DISCUSSION
We describe two boys with a clinical picture that included premature birth due to reduced umbilical blood flow, growth retardation, progressive microcephaly, hypothermia, micropenis, hypothyreosis, obesity, diabetes as well as exocrine pancreatic failure. We found that both boys carried a truncating pathogenic variant towards the C-terminal end of eIF2γ. , c.1394_1397del (p.Ile465Serfs*4). This is the exact same variant as described in the paper of Moortgat et al. 2016 (Moortgat et al., 2016). That family was of Spanish origin and the mother in our family originates from northern Sweden, and we do not suspect a common heritage indication that the variant has arisen independently at least twice. There are several similarities between the affected individuals in Family 2 described by Moortgat et al. (Moortgat et al., 2016) and the cases reported here; including characteristic facial dysmorphic features (fig 1B, 1C), poor development, severe microcephaly (-3SD vs -4SD), initial hypoglycaemia, epilepsy, hypertonia, micropenis and finally death due to multiorgan failure. In contrast, our patients survived longer (4 years vs 12 months), which may partially explain the additional phenotypes. Some phenotypes were known from other MEHMO cases, such as diabetes, poor pancreas function and obesity (Borck et al., 2012, Gregory et al., 2019, Skopkova et al., 2017, Stanik et al., 2018, Steinmuller et al., 1998, Kotzaeridou et al., 2020). However, nor the hypothermia, neither the reduced umbilical blood flow, that resulted in premature delivery in our boys was previously described.
Human body temperature is sensed by a system of thermoreceptors located in the core and the periphery, in order to detect real and anticipated temperature alternations, respectively. Signals from these are connected to the lateral parabrachial nucleus (LBP) of the pons and the pre optic area (POA) located just by the anterior hypothalamus. Signals indicating low temperature will activate physiological responses such as vasoconstriction, shivering and non-shivering brown adipose thermogenesis. Structural damage to the LBP is known to abolishes behavioural temperature responses (Yahiro et al., 2017). POA is key to activation of all the physiological responses. Our patients had signs of vasoconstriction with colder extremities, though they were never seen shivering, indicating a partial failure to activate compensating systems. In addition, the anterior hypothalamus is important for thyroid regulation, growth hormone and gonadotropic hormones, all affected in our boys. Structural defects in the hypothalamus were not detected in our patients, but the MR investigations were not optimized to study the hypothalamus.
The ultrasounds performed during pregnancy indicated initial normal fetal growth, but in mid pregnancy (week 31) reduced fetal growth was noted. The boys were delivered by C-section at 34+4 and 35+3 due to absent umbilical artery end diastolic flow, indicating primary increased placental resistance or secondary such due to fetal hypoxia. Neither the MR performed, nor the clinical picture, indicated chronic or acute hypoxia. The molecular cause remains elusive.
The 2 novel phenotypes, hypothermia and reduced umbilical flow has to our knowledge not been associated with any related condition such as Vanishing White Matter disease (MIM# 606686, MIM# 606454, MIM# 606273, MIM# 606687, MIM# 603945; EIF2B1, EIF2B2, EIF2B3, EIF2B4 and EIF2B5), varinats in PPP1R15B, Wolcott Rallisson syndrome (MIM# 226980; EIF2AK3), or MEDS syndrome (MIM# 614231; IER3IP1).
A recent paper has unravelled the exact molecular mechanism of this specific variant (Young-Baird et al., 2020). The authors show that the variant impairs eIF2 function and leads to a chronic activation of the integrated stress response and neuronal differentiation results. Intriguingly, this can be reversed by the small molecule ISRIB, which raises treatment hopes in this devasting disease.