NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease

Johanna Uusimaa, Riitta Kaarteenaho, Teija Paakkola, Hannu Tuominen, Minna K. Karjalainen, Javad Nadaf, Teppo Varilo, Meri Uusi-Mäkelä, Maria Suo-Palosaari, Ilkka Pietilä, Anniina E. Hiltunen, Lloyd Ruddock, Heli Alanen, Ekaterina Biterova, Ilkka Miinalainen, Annamari Salminen, Raija Soininen, Aki Manninen, Raija Sormunen, Mika KaakinenReetta Vuolteenaho, Riitta Herva, Päivi Vieira, Teija Dunder, Hannaleena Kokkonen, Jukka S. Moilanen, Heikki Rantala, Lawrence M. Nogee, Jacek Majewski, Mika Rämet, Mikko Hallman, Reetta Hinttala

Research output: Contribution to journalArticle

Abstract

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.

Original languageEnglish (US)
Pages (from-to)727-742
Number of pages16
JournalActa neuropathologica
Volume135
Issue number5
DOIs
StatePublished - May 1 2018

Keywords

  • Brain angiogenesis
  • Central nervous system
  • Cerebropulmonary disease
  • Interstitial fibrosis
  • Multi-organ disease
  • Neurodegeneration

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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