Biallelic P4HTM variants associated with HIDEA syndrome and mitochondrial respiratory chain complex I deficiency

Eleanor Hay,Bethan Hoskins,Shamima Rahman,Louise C Wilson,Pinki Munot,Martin Samuels

doi:10.1038/s41431-021-00932-8

Abstract

We report a patient with profound congenital hypotonia, central hypoventilation, poor visual behaviour with retinal hypopigmentation, and significantly decreased mitochondrial respiratory chain complex I activity in muscle, who died at 7 months of age having made minimal developmental progress. Biallelic predicted truncating P4HTM variants were identified following trio whole-genome sequencing, consistent with a diagnosis of hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy and eye abnormalities (HIDEA) syndrome. Very few patients with HIDEA syndrome have been reported previously and mitochondrial abnormalities were observed in three of four previous cases who had a muscle biopsy, suggesting the possibility that HIDEA syndrome represents a primary mitochondrial disorder. P4HTM encodes a transmembrane prolyl 4-hydroxylase with putative targets including hypoxia inducible factors, RNA polymerase II and activating transcription factor 4, which has been implicated in the integrated stress response observed in cell and animal models of mitochondrial disease, and may explain the mitochondrial dysfunction observed in HIDEA syndrome.

Highlights

The differential diagnosis for neonatal hypotonia is wide as it may result from abnormality at any level of the nervous system, and the underlying basis includes both environmental and genetic causes [1, 2]
We describe a patient presenting with a distinctive combination of persistent congenital hypotonia, central hypoventilation, abnormal visual behaviour, and minimal developmental progress
Biallelic loss of function variants in P4HTM have recently been reported in association with the syndrome of hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy and eye abnormalities

Summary

Introduction

The differential diagnosis for neonatal hypotonia is wide as it may result from abnormality at any level of the nervous system, and the underlying basis includes both environmental and genetic causes [1, 2]. Access to panel-based genetic testing and next-generation sequencing of both mitochondrial and nuclear genomes has greatly increased the potential to achieve a molecular genetic diagnosis. Biallelic loss of function variants in P4HTM have recently been reported in association with the syndrome of hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy and eye abnormalities

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Conclusion