American Journal of Medical Genetics Part A最新文献

{"title":"Refining Domain-Based Prognostication in DNM1 Encephalopathy: A Mild Phenotype Associated With a GTPase Domain Variant","authors":"Caroline Crain,&nbsp;Hope Northrup,&nbsp;Laura S. Farach,&nbsp;Sureni V. Mullegama,&nbsp;Kathleen Shields,&nbsp;Gretchen Von Allmen,&nbsp;Kate Richardson","doi":"10.1002/ajmg.a.70226","DOIUrl":"10.1002/ajmg.a.70226","url":null,"abstract":"<p>DNM1 encephalopathy is a rare autosomal dominant genetic condition characterized by a range of neurological and developmental manifestations. The typical phenotype is severe, including profound intellectual disability, treatment-resistant epilepsy, ataxia, and structural brain abnormalities. However, milder presentations have increasingly been reported, suggesting that the full phenotypic spectrum remains incompletely defined. We describe the case of a female patient who presents only with well-controlled epilepsy and mild dysmorphic features. Trio exome sequencing identified a <i>de novo</i> likely pathogenic variant in the GTPase domain of <i>DNM1</i>, supporting the diagnosis of DNM1 encephalopathy. Historically, disease-causing variants in the GTPase domain were thought to confer a more severe presentation. However, our patient demonstrates a more attenuated phenotype than previously reported cases, including those viewed as mild, which have consistently included some degree of developmental impairment. This supports an expanded and more variable phenotypic spectrum of DNM1 encephalopathy than previously recognized. This additionally complicates domain-based prognostication; though further cases will aid in elucidating genotype–phenotype correlation.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2558-2561"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Growth in Cardio-Facio-Cutaneous Syndrome","authors":"Kari Johnston,&nbsp;Sandesh C. S. Nagamani,&nbsp;Bradley S. Miller,&nbsp;Katherine A. Rauen,&nbsp;Richard D. Boyce,&nbsp;Salma Musaad,&nbsp;Pilar L. Magoulas","doi":"10.1002/ajmg.a.70218","DOIUrl":"10.1002/ajmg.a.70218","url":null,"abstract":"<p>Cardio-facio-cutaneous (CFC) syndrome is a rare, multiple congenital anomaly disorder in which individuals commonly experience faltering growth; however, systematic analysis of growth parameters in this disorder has not been performed. We recruited 69 participants with CFC through CFC International and collected data on assessing height, weight, and body mass index (BMI). We found that the height-for-age and weight-for-age <i>Z</i>-scores were consistently lower in individuals with CFC than in the reference population and that children with CFC experience growth restriction from infancy to adulthood. Our findings show that as individuals age, their height <i>Z</i>-scores remain constant (−2 to −3 SD). However, over time, their weight shows a progressive decrease from average. There were no significant differences between the mean <i>Z</i>-scores of the growth parameters based on an individual's history of enteral feeding, gene associated with diagnosis, nor growth hormone deficiency status. This implies that feeding modality and severity of feeding difficulties may not be directly related to growth. Other factors could be responsible, such as malabsorption of nutrients, constitutional growth delay, hormonal deficiencies or resistance, or cardiac abnormalities. Our study is one of the first to systematically characterize growth parameters and analyze the association of clinical covariates with these parameters in individuals with CFC syndrome. Accurate assessment of growth in this rare condition will allow providers to recognize outliers of growth in their patients with CFC when compared to other individuals with CFC and make necessary referrals and recommendations, which may ultimately improve outcomes.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2443-2453"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanded Phenotype Associated With an Intronic PPP1R12A Variant: A Case Report and Literature Review","authors":"Emily M. Bland,&nbsp;Amber Nakar Weinstein,&nbsp;Eric C. Kao,&nbsp;Xiaonan Zhao,&nbsp;Monika Weisz-Hubshman","doi":"10.1002/ajmg.a.70212","DOIUrl":"10.1002/ajmg.a.70212","url":null,"abstract":"<p>Autosomal dominant <i>PPP1R12A</i>-related genitourinary and/or brain malformation syndrome is a recently described multisystem disorder caused by loss-of-function variants in the protein phosphatase 1 regulatory subunit 12a (<i>PPP1R12A</i>) gene. To date, 22 affected individuals have been reported with variable brain malformations and genitourinary anomalies, including differences of sexual development. Of these cases, four probands had anomalies involving both organ systems. Here, we report a 12-year-old individual with global developmental delay, semi-lobar holoprosencephaly, microcephaly, spastic quadriplegia, bilateral polydactyly, and ambiguous genitalia. The proband was found to have a 46,XY chromosome complement. Trio genome sequencing with sequential RNA sequencing revealed a novel intronic variant that generates an out-of-frame transcript with a premature stop codon, supporting a loss-of-function mechanism. We review previously reported cases of PPP1R12A-related disease and summarize genotypes and frequency of reported clinical features, further illustrating the variable expressivity associated with this condition. Our findings broaden the phenotypic and genotypic spectrum of PPP1R12A and reinforce the role of transcript-level analysis in the evaluation of suspected splicing variants.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2519-2524"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health-Related Quality of Life and Its Related Factors in Adolescents and Adults With Prader–Willi Syndrome in Japan","authors":"Ayako Konishi,&nbsp;Makiko Tachibana,&nbsp;Yuji Oto,&nbsp;Kenichi Kashimada,&nbsp;Tomohiro Ishii,&nbsp;Yoko Aoki,&nbsp;Koji Muroya,&nbsp;Yutaka Takahashi,&nbsp;Kenji Kurosawa,&nbsp;Tsutomu Ogata,&nbsp;Masanobu Kawai","doi":"10.1002/ajmg.a.70222","DOIUrl":"10.1002/ajmg.a.70222","url":null,"abstract":"<div>\u0000 \u0000 <p>Prader–Willi syndrome (PWS) is a rare neurogenetic disorder characterized by endocrine, metabolic, behavioral, and psychiatric features. These manifestations may affect health-related quality of life (HRQOL). Evidence on HRQOL in adolescents and adults with PWS remains limited. This study evaluated HRQOL and examined sex, age, genetic, and behavioral factors associated with HRQOL in individuals with genetically confirmed PWS aged 16 years and over. A proxy-reported questionnaire survey was conducted through a Japanese national PWS support group, and responses from 119 participants (median age, 25 years) were analyzed. The primary outcome was a EuroQol five-dimension five-level (EQ-5D-5L) index value in the upper tertile of the study distribution (≥ 0.744). The median EQ-5D-5L index value was 0.665 (IQR, 0.549–0.775), and the mean was 0.652 (SD, 0.180). Only 4.3% of participants reported no problems in any dimension. Younger age (16–19 years) (OR, 4.62; 95% CI, 1.42–15.1), the deletion genetic subtype (4.79; 1.15–20.0), and lower problematic food-related behaviors (0.90; 0.83–0.97) were independently associated with an EQ-5D-5L index value in the upper tertile. Support during the transition from late adolescence to early adulthood and attention to problematic food-related behaviors may be important for improving the HRQOL of individuals with PWS.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2464-2471"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adult Case of Stüve–Wiedemann Syndrome","authors":"Christina Kelly,&nbsp;Megan Morand,&nbsp;Joseph W. Ray","doi":"10.1002/ajmg.a.70214","DOIUrl":"10.1002/ajmg.a.70214","url":null,"abstract":"<div>\u0000 \u0000 <p>Stüve–Wiedemann Syndrome (SWS) is a rare autosomal recessive skeletal dysplasia caused by variations in the leukemia inhibitory factor receptor (<i>LIFR</i>) gene. Due to its high rate of mortality in early life, current literature is largely limited to children with SWS. We present a case report of a 35-year-old female with SWS, one of the few documented adults with SWS. She was diagnosed at age 34 after clinical exome sequencing identified homozygous pathogenic variants in <i>LIFR</i> at c.756dup (p.Lys253*), a known pathogenic variant associated with SWS. Her past medical history consists of feeding and respiratory difficulties in infancy, recurrent fractures, a deep vein thrombosis of the upper extremity, osteoporosis, and an incidental finding of a brain aneurysm. Of note, she has undergone over 25 surgeries without complications from anesthesia. As an adult, her symptoms include heart palpitations, fatigue, restless leg syndrome, temperature dysregulation, poor dentition, and bone fragility. On physical exam, she displays short stature, blue sclera, kyphoscoliosis, significant loss of range of motion in multiple joints, and fusions in the fingers and toes. To our knowledge, she is the oldest reported individual in the literature with SWS, and her case provides insight into how symptoms evolve over time.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2525-2528"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-Occurrence of Achondroplasia and 16p11.2 Deletion Syndrome in a Child With Group 4 Medulloblastoma: Expanding the Spectrum of Dual Genetic Diagnoses","authors":"Hua Wang","doi":"10.1002/ajmg.a.70211","DOIUrl":"10.1002/ajmg.a.70211","url":null,"abstract":"<div>\u0000 \u0000 <p>Achondroplasia (OMIM #100800), the most common skeletal dysplasia, results from the recurrent FGFR3 c.1138G &gt; A (p.Gly380Arg) gain-of-function variant, which constitutively activates fibroblast growth factor receptor 3 signaling and impairs endochondral ossification. The 16p11.2 microdeletion (OMIM #611913) is a recurrent ~600 kb copy-number variant associated with developmental delay, autism spectrum disorder, epilepsy, and obesity, encompassing dosage-sensitive genes including MAPK3, KCTD13, and PRRT2. Recent genome-wide analyses have linked 16p11.2 deletion to a 13.9-fold increased risk of neuroblastoma, though no association with medulloblastoma has been documented. Medulloblastoma, the most common malignant pediatric brain tumor, is classified into molecularly defined subgroups—WNT-activated, SHH-activated, Group 3, and Group 4—each with distinct genetic drivers and clinical outcomes. We describe a 13-year-old male with achondroplasia confirmed by the pathogenic FGFR3 c.1138G &gt; A variant and a de novo 16p11.2 microdeletion who developed metastatic non-WNT/non-SHH (Group 4) medulloblastoma with leptomeningeal dissemination (M3) at age 12. Despite multimodal therapy including resection, craniospinal irradiation, and combination chemotherapy, the tumor recurred and progressed. The patient died at age 13. To our knowledge, this is the first report of co-occurring achondroplasia and 16p11.2 deletion complicated by medulloblastoma. Although neither condition independently confers established risk for this tumor, both perturb MAPK/ERK signaling—a pathway implicated in Group 4 medulloblastoma biology. This case underscores the importance of recognizing multilocus pathogenic variation and supports further investigation of potential interactions between developmental and oncogenic signaling networks.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2529-2536"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FLNC Complex Structural Variant Causing Distal Myopathy Identified by Family-Based Genome Sequencing","authors":"Dmitrii Subbotin,&nbsp;Anait Voskanyan,&nbsp;Artem Borovikov,&nbsp;Andrey Marakhonov,&nbsp;Anastasia Bobreshova,&nbsp;Maria Rosales-Sabino,&nbsp;Aysylu Murtazina","doi":"10.1002/ajmg.a.70223","DOIUrl":"10.1002/ajmg.a.70223","url":null,"abstract":"<div>\u0000 \u0000 <p>Distal myopathies (DM) are clinically and genetically heterogeneous neuromuscular disorders, and identifying a molecular genetic cause may remain challenging in a subset of cases. Moreover, DM may be misdiagnosed as hereditary neuropathies due to overlapping clinical features. Here, we report a novel structural variant in <i>FLNC</i> associated with DM identified through genome sequencing (GS). Two affected relatives initially presented independently with referral diagnoses of Charcot–Marie–Tooth disease and amyotrophic lateral sclerosis. Clinical re-evaluation led to a change of the diagnosis to DM. Muscle MRI revealed a consistent pattern of selective muscle involvement characteristic of DM, enabling identification of six affected individuals within the family. GS was performed in seven family members, including six affected individuals and one unaffected relative. The analysis identified an insertion of two inverted fragments derived from the adjacent intron 2 into exon 3 of the <i>FLNC</i> gene. This complex rearrangement was accompanied by short non-templated nucleotide insertions at the junctions and a 3-bp exonic deletion at the insertion site, ultimately resulting in a frameshift. The structural variant was segregated with disease and was confirmed by Sanger sequencing and one Oxford nanopore long-read sequencing. Our findings expand the mutational spectrum of <i>FLNC</i>-associated disorders and highlight the importance of GS combined with a detailed clinical examination for the diagnosis of DM.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2553-2557"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACAN-Related Short Stature and Skeletal Dysplasia: Expanding the Phenotypic and Genotypic Spectrum in a 47 Patient Cohort From Turkey","authors":"Abdulkerim Kolkiran,&nbsp;Behiye Sarıkaya Özdemir,&nbsp;Abdullah Sezer,&nbsp;Melike Ataseven Kulalı,&nbsp;Tuğba Daşar,&nbsp;Şenay Savaş Erdeve,&nbsp;Tarık Alay,&nbsp;Berna Uçan,&nbsp;Ahmet Kablan,&nbsp;Elifcan Taşdelen,&nbsp;Firdevs Dinçsoy Bir,&nbsp;Keziban Aslı Bala,&nbsp;Ayşe Derya Buluş,&nbsp;Hande Nur Şengil,&nbsp;Gönül Büyükyılmaz","doi":"10.1002/ajmg.a.70282","DOIUrl":"10.1002/ajmg.a.70282","url":null,"abstract":"<div>\u0000 \u0000 <p>Short stature is clinically and genetically heterogeneous, and defects in the extracellular matrix of growth plate cartilage represent a key disease mechanism. <i>ACAN</i> encodes aggrecan, the major proteoglycan of the growth plate cartilage extracellular matrix. Heterozygous <i>ACAN</i> variants are a recognized cause of familial short stature, often associated with advanced bone age and early growth cessation, yet they show a broad phenotypic spectrum. We aimed to delineate the clinical and molecular spectrum of <i>ACAN</i>-related short stature in a Turkish cohort. We retrospectively reviewed 47 individuals from 20 unrelated families with short stature (height ≤ −2 SDS) or predicted adult height &lt; −2 SDS. Anthropometric data, dysmorphic and musculoskeletal findings, radiologic assessments, and molecular genetic results were analyzed. Among 47 individuals (20 females, 27 males), 59.6% were children. Common clinical features included a high forehead, upslanted palpebral fissures, a depressed nasal bridge, low-set anteverted ears, mild pectus deformity, and brachydactyly. Osteochondritis dissecans, early-onset osteoarthritis, and advanced bone age were identified in 6.5%, 8.7%, and 28.6% of individuals, respectively. Vertebral findings included scoliosis (19.6%), increased lumbar lordosis (13%), and vertebral endplate changes (10.9%). Genetic testing revealed 15 heterozygous <i>ACAN</i> variants (2 previously reported in ClinVar; 13 novel): 6 nonsense, 2 splice-site, 5 frameshift, and 2 missense. Overall, 45 patients carried pathogenic/likely pathogenic variants (14 variants), and 2 carried VUS (1 variant). <i>ACAN</i>-related short stature represents an important subset of familial short stature. Skeletal and musculoskeletal findings may aid diagnosis, but advanced bone age is not consistent and bone age is often appropriate for chronological age.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2507-2518"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Prevalence of Co-Occurring Conditions and an Exploration of Social Factors Influencing Health in Down Syndrome","authors":"Mary E. Witt,&nbsp;Chengbo Zeng,&nbsp;Stephanie L. Santoro","doi":"10.1002/ajmg.a.70219","DOIUrl":"10.1002/ajmg.a.70219","url":null,"abstract":"<div>\u0000 \u0000 <p>Measuring health, a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity, in Down syndrome (DS) was recently achieved through creation of a new health measure. However, additional information on health-related medical topics and how health measurement varies in demographic groups from that cohort has not been presented. We surveyed caregivers of individuals age 0–21 with Down syndrome (DS) from a national sample about the health of their son or daughter with DS as part of a broader study to create a valid, reliable health measure in DS. In this manuscript, we present secondary analysis of survey items on health-related topics including co-occurring medical conditions, recurrent infections, and healthcare maintenance. We then conducted an analysis to compare caregiver-reported demographic traits to total health scores through regression modeling to identify predictors of health status. Survey responses from 542 caregivers of individuals with DS were received; rates of co-occurring medical conditions generally aligned with past results, rates of recurrent infections showed lower rates of persistent fungal infections in our cohort (<i>p</i> &lt; 0.0001) and completion of healthcare guidelines did not correlate with health scores (<i>p</i> = 0.13). In regression modeling, parent sex of respondent (male) and better parent health correlated with better total health scores of individuals with DS. Health-related topics show prevalence rates aligning with past literature, lower rates of some infections, and imperfect guideline adherence. Fathers and parents who feel that they are in better health reported better health of their sons and daughters with DS.</p>\u0000 <p>\u0000 <b>Trial Registration:</b> ClinicalTrials.gov, NCT04631237</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2480-2491"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positron Emission Tomography (PET) in Phenylketonuria: A Systematic Review of Brain Metabolism Beyond Phenylalanine","authors":"Yutaka Furuta,&nbsp;Shoji Yano,&nbsp;John A. Phillips III,&nbsp;Rory J. Tinker,&nbsp;Eishi Asano,&nbsp;Csaba Juhász,&nbsp;Hong Li","doi":"10.1002/ajmg.a.70238","DOIUrl":"10.1002/ajmg.a.70238","url":null,"abstract":"<div>\u0000 \u0000 <p>Phenylketonuria (PKU) is associated with neurocognitive and neuropsychological symptoms despite early treatment and well-controlled phenylalanine (Phe) levels. PKU impairs the conversion of Phe to tyrosine and causes excess phenylalanine to accumulate. This accumulation can competitively block some other amino acids from entering the brain. This may reduce production of key neurotransmitters like dopamine and serotonin, which can affect brain function and development. However, direct correlations between blood Phe levels and central nervous system (CNS) neurotransmitter concentrations have not been established, and reliable CNS biomarkers are lacking. Positron emission tomography (PET) enables in vivo assessment of brain metabolism and neurotransmitter-related processes; therefore, we aim to investigate its potential value as a biomarker. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to April 25, 2026. Studies evaluating brain PET imaging in individuals with PKU or hyperphenylalaninemia were included. Data on study design, patient characteristics, PET tracers, and key findings were extracted and synthesized qualitatively. A total of 380 records were screened, and 13 studies were included, with a mean sample size of 8.8 (median 6). PET tracers included ¹⁸fluorodeoxyglucose (FDG), amino acids, including tyrosine-, methionine-, leucine-, aminocyclohexanecarboxylate-based tracers, and fluorodopa-related tracers. FDG PET studies demonstrated regionally heterogeneous abnormalities in brain glucose metabolism, independent of plasma Phe levels. Amino acid PET studies demonstrated reduced cerebral protein synthesis associated with impaired large neutral amino acid transport and increased brain Phe levels. Fluorodopa-related PET studies indicated reduced dopaminergic activity, with no significant correlation between plasma Phe levels and striatal fluorodopa utilization. PET is a promising tool to bridge the gap between peripheral biochemical markers and CNS dysfunction in PKU. Further studies are needed to overcome limitations which include small sample sizes, heterogeneous metabolic control, restricted availability of tracer types, predominantly cross-sectional study designs, and lack of correlation with clinical signs and symptoms.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 11","pages":"2420-2432"},"PeriodicalIF":1.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}