Abnormalities in Fetal Brain MRI in Pyruvate Dehydrogenase Complex Deficiency

Background and Research Objective

Pyruvate Dehydrogenase Complex Deficiency (PDCD) is a mitochondrial metabolic disorder caused by pathogenic variants in multiple genes, including PDHA1. Classic neonatal brain imaging features have been described, mainly focusing on developmental abnormalities and brain parenchymal injury. However, there is currently no comprehensive description of PDCD manifestations in fetal brain MRI. The objective of the study is to further characterize PDCD fetal brain MRI manifestations through integrated fetal imaging and genetic testing, and to determine if diagnostic markers of PDCD can be identified in prenatal imaging.

Sources and Authors

The study was authored by experts including Olivier Fortin, Kelsey Christoffel, Abdullah B. Shoaib, Charu Venkatesan, Kate Cilli, Jason W. Schroeder, Cesar Alves, Rebecca D. Ganetzky, and Jamie L. Fraser, from institutions such as Children’s National Hospital, George Washington University School of Medicine and Health Sciences, University of Texas Southwestern Medical Center, Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital, and University of Pennsylvania Perelman School of Medicine. The article was published in the 103rd volume of Neurology in 2024.

Research Methods

1. Inclusion Criteria and Data Sources

Fetuses undergoing fetal MRI from January 1, 2010, to October 17, 2023, with a diagnosis of PDCD genetic results were selected from diagnostic centers. A retrospective review of maternal and fetal clinical data and imaging data was conducted, covering pregnancy history, family history, imaging features, genetic test results, and clinical outcomes. Data were analyzed and reported descriptively.

2. Fetal and Neonatal Imaging

All fetal MRI scans were consistently reviewed by a single pediatric neuroradiology expert (J.W.S.). Fetal imaging was performed on different centers’ 1.5T scanners, generating non-contrast rapid T1-weighted, T2-weighted, and diffusion-weighted images in different planes. Neonatal imaging was conducted using 1.5T or 3T scanners. Imaging results included multiple abnormalities such as corpus callosum deformation, hydrocephalus, and brain volume reduction.

3. Genetic Testing

Genetic testing strategies varied based on clinical assessment, including single-gene testing, multi-gene panels, and Exome Sequencing (ES). The pathogenicity of genetic variants from different sources, including MNG Laboratories, GeneDx, and Claritas Genomics, was evaluated in this study.

Main Research Findings

1. Fetal and Neonatal Imaging Analysis

The study included 10 fetuses, with 8 displaying corpus callosum developmental defects, 6 with abnormal gyri, 10 with reduced brain volume, and 9 with cystic lesions. Six fetuses showed ganglionic eminences (GEs) cystic lesions in the second trimester. Fetal MRI findings indicated GEs cystic lesions regressing by the second trimester, and periventricular cystic lesions noted in third trimester and post-birth MRIs.

2. Genetic Testing Results

Ultimately, nine fetuses were found to have heterozygous pathogenic or likely pathogenic variants in the PDHA1 gene, with another fetus found to have biallelic TPK1 gene variants. Some fetal genetic testing through amniocentesis received results post-delivery or post-miscarriage.

3. Pregnancy and Neonatal Outcomes

Among them, four pregnancies were terminated due to poor prognosis. The remaining fetuses (six) were delivered at full term, except for one born at 34-36 weeks of gestation. Neonatal outcomes varied; two newborns died in the neonatal period, and some were treated with a ketogenic diet and thiamine (vitamin B1) supplementation.

Discussion

The study illustrates PDCD fetal brain structural changes from fetal period to post-birth, noting that early diagnostic markers, like GEs cystic lesions, can be detected in the second trimester. Despite some brain abnormalities being more subtle in fetal imaging, these findings aid in early PDCD diagnosis, prenatal counseling, pregnancy decisions, and neonatal care planning. The study found that metabolic disturbances during pregnancy could manifest as varying degrees of unmet brain energy demands in the fetal period, leading to delayed brain tissue development, volume reduction, and structural disruption.

Conclusion

Through the study of PDCD fetal imaging manifestations, experts concluded that GEs cystic lesions could be early diagnostic markers of PDCD in second-trimester fetal MRI, although this requires further validation. It is suggested that when corpus callosum developmental defects, cortical dysplasia, or periventricular cystic lesions are found in fetal brain MRI, related PDCD gene testing should be conducted. Implementing rapid genetic testing strategies will aid in early diagnosis and provide better planning references for neonatal care.

Highlights Summary

1. Important Findings

• Fetal MRI findings correlate with neonatal brain imaging features, allowing for PDCD diagnosis in the second trimester.
• GEs cystic lesions might be early markers of PDCD, warranting further study for confirmation.

2. Existing Issues and Challenges

• The heterogeneity in detection results and treatment plans suggests a need for more standardized clinical guidelines.
• Accessibility and availability of genetic testing for prenatal diagnosis need further optimization.

3. Innovations in Methods and Processes

• Emphasized the clinical value of new fetal brain MRI methods and parameters, including GEs cystic lesions and ketogenic diet with B1 supplementation therapy.

Through this research, clinicians can better understand the imaging characteristics and clinical presentation of PDCD, thereby providing more accurate diagnosis and care planning for families affected by this rare disease.