Möbius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Möbius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients.

Two types of myoadenylate deaminase (MAD) deficiency have been described, primary or inherited, and secondary or acquired MAD deficiency. In this study, we investigated whether secondary MAD deficiency is indeed acquired or merely coincidental. We demonstrated the same underlying molecular defect, a C34T transition, in both types of deficiency. Furthermore, the same frequency of the mutant MAD allele was found in the general population as in patients with neuromuscular complaints. We therefore conclude that in the Dutch population, secondary MAD deficiency is merely a "coincidental" finding, and that MAD deficiency is a harmless genetic variant.

Möbius syndrome is more than a cranial nerve or nuclear developmental disorder. It is a syndrome of rhombencephalic maldevelopment involving predominantly motor nuclei and axons, as well as traversing long tracts. The authors also noted gaze palsies, Duane retraction syndrome, feeding and respiratory problems, and poor motor development, suggesting a regional developmental disorder.

We studied the nature and extent of facial muscle innervation and the involvement of the motor and sensory long tracts in Möbius syndrome, in order to shed light on the pathophysiological mechanism of the syndrome. Standardized blink reflexes, direct responses of the facial nerves to the orbicularis oculi muscles and concentric needle electrode electromyography in orbicularis oculi and/or oris muscles were measured in 11 patients with Möbius syndrome, of whom six participated in MRI studies, all showing absent facial nerves. We performed motor- and somatosensory-evoked potentials in seven Möbius patients. We demonstrated three distinct patterns of abnormalities suggesting different sites of the primary lesion in different patients. (i) Presence of normal blink reflexes and facial compound motor action potentials, normal habituation tests, a reduced recruitment in the facial muscles and an aberrant 'blink reflex-like' response of the orbicularis oculi muscle upon stimulation of the facial nerve region, which suggests a supranuclear origin of the defect. (ii) Absent blink reflexes, absent direct responses of the facial nerves and absent motor activity on needle electromyography, indicating a defect at the facial nuclear level. However, the nuclear defect might mask an additional supranuclear defect, which cannot, therefore, be excluded in these patients. (iii) A disperse pattern of facial compound action potentials combined with long latencies that were recorded with concentric needle electrodes, indicating involvement of motor axons in the facial nerve, possibly secondary to nuclear involvement. An additional supranuclear defect cannot be excluded in these cases. All evoked potentials studied were normal. The electrophysiological findings of the facial muscles show a spectrum of disturbances varying in degree of severity and diverse in the extent of structures involved, in 11 Möbius patients. At one end of the spectrum are patients with completely immobile faces in whom electrophysiological testing shows no signs of involvement of the facial nuclei, nerves or muscles, suggestive of a dysfunction at the supranuclear level. At the other extreme of the spectrum are patients with complete absence of responses upon facial nerve stimulation and absence of motor unit activity. This is at least indicative of a defect at the facial nuclear level. While a supranuclear defect is compatible with the concept that Möbius syndrome is a developmental disorder of the lower brainstem, intact facial nuclei as part of the syndrome has not been suggested before. The findings corroborate the concept of the Möbius syndrome being a complex regional developmental disorder of the brainstem.

Möbius syndrome (MIM 157900) consists of a congenital paresis or paralysis of the VIIth (facial) cranial nerve, frequently accompanied by dysfunction of other cranial nerves. The abducens nerve is typically affected, and often, also, the hypoglossal nerve. In addition, orofacial and limb malformations, defects of the musculoskeletal system, and mental retardation are seen in patients with Möbius syndrome. Most cases are sporadic, but familial recurrence can occur. Different modes of inheritance are suggested by different pedigrees. Genetic heterogeneity of Möbius syndrome has been suggested by cytogenetic studies and linkage analysis. Previously, we identified a locus on chromosome 3q21-22, in a large Dutch family with Möbius syndrome consisting essentially of autosomal dominant asymmetric bilateral facial paresis. Here we report linkage analysis in a second large Dutch family with autosomal dominant inherited facial paresis. After exclusion of >90% of the genome, we identified the locus on the long arm of chromosome 10 in this family, demonstrating genetic heterogeneity of this condition. The reduced penetrance suggests that at least some of the sporadic cases might be familial.

Neuropathologic findings confirm clinical observations that hereditary congenital facial palsy and Möbius syndrome are two different entities with a different pathogenesis.

The absent facial nerves on MRI and the unusual distribution of the facial weakness, which is characteristic of Möbius syndrome, suggests that other cranial nerves, possibly the trigeminal, hypoglossal, or glossopharyngeal nerve, aberrantly innervate some lower facial muscles. Radiologic findings support the notion that Möbius syndrome is part of a more complex congenital anomaly of the fossa posterior.

The rate of occurrence of mental retardation in our group of Möbius patients did not differ from that in the normal Dutch population. Furthermore, there was no evidence of attention and memory dysfunction in our group of Möbius patients.