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

Kraatari, Minna; Soikkonen, Leila; Myllykoski, Matti; Jamshidi, Yalda; Karimiani, Ehsan Ghayoor; Komulainen‐Ebrahim, Jonna; Kallankari, Hanna; Mignot, Cyril; Keren, Boris; Nouguès, Marie‐Christine; Alsahlawi, Zahra; Romito, Antonio; Martini, Javier; Toosi, Mehran Beiraghi; Carroll, Christopher J.; Tripolszki, Kornélia; Bauer, Péter; Uusimaa, Johanna; Bertoli‐Avella, Aida M.; Koivunen, Peppi; Rahikkala, Elisa

doi:10.1111/cge.14203

Cited by 8 publications

(9 citation statements)

References 18 publications

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“… (A) Pictures of the patient: face and profile. No specific dysmorphism is discriminated, but similarities with previous publications are encountered: global facial hypotonia, tented upper lip vermilion, and a low nasal bridge ( Kraatari-Tiri et al, 2022 ). (B) Weight and height curves of our patient (growth chart—Flanders, 2004, for girls, 1–5 years).…”

Section: Clinical Casesupporting

confidence: 57%

“…Few data regarding HIDEA are currently available in the literature. A recent cohort description has been published describing 24 previously reported patients and 6 new patients ( Rahikkala et al, 2019 ; Maddirevula et al, 2020 ; Hay et al, 2021 ; Kraatari-Tiri et al, 2022 ). A comparison with a ROHHAD descriptive cohort of 44 patients ( Harvengt et al, 2020 ) was made ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

“… The phenotypic features of HIDEA patients demonstrate an overlap with ROHHAD characteristics. For HIDEA: percentages based on the data of 31 patients—our patient and 30 patients—described in the review of Kraatari-Tiri et al (2022) . [which included 24 previously reported patients ( Kaasinen et al, 2014 ; Rahikkala et al, 2019 ; Maddirevula et al, 2020 ; Hay et al, 2021 ; Järvelä et al, 2021 ; Lim et al, 2022 ) and six new patients].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, this outcome is possibly lacking because some of the HIDEA patients are still young. The first complete phenotypic description of patients with biallelic loss-of-function P4HTM gene variants was recently detailed in 2019 and extended in 2022 (Kaasinen et al, 2014;Rahikkala et al, 2019;Kraatari-Tiri et al, 2022). P4HTM was previously not integrated in the panels of the core genes list of intellectual disabilities.…”

Section: Discussionmentioning

confidence: 99%

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HIDEA syndrome: A new case report highlighting similarities with ROHHAD syndrome

Harvengt

Lumaka²,

Fasquelle³

et al. 2023

Front. Genet.

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Context: ROHHAD syndrome presents a significant resemblance to HIDEA syndrome. The latter is caused by biallelic loss-of-function variants in the P4HTM gene and encompasses hypotonia, intellectual disabilities, eye abnormalities, hypoventilation, and dysautonomia. We report the first patient identified with HIDEA syndrome from our ROHHAD cohort.Clinical case: Our patient was a 21-month-old girl who had a history of severe respiratory infections requiring intensive care, hypotonia, abnormal eye movements, and rapid weight gain. Polysomnography identified severe central hypoventilation. During her follow-up, a significant psychomotor delay and the absence of language were gradually observed. The prolactin levels were initially increased. Hypothermia was reported at 4 years. Exome sequencing identified a new homozygous truncating P4HTM variant.Discussion: Our patient met the diagnosis criteria for ROHHAD, which included rapid weight gain, central hypoventilation appearing after 1.5 years of age, hyperprolactinemia suggesting hypothalamic dysfunction, and autonomic dysfunction manifesting as strabismus and hypothermia. However, she also presented with severe neurodevelopmental delay, which is not a classic feature of ROHHAD syndrome. HIDEA syndrome presents similarities with ROHHAD, including hypoventilation, obesity, and dysautonomia. To date, only 14% of endocrinological disturbances have been reported in HIDEA patients. Better delineation of both syndromes is required to investigate the eventual involvement of P4HTM, a regulator of calcium dynamics and gliotransmission, in ROHHAD patients.Conclusion: In the case of clinical evidence of ROHHAD in a child with abnormal neurological development or eye abnormalities, we suggest that the P4HTM gene be systematically interrogated in addition to the analysis of the PHOX2B gene. A better delineation of the natural history of HIDEA is required to allow further comparisons between features of HIDEA and ROHHAD. The clinical similarities could potentially orient some molecular hypotheses in the field of ROHHAD research.

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Section: Clinical Casesupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

HIDEA syndrome: A new case report highlighting similarities with ROHHAD syndrome

Harvengt

Lumaka²,

Fasquelle³

et al. 2023

Front. Genet.

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“…8B, Supplementary Table 2A). Among the top 40 affected genes were 23 genes linked to neuronal functions, behavior, or neurodevelopmental disorders (GeneIDs are detailed in Supplementary Table 2, sheet A): Ap2a1 (Vrahatis et al 2020), Cers1 (Godeiro Junior et al 2018), Gdf1 (Lee 1991), Hspbp1 (Jing et al 2021), Fip1l1 (Tennenbaum et al 2021), Msi2 (Luan et al 2016), Ssbp1 (Meunier et al 2021), Tmx3 (Chao et al 2010), Tmem179 (Carpanini et al 2017), Usp20 (Jolly et al 2022), Hspb11 (Shields et al 2019), Ints1 (Zhang et al 2020), P4htm (Kraatari-Tiri et al 2022), Atp13a2 (Pan & Yue 2014), Ccdc120 (Abidi et al 2016), Dpp3 (Ren et al 2021), Fam69b (Dudkiewicz et al 2013), Fbxo31 (Vadhvani et al 2013), Prr7 (Lee et al 2018), Rabac1 (Fenster et al 2000), Neurl4 (Imai et al 2015), Slc35a2 (Vals et al 2019), and Smpd1 (Alcalay et al 2019).…”

Section: Resultsmentioning

confidence: 99%

Repeated exposure to high-THCCannabissmoke during gestation alters sex ratio, behavior, and amygdala gene expression of Sprague Dawley rat offspring

Sandini

Onofrychuk

Roebuck

et al. 2023

Preprint

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Due to the recent legalization of Cannabis in many jurisdictions and the consistent trend of increasing THC content in Cannabis products, there is an urgent need to understand the impact of Cannabis use during pregnancy on fetal neurodevelopment and behavior. To this end, we repeatedly exposed female Sprague-Dawley rats to Cannabis smoke from gestational days 6 to 20 (n=12; Aphria Mohawk; 19.51% THC, <0.07% cannabidiol) or room-air as a control (n=10) using a commercially available system. Maternal reproductive parameters, behavior of the adult offspring, and gene expression in the offspring amygdala were assessed. Body temperature was decreased in dams following smoke exposure and more fecal boli were observed in the chambers before and after smoke exposure in those dams exposed to smoke. Maternal weight gain, food intake, gestational length, litter number, and litter weight were not altered by exposure to Cannabis smoke. A significant increase in the male-to-female ratio was noted in the Cannabis-exposed litters. In adulthood, both male and female Cannabis smoke-exposed offspring explored the inner zone of an open field significantly less than control offspring. Gestational Cannabis smoke exposure did not affect behavior on the elevated plus maze test or social interaction test in the offspring. Cannabis offspring were better at visual pairwise discrimination and reversal learning tasks conducted in touchscreen-equipped operant conditioning chambers. Analysis of gene expression in the adult amygdala using RNAseq revealed subtle changes in genes related to development, cellular function, and nervous system disease in a subset of the male offspring. These results demonstrate that repeated exposure to high-THC Cannabis smoke during gestation alters maternal physiological parameters, sex ratio, and anxiety-like behaviors in the adulthood offspring.

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Metabolic characteristics of transmembrane prolyl 4-hydroxylase (P4H-TM) deficient mice

Ala-Nisula,

Halmetoja,

Leinonen

et al. 2024

Pflugers Arch - Eur J Physiol

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Transmembrane prolyl 4-hydroxylase (P4H-TM) is an enigmatic enzyme whose cellular function and primary substrate remain to be identified. Its loss-of-function mutations cause a severe neurological HIDEA syndrome with hypotonia, intellectual disability, dysautonomia and hypoventilation. Previously, P4H-TM deficiency in mice was associated with reduced atherogenesis and lower serum triglyceride levels. Here, we characterized the glucose and lipid metabolism of P4h-tm−/− mice in physiological and tissue analyses. P4h-tm−/− mice showed variations in 24-h oscillations of energy expenditure, VO2 and VCO2 and locomotor activity compared to wild-type (WT) mice. Their rearing activity was reduced, and they showed significant muscle weakness and compromised coordination. Sedated P4h-tm−/− mice had better glucose tolerance, lower fasting insulin levels, higher fasting lactate levels and lower fasting free fatty acid levels compared to WT. These alterations were not present in conscious P4h-tm−/− mice. Fasted P4h-tm−/− mice presented with faster hepatic glycogenolysis. The respiratory rate of conscious P4h-tm−/− mice was significantly lower compared to the WT, the decrease being further exacerbated by sedation and associated with acidosis and a reduced ventilatory response to both hypoxia and hypercapnia. P4H-TM deficiency in mice is associated with alterations in whole-body energy metabolism, day-night rhythm of activity, glucose homeostasis and neuromuscular and respiratory functions. Although the underlying mechanism(s) are not yet fully understood, the phenotype appears to have neurological origins, controlled by brain and central nervous system circuits. The phenotype of P4h-tm−/− mice recapitulates some of the symptoms of HIDEA patients, making this mouse model a valuable tool to study and develop tailored therapies.

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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

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 8 publications

References 18 publications

HIDEA syndrome: A new case report highlighting similarities with ROHHAD syndrome

HIDEA syndrome: A new case report highlighting similarities with ROHHAD syndrome

Repeated exposure to high-THCCannabissmoke during gestation alters sex ratio, behavior, and amygdala gene expression of Sprague Dawley rat offspring

Metabolic characteristics of transmembrane prolyl 4-hydroxylase (P4H-TM) deficient mice

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