Community-Based Insights into Phenylketonuria in Northern Iraq and NinevehAbstract
In Iraq, prolonged conflict and disruption of health services have contributed to delayed phenylketonuria (PKU) diagnosis and limited management of affected children. A multidisciplinary task force was established to support children in Northern Iraq and Nineveh through collaboration between American dietitians and local pediatricians. This study evaluated all children diagnosed with PKU (n=19) between 2020 and 2024 in Northern Iraq and Nineveh, assessing their clinical characteristics, demographic features, and outcomes. Diagnosis was confirmed by repeatedly elevated phenylalanine concentrations in dried blood spots or plasma measured using LC-MS/MS, combined with clinical manifestations. Structured questionnaires were applied during patient follow-up to document clinical and demographic profiles. Participants ranged from one month to fifteen years of age, with male predominance and balanced representation between Iraqi Kurdish non-Yazidi and Kurdish-Yazidi groups. Consanguinity was common, particularly first-cousin marriages, and many parents had not undergone premarital medical screening. Moderate PKU predominated, followed by classic PKU. Diagnosis was frequently delayed until early childhood, with cerebral palsy being the most frequent misdiagnosis. Seizures were prevalent and often associated with cerebral palsy and microcephaly. These findings highlight the urgent need for comprehensive newborn screening and expanded metabolic care capacity in the region.
Keywords:
Phenylketonuria; Kurdish children; consanguinity; newborn screening; misdiagnosis; metabolic disorders; inborn errors of metabolism
Introduction
Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from complete or partial deficiency in phenylalanine hydroxylase enzyme activity, causing an elevation of blood phenylalanine (Phe) levels when untreated. If untreated, children with PKU remain at risk for mental health disorders, deficits in neurocognitive functioning, and physical health manifestations [1]. Genetic studies in Kurdish and neighboring populations have revealed a wide spectrum of PAH gene mutations, including specific VNTR alleles and mini-haplotypes, which may influence disease severity and response to dietary management [2,3]. Effective management involves newborn screening (NBS), a low-phenylalanine diet, and multidisciplinary care by healthcare providers (HCPs) including metabolic specialists [4]. Globally, NBS has transformed PKU outcomes, but in conflict-affected regions like Iraq, systemic challenges persist [5].
Four decades of instability have eroded Iraq's medical infrastructure, university education, and specialist training, resulting in an absence of a national NBS and limited metabolic expertise [5,6]. PKU incidence in Iraq is high but unquantified, exacerbated by consanguinity rates of 40-60% and low awareness [1,7]. In Northern Iraq (Kurdistan Region and Nineveh), cultural practices and geopolitical issues amplify risks, particularly among Kurdish and Yazidi communities [3,7,8].
The Restoration Act (TRA), a non-governmental organization, has partnered with the KRI Ministry of Health since 2020 to provide case management, education, and advocacy for PKU and has encouraged and supported the performance of this research [5,6].
To the best of our knowledge, this is the first report describing the PKU patient profile among the Northern Iraq and Nineveh Kurdish population. Collectively, the present findings highlight an urgent need for the implementation of universal NBS for PKU and other inborn errors of metabolism in the KRI and Nineveh Governorate. In addition, increasing clinician awareness, integrating metabolic testing into pediatric neurology evaluations, and strengthening genetic counseling services are essential strategies to reduce PKU-related morbidity.
Materials and Methods
Ethical Considerations
Ethical approval for this study was obtained from the Directorate of Health of Duhok Governorate and the Scientific Committee of the College of Science at the University of Duhok (Reference No. 30102024-9-33), in addition to approval from “The Restoration Act” (TRA). TRA maintains a Memorandum of Understanding with both the Directorate of Health in Duhok and the Ministry of Health of the Kurdistan Region of Iraq [6]. Written informed consent was obtained from the parents or legal guardians of all participants following a detailed explanation of the study procedures.
Study Design and Population
This is a a cross-sectional analysis of 19 Kurdish children diagnosed with PKU and identified by TRA between 2020 and 2024 in KRI and Nineveh [6]. This research work has addressed all the children diagnosed with PKU in the region during the mentioned time frame, who were under the care offered by TRA. From 19 patients, 15 were from Dohuk Governorate and 4 were from Shingal. Sub-ethnic groups: Iraqi Kurdish non-Yazidi, Iraqi Kurdish-Yazidi and Syrian-Kurdish.
Data Collection
PKU diagnosis was confirmed by repeatedly elevated phenylalanine dried blood spot concentration or plasma concentration combined with clinical symptoms. Regular follow-up family visits were performed in a weekly basis during 1-2 months with the support of the TRA team.
Determination of phenylalanine blood concentration
Blood samples were collected during the weekly family visits using filter paper for analysis of dried blood spots. A team of American metabolic specialists and dietitians organized by TRA helped with the PKU diagnosis and symptoms recognition working in partnership with local pediatricians. Phenylalanine blood concentration was performed in a private local laboratory in Dohuk city using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with high accuracy (~1.2% uncertainty). Confirmatory plasma amino acids and PAH gene testing were limited due to resource constraints [5,6]. PKU phenotypes were categorized as follows: classic PKU: > 20 mg/dL; moderate: 10-20 mg/dL; mild PKU: 6-10 mg/dL; and mild hyperphenylalaninemia: 2-6 mg/dL [9].
Demographic and clinic data
Questionnaires specially designed for data collection were applied during the weekly family visits. Demographics data included gender, date of birth, age at PKU diagnosis, and ethnicity. The parents were asked about the occurrence of consanguineous marriage, level of consanguinity and performance of pre-marital medical tests. Clinical data included occurrence of misdiagnosis, type of misdiagnosis, incidence of seizure and other comorbidities.
Statistical Analysis
Descriptive statistical analysis was performed to summarize the demographic and clinical characteristics of the study population. Categorical variables were expressed as frequencies (n) and percentages (%). Cohort size (n=19) aligns with all TRA’s identified cases in collaboration with Kurdistan Regional Government, Ministry of Health between 2020 and 2024 [6].
Results
Age, Gender and Ethnicity
This study analyzed a cohort of 19 children diagnosed with PKU in Kurdistan Region of Iraq (KRI) and Nineveh Governorate. The age of the children diagnosed with PKU ranged from 1 month to 15 years. Male predominance was found (male: 58%, n=11 and female: 42%, n=8). Figure 1 shows the distribution of Kurdish ethnic sub-groups among the children. A balanced ethnic distribution between Iraqi Kurdish non-Yazidi and Iraqi Kurdish-Yazidi (47%, n=9 each, respectively) was identified, besides a minority of Syrian Kurdish (5%, n=1).
Distribution (%) of Kurdish ethnic sub-groups among the children diagnosed with phenylketonuria in Northern Iraq and Nineveh.
Consanguinity and Performance of Pre-Marital Medical Tests
Figure 2 illustrates the frequency of consanguineous marriage among the children’s parents. A high consanguinity rate was found (84%, n=16 vs. 16% non-consanguineous, n=3) with 62.7% of marriages among first-cousins and 37.5% of marriages among second-cousins.
Figure 3 illustrates the occurrence of pre-marital medical tests among the PKU children’s parents. The majority (54%) declared not performing any pre-marital medical test. From those who declared performing pre-marital medical tests (46%), the following tests were included: 1- Infectious diseases - HIV, Hepatitis B and C, syphilis; 2- Hemoglobin electrophoresis - thalassemia and sickle cell screening; 3- Blood grouping, Rh factor and complete blood count. Neither parent reported having received any form of genetic counseling prior to marriage, not even those in consanguineous marriage.
Frequency (%) of consanguineous marriage and consanguinity level distribution (%) among parents of Kurdish children diagnosed with phenylketonuria.
Occurrence (%) and types of pre-marital medical tests performance among parents of Kurdish children diagnosed with phenylketonuria.
Phenotype Distribution
The Figure 4 demonstrates the children’s frequency for each severity classification according with phenylalanine blood concentration. Moderate PKU appeared as the predominant phenotype (53%, n=9) followed by classic PKU (41%, n=7) and hyperphenylalaninemia (6%, n=1). Two children did not have the reports of their initial phe levels before starting treatment. Mean values of dried blood spot or plasma phenylalanine concentration (mg/dL) calculated from three measurements obtained prior to the diagnosis of phenylketonuria are shown in Table 1.
Phenylketonuria phenotypic distribution (%) and occurrence (%) of hyperphenylalaninemia among Kurdish children.
Mean values of dried blood spot or plasma phenylalanine concentration (mg/dL) calculated from three measurements obtained prior to the diagnosis of phenylketonuria.
PKU Late Diagnosis
Figure 5 demonstrates the distribution of the children’s age when PKU was diagnosed. The study revealed delayed diagnosis, with the majority (53%, n=10) having received the PKU diagnosis with the age ranging from 1-5 years, followed by the age range of 6-10 years (16%), 11-15 years and 1-5 months (11% each, respectively) and only 5% diagnosed as newborn babies.
Distribution (%) of the study participants by age group at the time of phenylketonuria diagnosis.
PKU Misdiagnosis and Comorbidities
Figure 6 illustrates the frequency and types of misdiagnoses prior to PKU diagnosis. Misdiagnosis was common, occurring in 79% of cases (n=15). Cerebral palsy was the most frequent misdiagnosis (47%, n=7), followed by developmental delay (33%, n=5). Fetal dystocia, mental disability with corpus callosum abnormalities, and hydrocephalus were each reported in 7% of cases.
Figure 7 indicates that the incidence of seizures (81%, n=5) was found associated with cerebral palsy (60%) and microcephaly (20%). The figure also shows the treatments adopted to control the seizures.
Occurrence (%) of misdiagnosis and distribution (%) of the principal conditions initially diagnosed prior to the confirmed diagnosis of phenylketonuria.
Prevalence of seizures (%), their association (%) with cerebral palsy and microcephaly, and the treatments used for seizure control in Kurdish children diagnosed with phenylketonuria.
Discussion
Age, Gender and Ethnicity
This study describes a cohort of children with phenylketonuria (PKU) from the Kurdistan Region of Iraq and Nineveh Governorate, representing a wide pediatric age range, which reflects the heterogeneous timing of diagnosis commonly reported in regions lacking universal newborn screening programs [10,11]. The observed male predominance is consistent with previous reports indicating a slight excess of affected males in PKU cohorts, although PKU is an autosomal recessive disorder with no true sex predilection, suggesting that this difference is likely due to sampling variation rather than biological factors [9,12]. The relatively balanced distribution between Iraqi Kurdish non-Yazidi and Yazidi ethnic groups highlights the broad impact of PKU across different Kurdish subpopulations and supports previous evidence that PKU prevalence is influenced more by sociocultural practices, such as consanguinity, than by ethnicity alone [14 13,14]. The presence of a Syrian Kurdish case likely reflects recent population displacement and emphasizes the need for inclusive metabolic screening strategies for migrant and refugee populations [15].
Consanguinity and Premarital Medical Testing
The high rate of consanguineous marriage observed in this cohort is consistent with previous studies from the Middle East, where consanguinity remains a deeply rooted cultural practice and is a well-established risk factor for autosomal recessive disorders, including PKU [16-18]. First-cousin marriages constituted the majority of consanguineous unions, which is particularly relevant given the significantly increased probability of homozygosity for pathogenic PAH variants in such unions [19]. Despite the high genetic risk, most parents reported not undergoing premarital medical testing, and among those who did, testing was limited to infectious diseases and hemoglobinopathies, reflecting national premarital screening policies that generally exclude inborn errors of metabolism [20,21]. Notably, none of the parents reported having received genetic counseling prior to marriage, even in consanguineous unions, underscoring a critical gap in preventive genetic services and public health education in the region [17,22].
Phenotype Distribution
Moderate PKU was the most prevalent phenotype in this cohort, followed by classic PKU, which aligns with reports from populations with high consanguinity where severe PAH mutations are more frequently inherited in homozygous form [23,24]. The relatively low frequency of mild hyperphenylalaninemia is consistent with studies from regions without systematic newborn screening, where milder phenotypes often remain undiagnosed due to subtle or absent early clinical manifestations [25,26]. The absence of baseline phenylalanine measurements in some patients further reflects diagnostic and documentation challenges commonly encountered in resource-limited healthcare settings and in contexts of displaced population [11,13,27].
Late Diagnosis of PKU
A striking finding of this study is the predominance of late PKU diagnosis, with most children diagnosed between 1 and 5 years of age, which contrasts sharply with high-income countries where diagnosis typically occurs in the neonatal period through newborn screening programs [28,29].
In PKU literature, delayed diagnosis is consistently associated with greater risk for neurocognitive difficulties, executive functioning challenges, behavioral and emotional concerns, neurological complications, and poorer developmental outcomes. Current research demonstrates that many of these complications can be significantly reduced or prevented through early and continuous treatment initiated shortly after birth. Early dietary intervention refers to the prompt introduction of a lifelong phenylalanine-restricted diet and management, including specialized medical formula, and regular metabolic monitoring to maintain blood phenylalanine levels within recommended therapeutic ranges [30-32]. The very low proportion of newborn diagnoses in this cohort underscores the absence or limited coverage of newborn screening for PKU in Iraq and neighboring regions [10,33].
Misdiagnosis and Comorbidities
The high rate of PKU misdiagnosis observed in this cohort reflects the nonspecific and progressive neurological manifestations of untreated PKU, which often mimic other neurodevelopmental disorders [34,35]. Cerebral palsy and global developmental delay were the most common misdiagnoses, consistent with previous studies reporting frequent diagnostic confusion in late-presenting PKU cases [36,37]. The high prevalence of seizures, particularly among children misdiagnosed with cerebral palsy, aligns with established evidence that elevated phenylalanine levels exert neurotoxic effects, leading to impaired neurotransmitter synthesis and increased seizure susceptibility [38-40]. These findings highlight the urgent need for increased clinical awareness of PKU and improved access to biochemical testing in children presenting with unexplained neurodevelopmental disorders.
Conclusion
This study provides insight into the clinical and epidemiological characteristics of phenylketonuria in children from the Kurdistan Region of Iraq and Nineveh Governorate, highlighting substantial gaps in early detection, preventive genetic services, and clinical awareness. The high prevalence of consanguineous marriage among affected families underscores its significant contribution to the burden of autosomal recessive disorders such as PKU in this population. Despite this elevated genetic risk, premarital medical testing was limited in scope and did not include metabolic or genetic screening, and parents reported not receiving genetic counseling prior to marriage.
The predominance of moderate and classic PKU phenotypes, together with the low frequency of mild hyperphenylalaninemia, likely reflects underdiagnosis of milder forms and delayed clinical recognition in the absence of universal newborn screening. Late diagnosis was common, with most children identified well beyond infancy, a finding that is strongly associated with preventable neurodevelopmental impairment. This delay contributed to a high rate of misdiagnosis, most frequently as cerebral palsy or nonspecific developmental delay, and was often accompanied by severe neurological comorbidities, including seizures and microcephaly.
Collectively, these findings emphasize the urgent need for the implementation of comprehensive newborn screening programs for PKU and other inborn errors of metabolism, integration of metabolic testing into pediatric neurology evaluations, integration of genetic counseling into premarital services, improvement of clinician awareness of metabolic disorders in children presenting with neurodevelopmental abnormalities, in addition the need for specialized metabolic professionals in the region. Strengthening these preventive and diagnostic strategies is essential to reduce diagnostic delay, prevent permanent neurological damage, and improve long-term outcomes for children with PKU in this region.
Acknowledgments
The authors express their sincere gratitude to the Kurdistan Regional Government (KRG) Ministry of Health and to the families of children with phenylketonuria (PKU) for their trust, cooperation, and invaluable participation in this initiative.
We are deeply grateful to the U.S.-based metabolic dietitians who provided expert clinical guidance and ongoing support throughout the project: Therese Breunig, RD, CLC (University of Wisconsin-Madison); Anne C. Kozek, MS, RD, LDN (Ann & Robert H. Lurie Children's Hospital of Chicago); and Jodi Wright, RD, CSP (Stanford Medicine Children's Health). Their expertise was instrumental in advancing the care and management of children with PKU.
We also extend our sincere appreciation to the dedicated team of The Restoration Act (TRA), an international nonprofit non-governmental organization, for their invaluable contributions to patient care, capacity building, and program implementation. Special recognition is given to Rebecca A. Thompson, Founder and President of The Restoration Act; Brian Schatz (former Project Manager) and Lynette Schatz; Layla Dakhil Joko Zandin, BScN (The Restoration Act and Sinjar General Hospital, Iraq); Nofa Edoo Qassim, BScN (The Restoration Act and Sinjar General Hospital, Iraq); Ibrahim Khudeeda Brahim, BScN (The Restoration Act and Khanasor Primary Health Center, Iraq); and Jack Christensen (volunteer). Their dedication, compassion, and unwavering support were essential to the development and success of this initiative.
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Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Data Availability
The full dataset supporting the findings of this study is available upon request to the corresponding author Prof. Dr. Daniele Suzete Persike or “The Restoration Act”, subject to applicable ethical and institutional approval requirements. The dataset is not publicly available because it contains information that could compromise the privacy and confidentiality of the research participants.
The full dataset supporting the findings of this study is available upon request to the corresponding author Prof. Dr. Daniele Suzete Persike or “The Restoration Act”, subject to applicable ethical and institutional approval requirements. The dataset is not publicly available because it contains information that could compromise the privacy and confidentiality of the research participants.
