SUMMARY: Pathogenic variants in the polymerase γ gene (POLG) cause a diverse group of pathologies known as POLG-related disorders. In this report, we describe brain MR imaging findings and electroencephalogram correlates of 13 children with POLG-related disorders at diagnosis and follow-up. At diagnosis, all patients had seizures and 12 had abnormal MR imaging findings. The most common imaging findings were unilateral or bilateral perirolandic (54%) and unilateral or bilateral thalamic signal changes (77%). Association of epilepsia partialis continua with perirolandic and thalamic signal changes was present in 86% and 70% of the patients, respectively. The occipital lobe was affected in 2 patients. On follow-up, 92% of the patients had disease progression or fatal outcome. Rapid volume loss was seen in 77% of the patients. The occipital lobe (61%) and thalamus (61%) were the most affected brain regions. Perirolandic signal changes and seizures may represent a brain imaging biomarker of early-onset pediatric POLG-related disorders.

Purpose: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs’ evolving contributions to the literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. Methods: Publications were cataloged by members of the Section of Genetic Counseling (Section), established at the Children’s Hospital of Philadelphia and the University of Pennsylvania in 2014, including publication year, journal, impact factor, and author position. Data were organized using the “My Bibliography” tool on the National Center for Biotechnology Information website and a Research Electronic Data Capture database created to initially collect manuscripts published through 30 June 2020. A subsequent survey captured publications through 5 February 2024. Results: An amount of 52 of 120 (43%) GCs shared their curriculum vitae/papers. 992 unique publications were identified from 1986 to 2024. Since 2013, no less than 32 papers were published annually by Section members and no less than 10 GCs contributed to publications yearly. Impact factors typically averaged >5.0 per year. Areas of foci diversified considerably since 2015. Conclusions: Here, we establish that GCs indeed contribute to scholarly work as evidenced by the number of publications alone. The establishment of an academic home may have contributed, given publications increased concurrent to launching the Section, providing a model for organizing GCs at institutions nationally and internationally. Highlighting such achievements will foster the expansion of GC roles in the era of precision genomic medicine and therapy. Considering ways to support GCs towards expanding these activities is equally important.

Background: While somatic mitochondrial dysfunction occurs in diverse cancers, the association between oncogenesis and germline mitochondrial gene pathogenic variants remains unclear. Further, few clinical observations have been reported of cancer occurring in primary mitochondrial disease (PMD) patients. Objectives: To improve understanding of the potential modulating role for PMD gene disorders in cancer prevalence. Design: 727 individuals, including 100 with PMD, from 97 unrelated families were retrospectively surveyed to assess their history of individual cancer occurrence. Methods: We evaluated survey responses by characterizing the cancer prevalence among the study cohort and comparing to the general U.S. population via the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database. Odds ratio calculation was performed to determine the association of survey responses and cancer prevalence. Results: Although overall cancer prevalence in PMD probands and their families was elevated compared to the NCI SEER rate (8800 vs 5600 cases per 100,000), odds ratio calculation determined that PMD did not significantly increase the likelihood of developing cancer, with a non-significant trend observed toward less cancer occuring in PMD that needs to be explored in further studies. Cancer prevalence was significantly correlated with advanced age. Significantly reduced prevalence of prostate cancer was seen across the entire cohort. Surprisingly, while low absolute prevalence ( n = 3), a 9-fold increased odds ratio of cancer was seen in POLG patients relative to those with other causes of PMD. Conclusion: No evidence of increased cancer odds was identified in a cohort of PMD patients and their close relatives. Interestingly, a possible inverse association, which did not reach statistical significance, was suggested between mitochondrial disease status and cancer odds. Future prospective investigations in larger PMD kindreds are warranted to validate and evaluate potential mechanistic relations between cancer prevalence and PMD.

Background/Objectives: Patient registries are essential for rare disease research, yet the extensive genetic and phenotypic heterogeneity of primary mitochondrial diseases (PMDs) makes traditional registry development slow and resource-intensive. We established the MSeqDR PMD virtual registry (PMD-VR) to address this gap through systematic literature mining and semi-automated data harmonization. Methods: The PMD-VR captures, standardizes, and harmonizes published case-level PMD data using a semi-automated curation pipeline. A data transformation framework maps heterogeneous raw data terms to standardized common data elements (CDEs). A generative AI (GenAI) platform leveraging large language models (LLMs), augmented by Human Phenotype Ontology (HPO) and external biomedical knowledge sources, accelerates data transformation and generates simulated clinical reports. Results: Currently, PMD-VR contains approximately 11,000 de-identified literature-derived cases, including over 2300 Leigh syndrome spectrum (LSS), 278 MELAS, and 300 CPEO cases. The pipeline mapped 872 heterogeneous terms to 102 standardized CDEs. Pathogenicity assessments were captured for variants in over 7900 cases, including 3800 with mtDNA pathogenic or likely pathogenic variants. Modes of inheritance were inferred for 5212 cases. PMD-VR has supported ClinGen Mitochondrial Diseases Gene Curation Expert Panel (Mito-GCEP) efforts, providing phenotyped evidence for 440 curated LSS cases across 113 PMD genes. Conclusions: PMD-VR is among the largest single PMD registries, offering a scalable, web-accessible platform for generating analysis-ready cohorts from the published literature. It represents a rich resource enabling comprehensive PMD characterization with unprecedented breadth of genetic and phenotypic knowledge.

We describe a 27-year-old female of mixed European ancestry with rare/novel variants in MPV17 confirmed on whole exome sequencing with a multisystemic, predominantly neuropathic phenotype. She presented at birth with growth faltering, but was otherwise well. At the age of 9 years, she presented with persistent mild elevation in liver transaminases, hypoglycemia, and unilateral ptosis following a gastroenteritis episode. At 16 years, her growth had improved, but she developed a rapidly progressive sensory and motor axonal neuropathy with distal weakness and muscle atrophy, bilateral sensorineural hearing loss, liver nodules, hypothyroidism and primary amenorrhea. She also reported onset of unilateral fatigable ptosis several years prior. Trio whole exome sequencing (GeneDx) revealed compound heterozygous likely pathogenic variants in MPV17 (NM_002437.4), c.191C>T; p. Pro64Leu and c.375+5G>T. Diagnostic muscle biopsy performed at age 16.8 years revealed proliferated mitochondrial (mt)DNA content of 149% of the control mean value in skeletal muscle tissue, while liver biopsy at age 18.6 years demonstrated mtDNA depletion, at 15% of the control mean value. Although classic MPV17- mtDNA depletion syndromes (MDS) are typically associated with early mortality secondary to liver failure, this patient presented in adolescence with multisystem disease with a predominant peripheral neuropathy phenotype and non-progressive, mild liver involvement with preserved synthetic function. Eleven years following her initial presentation, her clinical picture remains predominantly neuropathic, with only mild liver involvement.