Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease.

Autor:	Tallgren A; Research Unit of Clinical Medicine and Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland., Kager L; St. Anna Children's Hospital, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria., O'Grady G; Paediatric Neuroservices, Starship Children's Health, Te Whatu Ora Health New Zealand, Auckland, New Zealand., Tuominen H; Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland., Körkkö J; Center for Intellectual Disability Care, Oulu University Hospital, Oulu, Finland., Kuismin O; Research Unit of Clinical Medicine and Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.; Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland., Feucht M; Department of Paediatrics, Center for Rare and Complex Epilepsies, Medical University of Vienna, Vienna, Austria., Wilson C; National Metabolic Service, Auckland City Hospital, Auckland, New Zealand., Behunova J; Department of Medical Genetics, Medical University of Vienna, Vienna, Austria., England E; Mendelian Genomics, Programme in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States., Kurki MI; Programme in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States., Palotie A; Programme in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States.; Department of Neurology, Massachusetts General Hospital, Boston, MA, United States.; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland., Hallman M; Research Unit of Clinical Medicine and Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.; Clinic for Children and Adolescents, Oulu University Hospital, Oulu, Finland., Kaarteenaho R; Research Unit of Internal Medicine, University of Oulu, Oulu, Finland.; Center of Internal Medicine and Respiratory Medicine and Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland., Laccone F; Department of Medical Genetics, Medical University of Vienna, Vienna, Austria., Boztug K; St. Anna Children's Hospital, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Hinttala R; Research Unit of Clinical Medicine and Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.; Biocenter Oulu, University of Oulu, Oulu, Finland., Uusimaa J; Research Unit of Clinical Medicine and Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.; Clinic for Children and Adolescents, Oulu University Hospital, Oulu, Finland.
Jazyk:	angličtina
Zdroj:	Frontiers in neuroscience [Front Neurosci] 2023 Apr 27; Vol. 17, pp. 1123327. Date of Electronic Publication: 2023 Apr 27 (Print Publication: 2023).
DOI:	10.3389/fnins.2023.1123327
Abstrakt:	Purpose: FINCA disease (Fibrosis, Neurodegeneration and Cerebral Angiomatosis, OMIM 618278) is an infantile-onset neurodevelopmental and multiorgan disease. Since our initial report in 2018, additional patients have been described. FINCA is the first human disease caused by recessive variants in the highly conserved NHLRC2 gene. Our previous studies have shown that Nhlrc2 - null mouse embryos die during gastrulation, indicating the essential role of the protein in embryonic development. Defect in NHLRC2 leads to cerebral neurodegeneration and severe pulmonary, hepatic and cardiac fibrosis. Despite having a structure suggestive of an enzymatic role and the clinical importance of NHLRC2 in multiple organs, the specific physiological role of the protein is unknown. Methods: The clinical histories of five novel FINCA patients diagnosed with whole exome sequencing were reviewed. Segregation analysis of the biallelic, potentially pathogenic NHLRC2 variants was performed using Sanger sequencing. Studies on neuropathology and NHLRC2 expression in different brain regions were performed on autopsy samples of three previously described deceased FINCA patients. Results: One patient was homozygous for the pathogenic variant c.442G > T, while the other four were compound heterozygous for this variant and two other pathogenic NHLRC2 gene variants. All five patients presented with multiorgan dysfunction with neurodevelopmental delay, recurrent infections and macrocytic anemia as key features. Interstitial lung disease was pronounced in infancy but often stabilized. Autopsy samples revealed widespread, albeit at a lower intensity than the control, NHLRC2 expression in the brain. Conclusion: This report expands on the characteristic clinical features of FINCA disease. Presentation is typically in infancy, and although patients can live to late adulthood, the key clinical and histopathological features are fibrosis, infection susceptibility/immunodeficiency/intellectual disability, neurodevelopmental disorder/neurodegeneration and chronic anemia/cerebral angiomatosis (hence the acronym FINCA) that enable an early diagnosis confirmed by genetic investigations. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Tallgren, Kager, O’Grady, Tuominen, Körkkö, Kuismin, Feucht, Wilson, Behunova, England, Kurki, Palotie, Hallman, Kaarteenaho, Laccone, Boztug, Hinttala and Uusimaa.)
Databáze:	MEDLINE
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