De novo mutations in PLXND1 and REV3L cause Möbius syndrome.

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.

The spectrum of Mobius syndrome: an electrophysiological study.

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.

Radiologic evidence for absence of the facial nerve in Möbius syndrome.

OBJECTIVE: To detail the radiologic findings in Möbius syndrome, in order to clarify its pathogenetic mechanisms. METHODS: High resolution three-dimensional T1 (MP rage) and T2 (CISS) weighted MRI were used to study the cisternal and canalicular portion of the seventh cranial nerve in six Möbius patients. Also, the anteroposterior dimension of the brainstem was measured at the level of the pons in the authors' 6 patients and in 20 age-matched healthy control subjects. Furthermore, the MRIs were evaluated for associated congenital brain anomalies. RESULTS: The facial nerves were absent in all six patients despite residual function in some facial muscles. The authors confirmed brainstem hypoplasia but did not find tegmental calcifications. The anteroposterior dimension of the brainstem ranged between 17 and 25 mm vs 20 to 27 mm for controls. In three patients there were congenital abnormalities in the posterior fossa. CONCLUSION: 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.

Electrophysiological assessment in patients with Möbius syndrome and clumsiness.

The authors studied the nature of clumsiness in Möbius syndrome in terms of motor or sensory deficits, and sought to clarify the pathophysiological mechanism of the syndrome. Standardized electrophysiologic studies were conducted, with special emphasis on the long motor and sensory tracts and peripheral nerves, in seven Möbius patients with clumsiness, of whom six participated in MRI studies; five of them showing brainstem hypoplasia. All performed motor-evoked potentials were normal. In all patients, normal somatosensory-evoked potentials were recorded and peripheral nerve conduction assessment revealed no abnormalities. The electrophysiologic data indicate that the traversing motor and sensory tracts through the brainstem, and the peripheral nerves are not affected in Möbius syndrome.

Sequence analysis of the PLEXIN-D1 gene in Möbius syndrome patients.

Möbius syndrome is a rare congenital disease characterized by the paralysis of the facial nerve, accompanied by impaired ocular abduction. We have performed an extensive mutation analysis on a recently identified positional candidate gene, PLEXIN-D1, for Möbius syndrome 2 mapping to chromosome 3q21-q22. Southern analysis of patients from the Möbius syndrome 2 family and 41 isolated Möbius syndrome patients did not reveal chromosomal abnormalities in the PLEXIN-D1 gene. Direct sequencing of deoxyribonucleic acid from familial patients, and single-strand conformational polymorphism analysis of PLEXIN-D1 in 41 isolated patients identified 18 nucleotide changes. Seventeen of these 18 changes could be dismissed as polymorphisms, as they did not co-segregate with the disease, or were present in a control group. A single nucleotide change identified in intron 29 of an isolated Möbius syndrome patient could not be identified in a control group. However, the position of this nucleotide change makes it highly unlikely that it could be causative for Möbius syndrome in this patient because it does not affect known splicing sequences. Likewise, reverse transcriptase polymerase chain reaction analysis in patients from the Möbius syndrome 2 family did not reveal splicing aberrations, and revealed bi-allelic expression, ruling out the possibility of promoter disrupting mutations. Taken together, these results lead to the exclusion of the PLEXIN-D1 gene as the causative gene in Möbius syndrome 2, and in isolated Möbius syndrome.

Möbius syndrome redefined: a syndrome of rhombencephalic maldevelopment.

OBJECTIVE: To investigate the variable clinical picture of Möbius syndrome (MIM no. 157900) and to further understand the pathogenesis of the disorder. METHODS: A standardized questionnaire was submitted to 37 Dutch patients with Möbius syndrome. All underwent standardized neurologic examination with special attention to cranial nerve functions, motor skills, and facial and limb anomalies. RESULTS: Of 37 patients with facial paresis, 97% had bilateral and 3% had unilateral ocular abduction weakness. Further analysis showed isolated abducens nerve palsy in 9%, a conjugated horizontal gaze paresis in 48%, features of Duane retraction syndrome in 34%, and congenital fibrosis of the extraocular muscles in 9%. Other signs included lingual involvement (77%), dysfunction of palate and pharynx (56%), general motor disability (88%), poor coordination (83%), and respiratory abnormalities (19%). CONCLUSION: 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.