Table 1.
All LATAM PKU studies evaluating at least one of the pre-specified patient-important or economic burden outcomes (N = 64)
| Author, year | LATAM country | #of patients | Age, Mean¥ (SD), y | Female (%) | Phenotype (%) | Exclusion criteria | Individual and/or population outcomes | Type of burden outcomes | Specific outcomes | Early or late diagnosed** | Specify the type of treatment | Age (days) at start of treatment | Follow-up (months) | Reasons why the study was excluded from the analysis |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Benítez et al. 2001 [32] | Uruguay | 2 | 12 | 0.0 | NR | NR | Individual and economic | Neurological, neurocognitive and neuropsychiatric impairments | Mental disorders—repetitive behaviors (rocking, flapping, etc.); motor deficits—march with aid; speech deficits—only emits a word | NR | NR | NR | NR | Not included as did not report whether the treatment was implemented at an early or late age |
| Bernal, 2017 [33] | Argentina | 3 | NR | 100.0 | NR (66.66) and classic (33.33) | NR | Individual and economic | Patient adherence to clinical recommendations | NR | Early (66.7%) and late (33.3%) | Phe-restricted diet | 3.80** | NR | Not included as did not report data separately for early versus late treated |
| Neurological, neurocognitive and neuropsychiatric impairments | Speech deficits; intellectual disability; aggressiveness; low frustration tolerance | |||||||||||||
| Cornejo et al. 1995 [42] $ | Chile | 17 | 18.8 | NR | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Slight retardation; normal mental development | Early | Phe-restricted diet and education program | 20.3**· | NR | Included in Fig. 3D |
| Cornejo et al. 2003 [41] $ | Chile | 19 | 19.9¢ | 52.63 | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Low motor development | Early | Direct breast feeding, and a special formula without Phe | 19.9** | 6 | Included in Fig. 3E |
| Cornejo et al. 2012 [40] $ | Chile | 184 | 0 to 20₠ | 46.73 | Classic and moderate (NR) | NR | Individual | Overweight and obesity | – | Early | Phe-restricted diet and education program | 18 | NR | Included in Fig. 4A and B |
| Neurological, neurocognitive and neuropsychiatric impairments | Average total IQ in preschoolers, schoolers and teenagers | |||||||||||||
| Diament & Lefevre, 1967 [45] | Brazil | 6 | 4.36 | 66.66 | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Irritability; language delay; mental retardation; hyperactive patient | Late | Phe-restricted diet | NR | NR | Not included as population was not early diagnosed/treated |
| Figueira, 2018 [22] $ | Brazil | 78 | 9.2 | 59.0 | Classic (100.0) | Patients with less than 4 consultations in medical records and whose medical records are not filled out | Individual | Patient adherence to clinical recommendations | Non-adherence to Phe-restricted diet | Early (56.4%) and late (43.6) | Phe-restricted diet | NR | NR |
Included in Figs. 3C, E, F, and 4E Not included as did not report data separately for early versus late treated |
| Neurological, neurocognitive and neuropsychiatric impairments | Learning disability; neuropsychomotor development delay; neuromotor restriction; aggressivenes; autistic behaviour; speech deficits | |||||||||||||
| Gelvez et al. 2016 [54] | Colombia | 4 | 13 | 75.0 | Classic (100.0) | NR | Individual and economic | Neurological, neurocognitive and neuropsychiatric impairments | Speech deficits; neuropsychomotor development delay; aggressiveness; anxiety; attention deficit symptoms; executive function deficit | Late | Phe-restricted diet and education program | 13** | NR | Not included as population was not early diagnosed/treated |
| Skin problems | Hypopigmentation | |||||||||||||
| Socioeconomic impact | Poor school performance | |||||||||||||
| Jiménez-Péres et al. 2015 [55] $ | Mexico | 6 | 7 | 33.33 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Global neurodevelopment impairment | Late | NR | 690 | NR |
Included in Fig. 4C Not included as population was not early diagnosed/treated |
| Skin problems | Eczema skin; lightening of the skin | |||||||||||||
| Lamônica et al. 2012 [58] $ | Brazil | 10 | NR | 40.0 | NR | Chronic disease | Individual | Executive function deficit | Receptive auditory, expressive auditory and visual functions | Early | Phe-restricted diet and mixed formula | Before 30 days of life | NR | Included in Figs. 3A, C; 4D, and 5 |
| Mahfoud et al. 2008 [60] $ | Venezuela | 5 | NR | 40.0 | Classic (60.0) and mild (40.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Global development impairment; isolation; hyperactivity; speech deficits | Early | Phe-restricted diet and special formula | 480 | NR | Included in Fig. 3A, C, F, and 4D |
| Executive function deficit | Irritability; sleeping disorder | |||||||||||||
| Martins, 2007 [23] | Brazil | 15 | 9 to 29₠ | 66.7 | NR | NR | Individual | Overweight and obesity | – | NR | Phe-restricted diet | NR | 6 | Not included as did not report whether the treatment was implemented at an early or late age |
| Osteopenia | Osteopenia | |||||||||||||
| Queiroz & Pondé, 2015 [84] | Brazil | 8 | NR | 37.5 | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Hyperactivity; attention deficit; aggressiveness; intellectual disability; autism | Early (50%) Late (50%) | Phe-restricted diet | 3,698** | NR | Not included as did not report data separately for early versus late treated |
| Sánchez-Peña et al. 2008 [85] | Mexico | 3 | 5.6 | 100.0 | Classic (66.6) and moderate (33.3) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Personal-social development delay; adaptive-motor delay; language delay; hyperactivity; aggressiveness; irritability; autistic behaviour | Early (66.7%) Late (33.3%) | Phe-restricted diet and special formula | 2,044** | At least 3 | Not included as did not report data separately for early versus late treated |
| Silva et al. 2016 [70] | Brazil | 36 | NR | 52.77 | NR | NR | Individual | Patient adherence to clinical recommendations | Noncompliance to treatment | Early (80.55%) | Phe-restricted diet | NR | NR | Not included as quantitative data on outcome of interest not provided in paper |
| Steiner et al. 2007 [86] | Brazil | 3 | 17.33 | 33.33 | NR | NR | Individual and economic | Neurological, neurocognitive and neuropsychiatric impairments | Body shaking; autism spectrum disorder; no verbal language; aggressivenes; hyperactivity | Early | Phe-restricted diet | NR | NR | Not included as quantitative data on outcome of interest not provided in paper |
| Socioeconomic impact | School for autistic children | |||||||||||||
| Impact of PKU on caregiver health-related quality of life | Did not acquire toilet training | |||||||||||||
| Tanaka et al. 2018 [72] | Brazil | 18 | 10 | 39.0 | NR | Patients who did not adhere to the dietary treatment (evaluated by the food anamnesis) associated with no intake of elemental formula free of Phe in the recommended amount and those who were receiving a drug supplement of calcium | Individual | Overweight or obese | – | NR | Phe-restricted diet and special formula | NR | 34¢ | Not included as did not report whether the treatment was implemented at an early or late age |
| Valle et al. 2019 [87] | Argentina | 133 | 2 months to adulthood | NR | Moderate (30.8), mild (67.6), and HPA (33.08) | NR | Individual |
Neurological, neurocognitive and neuropsychiatric impairments Others |
Neurocognitive evaluation Successful pregnancies Patient adherence to clinical recommendations |
Early (24.06%) and late (3.75%) | Phe-restricted diet + protein substitute (54.13%); Phe-restricted diet + glycomacropeptides (1.50%); and diet counselling (31.57%); BH4 (9.77%) | NR | Until age five and monthly thereafter | Not included as did not report data separately for early versus late treated |
| Andere et al. 1988£ [96] $ | Brazil | 35 | 4* to 11₠ | 48.57 | Classic (100.0) | NR | Individual | Skin problems | Keratosis pilaris, ammonia dermatitis, dry skin, reticular livedo and dermographism; during the dietary treatment darkening of skin, hair and eyes; lightening of the skin and hair | NR | Phe-restricted diet | NR | NA | Included in Fig. 4C |
| Beckhauser et al. 2020 [31] $ | Brazil | 34 | 12 | 47.0 | NR | Patient who started treatment after 60 days of age, who failed to maintain Phe levels below 6 mg/dL or who failed to adhere to regular medical follow-ups | Individual | Neurological, neurocognitive and neuropsychiatric impairments | ADHD | Early | Regularly treated since birth according to the “Brazilian Phenylketonuria Clinical and Therapeutic Guidelines”, consisting of a diet and protein formula diet, with Phe restrictions | Before 60 days of life (treated since birth) | NA | Included in Fig. 3A |
| Brandalize, 2004 [75, 88] | Brazil | 32 | 0 to 6₠ | 56.3 | NR (84.40) and moderate (16) | Children who started early treatment in the pioneering program of the Association of Parents and Friends of the Exceptional of São Paulo (APAE-SP), late diagnoses, and early diagnosis due to age above the rest of the group (11, 13 and 14 years) | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Low development of gross motor function; mean gross motor function of PKU and HPAP children; for PKU and HPAP, low development of gross motor function | Early | Phe-restricted diet | For PKU, 8 days to 30 days after born (n = 23 patients) and 31 days to 60 days after born (n = 4 patients); for HPAP, 2 months to 1 year after born (n = 5 patients) | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Pardo-Campos et al. [35–37]£ | Argentina | 30 | 8 to 11₠ | 10.4 | NR | NR | Individual and economic |
Executive function deficit Impact of PKU on caregiver health-related quality of life |
Coping strategies (facing conflicts, relationship with impulsivity); cognitive profile; organization; IQ; memory, visuospatial skills, reaction times, processing speed or in language Parenting styles perceived by the children |
Early | NR | NR | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Chiesa et al. 2012 [38] | Argentina | NR | NR | NR | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | NR | NR | Phe-restricted diet, and free animal food | NR | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Camatta, 2020 [76, 80] $ | Brazil | 94 | 14 | 53.0 | NR | Tetrahydrobiopterin (BH4) deficiency, use of pacemaker, pregnancy, growth-related disorder, and abandonment of treatment over the two previous years | Individual | Overweight and obese | – | Early | Phe-restricted diet and special formula | Up to 30 days of life | NA | Included in Fig. 4A |
| Castro et al. 2012 [77, 81] | Brazil | 63 | 6 to 12₠ | 52.4 | Classic (82.5) and mild (17.5) | Not having a free and informed consent form; child's disagreement; and lack of information on Phe dosages of the transferred patients | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Intellectually disabled from total IQ | Early | Phe-restricted diet | Up to 90 days after born | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Cerqueira, 2004 [20] | Brazil | 101 | 34.23§ | 84.2 | NA | NR | NR | NR | NR | NR | NR | NR | NA | Not included as did not report whether the treatment was implemented at an early or late age |
| Colombo et al. 1988 [39] $ | Chile | 44 | 3.11 | NR | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Language delay; isolated psychomotor developmental delay; mental retardation; hyperactivity; irritability; psychomotor or mental retardation; psychometric evaluation; MRI | Late | Phe-restricted diet | 3 years 11 months | NA |
Included in Fig. 3A, C, and D Not included as population was not early diagnosed/treated |
| Da Silva et al. 2020 [43] | Brazil | 31 | 17.4 | 51.6 | Classic (30.8) and mild (69.2) | To be in an irregular clinical follow-up in the last 12 months; (2) to have a clinical diagnosis of intellectual disability or diagnosis of other associated genetic, psychiatric, or neurological diseases which compromise the assessment of ADHD | Individual | Neurological, neurocognitive and neuropsychiatric impairments | ADHD | Late | Phe-restricted diet and special formula | 26** | NA | Not included as population was not early diagnosed/treated |
| Dutra et al. 2013£ [21] | Brazil | 21 | 9.52 | 42.9 | Classic (4.76) and mild (57.14) and HPAP (38.1) | Children and adolescents whose parents or legal guardians have not signed the ICF; with confirmed diagnosis of neurological and / or psychiatric illness or other syndromes that cause delays in cognitive development | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Neuropsychological assessment; executive function of IQ; verbal of IQ; verbal comprehension index; perceptual organization index; distraction resistance index; Stroop | Early | NR | Up to 90 days after born | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Executive function deficit | Processing speed index; RAVLT total score; Late RAVLT; RAVLT recognition; RVDLT total score; Late RVDLT; RVDLT recognition; time for test (seconds) for TMT A and B; number of errors for TMT A and B | |||||||||||||
| Gejão et al. 2009 [53] $ | Brazil | 25 | 1 to 10₠ | NR | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Alterations in fine motor adaptative, gross motor, language, and personal-social behaviour; motor alterations; language alterations; cognitive alterations; self-care alterations; socialization alterations; alterations in expressive auditory, receptive auditory, and visual auditory; LDES; alterations in PPVT, and Total Score ABFW Child Language Test-phonology; alterations in Visual reception, auditory association, visual association, auditory memory, visual memory, auditory closure, grammatical closure, visual closure, verbal expression, manual expression, sounds combination; difficulty in attention time maintenance; hyperactivity | Early | According to national guidelines | Up to 30 days of life | NA | Included in Figs. 3A, E, and F |
| Kanufre et al. 2015 [56] | Brazil | 58 | 9.15 | 48.27 | NR | NR | Individual | Overweight | Overweight | NR | Phe-restricted diet | NR | NA | Not included as did not report whether the treatment was implemented at an early or late age |
| Keselman 2005 et al. [17]£ | Argentina | 11 | 8.7 to 13₠ | 18.28 | Classic (100.0) | NR | Individual | Osteopenia | Bone mineralization and lumbar spine | Early | Phe-restricted diet | NR | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Lamônica et al. 2015 [59] $ | Brazil | 17 | 10.2 | 36.0 | Classic (100.0) | NR | Individual and economic | Neurological, neurocognitive and neuropsychiatric impairments | ADHD; IQ; low Reading School Performance Test—Number of patients classified as Inferior; low Writing School Performance Test—Number of patients classified as Inferior; irritability | Early | Phe-restricted diet | 76.47% before 30 days of life and 23.53% after 30 days of life | NA | Included in Figs. 3A, C; 4D, and 5 |
| Executive function deficit | Peabody Picture Vocabulary Test—Number of patients classified as Low | |||||||||||||
| Sleeping disorders | Sleeping disorder | |||||||||||||
| Socioeconomic impact | Poor school performance | |||||||||||||
| Malloy-Diniz et al. 2004 [61] £ | Brazil | 21 | 274¢ | 61.9 | NR | Average phe level below 120 μmol/l | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Bayley Scale of Infant Development | Early | Phe-restricted diet | 27.5** | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Executive function deficit | A not B task Piaget | |||||||||||||
| Mancini et al. 2010 [62] £$ | Brazil | 33 | 7.67 | 52.38 | NR | NR | Individual | Patient adherence to clinical recommendations | Serum PKU | Early | Phe-restricted diet | Up to 21 days of life | NA | Included in Fig. 4E |
| Martins et al. 2020 [30] | Brazil | 228 | Newborn, 90%; between 1 and 5 years old, 8%; and over 10 years old (2%) | 21.49 | NR | NR | Individual and economic |
Neurological, neurocognitive and neuropsychiatric impairments Socioeconomic impact; the impact of PKU on the daily lives of patients and caregivers; the main difficulties faced by PKU patients and their caregivers; cognitive and emotional symptoms |
Irritability, anxiety, and lack of concentration Financial impact related to the PKU management; stop working to care for the PKU patient; need to hire a caregiver to assist the PKU patient; absence of neuropsychological care; did not receive the support of a day-to-day psychologist; limitation on social activities; impact on professional life; and effect on self-esteem |
Early (89.92%) and late (10.08%) | Phe-restricted diet and supplements | NR | NA | Not included as did not report data separately for early versus late treated |
| Mendes, 2006 [19] | Brazil | 17 | NR | 70.58 | NR | NR | Individual | Osteopenia | Osteopenia | NR | Phe-restricted diet | NR | NA | Not included as did not report whether the treatment was implemented at an early or late age |
| Morão, 2017 71] | Brazil | 20 | NR | NR | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Verbal fluency test; Children Behavior Checklist 6/18; Wechsler Intelligence Scale for Children (WISC-IV); Word and Pseudoword Reading Competency Test; Snap automatic naming test; SNAP—IV (attention deficits) | NR | NR | NR | NA | Not included as did not report whether the treatment was implemented at an early or late age |
| Executive function deficit | Children Gambling Task; delay of gratification adapted; Rey complex figure; five digit test; RAVLT | |||||||||||||
| Nalin et al. 2010 [66] | Brazil | 45 | 11 | 49.0 | NR (18.0) and classic (53.0) and mild (29.0) | NR | Individual | Patient adherence to clinical recommendations | Patient adherence to treatment | Early | Phe-restricted diet and special formula | 90 | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Viera Neto et al. 2018 [67] £ $ | Brazil | 51 | 6 to 17₠ | 43.13 | NR (2.0) and classic (64.7) and mild/moderate (33.3) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Intellectual capacity classified as below average or intellectual defective | Early | Phe-restricted diet and special formula | 48 | NA | Included in Figs. 3B and 4E |
| QoL | Total score; physical health; emotional functioning; social functioning; school functioning; psychosocial health | |||||||||||||
| Patient adherence to clinical recommendations | Adequate serum PKU levels | |||||||||||||
| Paneque et al. 2013 [68] | Cuba | 12 | NR | NR | NR | NR | Individual and economic | Neurological, neurocognitive and neuropsychiatric impairments | Intelligence test, group attention test, and psychometric test (Weil's non-verbal intelligence test) | NR | Phe-restricted diet | NR | NA | Not included as did not report whether the treatment was implemented at an early or late age |
| Overweight | Overweight according to the growth and development tables of the Cuban population (weight for height, height for age and weight for age) | |||||||||||||
| Skin problems | Skin alterations | |||||||||||||
| Osteopenia | Bone alterations | |||||||||||||
| Socioeconomic impact | Current worker | |||||||||||||
| Peredo et al. 2010 [89] | Chile | 20 | 13.4 | 100.0 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | IQ | Early | Special milk-based formula | 17.9** | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Overweight | Overweight | |||||||||||||
| Pérsico et al. 2019 [97] | Brazil | 15 | 16 | 53.33 | Classic (53.3) and mild (46.7) | Presence of associated comorbidities and/or use of medications unrelated to specific diet therapy with the possibility of interfering with bone metabolism | Individual | Overweight | Overweight | NR | Phe-restricted diet, special formula, and supplement | NR | NA | Not included as did not report whether the treatment was implemented at an early or late age |
| Poloni et al. 2021 [7] | Brazil, Argentina, Colombia, Venezuela, Costa Rica, Chile, Mexico, Paraguay, Peru, Dominican Republic, Panama, Uruguay, and Cuba | NR | NR | NR | NR | NR | Individual and economic |
Poor adherence Low purchasing power, limited/insufficient availability of low-protein foods, lack of technical resources to manage the diet, and did not have low-protein foods; no alternative treatments available |
– | NR | Phe-restricted diet, unflavored powdered amino acid substitutes | NR | NA | Not included as did not report whether the treatment was implemented at an early or late age |
| Sena, 2018 [26] | Brazil | 31 | 6.5 | 48.4 | NR | Patients who were not accompanied by legal guardians advised at the time of collection, individuals hospitalized in any hospital units and patients who were diagnosed with chronic non-communicable diseases such as hypertension, diabetes and cancer | Individual | Overweight | Overweight | NR | Phe-restricted diet | NR | NA | Not included as did not report whether the treatment was implemented at an early or late age |
| Silva, 2010£ [98] £ $ | Brazil | 10 | 5.18 | 50.0 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Hyperactivity; attention deficit; below average for personal-social area; below average for adaptative, language, gross motor, and fine motor; vocabulary classified as below average; mild to moderate speech disorder; deficit for personal-social area, fine motor-adaptative area, language area, and gross motor area | Early | Phe-restricted diet | 5.18** | NA | Included in Fig. 3A, E, and F |
| Silva, 2016 [91] | Brazil | 24 | 15.8 | 50.0 | Classic (50.0) and mild (50.0) | There was no exclusion criterion for samples | Individual | Neurological, neurocognitive and neuropsychiatric | Neuropsychomotor impairment; behavioral alterations | Early | Phe-restricted diet and special formula | 92.29** | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Silva, 2018 [78]$ | Brazil | 31 | 17.4 | 51.6 | Classic (51.6) and mild (48.4) | Have a clinical diagnosis of mild, moderate, severe or profound intellectual disability; have a diagnosis of other associated genetic diseases, depression, bipolar mood disorder or epileptic encephalopathy | Individual | Neurological, neurocognitive and neuropsychiatric |
ADHD Osteopenia |
Early | Phe-restricted diet and special formula | 26 | NA | Included in Fig. 3A |
| Osteopenia | ||||||||||||||
| Silveira et al. 2021 [71]$ | Brazil | 101 | 14.0 | 45.5 | Classic (56.4) and mild (43.6) | Patients with late diagnosis and patients diagnosed with tetrahydrobiopterin (BH4) deficiency | Individual | Overweight and obesity | – | Early | NR | NR | NA | Included in Fig. 4A, and B |
| Teruya, 2019 [79, 82] | Brazil | 23 | 18 | 39.0 | Classic (47.8) and mild (52.2) | NA | Not included as quantitative data on outcome of interest not provided in paper | Patient adherence to clinical recommendations | Poor current adherence to Phe-restricted diet; poor current median adherence to Phe-restricted diet | Early (65.2%) | Phe-restricted diet and special formula | Up to 90 days after born | ||
| Tonon et al. 2019 [73]£ | Brazil | 25 | 19.3 | 52.0 | Classic (52.0) and mild (48.0) | NR | Individual | Overweight or obese | – | Early | Phe-restricted diet and special formula | 52.8** | NA | Not included as quantitative data on outcome of interest not provided in paper |
| Vieira, 2010 [29]$ | Brazil | 56 | 12 | 55.35 | NR (12.5), classic (58.9) and mild (28.6) | NR | Individual and economic | Neurological, neurocognitive and neuropsychiatric | Mental retardation; learning disability; hyperactivity; aggressiveness; attention deficit | Early | Phe-restricted diet and special formula | 60 | NA | Included in Figs. 3A, C, D, 4E, and 5 |
| Patient adherence to clinical recommendations | Nonadherent to treatment | |||||||||||||
| Socioeconomic impact | Special Education | |||||||||||||
| Blanco et al. 2012 [34] | Argentina | 1 | 34 | 100.0 | Mild (100.0) | NR | Individual | Executive function deficit | Mental retardation mild-moderate | Late | Phe-restricted diet | 34 years | 3 | Not included due to design |
| De Lucca et al. 2017 [44] | Ecuador | 1 | 15 | 100.0 | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Autism; psychomotor retardation | Early | Phe-restricted diet and special formula | 3 years and 11 months | NR | Not included due to design |
| Executive function deficit | Delayed severe mental | |||||||||||||
| Skin problems | Musty smell; hair hypopigmentation | |||||||||||||
| Escaf, 2003 [48] | Colombia | 1 | NR | NR | HPAP (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Irritability; sporadic seizures | NR | Phe-restricted diet | NR | NR | Not included due to design |
| Skin problems | Eczema | |||||||||||||
| Others | Vomiting | |||||||||||||
| Figueiró-Filho et al. 2004 [51] | Brazil | 1 | 22 | 100.0 | NR | NR | Individual | Others | Maternal PKU | Late | Phe-restricted diet and supplementation with protein hydrolyzate | 22 | NR | Not included due to design |
| Mariño & Zarzalejo, 2000 [63] | Venezuela | 1 | 0.1 | 0.0 | HPA (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Motor deficits; mental development | Early | Breastfeeding and special formula | 28 | 9 | Not included due to design |
| Skin problems | Erythema | |||||||||||||
| Patient adherence to clinical recommendations | Adherence to Phe-restricted diet | |||||||||||||
| Menezes et al. 2019 [64] | Brazil | 1 | 82¢ | 100.0 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Psychomotor retardation; language impairment | Early | Phe-restricted diet and special formula associated with the milk formula | 40 | NR | Not included due to design |
| Executive function deficit | Adynamia | |||||||||||||
| Skin problems | Pale skin; hair loss | |||||||||||||
| Patient adherence to clinical recommendations | Poor acceptance of the diet | |||||||||||||
| Others | Weight-height deficit; vomiting | |||||||||||||
| Patricio & Maritza, 2018 [92] | Ecuador | 1 | 29Φ | 0.0 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Seizures; neurological complications | Early | Phe-restricted diet and special formula | 30 | 6 | Not included due to design |
| Executive function deficit | Axial hypotonia | |||||||||||||
| Others | Persistent respiratory acidosis; abdominal distention | |||||||||||||
| Pereda-Torales et al. 2008 [93] | Mexico | 1 | 0.2 | 0.0 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Neuropsychomotor development | Early | Phe-restricted diet and special formula | 60 | 12 | Not included due to design |
| Patient adherence to clinical recommendations | Adherence to Phe-restricted diet | |||||||||||||
| Rasner et al. 2014 [90] | Uruguay | 1 | 10* | 0.0 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Losing the cephalic support; irritability; myoclonia of all four members; hypotonia | Early | NR | 10 months | NR | Not included due to design |
| Executive function deficit | Regression of the tracking with the look; regression picking up objects | |||||||||||||
| Santos & Haack, 2013 [94] | Brazil | 1 | 5 | 100.0 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Seizures | Early | Phe-restricted diet and special formula | 20 | 60 | Not included due to design |
| Others | Gastroesophageal reflux; bronchitis; vomiting | |||||||||||||
| Schmidt et al. 2016 [69] | Brazil | 1 | 13 | 0.0 | NR | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Hypoactivity | Early | Phe-restricted diet | NR | NR | Not included due to design |
| Others | Megaloblastic anemia | |||||||||||||
| Urbanes et al. 2006 [74] | Colombia | 1 | 8 | 0.0 | Classic (100.0) | NR | Individual | Neurological, neurocognitive and neuropsychiatric impairments | Restless; aggressive; inconsistent language; neuromotor restriction; intellectual deterioration; poor socialization | Late | NA | NA | NR | Not included due to design |
ADHD Attention Deficit Hyperactivity Disorder, HPA hyperphenylalaninemia, HPAP hyperphenylalaninemia persistent, IQ intelligence quotient, LATAM Latin America, LDES Total Score Language Development Evaluation Scale, NR not reported, NA not applicable, Phe phenylalanine, PKU phenylketonuria, PPVT alterations in Total Score Peabody Picture Vocabulary Test, RAVLT Rey auditive verbal learning test, RVDLT Rey visual design learning test, SD standard deviation, TMT (partes A e B) Trail making test (partes A e B), USP Universidade de São Paulo, UFMG Universidade Federal de Minas Gerais, y years
***We considered that late diagnosed refers to children diagnosed between the ages of 3 months to 7 years (≥ 3 months to < 7 years); untreated PKU refers to patients untreated by 7 years of age and over
¢Days
*Months
**Mean
·Only in two was it done after 30 days
#Number
₠Range
£Comparative cross-sectional studies
ΦWeeks of gestational age
§Caregivers’ age
¥For the case reports, age is expressed as absolute number
$Included in the analysis