 years of life (at minimum) to ensure that levels do not drift upward with higher protein intake. (Tier 2) [4, 6, 12, 14, 15, 18]

For late diagnosed/late treated individuals (defined heterogeneously in the literature as being diagnosed and/or starting treatment anywhere from 90 days after birth to 7 years of age) and untreated adults, there is some evidence that individuals may exhibit improvements in intellectual performance, behavior, psychiatric symptomatology, and seizure control. Most guidelines agree that a trial treatment including initiation of a Phe-restricted diet for a minimum of 6 months with blood Phe monitoring and a sapropterin response test should always be considered, regardless of age of diagnosis. One guideline indicates that initiation of treatment should always be considered for individuals diagnosed before 7 years of age, but in those age 7 years and older, consideration of treatment should be on an individual basis. (Tier 2) [4, 6, 12, 14, 15]

Practices vary with regards to initiation of dietary therapy for individuals with HPA who have blood Phe levels consistently between 360-600 μmol/L on an unrestricted diet. These individuals are considered by many experts not to be at higher risk of developing intellectual, neurologic, and neuropsychological impairment than are individuals without PAH deficiency. However, since evidence suggests that individuals with severe PAH deficiency have demonstrable neurophysiologic changes when Phe levels are between 360-600 µmol/L, some guidelines recommend lifetime Phe restriction for any individual who has Phe levels between 360-600 µmol/L on an unrestricted diet. One guideline recommends individuals with untreated Phe levels between 360-600 μmol/L be treated through the age of 12 years, since good metabolic control during childhood appears essential to prevent cognitive function impairment in PAH deficiency. (Tier 2) [12, 14, 15]

EVIDENCE FOR EFFECTIVENESS OF DIETARY MANAGEMENT

Late Diagnosed/ Late Treated Individuals
Late diagnosed individuals may significantly benefit from the introduction of a low Phe diet, which may improve intellectual performance. Reversibility of IQ loss may occur especially in early childhood. A retrospective chart review identified 28 adults with PAH deficiency who were diagnosed later than 3 months of age, were and have remained on a Phe-restricted diet during the intervening years. Mean diagnostic Phe-level was 1800 μmol/L (range of 1030-3630 μmol/L) and mean age of diagnosis was 8 years (range of 3 months to 44 years). Twenty-five of the 28 late diagnosed persons who remained on a restricted diet showed significant intellectual improvement. Seven attended college, 9 were employed, 12 were attending workshops and/or day care programs, and 18 were living independently. However, the one included individual diagnosed as an adult (age 44) did not have a reported improvement. In a second retrospective analysis of 37 individuals with PAH deficiency, the mean age of diagnosis was 2.4 years (range 0.7-7 years) with Phe levels between 1030-2600 μmol/L). and 38 started dietary treatment between 8 months and 7 years of age. There was a highly significant (P < 0.0001) improvement in developmental quotient/intelligence quotient (DQ/IQ) between diagnosis and final reported IQ (mean IQ 79.0, SD-16.4, mean age 33.5 years, range: 20-44 years). (Tier 2) [14, 15]

Untreated Adults on Dietary Therapy
Several case reports and cohorts describe changes in symptoms in untreated adults after commencement of dietary treatment, although benefit is not seen in all individuals. In case reports, mainly improvement of motor function (tremors/spasticity) and behavior (less restless and irritable, more alter/responsive and less aggressive) have been described. A crossover RCT of the Phe restricted diet was conducted in a group of 34 late diagnosed adults (aged 21-61 years) who had never been treated and had severe challenging behavior. Only half completed the 60-week study, and significant challenges were encountered in instituting the Phe-restricted diet in this population. While levels of blood Phe were found to be lower during the treatment period, no differences were demonstrated in assessments of behavior. However, 76% of carers’ comments were scored as positive during the active phase, compared with 54% during the placebo phase (p<0.001), indicating potential benefits of quality of life (QoL) for individuals with PAH deficiency and their carers. (Tier 2) [14, 15]

Hyperphenylalaninemia
The evidence is inconsistent regarding the clinical impact of untreated blood PHE levels between 360-600 μmol/L on cognitive and executive function, and whether treatment is necessary. A study of 31 individuals with HPA, aged 11-30 years, who were never treated and whose blood Phe levels where consistently between 360-600 μmol/L had normal cognitive neuropsychological development, including intelligence scores, school performance, job status, and sustained attention; compared to sibling controls and/or age-/sex-/socioeconomic--matched controls. Only 7 of the 31 individuals had untreated Phe levels >500 μmol/L. A different study compared cognitive functions in 35 untreated individuals with mild HPA (aged 3-17 years old) with Phe levels <360 μmol/L to those of 37 children and young adults with severe PAH deficiency (aged 3-19 years old) who were treated early and continuously with a low-Phe diet and 29 unaffected controls. The group with mild HPA performed significantly lower on one of the three tests of executive function compared to the control group and in general obtained scores that lay between those of the group with severe PAH deficiency and the control group for the cognitive functions assessed. (Tier 2) [4, 12, 14]

SUBOPTIMAL OUTCOMES IN EARLY-TREATED INDIVIDUALS

Cognitive and Neuropsychological Outcomes
Although serious neurological impairments are now preventable in treatment-adherent individuals with PAH deficiency, there is increasing recognition of more subtle physical, cognitive, and behavioral findings in these individuals. Two SRs (16 and 150 studies) and 4 meta-analyses (between 20-33 studies) have been published on neuropsychological and cognitive outcomes in early treated individuals with PAH deficiency. The studies included primarily adults with PAH deficiency who were diagnosed and treated early with dietary therapy only. Compared to controls or the general population, meta-analyses reported that early treated individuals with PAH deficiency experienced suboptimal outcomes including:
•Significant impairments in executive functioning (reasoning, visuo-spatial attention, sustained attention, flexibility, planning, social cognition, verbal short-term/working memory, inhibition, visuo-motor control, visual learning, higher language skills, visuo-spatial skills)
•Significantly poorer performance among measures of intelligence (total, full-scale, verbal, and performance IQ)
•Higher incidence of ADHD and hyperactivity (40% of individuals with PAH), intellectual disability (18%), irritability/aggressiveness (44%), mental disorders (16%), and speech deficits (35%)
•Higher incidence of depression, anxiety.
Additional suboptimal outcomes reported by the two SRs included deficits in vigilance/focus, motor skills, and reduced processing speed. (Tier 1) [14, 19, 27, 28, 29, 30]

Growth
A meta-analysis that investigated the effects of dietary therapy on long-term growth in children with PAH deficiency (3 studies, 352-505 individuals) demonstrated that on dietary therapy, “optimal” growth outcomes were not attained in those with PAH deficiency. Children with PAH deficiency were significantly shorter than healthy controls from 6 months of age until the end of adolescence and had lower weights for their age than reference populations from 1 year through 4 years of age. Another SR evaluating outcomes in individuals with PAH deficiency treated early with diet alone, found that 29 of the 34 included studies on growth and nutrition reported suboptimal outcomes in individuals with PAH deficiency compared to control groups or standardized norms/reference values. These outcomes included reduced height and head circumference, increased BMI, and vitamin and nutrient/micronutrient deficiencies. (Tier 1) [19, 23]

Clinical Bone Outcomes
There have been 3 SRs (6, 9, and 11 studies) of clinical bone outcomes in young individuals (up to age 45 years) with PAH deficiency on dietary therapy. Sub-optimal outcomes reported include osteopenia, osteoporosis, and fractures. In a single controlled study, self-reported clinical fractures occurred in 21 of 85 individuals with PAH deficiency (25%) compared to 18 of 98 healthy sibling controls (18%), and the fracture rate was 2.6-fold higher in cases than controls. Recent case series report fracture rates between 7-19%. One SR and meta-analysis of 360 early-treated individuals with PAH deficiency reported that the prevalence of osteopenia and osteoporosis ranged from 28–46% and 5–14%, respectively (Tier 1) [19, 31, 32]

Additional Outcomes
A recent meta-analysis of observational studies (k=20) of burdensome outcomes of PAH deficiency evaluated motor delay as an outcome (4 studies; N=132) and found that motor delay was present in 15% individuals diagnosed and treated with dietary therapy only in the first 3 months of life. Of note, the analysis also reported that patient adherence to clinical recommendations, including dietary management, was 53% (5 studies, N=260). (Tier 1) [30]

A SR of outcome data in diet-alone early-treated individuals (diet only) found that the majority of publications (140/150) reported at least one suboptimal outcome in individuals with PAH deficiency compared to control groups or standardized norms/reference values. Suboptimal outcomes were reported in the following areas for both children and adults with PAH deficiency:
•Quality of life (QoL, 4 of 6 studies)
•Brain pathology (30 of 32 studies reported suboptimal outcomes including white matter abnormalities and altered brain biochemistry). (Tier 1) [19]

PHARMACOLOGIC THERAPIES

Sapropterin (BH4) Therapy
Sapropterin is recommended as an oral pharmacologic therapy option for individuals with PAH deficiency proven to be responsive to the treatment, with the goal of increasing natural protein intake and/or improving biochemical control. Responsiveness is determined by a sapropterin loading test (24 hours to 7 days, if not performed at diagnosis) and a subsequent trial (1-6 months), with consideration of genotype (which may be predictive of response but are imperfect). The necessity of a loading test, consideration of genotype, length of loading test and/or trial, definition of responsiveness, and maximum age (if any) eligible for treatment differ by guidance. Responsiveness varies according to metabolic phenotype, where individuals with milder metabolic phenotypes are more likely to respond and patients with severe PAH deficiency are less likely. One guideline recommends sapropterin for individuals of all ages, including those with later or untreated PAH deficiency. However, a second guideline from the United Kingdom only allows treatment up through 21 years of age, mainly because the price of the drug was too high to be considered an acceptable use of National Health Service resources. Sapropterin has been shown to be safe and effective in improving blood Phe in 20-50% of those tested by genotyping or loading test. It has also been shown to increase Phe tolerance, improve metabolic control, and reduce fluctuation of blood Phe (which has been positively correlated with improved outcomes). (Tier 1) [14, 16]

Four SRs including a collective total of 4 randomized controlled trials (RCTs) (N=307 individuals, follow-up of 6-26 weeks) and 3 uncontrolled open label extension studies (N=206) found that sapropterin reduced blood Phe levels in some individuals with PAH deficiency. Trials included between 29-118 children and adults who were responsive to BH4 in initial loading trials. One SR reported that Phe levels were reduced by at least 30% (often cited in the literature as evidence of effective Phe reduction) in 32-50% of treated individuals. In one RCT comparing placebo on likelihood of a 30% reduction in Phe, 9% of the placebo group achieved this effect, compared with 44% of the treated group after 6 weeks. A meta-analysis of the 4 RCTs reported a significant decrease in blood Phe level in sapropterin-treated participants with baseline Phe concentrations of >600 μmol/L (p<0.00001). For participants with baseline Phe levels <600 μmol/L, there was no difference in change of blood Phe concentration between sapropterin and Phe‐restricted diet only. In both groups, sapropterin increased dietary Phe tolerance, making partial relaxation of dietary restrictions possible for patients. A meta-analysis including 2 trials (N=99, follow-up of 10 and 22 weeks) demonstrated that dietary Phe tolerance was significantly improved in the sapropterin group (p<0.0001), making partial relaxation of dietary restrictions possible. (Tier 1) [5, 7, 8, 16]

A recent SR of outcomes in individuals on long-term sapropterin therapy included 18 studies (N=306 participants, sample sizes ranged from 6-51). In total there were 31 participants with HPA (4 studies) included. Sapropterin therapy was started between 5 months and 18 years of age and mean follow-up ranged from 3 months to 5.7 years (maximum 8.8 years). A meta-analysis demonstrated a significant increase in Phe (12 studies, improvement seen in 90-100% of responders and Phe intake increased between 2.2-4.3-fold) and significant increases in natural protein intake (6 studies, increased ranged from 51-157% increase from baseline). The analysis also reported a significant decrease in Phe-free L- AA intake with sapropterin therapy (≥80% from baseline in 9 studies and ≥40% in another 5 studies). Phe-free L- AAs were discontinued in 51% of individuals. Overall, normal growth was maintained (5 of 9 studies) or improved (2 or 9 studies) with sapropterin treatment. (Tier 1) [33]

Enter value here...Anecdotal evidence suggests that sapropterin therapy may reduce blood Phe levels and/or improve behavior (e.g., reduce anxiety or nervousness) in late-treated and untreated PKU adults. (Tier 2) [14]

Pegvaliase Therapy
Pegvaliase has been recently approved in several countries, with the long-term goal of allowing for an unrestricted diet and discontinuation of medical food. Also known as pegylated recombinant phenylalanine ammonia lyase or PAL, this enzyme substitution therapy, administered via subcutaneous injection, reduces blood Phe in individuals with PAH independent of genotype. Guidance based on clinical trial experience states that pegvaliase should be considered for non-pregnant adults with blood Phe >600 μmol/L, adults on sapropterin therapy, adults with blood Phe <600 μmol/L who want to achieve an unrestricted diet, and adults with neurocognitive deficits (including late treated individuals). (Tier 2) [12, 17, 18]

In a review of clinical trials of pegvaliase and their extension studies, pegvaliase showed high clinical efficacy in reducing and maintaining blood Phe levels within target ranges in most participants, while allowing a diet with intact protein intake close to that recommended for general population. In a phase 2 extension study (68 participants) there was a 59% reduction of Phe at 1 year and a 72% reduction at 2.5 years. In a phase 3 trial (261 participants, many with unrestricted diets before the trial) there was a 51% reduction of Phe at 1 year and a 69% reduction at 2 years. Within 24 months, 68%, 61%, and 51% of participants achieved blood Phe levels of ≤600 µmol/L, ≤360 µmol/L, and ≤120 µmol/L, respectively. Improvement in attention and mood were observed with reduction of blood Phe and were sustained long-term. A long-term comparative effectiveness study compared a pegvaliase-treated group to one comparator group of individuals on diet alone (120 matched pairs, controls from a historic cohort) and a second comparator group of individuals on diet + sapropterin (60 matched pairs) in adults with PAH deficiency. After 2 years, pegvaliase allowed for a higher natural intact protein intake than diet alone or diet + sapropterin (57g/day with pegvaliase, 22g/day with diet alone, 28g/day with diet + sapropterin). Pegvaliase reduced blood Phe to ≥360 μmol/L in 65-72% of participants after 2 years compared to 2% and 8% of adults on diet alone and diet + sapropterin, respectively. (Tier 2) [12, 17, 18]

PAH DEFICIENCY IN PREGNANT PEOPLE
Phe is a potent teratogen with both physical and cognitive consequences for the developing fetus. Individuals who are planning on getting pregnant or who are pregnant who have untreated blood Phe values >360 umol/L require treatment to lower blood Phe before or during pregnancy, with a target range of 120-360 umol/L. (Tier 2) [14, 15]

Guidance differs on when target Phe levels should be achieved pre-conceptionally, ranging from a minimum of 2 weeks to 3 months. Individuals with PAH deficiency with a capacity for pregnancy in whom no treatment has been initiated but who have persistent blood Phe levels between 360-600 μmol/L should receive regular monitoring and education, as they will require treatment prior to and during pregnancy. (Tier 2) [4, 6, 14, 25]

Management of individuals with PAH deficiency including HPA with a capacity for pregnancy during childbearing years, pre-conception, during pregnancy, and post-pregnancy should also include:
•Pre-conception consultation with a maternal–fetal medicine specialist and genetic counseling.
•Nutrition management by a metabolic team. The Phe requirements and intake for pregnant people with PAH deficiency change significantly throughout gestation, necessitating frequent testing and diet adjustments to ensure adequate nutrition is being provided.
•Care in consultation with a multidisciplinary team familiar with PAH deficiency who have experience in managing high-risk pregnancy.
•Significant effort should be undertaken to avoid unplanned pregnancies, with timely education and contraceptive methods being key elements.
•Individuals who become pregnant without appropriate Phe control should be seen within 24 hours for blood Phe measurement and initiation of immediate dietary treatment. These individuals require intensive intervention and will need significant support to attain Phe levels within the recommended therapeutic range in a timely fashion. Hospitalization may be required for intensive dietary intervention.
•Fetal evaluations should also include serial fetal growth assessments, detailed ultrasonographic examinations for organ development, and fetal echocardiography to detect abnormalities. (Tier 2) [4, 6, 12, 14, 18, 25, 26]

Initiation and/or continuation of sapropterin is recommended during pregnancy. (Tier 1) [16]

However, the use of sapropterin during pre-conception and post-pregnancy periods differs by guideline, with response ideally being determined prior to pregnancy. After pregnancy, follow-up with the individual’s metabolic specialist is important. Dietary therapy and target Phe levels should also be maintained postpartum (including during lactation) for optimal pregnancy outcomes. [4, 6, 12, 14, 18, 24, 25]

A SR assessed preconception care services among individuals with HPA (including PAH deficiency) with a capacity for pregnancy, including screening to detect Phe levels, education and counseling regarding preconception, and prenatal dietary control of Phe. All four studies showed that preconception dietary restrictions (resulting in reduced Phe levels) were associated with improved neonatal outcomes including one or more of the following: birth weight, length, head circumference, congenital malformations (particularly congenital heart defects), and neonatal deaths. In these studies, pre-conceptional or very early prenatal dietary control was associated with better outcomes than later prenatal dietary control. (Tier 1) [34]

A SR of the evidence assessing the impact of preconception management on pregnancy outcomes in individuals with PAH deficiency identified 7 studies (26-572 pregnancies per study) and reported the following:
•A strict preconception diet was significantly associated with increases in mean birth weight and head circumference of the offspring compared to newborns born to pregnant people with PAH on an unrestricted diet (1 study)
•Improved infant growth markers were associated with following a strict preconception diet (2 studies)
•A preconception diet led to lower first trimester Phe levels compared to those on a post-conception diet (2 studies)
•Abnormalities in the offspring increased in frequency as Phe control in the pregnant person was delayed (2 studies)
•The percentage of offspring with >3 dysmorphic features increased from 19% in offspring of mothers in control before pregnancy to 62% when control was not achieved before 20 weeks’ gestational age (1 study)
•In individuals with PAH deficiency with a capacity for pregnancy who were preconceptionally treated with good control, microcephaly occurred in 3.6% of the pregnancies compared to 73% reported previously in studies of untreated pregnant individuals
•None of the pregnant people who achieved diet control before conception had offspring with CHD, three (4%) in control between 0-10 weeks had offspring with CHD, 11 (14%) in control between 10-20 weeks had offspring with CHD and 18 (13%) in control after 20 weeks had offspring with CHD (1 study of 572 pregnancies resulting in 413 live births). (Tier 1) [35]

Surveillance

Blood Phe levels should be regularly measured to assess metabolic control, as they are the most clinically relevant biomarker. (Tier 1) [14]

In addition to blood Phe levels, individuals with PAH deficiency should undergo regular biochemical screenings including Tyr and other AAs, transthyretin, albumin/total protein, ferritin, vitamin D 25-OH, homocysteine or methylmalonic acid, hemoglobin, mean corpuscular volume, and complete blood count. The frequency of these screenings varies largely by age and should be performed more frequently during infancy, childhood, preconception, pregnancy, and the postpartum period. Various life events, such as change of school, starting work, and living independently, might necessitate a higher frequency of screening. For adults, the type of assessments and the frequency also depend on their treatment experience (untreated, early- or late treated, returning to treatment). Other biochemical tests to consider, if clinically indicated, can include a comprehensive metabolic panel, parathyroid hormone, vitamins (A, B12, B6), folate, calcium, zinc, copper, selenium, and essential fatty acids. (Tier 2) [4, 12, 14, 15, 25, 26]

Individuals with PAH deficiency should undergo regular clinical and nutritional assessments. The frequency of monitoring varies with age and clinical status, ranging from twice weekly to every 3 months (varies by assessment) in infants to every 6-12 months in individuals over 8 years. Monitoring should also be more frequent during pregnancy (monthly to per trimester) and post-partum (at 6 weeks postpartum and then every 6 months). Assessments should include:
•Patient medical, surgical, and social history
•Anthropometric evaluations
•Nutrition-focused physical evaluations (e.g., abnormal skin or hair characteristics, weight status, gastrointestinal symptoms)
•Food and nutrition-related history (e.g., history of food intake, protein aversion, nutrient deficiencies, adherence to recommendations, feeding difficulties)
•Ongoing evaluation for adequacy and effectiveness of current dietary therapy prescription (e.g., Phe and TYR intake, total nutrient intake, medical food consumption)
•For individuals 16 years of age and older, history of weight management, obesity, and eating disorders. Assess and discuss weight management strategies, and common behaviors and physical signs of eating disorders.
•Visits that include diet adjustments based on blood Phe and/or counseling should occur with a frequency that varies with age, ranging from twice weekly to weekly in infants, to monthly for all adults, and more frequently during pregnancy (twice weekly to weekly) and postpartum (weekly to monthly). (Tier 2) [4, 12, 14, 15]

Due to the increased risk for neurocognitive and psychological issues in individuals with PAH deficiency, all individuals should undergo age-specific neuropsychiatric and cognitive testing tailored according to an individual’s clinical needs and life conditions. Clinical assessment for these issues should begin in childhood, but the age at which to start testing and the frequency differs by guideline. Adaptive issues (e.g., clinically relevant behavioral problems) should be assessed/discussed annually. Neurological examinations should start in adulthood, or sooner if neurodegeneration occurs. QoL should be assessed at least annually using age- and condition-specific instruments when possible. (Tier 2) [4, 12, 14, 18, 26]

Based on evidence from other chronic conditions, psychosocial functioning and wellbeing should also be discussed during clinic visits. (Tier 1) [14]

Screening for abnormal bone mineral density (BMD) may be considered. However, the utility of routine dual-energy X-ray absorptiometry (DEXA) scans to monitor BMD in individuals with PAH deficiency has not yet been established. Most experts agree that an initial DEXA scan is appropriate before adulthood (age varies by guideline), but the necessity of further monitoring scans in asymptomatic individuals is controversial. (Tier 2) [6, 12, 14, 15]

Two SRs and one meta-analysis of studies on bone health in PAH deficiency (the largest SR including 11 studies with 360 early treated individuals) found that BMD was significantly lower in individuals with PAH deficiency than controls but typically still within the normal range, based on World Health Organization and International Society for Clinical Densitometry recommendations. It is unclear whether lower BMD results in a higher rate of clinical or morphometric vertebral fracture in childhood or later life. (Tier 1) [31, 32, 36]

Circumstances to Avoid

Persons with PAH deficiency should try to avoid products containing aspartame particularly from beverage and tabletop sweeteners. Most of the studies that have evaluated the impact of aspartame in individuals with PAH deficiency have demonstrated small but consistent increases in blood Phe levels with ingestion of the artificial sweetener. (Tier 1) [14]

LNAAs should not be used in infants, young children, or individuals who are pregnant or may become pregnant (Tier 2) [4, 12, 14]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [4, 10, 11, 14, 20]

Prevalence of Genetic Variants

Pathogenic variants in PAH can be detected in 97-99% of individuals with PAH deficiency. (Tier 3) [11]

Carrier frequencies are variable across populations, ranging from 1/26 to 1/225. (Tier 3) [4, 6, 11]

Penetrance

In a meta-analysis of reported neuropsychiatric complications (k=17) and executive function deficits (k=13) in adults with PAH deficiency, the following symptom prevalence (with 95% confidence intervals) was reported in a combined cohort of late treated (>90 days after birth) and untreated adults:
•Inattention (219 participants): 68% (54-81%)
•Hyperactivity (200 participants): 34% (20-51%)
•Anxiety (219 participants): 49% (26-72%)
•Depression (200 participants): 35% (16-58%)
•Epilepsy/seizures (283 participants): 21% (17-26%)
•Tremors (283 participants): 40% (17-65%) (Tier 1) [27]

A study of individuals with untreated PAH deficiency found 98 adults who had not been treated in infancy, 50 of whom had never tried the phenylalanine-restricted diet. The 50 never-treated adults had the following characteristics:
•84% needed 24-hour support
•20% were not ambulant
•60% mainly communicated non-verbally
•64% could only say single words or less
•48-68% exhibited challenging behaviors (e.g., behaviors that put their own or others safety at risk)
•28% had epilepsy. (Tier 3) [12, 14]

Approximately 98% of individuals with untreated PAH deficiency fall within the range of global intellectual disability. (Tier 3) [16]

An SR evaluated the cognitive function of untreated individuals with mild HPA (age range 4-41 years), including 15 studies (N= 176 individuals with Phe levels <360 µmol/L, 72 individuals with Phe levels between 360-600 µmol/L, and 87 individuals with Phe levels between 120–600 µmol/L. Four studies reported a worse cognitive outcome compared to controls, with single studies also reporting defects in attention and working memory, and significantly lower verbal comprehension. Another study reported significantly lower IQ in individuals with HPA compared to the general population. Three additional studies reported significant negative correlations between Phe level and IQ score. Seven studies reported normal IQ levels and no significant cognitive defects. (Tier 1) [37]

A historic international survey of pregnant people with PAH deficiency and blood Phe levels ≥1200 µmol) on unrestricted diets documented an increased risk of spontaneous miscarriage (24%, 297 pregnancies), as well as microcephaly (73%, 138 pregnancies), intellectual disability (92%, 172 pregnancies), congenital heart defects (12%, 225 pregnancies), and low birth weight (40%, 89 pregnancies) in their offspring. (Tier 3) [11]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Both genetic and environmental (dietary consumption) components contribute to an affected individual's total blood Phe level. (Tier 4) [11]

Some untreated individuals with PAH deficiency and biallelic PAH pathogenic variants that usually result in severe PAH deficiency have elevated blood Phe level but normal intelligence. In other instances, siblings with the same genotype have different clinical and metabolic phenotypes. (Tier 4) [11]

In adults with PAH deficiency there is a spectrum of cognitive outcomes (variable neurocognitive abilities and executive function deficits), co-morbidities, and life outcomes. This variability may be, in part, a reflection of their heterogeneous treatment experiences. (Tier 4) [26]

4. What is the Nature of the Intervention?

Nature of Intervention

Treatment for PAH deficiency is complex, costly, restrictive, and lifelong. Dietary therapy required to maintain target blood Phe levels needs frequent modification and can lead to various nutritional deficiencies and weight gain. Regular support is needed from a specialist team. Adherence to recommendations diminishes with age, and by late adolescence and adulthood over 70% of individuals with PAH deficiency are non-compliant. Compliance is also a challenge for those preparing for or during pregnancy. Many individuals find the diet difficult to adhere to due to the unpalatable, bland nature of many Phe-free products and the volumes at which they must be consumed. AA supplements must be evenly administered throughout the day and can cause gastrointestinal upset. Life-long and higher intake of AA supplements has been linked to proteinuria and decreased glomerular filtration rates in adults. Access to medical foods is challenging due to a variety of socioeconomic factors, such as economic, insurance coverage, and health care system issues. Trials of sapropterin identified adverse events (AEs) in up to 35% of participants with the most common being upper respiratory tract infection, headache, and vomiting, which occurred similarly in the treatment and placebo arms. Severe AEs were rare (<1%) but 12% of AEs culminated in permanent discontinuation of sapropterin. Trials of pegvaliase have reported hypersensitivity reactions, including generalized skin reactions (21%), injection site reactions (88%), and arthralgia (71-83%). Severe hypersensitivity reactions (anaphylaxis events, reported in 5-9%) occurred at any time during treatment and, although rare, required administration of epinephrine and permanent discontinuation. The most common AEs reported (in ≥20%) were injection site reactions and arthralgia, with most events subsiding over time. Rarely, arthralgia was severe enough to delay scheduled dose increases and warranted the use of premedication with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, and corticosteroids. [4, 5, 6, 7, 8, 12, 13, 14, 15, 16, 17, 18, 19, 38, 39, 40, 41, 42]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Since the initiation of newborn screening during the 1960’s in North America, almost all individuals with PAH deficiency are diagnosed following a positive newborn screening test. (Tier 3) [4]

Since the appearance of universal newborn screening in many countries worldwide, symptomatic classic PAH deficiency is infrequently seen. The predicted incidence of severe intellectual disability resulting from PAH deficiency in screened populations of fewer than one in a million live births reflects those children not detected by newborn screening. (Tier 4) [11]

Date of Search: 11.01.2022 (updated 03.27.2023)

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