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

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.

HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H‐TM protein

“…Here, we report six new unrelated patients and review the clinical details of all 24 previously published HIDEA patients. The phenotype of the patients identified in the current study is comparable to the phenotype described in the literature 1,2,5–8 . One patient in this study has dystonia, which has not previously been described in HIDEA.…”

“…To the authors' knowledge, P4HTM p.(Glu312Lys), p.(Thr361Ile), and p.(Trp457*) variants have not previously been reported as disease‐causing, hence expanding the genotypic spectrum of the disease. To date, including the cases reported in the present study, there are 15 different pathogenic variants of P4HTM reported to cause HIDEA syndrome 1,2,5–8 …”

“…The phenotype of the patients identified in the current study is comparable to the phenotype described in the literature. 1,2,[5][6][7][8] One patient in this study has dystonia, which has not previously been described in HIDEA. Dystonia is a movement disorder thought to result from an abnormality or damage to the basal ganglia or other brain regions controlling movement.…”

“…To date, including the cases reported in the present study, there are 15 different pathogenic variants of P4HTM reported to cause HIDEA syndrome. 1 , 2 , 5 , 6 , 7 , 8 …”

“…4 To the authors' knowledge, 24 HIDEA patients with 12 different disease-associated P4HTM variants have been described in the medical literature. 1,2,[5][6][7][8] Here, we review the clinical and molecular data from all the published patients and describe six previously unpublished patients with HIDEA caused by five different biallelic pathogenic P4HTM variants.…”