Phenotypic Spectrum of PNPT1: Interferonopathy or Not?

Background/Purpose: PNPT1 encodes for polynucleotide nucleotidyltransferase 1, a mitochondrial enzyme involved in processing and degradation of RNA. Mutations in PNPT1 cause combined oxidative phosphorylation deficiency [OMIM #614932]. Recently, a phenotypic overlap with Aicardi-Goutières syndrome (AGS) was reported.

Methods: Case report of two female patients with mutations in PNPT1 with clinical data, cranial MRI, and interferon signature in blood. The genetic workup included whole exome sequencing and segregation analysis of the likely causal mutation.

Results: Both patients (A: 8J and B: 2J) show very severe global retardation with microcephaly and dystonic movement disorder, and both suffer from severe epilepsy, refractory to treatment. Cranial MRI shows hypoplasia of the corpus callosum with delayed myelinization (both patients) and pontocerebellar hypoplasia (only Patient A). Patient B had fever episodes in early infancy and a sterile pleocytosis in later analysis of CSF. In patient B, we found an interferon signature, but not in patient A. Mutations in PNPT1 were identified in both patients (Pat A: compound heterozygous [c.1498G>A; p.Val500Ile and c.1073G>C; p.Arg358Thr]; Pat B: homozygous [c.1399C>T; p.Pro467Ser]).

Conclusion: A phenotypic overlap to AGS is evident in one of our patients, who also exhibit an interferon signature. Available published reports suggest AGS-like phenotypes as a possible but not obligatory feature in PNPT1 spectrum diseases.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
28 October 2021