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

Abstract

PurposeFINCA 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.MethodsThe 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.ResultsOne 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.ConclusionThis 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.

FINCA disease mouse model exhibits altered behaviour and immune response

“…Pulmonary fibrosis, including unique granuloma-like lesions, is one of the main and often fatal manifestation of FINCA disease (Badura-Stronka et al, 2022;Rapp et al, 2021;Sczakiel et al, 2023;Tallgren et al, 2023;Uusimaa et al, 2018). Despite the significant decrease in NHLRC2 in the FINCA mouse lungs, we have not observed any abnormalities in the tissue histology or signs of granuloma-like lesions and fibrosis (Hiltunen et al, 2020).…”

“…As neurodevelopmental delay is one of the main manifestations of FINCA disease (Badura-Stronka et al, 2022;Brodsky et al, 2020;Li et al, 2022;Rapp et al, 2021;Sczakiel et al, 2023;Tallgren et al, 2023;Uusimaa et al, 2018), we conducted a behavioural neurophenotyping of FINCA mice and their WT littermates at 2.5 months and again at 9 months of age. At 2.5 months, the FINCA mice showed increased ambulatory distance (1362 cm vs. 1677 cm, p = 0.015) and decreased mean rest time (124 s vs 94 s, p = 0.03) in the TruScan apparatus compared to the WT littermates (Fig 2A).…”

“…Another common manifestation of FINCA disease is recurrent infections (Badura-Stronka et al, 2022;Brodsky et al, 2020;Li et al, 2022;Rapp et al, 2021;Sczakiel et al, 2023;Tallgren et al, 2023;Uusimaa et al, 2018), suggesting that NHLRC2 deficiency affects the immune system. To evaluate the innate immune response of FINCA mice, we used lipopolysaccharide (LPS) induction and measured 13 common cytokines as a first screen from serum samples obtained 1.5 and 6 h post- induction from 8-week-old mice.…”

“…The disease is characterized by neurodevelopmental disorder, intellectual disability, progressive neurodegeneration, tissue fibrosis, infection susceptibility/immunodeficiency and chronic haemolytic anaemia (Tallgren et al, 2023;Uusimaa et al, 2018). Since our initial characterisation, 33 patients from various ethnic backgrounds have been reported with different combinations of recessive pathogenic variants in NHLRC2 broadening the phenotypic spectrum of the disease (Badura-Stronka et al, 2022;Brodsky et al, 2020;Li et al, 2022;Rapp et al, 2021;Sczakiel et al, 2023;Tallgren et al, 2023). Thus far, all reported FINCA patients presented with developmental delay and variable disease progression with or without pulmonary involvement.…”

“…Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) (OMIM 618278) is a rare infantileonset disease caused by variants in the NHL-repeat-containing 2 (NHLRC2) gene. The disease is characterized by neurodevelopmental disorder, intellectual disability, progressive neurodegeneration, tissue fibrosis, infection susceptibility/immunodeficiency and chronic haemolytic anaemia (Tallgren et al, 2023;Uusimaa et al, 2018). Since our initial characterisation, 33 patients from various ethnic backgrounds have been reported with different combinations of recessive pathogenic variants in NHLRC2 broadening the phenotypic spectrum of the disease (Badura-Stronka et al, 2022;Brodsky et al, 2020;Li et al, 2022;Rapp et al, 2021;Sczakiel et al, 2023;Tallgren et al, 2023).…”