Systematic literature review of the somatic comorbidities experienced by adults with phenylketonuria

Abstract

Background: Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism that, if untreated, causes Phe accumulation in the brain leading to neurophysiologic alterations and poor outcomes. Lifelong management centers on dietary Phe restriction, yet long-term complete metabolic control is unachievable for many adults. High blood Phe levels or chronic Phe and intact protein restriction in the diet may lead to somatic comorbidities. A systematic literature review was conducted to evaluate somatic comorbidities experienced by adults with PKU.

Methods: Clinical and observational studies reporting somatic comorbidities experienced by individuals with PKU aged ≥ 16 years (or classified as adults) evaluating a Phe-restricted diet with or without pharmacologic therapy versus no therapeutic intervention (including healthy controls), or pharmacologic therapy versus a Phe-restricted diet alone, were identified. PubMed® was searched (February 1, 2022 and updated November 1, 2023), using a pre-defined search strategy, followed by two-stage screening and data extraction. Included studies were grouped by PKU population comparison.

Results: 1185 records were screened; 51 studies across 12,602 individuals were extracted. Bone-related abnormalities were the most reported outcome (n = 21); several outcome measures were used. Original study groupings included: Phe-restricted diet versus healthy controls or reference values (n = 40); treatment-adherent versus those non-adherent (n = 12). Additional groups added as part of a protocol amendment included: different Phe-restricted diets (n = 4); severe versus less severe disease (n = 5). Vote counting indicated a higher burden of ≥ 1 comorbidity (or outcome measure) for the Phe-restricted diet group by 37 of 38 studies included in the analysis of Phe-restricted diet versus healthy controls; higher burden in healthy controls was reported in 12 studies. Vote counting was similar between those treatment adherent (n = 7) versus non-adherent (n = 10).

Conclusions: Adults with PKU have a higher comorbidity burden than a non-PKU population. More robust studies are needed to better understand the relationship between effective metabolic control and comorbidity burden, using consistent outcome measures. This SLR was supported by BioMarin Pharmaceutical Inc., Novato, CA, and is registered with the Research Registry (reviewregistry1476).

Keywords: Adherence; Comorbidity; Diet; Disease burden; Nutritional status; Phenylalanine; Phenylalanine hydroxylase; Phenylketonuria; Systematic review.

Fig. 1

PRISMA diagram showing article selection process. Articles were excluded on a hierarchical basis, in the order that questions were asked (i.e., if the answer to the first question was no, this was given as the main reason for exclusion, but articles may have met or not met other criteria). Abbreviation: SLR, systematic literature review. ^aFive systematic reviews were identified via the database search and used for backwards citation-searching only plus one additional systematic review identified via backwards citation-searching that was then used for further backwards citation-searching; ^bIncludes studies that did not present outcomes in a meaningful way which answered one or more of the pre-specified research questions; ^cOther studies include open interventional trials, pooled analyses, and cost analyses

Fig. 2

Distribution of studies by comorbidity type. Abbreviations: COPD, chronic obstructive pulmonary disease. ^aOther comorbidities include: acute upper respiratory infections of multiple and unspecified sites; allergic and chronic rhinitis; anemia; adverse events, not elsewhere classified; calculus of kidneys; Charlson Comorbidity Index score; chronic kidney disease; congenital deformities of feet; dizziness and giddiness; dorsalgia; esophageal disorders; gallbladder disease; grip force; gynecological symptoms; hypothyroidism; menopausal and other perimenopausal disorders; metabolic syndrome; ophthalmological symptoms; other disorders of the urinary system; other hypothyroidism; other non-inflammatory disorders of the vagina; other non-toxic goiter; other and unspecified dorsopathies; other and unspecified soft tissue disorders; otolaryngological symptoms; refraction and accommodation disorders; renal insufficiency with hypertension; renal insufficiency without hypertension; thyroid function; upper respiratory traction infection; varicose veins of lower extremities; vasomotor and allergic rhinitis

Fig. 3

Burden of somatic comorbidities in individuals with PKU on a Phe-restricted diet versus healthy controls or reference values as assessed by vote counting. Abbreviations: COPD, chronic obstructive pulmonary disease; Phe, phenylalanine; PKU, phenylketonuria. Note: Total number of studies = 38. ^aStudies with a higher burden of ≥ 1 comorbidity or outcome measure, for a given comorbidity category, in individuals with PKU who adhered to a Phe-restricted diet. ^b Studies with a higher burden of ≥ 1 comorbidity or outcome measure, for a given comorbidity category, in healthy control individuals or a normal reference population. Some studies reported more than one comorbidity or outcome measure per category. Studies reporting a differing direction of effect between comorbidities or outcome measures within a category, are indicated below. Details of studies with consistent direction of effect are not listed below (but are included in Table 2). Vote counting was conducted on the basis of numerical differences in the direction of effect, regardless of statistical significance or clinical relevance. Abdominal and pelvic pain: Higher burden in PKU (n = 2) [15, 22]. Bone-related abnormalities: Higher burden in PKU (n = 21) [, , –42]; negative BMD for distal radius, total body, and trabecular bone; proximal radius, total body, and worse measures of bone geometry and strength in PKU group [24], lumbar and femoral BMD Z-score < –2 in 5.0% and 7.0% of all patients, negative median BMD in adults for hip bone, higher percentage of all patients with fracture history in PKU group [26], lower vitamin D status, higher concentrations of all bone resorption markers, lower concentrations of all bone formation markers except alkaline phosphatase, and higher calcium and phosphorus excretion in PKU group [37]; higher burden in controls (n = 3) [24, 26, 37], positive BMD for proximal radius cortical bone in PKU group [24], positive median BMD in adults for femur in PKU group [26], higher concentration of alkaline phosphatase in PKU group [24, 37]. Cardiovascular outcomes: Higher burden in PKU (n = 5) [15, 22, 43, 46, 47], higher arterial stiffness in PKU group [47]; higher burden in controls (n = 1), higher intima media thickness in control group [47]. COPD/asthma: Higher burden in PKU (n = 2) [15, 22]. Dermatologic disorders: Higher burden in PKU (n = 1) [15]. Diabetes: Higher burden in PKU (n = 3) [15, 22, 44]. Gastrointestinal disorders: Higher burden in PKU (n = 2) [15, 22], numerically higher frequency of diverticular disease of intestine in individuals with PKU versus non-PKU control [22]; higher burden in controls (n = 1) [22], numerically higher frequency of gastritis and duodenitis in non-PKU controls versus individuals with PKU and numerically higher frequency of constipation in non-PKU controls compared with the early-diagnosed PKU subgroup only (null effect on constipation between the overall PKU group and non-PKU controls) [22]. Hypertension: Higher burden in PKU (n = 2) [15, 22]. Musculoskeletal outcomes: Higher burden in PKU (n = 3) [22, 24, 33], muscle size and performance were preserved in individuals with PKU and regression lines were comparable to the reference population (null effect, excluded from vote counting [24]). Nutritional outcomes: Higher burden in PKU (n = 9) [22, 26, 45, 48, 49, 54, 56, 58, 59], decreased concentration of vitamin B12 in relaxed diet and unrestricted diet groups versus control [54], concentration of vitamin D, selenium and zinc below reference range [26], individuals with PKU were less likely to achieve adequate choline intake compared with controls [56]; higher burden in controls (n = 3) [26, 33, 54], increased concentration of vitamin B12 in strict diet group and increased concentration of folate in all diet groups versus control (within or above normal range) [54], concentration of magnesium, folate, vitamin B12 and B6 above reference range [26, 54], analysis only considered the PKU population who consumed adequate protein substitute without Phe and maintained strict metabolic follow-up [33]; one study investigating mean probability of adequacy for vitamin B6, B12, and folate reported a null effect for individuals with PKU on Phe-restricted diet with medical food and dietary supplements versus healthy controls (excluded from vote counting) [56]. Overweight/obesity: Higher burden in PKU (n = 8) [, , , , –53], percentage of females with BMI > 30 kg/m2 was higher than in all UK countries assessed, percentage of females with BMI > 25 kg/m2 was higher than in Northern Ireland only [53], percentages of individuals with PKU who were obese was higher than in the general population in 2/6 centers [52], fat-free mass (Kg) was numerically lower in individuals with PKU versus healthy control [51], no controls below normal range for BMI as opposed to PKU group; higher burden in controls (n = 7) [, –53, 55, 56], adults > 16 years subgroup had higher prevalence of overweight/obesity in control versus PKU [55] but percentage body fat was equal (excluded from vote counting) [55], percentage of males with BMI > 25 and > 30 kg/m2 was higher than in all UK countries assessed, percentage of females with BMI > 30 kg/m2 was higher than in England and Scotland only [53], percentages of individuals with PKU who were overweight and obese were lower than those in the general population in 5/6 and 3/6 study centers, respectively (percentage of individuals with PKU who were obese was the same as that for the general population in 1/6 centers (excluded from vote counting) [52], bodyweight and BMI was numerically lower in individuals with PKU versus healthy control but both groups were only borderline overweight, percentage fat-free mass was numerically higher in individuals with PKU versus healthy control [51], bodyweight, percentage fat mass, and BMI were numerically less in individuals with PKU than healthy controls and BMI of more controls was above normal range, percentage fat-free mass was higher in individuals with PKU than in healthy controls [50]. Other: Higher burden in PKU (n = 3) [15, 22, 57]; higher burden in controls (n = 1) [55]. In the majority of studies, all individuals were on a Phe-restricted diet, with the following exceptions: one study (n = 83) of which 31 were on an unrestricted diet – no formal protein restriction and not taking amino acid supplements, 30 were on a relaxed diet – total protein intake of approximately 1 g/kg/d (50% from natural protein/ 50% from amino acid, vitamin and mineral supplements), and 22 were on a strict low-Phe diet, including amino acid, vitamin, and mineral supplements [54]; one study with a mixture of individuals on and not on a Phe-restricted diet [25]; one study in which some individuals were on sapropterin dihydrochloride or pegvaliase in addition to a Phe-restricted diet [25]; one study in which some individuals received sapropterin dihydrochloride, some were on a Phe-restricted diet, and, for some, it was not clear whether they were on a Phe-restricted diet or not [15]; one study in which some individuals were treated with sapropterin dihydrochloride in addition to dietary treatment [46]; one study (n = 164) in which the majority of individuals were on a Phe-restricted diet, up to 20 adults received additional BH4, and up to 11 adults received BH4 alone [52]; one study (n = 1911) in which 29% of individuals received amino acid supplementation and 5% received sapropterin dihydrochloride (unclear if remaining individuals were on Phe-restricted diet) [22]; one study in which 80% of individuals were on Phe-restricted diet and 20% were on sapropterin dihydrochloride with or without amino acid supplementation [32]; one study in which individuals on BH4 were excluded and it was unclear whether individuals were on a Phe-restricted diet or not [51]

Fig. 4

Overview of measures used to report bone-related abnormalities in individuals with PKU on a Phe-restricted diet versus healthy controls or reference values. Abbreviations: BMD, bone mineral density; OC, osteoclastogenesis; Phe, phenylalanine; PKU, phenylketonuria; PR, prevalence ratio. Studies in bold font showed a statistically significant difference between groups. All 21 studies indicated a higher clinical burden of ≥ 1 outcome measure in the PKU group (or a particular subgroup) compared with healthy controls; with 15 studies reporting a statistically significant difference [, , , –, –, –42], two studies that did not find a statistically significant difference for any outcome measure [15, 33], and four studies that did not test for statistical significance between PKU group and controls [25, 26, 31, 32]; in seven studies the difference between groups was not statistically significant for all outcome measures [29], outcomes [24, 27, 28, 30, 37], or in the comparison of the overall PKU population [35]. ^aUnits: osteocalcin (μg/L), bone alkaline phosphatase (BAP; μg/L), deoxypyridinoline (μmol/mol creatine), calcium/creatine index (no units reported); ^b Units: osteocalcin (ng/mL), BAP (U/I), intact parathyroid hormone (pg/mL), 1,25 (OH)₂ vitamin D (pg/mL), 25 (OH) vitamin D (ng/mL), urinary deoxypyridinoline (nmol/mmol creatinine), urinary N-telopeptides of type collagen (nmol/mmol creatinine), ICTP (pyridinoline cross-linked telopeptide domain of type I collagen; ng/mL), osteoprotegerin (pmol/L), urinary calcium/creatine index (mmol/mmol creatinine), urinary phosphorus/creatine index (mmol/mmol creatinine); ^c Units: osteocalcin (no reported units), BAP (μg/L); ^d Units: BAP (μg/L); ^e Lifetime fracture prevalence was measured as percentage of the population; ^f Risk of fracture was measured between 0 and 20 years of age using a Kaplan–Meier graph (cumulative proportion with fracture vs age)

Fig. 5

Burden of somatic comorbidities in individuals with PKU adherent to versus those not adherent to a Phe-restricted diet as assessed by vote counting. Abbreviations: COPD, chronic obstructive pulmonary disease; Phe, phenylalanine; PKU, phenylketonuria. Note: Total number of studies = 11. ^aStudies with a higher burden of ≥ 1 comorbidity or outcome measure, for a given comorbidity category, in individuals with PKU who adhered to a Phe-restricted diet. ^b Studies with a higher burden of ≥ 1 comorbidity or outcome measure, for a given comorbidity category, in individuals with PKU who did not adhere to a Phe-restricted diet. Studies reporting more than one comorbidity or outcome measure per category, or those with a differing direction of effect between comorbidities or outcome measures within a category, are indicated below. Vote counting was conducted on the basis of numerical differences in the direction of effect, regardless of statistical significance or clinical relevance. Bone-related abnormalities: higher burden in adherent (n = 2) [29, 33], lower lumbar, femoral neck, and total body BMD Z-scores [29], lower spine BMD and null effect for femoral BMD (excluded from vote counting) [33]; higher burden in non-adherent (n = 1) [63]. Cancer: higher burden in adherent (n = 1), higher incidence in discontinued and restarted (group 3) compared with never treated (group 4) and off-diet (group 2) [60]; higher burden in non-adherent (n = 1), higher incidence in off diet (group 2) compared with adherent since birth (group 1) [60]; no reports of cancer in either group (excluded from vote counting) [61]. Cardiovascular outcomes: higher burden in non-adherent (n = 2) [60, 61], heart disease in larger proportion of participants [61], higher incidence of cardiovascular symptoms in off-diet (group 2) compared with discontinued and restarted (group 3) and adhered since birth (group 1), and higher incidence in never treated (group 4) compared with all other groups [60]. COPD/asthma: higher burden in adherent (n = 1), higher incidence of asthma in discontinued and restarted (group 3) than in off-diet (group 2) and never treated (group 4) [60]; higher burden in non-adherent (n = 2) [60, 61], higher incidence of asthma in never treated (group 4) than in adhered since birth (group 1) [60], asthma reported in larger proportion of participants [61]. Dermatologic disorders: higher burden in adherent (n = 1), higher incidence of dermatologic symptoms in discontinued and restarted (group 3) than in off-diet (group 2) and never treated (group 4) [60]; higher burden in non-adherent (n = 2) [60, 61], eczema reported in larger proportion of participants [61], higher incidence of dermatologic disorders in off diet (group 2) compared with adherent since birth (group 1), higher incidence of dermatologic disorders in never treated (group 4) compared with adherent since birth (group 1) and off-diet (group 2) [60]. Gastrointestinal disorders: higher burden in adherent (n = 1), higher incidence in discontinued and restarted (group 3) compared with off diet (group 2) and never treated (group 4) [60]; higher burden in non-adherent (n = 1), higher incidence in discontinued and restarted (group 3) compared with adherent since birth (group 1) [60]. Hypertension: higher burden in adherent (n = 1), hypertension reported in larger proportion of participants [61]. Migraine/headache: higher burden in adherent (n = 1), higher incidence of headaches in adherent since birth (group 1) compared with off-diet (group 2) and higher incidence of headaches in discontinued and restarted (group 3) compared with off-diet (group 2) and never treated (group 4) [60]; higher burden in non-adherent (n = 2) [60, 61], higher incidence of headaches in discontinued and restarted (group 3) compared with adherent since birth (group 1) [60], headaches reported in larger proportion of participants [61]. Musculoskeletal outcomes: higher burden in adherent (n = 1), decreased left and right hand-grip strength in adherent versus non-adherent [33]; higher burden in non-adherent (n = 2) [60, 63], higher incidence of arthritis/musculoskeletal symptoms in discontinued and restarted (group 3) compared with adherent since birth (group 1) [60]. Nutritional outcomes: higher burden in adherent (n = 3) [32, 45, 62], decreased concentrations of total protein and pre-albumin [45], lower concentrations of vitamin B12 and niacin in males [62], lower vitamin B12 in controlled versus uncontrolled population and almost significant increase in percentage of individuals with vitamin B12 deficiency [32]; higher burden in non-adherent (n = 5) [5, 33, 45, 54, 62], lower concentrations of phosphorus and vitamin B12 [45], lower concentrations of vitamin B12 and niacin in females as well as all other nutrients measured [62], lower intakes of iron, zinc, vitamin D3, magnesium, calcium, selenium, iodine, vitamin C, vitamin A, and copper, which were below UK Reference, and lower intakes of thiamin, riboflavin, niacin, vitamin B6, and phosphorus, which met UK Reference [5], lower concentrations of vitamin B12 and folate but levels were within or above normal range [5, 45, 54, 62], significantly lower serum vitamin D3 and vitamin B12, below reference range, versus above reference range in adherent, lower serum folic acid and higher serum homocysteine but both within reference range [33]. Overweight/obesity: higher burden in adherent (n = 2) [33, 62], obesity reported in larger proportion of participants [61], increased total fat free mass in non-adherent versus adherent [33]; higher burden in non-adherent (n = 3) [32, 33, 63], increased total fat mass, bodyweight, WC and BMI in non-adherent versus adherent (BMI within normal range for adherent), and decreased appendicular fat free mass in non-adherent versus adherent [33], significantly increased BMI in uncontrolled vs controlled (total population and women only), numerical increase in BMI of uncontrolled vs controlled men (controlled groups within normal range) [32]. Other: higher burden in adherent (n = 1) [60], higher incidence of otolaryngologic symptoms in adherent since birth (group 1) compared with off diet (group 2) and never treated (group 4), and gynecologic symptoms in adherent since birth (group 1) compared with never treated (group 4), higher incidence of arthritis/musculoskeletal symptoms in discontinued and restarted (group 3) compared with never treated (group 4) and off-diet (group 2), higher incidence of ophthalmologic and gynecologic symptoms in adherent since birth (group 1) compared with never treated (group 4) [60]; higher burden in non-adherent (n = 2) [57, 60], higher incidence of gynecologic and ophthalmologic symptoms in off diet (group 2) compared with adherent since birth (group 1), higher incidence of otolaryngologic symptoms in discontinued and restarted (group 3) compared with adherent since birth (group 1), higher incidence of ophthalmologic symptoms in off diet (group 2) compared with discontinued and restarted (group 3), higher incidence of gynecologic symptoms in discontinued and restarted (group 3) compared with never treated (group 4), and higher incidence of ophthalmologic symptoms in never treated (group 4) compared with adherent since birth (group 1) [60], poorer thyroid function as measured by serum TSH, UIC and UIC/Cr [57]. Definitions of adherence versus non-adherence: Adamczyk et al. 2011. [63], all individuals on Phe-restricted diet from within the first month of life, with blood Phe level assessment at least every second month: subgroup 2a (adherent) had recommended blood Phe levels for treated patients (2–10 mg/dL for children > 12 years), subgroup 2b (non-adherent) had blood Phe levels above the recommended level; Crujeiras et al. [45], those with high adherence to a natural protein restricted diet and supplementation with Phe-free amino acids mixture versus those with low adherence; Dios-Fuentes et al. [32], good metabolic control was defined as Phe levels < 600 µmol/L; Green et al. [5], minimum of 20 g protein equivalent from a low-Phe protein substitute per day for ≥ 1 month prior to inclusion with good adherence versus maximum of 20 g protein equivalent from a low-Phe protein substitute per day for ≥ 1 month prior to inclusion and blood Phe ≥ 600 µmol/L (of n = 14 in this group: n = 2 with 20 g of protein equivalent and no natural protein restriction; n = 1 with low protein diet but no low-Phe protein substitute; n = 11 with unrestricted diet and no low-Phe protein substitute); Guest et al. [60], remaining on Phe-restricted diet since < 1 year of age (group 1) versus discontinuation by 15–25 years of age (group 2) versus those off diet by 15–25 years of age but restarted diet at a mean of 30 years of age (group 3) versus those never treated (group 4); Koch et al. [61], Phe-restricted diet from infancy until ≥ 10 years of age and taking medical food as the primary protein source versus discontinuation of dietary restriction by age 10; Moden-Moses et al. [29], classified as diet-adherent or non-adherent based on self-report; Rojas-Agurto et al. [33], participants with a neonatal diagnosis of PKU, who continued with nutritional treatment, received an adequate supply of protein substitute without Phe, and kept strict follow-up were categorized as adherent, participants with a neonatal diagnosis of PKU, who discontinued the protein substitute and micronutrient supplementation (calcium, iron, and zinc) at 18 years of age and stopped attending metabolic control appointments; Robinson et al. [54], strict low-Phe diet with amino acid, mineral, and vitamin supplements versus no formal protein restriction and no amino acid vitamin and mineral supplementation (those on a total protein intake of approximately 1 g/kg/d with roughly 50% of this from natural protein and 50% from amino acid, mineral, and vitamin supplements were not included in the vote counting); Schulz et al. [62] taking amino acid mixture versus not taking amino acid mixture; Sumanszki et al. [57], mean blood Phe concentration for the 12-month period prior to the study < 600 μmol/L versus > 600 μmol/L