Group I
Hypoplasia/absence of brainstem nuclei: Brainstem nuclei including the abducens and facial nerve nuclei are not formed or are significantly reduced in size.
Moebius Syndrome
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Möbius Syndrome?
Section titled “1. What is Möbius Syndrome?”Möbius syndrome is a rare congenital disorder characterized by non-progressive facial muscle paralysis and horizontal gaze palsy due to congenital dysfunction of the 6th (abducens) and 7th (facial) cranial nerves. It is classified under Congenital Cranial Dysinnervation Disorders (CCDDs) 1).
Incidence is estimated at 1 in 50,000 to 500,000 births. There is no sex predilection. Most cases are sporadic, but rare autosomal dominant families have been reported. It is usually bilateral abducens nerve palsy, but can be unilateral. When accompanied by limb abnormalities, it is called Poland-Möbius syndrome.
Pathologically, hypoplasia or atrophy of brainstem nuclei including the abducens nucleus is observed. The NINDS pathological classification categorizes it into the following four groups.
Group II
Peripheral nerve degeneration: The main feature is neuronal loss and degeneration in the peripheral facial nerve.
Group III
Necrosis/sclerosis of nerve nuclei: In addition to neuronal loss and degeneration in brainstem nuclei, there are microlesions and sclerosis.
Group IV
No cranial nerve lesions: There are no clear cranial nerve lesions, and muscle symptoms are predominant.
Q
How rare is Moebius syndrome?
A
It is a rare disease estimated to occur in 1 in 50,000 to 500,000 births. There is no gender difference, and most cases are sporadic with low heritability, but rare autosomal dominant families have been reported.
2. Main symptoms and clinical findings
Section titled “2. Main symptoms and clinical findings”Subjective symptoms (chief complaints in infancy/symptoms noticed by caregivers)
Section titled “Subjective symptoms (chief complaints in infancy/symptoms noticed by caregivers)”- Mask-like facies: Lack of facial expression, inability to smile. Caused by facial muscle paralysis due to facial nerve palsy.
- Mouth constantly open: Difficulty closing the mouth due to relaxation of facial muscles.
- Drooling and feeding difficulties: Often present as problems with sucking and feeding in infancy.
- Excessive tearing: Tears may overflow due to incomplete eyelid closure.
In many cases, the diagnosis is made during infancy based on poor feeding, incomplete eyelid closure, mask-like facies, and hypoplasia of the tongue.
Clinical Findings (Findings Confirmed by Physician Examination)
Section titled “Clinical Findings (Findings Confirmed by Physician Examination)”Ocular Movement Disorders
Section titled “Ocular Movement Disorders”- Bilateral horizontal gaze palsy: Characteristic inability to abduct the eyes. Vertical eye movements are preserved1).
- Most cases show bilateral horizontal gaze palsy in primary position. Some cases present only with esotropia and abduction limitation.
- Rarely, cases may also involve vertical gaze palsy.
Facial Nerve Palsy
Section titled “Facial Nerve Palsy”- Paralytic ectropion: The lower eyelid turns outward.
- Lagophthalmos: The eyeball is exposed due to incomplete eyelid closure.
- Incomplete eyelid closure: The eyelids do not close completely, including during sleep.
- Symptoms are bilateral in the majority, but unilateral and asymmetric cases have also been reported.
Other Cranial Nerve Disorders
Section titled “Other Cranial Nerve Disorders”Associated cranial nerve lesions that may occur are listed below.
| Cranial Nerve | Clinical Symptoms Due to Impairment |
|---|---|
| CN5 (Trigeminal nerve) | Facial sensory disturbance |
| CN8 (Vestibulocochlear nerve) | Sensorineural hearing loss |
| CN10 (Vagus nerve) | Dysphagia and dysarthria |
| CN12 (Hypoglossal nerve) | Tongue atrophy and dysarthria |
Associated systemic abnormalities
Section titled “Associated systemic abnormalities”- Limb malformations: clubfoot, adactyly, brachydactyly, syndactyly, arthrogryposis, congenital amputation
- Facial and oral abnormalities: epicanthal folds, ptosis, external ear malformations, micrognathia, high-arched palate, tongue atrophy/hypoplasia, cleft palate, cleft lip
- Others: hearing loss, muscle atrophy, impaired coordination and balance
- Intellectual disability: some cases may be accompanied by intellectual disability.
Q
Does Moebius syndrome cause complete immobility of the eyes?
A
Horizontal eye movement is impaired, but vertical (up and down) movement is preserved1). Severity varies among individuals, ranging from cases with only abduction limitation to complete horizontal gaze palsy.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”Several hypotheses have been proposed regarding the etiology of Möbius syndrome, and it is considered multifactorial rather than having a single cause.
- Vascular theory: During fetal development, blood flow to the brainstem watershed area (a border zone with vulnerable blood supply) where the CN6 and CN7 nuclei are located is compromised, leading to improper development of the cranial nerves.
- PLXND1 gene mutation: Encodes plexin D1, a membrane receptor protein involved in nervous system vascular formation and motor neuron migration and proliferation. An association with Möbius syndrome has been suggested1).
- ECEL1 gene mutation: Mutations in the gene encoding endothelin-converting enzyme-like 1 (ECEL1) have been reported to cause abnormal axonal guidance of the abducens nerve1). The C760R and G607S mutations produce similar phenotypes through different molecular mechanisms (abnormal protein localization and mRNA degradation, respectively).
- Exposure to teratogenic substances: Exposure to cocaine, ergotamine, benzodiazepines, misoprostol, and thalidomide during the first trimester of pregnancy has been reported. These are thought to cause temporary ischemia in the brainstem, leading to necrosis of cranial nerve nuclei.
- HOXA1 gene mutation: Encodes a transcription factor necessary for hindbrain patterning. Homozygous loss-of-function mutations present with a syndrome including bilateral Duane syndrome, sensorineural hearing loss, facial weakness, central hypoventilation, vascular malformations, and intellectual disability1).
- Pathomechanisms of CCDDs: Two main mechanisms are proposed: (a) abnormal neuronal specification due to disruption of transcription factors required for brainstem patterning, and (b) impaired growth and guidance of cranial nerve axons1).
Pathologically, hypoplasia or atrophy of brainstem nuclei including the abducens nucleus is observed. Although often sporadic, autosomal dominant inheritance has also been reported.
Q
Is Möbius syndrome genetic?
A
Most cases are sporadic, and the disease is not easily inherited. Multiple etiological hypotheses have been proposed, including PLXND1 and ECEL1 gene mutations and exposure to teratogenic substances in early pregnancy. Rare familial cases with dominant inheritance have been reported, but even in familial cases, they often do not meet the full diagnostic criteria1).
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”The diagnosis of Möbius syndrome is primarily clinical. There is currently no universally accepted diagnostic criteria.
Key Points for Diagnosis
Section titled “Key Points for Diagnosis”- The combination of bilateral horizontal gaze palsy (inability to abduct) and facial muscle paralysis is the core of the diagnosis.
- Differentiation from isolated cranial nerve palsy (especially isolated CN6 palsy) is important.
- In pontine lesions, the CN7 runs near the CN6 nucleus, providing an anatomical basis for CN6 palsy accompanied by CN7 palsy2).
Differential Diagnosis
Section titled “Differential Diagnosis”Representative differential diagnoses are shown below.
| Disease | Key Points for Differentiation |
|---|---|
| Duane syndrome | Abduction deficit + globe retraction and palpebral fissure narrowing on adduction. Unilateral in 82%, more common in the left eye. No facial palsy. |
| CFEOM (Congenital Fibrosis of the Extraocular Muscles) | Ptosis and limited elevation are predominant1). Horizontal movement disorder is not a main symptom. |
| HGPPS (Horizontal Gaze Palsy with Progressive Scoliosis) | Both abduction and adduction are impossible, but no globe retraction1). Association with scoliosis is characteristic. |
Imaging Studies
Section titled “Imaging Studies”- MRI: Used for morphological evaluation of the brainstem. Useful for confirming hypoplasia or atrophy of brainstem nuclei and excluding other neurological abnormalities2).
5. Standard Treatment
Section titled “5. Standard Treatment”There is no curative treatment. Symptomatic treatment is the mainstay, and an interdisciplinary approach involving ophthalmology, plastic surgery, and dentistry is necessary.
Facial Reconstruction
Section titled “Facial Reconstruction”- Gracilis muscle transfer: This surgery aims to restore facial muscle function. It is performed to enable expressions such as smiling. Collaboration with plastic surgery is necessary.
Eye Management
Section titled “Eye Management”The highest priority is preventing corneal damage due to incomplete eyelid closure from facial nerve palsy.
- Temporary tarsorrhaphy: Performed as early intervention for dry eye and decreased blink rate. Prevents corneal exposure due to lagophthalmos and incomplete eyelid closure.
- Ectropion repair, midface lift, eyelid retraction repair: May be effective in some cases.
- Artificial tears and eye ointment: Used continuously for corneal protection.
Strabismus Surgery
Section titled “Strabismus Surgery”For esotropia, bilateral medial rectus muscle recession is the first choice. Additional surgeries such as lateral rectus resection or vertical rectus muscle transposition are selected as needed.
- Many ophthalmic surgeons tend to consider surgical treatment carefully.
- The goal of surgery is to eliminate diplopia in primary gaze and secure a single binocular visual field, but diplopia in extreme lateral gaze may persist 2).
- Because postoperative outcomes are inconsistent, surgical options should be considered carefully.
Psychological and Behavioral Aspects
Section titled “Psychological and Behavioral Aspects”- Many patients experience prejudice and bullying due to difficulty in communication through facial expressions.
- Behavioral therapy is recommended. Communication support and psychological support are important.
Q
Can a smile be restored in Moebius syndrome?
A
Gracilis muscle transfer may restore facial muscle function and enable smiling. Collaboration with plastic surgery is necessary, and it is not indicated for all cases.
6. Pathophysiology and detailed pathogenesis
Section titled “6. Pathophysiology and detailed pathogenesis”The pathophysiology of Moebius syndrome is understood within the framework of CCDDs. The main pathogenic mechanisms are the following two 1).
(a) Impaired specification of neurons
The sequential expression of transcription factors required for brainstem patterning is disrupted, leading to the loss of specific motor nuclei (CN6 and CN7 nuclei). In this mechanism, the developmental ‘map’ of the brainstem itself is not formed, resulting in the absence of target nuclei.
(b) Impaired axon growth and guidance
Neurons are present, but the axons of cranial nerves cannot reach the target muscles. Misrouting may cause innervation of muscles different from the intended ones.
PLXND1 gene and ECEL1 gene and pathology
Section titled “PLXND1 gene and ECEL1 gene and pathology”The PLXND1 gene encodes the membrane receptor protein plexin D1, which is involved in neural vascular formation and motor neuron migration and proliferation 1). An association with Moebius syndrome has been suggested.
Regarding mutations in the ECEL1 (endothelin-converting enzyme-like 1) gene, the following has been shown in mouse models 1).
- C760R mutation: The protein localizes to the cell body rather than the axon, resulting in abducens nerve stalling and misrouting.
- G607S mutation: Nonsense-mediated decay of mRNA leads to a severe reduction in protein levels, causing a similar phenotype.
PLXND1 and ECEL1 are independent genes; C760R and G607S mutations have been reported as mutations in ECEL1.
Vulnerability of the brainstem watershed region
Section titled “Vulnerability of the brainstem watershed region”The CN6 and CN7 nuclei are located in the brainstem watershed region (a border zone with fragile blood supply), making them particularly vulnerable to ischemia. Transient ischemia due to teratogens or vascular abnormalities can lead to necrosis of these cranial nerve nuclei.
Due to the anatomical relationship where CN7 runs near the CN6 nucleus in the pons, both nerves are prone to simultaneous damage2).
MacKinnon et al. (2014) reported that most cases of Möbius syndrome are sporadic, and even familial cases often do not meet the full diagnostic criteria (some cases present with facial palsy alone without abduction deficit)1).
A possible association with tubulinopathies has also been suggested, and a family with autosomal dominant bilateral facial palsy, ptosis, and velopharyngeal dysfunction has been reported1).
7. Latest research and future perspectives (reports at research stage)
Section titled “7. Latest research and future perspectives (reports at research stage)”Functional analysis of the ECEL1 gene
Section titled “Functional analysis of the ECEL1 gene”Functional analysis of CCDD-related genes including ECEL1 and PLXND1 is progressing. Elucidation of axon guidance abnormalities in mouse models is deepening the understanding of the genetic basis of CCDDs, including Möbius syndrome1).
Nagata et al. (2017) reported that the C760R and G607S mutations in ECEL1 cause abducens nerve axon guidance abnormalities through different molecular mechanisms (abnormal protein localization and mRNA degradation)1).
Progress in Identifying Causal Genes for CCDDs
Section titled “Progress in Identifying Causal Genes for CCDDs”The identification of causal genes associated with CCDDs is progressing, and research continues to elucidate the genetic diversity and pathophysiological mechanisms of congenital cranial dysinnervation disorders, including Moebius syndrome 1).
Association with Tubulinopathies
Section titled “Association with Tubulinopathies”It has been suggested that the disease spectrum of tubulinopathies may extend to CCDDs, and further detailed elucidation through future genetic analysis studies is expected 1).
8. References
Section titled “8. References”-
Whitman MC. Axon guidance deficits cause cranial nerve dysinnervation disorders (CCDDs). Annu Rev Vis Sci. 2020;6:819-842.
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American Academy of Ophthalmology. Adult Strabismus Preferred Practice Pattern. Ophthalmology. 2020.