"Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has."
Cureus is on a mission to change the long-standing paradigm of medical publishing, where submitting research can be costly, complex and time-consuming.
The SIQ for this article will be revealed
case report, missense mutation, p.gln61arg, lmx1a, moebius syndrome
Cite this article as: Alnefaie G O (October 10, 2022) A Missense Mutation in LMX1A in a Patient With Moebius Syndrome: A Case Report. Cureus 14(10): e30127. doi:10.7759/cureus.30127
Moebius syndrome is characterized by congenital complete or partial paralysis of the facial nerve and is often associated with orofacial and limb malformations. It is a rare syndrome that affects the sixth and seventh cranial nerves. Facial paralysis results in abnormal abduction of one or both eyes and facial paralysis or weakness. Moebius syndrome is an uncommon condition and only a few hundred cases have been reported in the literature. A seven-year-old girl with Moebius syndrome is featured in this report. She had asymmetrical facial expressions, ocular abduction anomalies, and swallowing difficulties. She also had mild low-set ears, hypertelorism, a short nose, and restricted jaw movements. Array-comparative genomic hybridization analysis of exosome sequencing showed a mutation p.Gln61Arg in exon 3 of LMX1A.
Moebius syndrome (MBS), a rare congenital disease, was first described by Von Graefe in 1880 and then named after Moebius in 1888 [1]. It is characterized by unilateral or bilateral facial and abducens palsy, which leads to a loss of facial expressions, and an inability to smile or swallow [1]. Moreover, patients with MBS also suffer from orofacial and limb defects. The estimated prevalence is 1/250,000, with an equal incidence in both genders [2]. The condition affects one in 50,000 to one in 500,000 newborns [3]. The unclear diagnostic criteria have led to difficulty in the clinical assessment, prognosis, and genetic analysis of patients with MBS. Since 1888, the pathogenesis of the disease has been unclear; till 2007 when MBS was defined as “congenital unilateral or bilateral, non-progressive facial weakness and limited abduction of the eye” [2].
Furthermore, de novo mutations in the PLXND1 and REV3L have been recorded in many MBS cases. PLXND1 plays a role in regulating the migration of a wide spectrum of cell types in the striatum and is selectively expressed in direct-pathway medium spiny neurons [4]. Although REV3L functions in the translation of DNA synthesis, it can also protect DNA from damage [5].
A seven-year-old female experienced global developmental delay and weakness of the facial muscles. On examination: the patient had dysmorphic features such as hypotonia and bilateral epicanthal fold and was born with a small chin (micrognathia), a broad nasal bridge, and a small mouth (microstomia) with an unusually shaped tongue. She had difficulty making eye contact, her eyes were misaligned (strabismus), and she exhibited a lack of facial expression, including smiling, frowning, raising eyebrows, puckering lips, and closing her eyes (Figure 1).
She also exhibited a weak muscle tone (hypotonia). In general, the patient experienced delayed development of motor skills (such as crawling and walking), difficulties with speech, frequent drooling, and difficulty swallowing or sucking. She also had a low-set ear, hypertelorism, a short nose, a short philtrum, a carpal moth, and restricted jaw movement (Table 1). Mild puffiness of the cheeks and mild asymmetry was observed during unsupported walking. Dental abnormalities included missing and misaligned teeth which contributed to speech difficulties. All clinical features mentioned earlier indicated MBS.
Very long-chain fatty acids (VLCFA) testing was performed due to the matching of many of the clinical features of the case above with the known features of Zellweger syndrome including dysmorphic facies, hearing loss, and hypotonia. The test result came back normal, so Zellweger syndrome was ruled out. Her metabolic screening and toxoplasmosis, rubella cytomegalovirus, herpes simplex, and HIV (TORCH) titers were normal, with no cherry-red spot-on ophthalmology, which may be present in many lysosomal storage diseases. Electroencephalography (EEG) showed no abnormal electric activity that may point out possible seizures.
Brain and abdominal ultrasound findings were normal. Moreover, magnetic resonance imaging (MRI) of the brain showed increased intensity at the lentiform nucleus, mainly at globus pallidus initially; however, on follow-up, MRI revealed a significant reduction of the signals observed earlier in the basal ganglia. Hydrocephalus was observed. Her results for tandem mass spectrometry and lateral flow test for blood gases were all within normal levels. The rest of the blood tests were normal including haematology and chemistry. (Table 2).
SVD: spontaneous vaginal delivery; CBC: complete blood count; TORCH: toxoplasmosis, rubella cytomegalovirus, herpes simplex, and HIV; DDH: developmental dysplasia of the hip; GVS: galvanic vestibular stimulation; BCG: bacille Calmette-Guerin; PICU: pediatric intensive care unit; FISH: fluorescence in situ hybridization; VLCFA: very long-chain fatty acids; TMS: transcranial magnetic stimulation; CGH: comparative genomic hybridization; CARS: childhood autism rating scale
She had non-consanguineous parents who had three abortions (Figure 2), with no deaths or similar conditions. The normal female karyotype 46 XX and Prader-Willi/Angelman (15q11-13) duplication in SNRPN were negative.
*Showing a heterogeneous p.Gln61Arg mutation in exon 3 of LMX1A
**Not showing p.Gln61Arg mutation in exon 3 of LMX1A
Whole exome sequencing showed a heterogeneous p.Q61R mutation in exon 3 of LMX1A. A de novo heterozygous missense variant c.182A>G (p.Gln61Arg) in the LMX1A gene is not reported by GnomAD. In addition, a whole exome analysis was also conducted for parents in order to determine whether the variation in LMX1A was inherited from the parents or whether it was a de novo event. Due to this, neither parent has c.182A>G, suggesting that it is de novo. In addition, the PLXND1 and REV3L genes, which are related to Moebius syndrome, were investigated to determine whether there is any gene defect that contributes to patient characteristics. However, no mutations were identified.
The patient’s hearing dysfunction and left middle ear effusion were managed using a eustachian tube. Her vision was treated with supporting glasses, and she underwent speech therapy with a specialist. There is no specific treatment course for Moebius syndrome. The treatment, in this case, was supportive and in accordance with the symptoms that were presented. Infants may require feeding tubes or special bottles to provide sufficient nutrition. In this case, the patient had a gastrostomy tube placed at birth, which was removed later at age of three years. As a part of surgical treatment, tarsorrhaphy and smile surgery can be performed later in life. Physical and speech therapy often improves motor skills and coordination and leads to better control of speaking and eating abilities. Plastic reconstruction surgery may be beneficial, and nerve and muscle transfers to the corners of the mouth can be performed to provide a limited ability to smile.
The patient was recommended to attend the follow-up to make a general check-up to assess the physical, vision and hearing progress and to visit a dentist clinic. The physical progress has been appreciated by the patient and her parents. That progress comes from parent support by keeping their faith and constantly attending the follow-up session.
Genetic abnormalities in most MBS cases are unclear, as they generally show sporadic mutation [6]. However, a familiar trend has been indicated in patterns of both autosomal dominant and recessive inheritance [7]. Moreover, the inherent genetic risk ranges between 2% and 30% according to clinical features [4]. The risk is reduced to 2% if MBS affects only the musculoskeletal system [5]. However, if MBS presents facial palsy, deafness, and abduction limitation of the eye, the risk increases to 25-30% [5]. Studying the genetics of MBS cases is difficult because they are heterogeneous. Many genetic studies have been conducted to investigate the specific locus in selected genes (1p22, 3q21-22, 10q21.3-q22.1, and 13q12.2-q). The selected loci indicated MBS1 at 13q12.2-q1311 [8]. The loci selected for investigation are also linked to homeobox genes (HOXA1 and HOXB1) and SRY-box transcription factor 14 (SOX14), which are critical for brain development. Verzijl et al. defined MBS3 as 10q21.3-3q22.1, in a Dutch family [9]. Some of the investigated genes are important in neural development (PLEX1N-A1, GATA2, EGR2, BASP1, and TUBB3) [10] and remain linked to growth; for example, FLT1/VEGFR1 [11]. The most noticeable sporadic mutations reported in six MBS cases were found in PLXND1 and REV3L, which are responsible for facial branchiomotor neuron migration and craniofacial bone abnormality [12].
In this case report, a mutation in LMX1A was identified in a patient with MBS. Encoding a protein, LMX1A is a transcription factor that positively regulates insulin gene transcription. It also plays a role in the development of dopamine-producing neurons during embryogenesis. However, a mutation in LMX1A is associated with an increased risk of developing Parkinson’s disease [13]. The point mutation (c) that occurred in the patient’s chromosome is heterozygous missense variant c.182A>G (p.Gln61Arg).
One study identified that the heterozygous missense variant c.182A>G (p.Gln61Arg) leads to non-syndromic hearing impairment and vestibular dysfunction [14], which points to one of the features of MBS. Furthermore, LMX1A has been reported to play a role in the development and specification of dorsal cell fates in the central nervous system and in developing vertebrae [15] which may be linked to weakness of palsy of multiple cranial nerves in MBS, which most patients with MBS experience, including the patient in this case. Several SNPs of the LMX1A gene have been found to be associated with congenital scoliosis and other forms of congenital malformations phenotypes of congenital scoliosis [16].
At present, only deafness, autosomal dominant 7 (OMIM#601412), is associated on the Online Mendelian Inheritance in Man (OMIM™) website. Though this variant is absent in the Genome Aggregation Database (gnomAD), it has been predicted to be benign by various in silico tools. More importantly, variants in the LMX1A gene were reported to be related to autosomal dominant deafness. The relationship between the LMX1A gene and Moebius syndrome has not been well established.
Although MBS has been reported in several studies, the genetic etiology remains unclear. Efforts are ongoing to recognize the genetic mutations in all MBS cases to characterize a clear guide for the mechanism and causes of Moebius syndrome. Therefore, this case report helps enrich this field with a new aspect.
Department of Pathology, College of Medicine, Taif University, Taif, SAU
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
I express my sincere gratitude and appreciation to Taif University for its sustained assistance.
Alnefaie G O (October 10, 2022) A Missense Mutation in LMX1A in a Patient With Moebius Syndrome: A Case Report. Cureus 14(10): e30127. doi:10.7759/cureus.30127
Peer review began: September 25, 2022 Peer review concluded: October 06, 2022 Published: October 10, 2022
© Copyright 2022 Alnefaie. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
*Showing a heterogeneous p.Gln61Arg mutation in exon 3 of LMX1A
**Not showing p.Gln61Arg mutation in exon 3 of LMX1A
SVD: spontaneous vaginal delivery; CBC: complete blood count; TORCH: toxoplasmosis, rubella cytomegalovirus, herpes simplex, and HIV; DDH: developmental dysplasia of the hip; GVS: galvanic vestibular stimulation; BCG: bacille Calmette-Guerin; PICU: pediatric intensive care unit; FISH: fluorescence in situ hybridization; VLCFA: very long-chain fatty acids; TMS: transcranial magnetic stimulation; CGH: comparative genomic hybridization; CARS: childhood autism rating scale
Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. Learn more here.
This link will take you to a third party website that is not affiliated with Cureus, Inc. Please note that Cureus is not responsible for any content or activities contained within our partner or affiliate websites.
Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. SIQ™ assesses article importance and quality by embracing the collective intelligence of the Cureus community-at-large. All registered users are invited to contribute to the SIQ™ of any published article. (Authors cannot rate their own articles.)
High ratings should be reserved for work that is truly groundbreaking in its respective field. Anything above 5 should be considered above average. While all registered Cureus users can rate any published article, the opinion of domain experts is weighted appreciably more than that of non-specialists. An article’s SIQ™ will appear alongside the article after being rated twice and is recalculated with each additional rating.
Visit our SIQ™ page to find out more.
Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. SIQ™ assesses article importance and quality by embracing the collective intelligence of the Cureus community-at-large. All registered users are invited to contribute to the SIQ™ of any published article. (Authors cannot rate their own articles.)
Already have an account? Sign in.
Please note that by doing so you agree to be added to our monthly email newsletter distribution list.
By joining Cureus, you agree to our Privacy Policy and Terms of Use.