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Page 264 Lyulcheva-Bennett et al. J Transl Genet Genom 2023;7:259-73 https://dx.doi.org/10.20517/jtgg.2023.33

Historically, the structural anomalies associated with MBS have been attributed to aberrations during the
embryonic development of the mesencephalon-rhombencephalon, specifically between the 4th and 5th
weeks of embryonic development . This period is critical for dorsoventral patterning, and disruptions
[22]
during this phase can lead to the characteristic manifestations of MBS. The primary histopathological
hallmark of MBS is observed in the facial colliculus, situated in the pontine tegmentum. This region houses
[23]
the nuclei for the intra-axial fibres of CNVI and CNVII . The prevailing developmental model posits that
an initial insult during this embryonic period triggers a cascade of secondary events, culminating in the
[14]
clinical presentation of MBS . This primary insult is believed to be localised ischaemia in the dorso-medial
aspect of the brain stem. This region is particularly vulnerable to hypoxic-ischemic injury because of the
distribution pattern of the embryonic basilar artery branches [18,24] .

Several environmental factors have been implicated in the pathogenesis of MBS. The theory of vascular
disruption, particularly in the territory of the subclavian artery during the sixth week of embryogenesis, has
[4]
gained traction . This disruption could arise from foetal vascular events, including thrombus formation,
embolism, or haemorrhage. Additionally, vasoconstrictive agents, such as cocaine , ergotamine , or
[5]
[25]
misoprostol-induced uterine contractions [26,27] , can attenuate blood flow during critical developmental
windows, potentially precipitating MBS [23,28] . However, it is worth noting that the involvement of the
subclavian artery does not fully account for the clinical manifestations of MBS, necessitating further
exploration.

The aetiology of MBS is likely multifactorial [Figure 3], with a combination of genetic, environmental, and
[4]
perhaps stochastic factors converging to manifest the syndrome . This complexity necessitates a
multidimensional approach to research, integrating genetic studies with environmental and epidemiological
data to holistically understand MBS’s origins. In particular, the role of genetic factors in the aetiology of
MBS cannot be overlooked . The inherent complexity of MBS suggests that disruptions in various cellular
[4]
[29]
and developmental processes might converge on a common outcome . Consequently, multiple genes, each
involved in distinct pathways, might collectively contribute to MBS’s pathophysiology. This notion of
genetic heterogeneity is further supported by the observation that different genes might be implicated in
MBS across different families [4,12,29] . The interplay between genetic predispositions and environmental factors
[Figure 3] might render certain individuals more susceptible to the environmental insults that precipitate
MBS.

The aetiological landscape of Moebius Syndrome is intricate, with multiple layers of complexity. While
significant strides have been made in understanding its embryonic, environmental, and genetic facets, many
questions remain unanswered. The potential involvement of multiple genes, each contributing to a shared
clinical outcome, underscores the need for comprehensive genetic analyses. It is hoped that a better
understanding of the genetic factors in MBS will help devise aetiology-based disease classifications and offer
opportunities for personalised medical management of MBS patients.

GENETIC LANDSCAPE OF MBS
Recent advances in genetic testing, particularly whole-exome and genome sequencing, have ushered in a
new era of understanding for neurodevelopmental disorders. However, the genetic basis of MBS is still not
fully understood. The majority of MBS cases are sporadic, presenting a notably low recurrence risk among
siblings (which is often quoted to be around 2%-3% ). Such a pattern could align with several genetic
[8]
scenarios: dominant de novo mutations, the interplay of environmental factors, or polygenic inheritance
mechanisms. Another possibility is that causative genetic alterations exhibit pronounced reduced
penetrance and variable expressivity. This makes the task of characterising the genetic factors integral to
MBS particularly daunting, especially given the syndrome’s rarity and its phenotypic pleiotropy.