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.