A Case of Facial-Onset Sensory Motor Neuronopathy – A Rare Variant of Motor Neuron Disease

Introduction Facial-onset sensory motor neuronopathy (FOSMN) is a rare disorder with a very characteristic pattern of onset and progression of symptoms, starting in the face with rostro-caudal progression. The etiology and pathogenesis of this condition are yet to be established. We report a case of FOSMN with mutation of SETX gene, which is not reported so far, favoring neurodegenerative etiology. This is the first case report of FOSMN from India to the best of our knowledge. Case Description A 46-year-old lady, born out of nonconsanguineous marriage, with no known comorbidities presented with numbness of right lower half of the face of 8 months duration, followed by numbness and decreased perception of hot and cold sensations of the right upper limb and right half of the upper trunk. Two months into the illness, she developed difficulty in swallowing both solids and liquids, slurring of speech in the form of nasal twang, and flail-type weakness of right followed by left upper limb in the form of difficulty in lifting the arm above the shoulder, taking food bolus to the mouth, and gripping objects in the hand. She also had difficulty in lifting the neck off pillow and turning to the right side in bed. Symptoms were slowly progressing in severity without any fluctuation. She had no history of behavioral changes or memory disturbances and no history suggestive of any other cranial nerve involvement. She did not report unsteadiness while walking, slowness of activities of daily living, tightness of limbs, involuntary movements, bowel or bladder symptoms. She had no history of similar illness in the family. On examination, her higher mental functions were normal [mini-mental state examination (MMSE) and the Montreal Cognitive Assessment (MoCA) were normal]. Cranial nerve examination revealed the following: impairment of all sensory modalities in the right half of the face, predominantly in V2 and V3 distribution, with bilateral absent corneal and conjunctival reflexes; facial muscle weakness, predominantly in the lower half of the face, right more than left, with normal taste sensation, normal tearing from eyes (normal Schirmer’s test); decreased palatal movements bilaterally with diminished gag reflex, right more than left, with normal palatal and pharyngeal sensations; bilateral trapezius and sternocleidomastoid were weak; and tongue atrophy with fasciculations in the right lateral border of the tongue, with reduced power. Rest of the cranial nerve examination were normal. Spinomotor examination revealed atrophy and fasciculations over the posterior fibers of deltoid and thenar muscles with polyminimyoclonus in the right hand and hypotonia of the right upper limb. Asymmetrical weakness, with differential involvement within the distribution of nerve or myotome was noted; predominantly, upper limbs were more involved than the lower limbs, with proximal muscles weaker than the distal muscles and right-side limbs weaker than the left-side limbs. Neck and trunk muscle weakness [Figure 1a] were noted, with equal involvement of flexors and extensors. Superficial reflexes including corneal, conjunctival, and superficial abdominal reflexes were absent bilaterally. Deep tendon reflexes were exaggerated in all four limbs, with positive Hoffman’s sign on the right side. Jaw jerk was present. Bilateral plantar reflex was mute. Sensations were reduced in the right upper limb and right half of the trunk from C2 to T6 level, including right half of the face, predominantly in the lower half [Figure 1b] for all the modalities. Coordination was intact. Spine and cranium were normal, with a normal height to neck ratio of 11.3. There was no evidence of involvement of autonomic nervous system; no Horner’s syndrome and mirror movements were noted; skull and spine were normal.Figure 1: (a) Pattern of motor weakness; (b) pattern of sensory involvement (darker color indicates more severe involvement)Magnetic resonance imaging of the brain and cervical spine was already done in another hospital 3 months before for the same complaints. This revealed tonsillar ectopia, with a tiny T2 hyperintensity noted in the spinal cord at the cranio-vertebral (CV) junction, suggestive of syrinx [Figure 2a and b]. Repeat imaging was done, which showed same findings. However, these lesions could not explain the clinical manifestations of this patient. The clinical features were suggestive of lower motor neuron (LMN) and upper motor neuron (UMN) syndrome with the possible structures involved being the nuclei of bilateral trigeminal, facial, vagal, spinal accessory, and hypoglossal nerves; anterior horn cells at the cervical, thoracic, and lumbosacral levels; and dorsal root ganglion (DRG) or sensory roots at the right C2–T6 level as it is in a dermatomal distribution involving all sensory modalities. Hence, we proceeded with nerve conduction studies, which showed reduced compound motor action potential (CMAP) amplitudes in the right median, right radial, and bilateral ulnar nerves with absent peroneal nerve CMAP on the right side and absent sensory nerve action potential (SNAPs) in the right median, ulnar, and radial nerves with normal SNAPs in the left upper limb and bilateral sural nerves. Blink reflex was absent bilaterally. Needle electromyography showed features of chronic denervation at the bulbar, cervical, thoracic, and lumbar levels. Electrodiagnostic studies were suggestive of asymmetrical sensory and motor neuronopathy at the bulbar, cervical, thoracic, and lumbar levels.Figure 2: MRI cervical spine T2, sagittal section (a) and axial section (b) showing hyperintensity in the spinal cord at the CV junction, suggestive of syrinx. MRI = magnetic resonance imagingBased on the clinical features and electrophysiology findings, she was provisionally diagnosed as a case of atypical motor neuron disease, with sensory neuronopathy consistent with FOSMN, after excluding other possible secondary causes for this type of presentation. Her routine biochemical parameters including complete blood count, renal function tests, liver function tests, and electrolytes were normal. Autoimmune workup with anti nuclear antibody (ANA)/ extractable nuclear antigen (ENA) profile, cytoplasmic anti neutrophil cytoplasmic antibody (c-ANCA), and peripheral anti neutrophil cytoplasmic antibody (p-ANCA) was normal, except for positive rheumatoid factor (RF), anti cyclic citrullinated peptide antibodies (anti-CCP), and anti thyroid peroxidase (anti-TPO). Thyroid function test (TFT) revealed hypothyroidism and she was started on thyroxine. Fasting lipid profile was normal, which is not in favor of Tangier disease; moreover, she did not have orange tonsils or organomegaly. Infection panel for human immunodeficiency virus, hepatitis B and C, and syphilis was negative. Serum calcium was normal. Chest X-ray did not show any hilar lymphadenopathy. Serum angiotensin-converting enzyme levels were within normal limits, ruling out sarcoidosis. To rule out any paraneoplastic etiology, ultrasound of the abdomen and pelvis was done, which was normal except for grade II fatty liver. Serum protein electrophoresis was normal with negative urine Bence Jones proteins. Although her initial neurologic manifestations were similar to familial amyloid neuropathy type IV, she did not have any other associated features like corneal clouding, skin changes, or features suggestive of carpal tunnel syndrome. Anti-ganglioside antibody and serum polymerase chain reaction for Lyme disease were not performed as they were not feasible. Cerebrospinal fluid analysis was suggested, but patient was not willing for invasive procedures. Nerve biopsy was also not performed due to the same reason. The significance of positive anti-CCP, RF, and TPO is not clear. Even though several antibodies were positive in most of the cases reported so far, supporting an immune-mediated etiology, none of the antibodies were consistently positive. She was initially started on a trial of pulse intravenous (IV) methylprednisolone 1 g for 5 days followed by a 5-day course of IV immunoglobulin (20 g/day), considering the possible immune-mediated etiology of FOSMN and evidence from literature suggesting improvement of symptoms with immunotherapy. She had subjective improvement in the sensory symptoms; however, her weakness gradually worsened. Later on, whole exome sequencing was done, which revealed presence of SETX gene (c. 4082del) of likely pathogenic variant, with autosomal recessive pattern of inheritance. The genetic study report was negative for ABCA1, GSN, PABPN1, SLC52A2, and SLC52A3 genes, ruling out Tangier disease, familial amyloidosis neuropathy type IV, ocular pharyngeal muscular dystrophy, Brown–Vialetto–Van-Laere syndrome, and Fazio–Londe syndrome, respectively. The presence of SETX gene mutation, previously reported in juvenile amyotrophic lateral sclerosis (ALS) and ataxia with oculomotor apraxia, favors a neurodegenerative etiology for FOSMN. She was then started on riluzole, considering FOSMN as a variant in the Frontotemporal dementia (FTD)–ALS spectrum, and is under follow up. Discussion FOSMN is a rare disease, with a characteristic asymmetrical facial onset of sensory symptoms, starting in the perioral region and progressing in a rostro-caudal pattern. Lower motor neuron symptoms may manifest alongside sensory symptoms or later as the disease progresses; it includes dysphagia, dysarthria, atrophy, fasciculations, and muscle weakness with progression in the same rostro-caudal pattern. The pathogenesis of this entity still remains uncertain, with neurodegenerative versus immune-mediated pathology considered as the likely cause. FOSMN was first described in 2006 by Vucic et al.[1] They proposed FOSMN as a novel syringomyelia-like syndrome that appears to have a neurodegenerative etiology. They described four male patients; all of them presented with facial-onset paraesthesia and numbness, which then progressed to involve the scalp, neck, trunk, and upper and lower limbs in the same order, followed by motor manifestations. Electrophysiological studies showed generalized sensory motor neuronopathy, with low SNAP in the upper limbs and preserved sural SNAPs with evidence of axonal loss in electroneuromyography (ENMG) testing. Autopsy in one of their patients revealed degeneration of the anterior horn cells and hypoglossal nucleus. Hence, they reported FOSMN as a “slowly progressive neurodegenerative disorder, pathogenesis of which is yet to be determined.” In 2022, de Boer et al.[2] published the largest case series of FOSMN including 100 patients. As per the study, 55 years is the mean age of onset, with range of age being 7–78 years and with slight male preponderance. In 91% of the cases described, the symptoms started as sensory manifestations in the face. Motor manifestations in FOSMN are predominantly of the lower motor neuron type, with only 16.9% of the patients having pyramidal signs. Eight out of 100 patients had frontotemporal dementia, reinforcing the probability of FOSMN being a part of the FTD–ALS spectrum. Moreover, autopsy performed for six patients in the case series showed loss of motor neurons in the facial nerve nucleus, hypoglossal nerve nucleus, and cervical anterior horn cells; loss of sensory neurons in the main sensory nucleus of the fifth nerve, nucleus of tractus solitarius, and dorsal root ganglia; and transactive response DNA binding protein (TDP-43)–positive glial inclusions in four of the cases. In another case series (four new cases and 67 literature cases) and systematic review published by Hu et al.[3] in 2023, results were similar to the study by de Boer et al.[2] Even though the pattern of disease progression is characteristic, isolated cases of atypical presentation are also reported. In a case series of six cases by Broad et al., one patient developed sensory symptoms 10 years after the onset of motor symptoms.[4] In another case reported by Zhang et al., the sensory symptoms were not of facial onset, but started in the upper limb and then progressed to the face.[5] Isolated unilateral or bilateral facial numbness and/or pain alone is reported in some patients due to trigeminal neuropathy, without any other underlying causes like connective tissue disorders. Some of them progressed to develop all features of FOSMN over a period of 10 ± 3.8 years.[6] The symptoms remained restricted to the trigeminal distribution in others and it is referred to as trigeminal isolated sensory neuropathy (TISN). TISN is presumed to have a similar pathophysiology as FOSMN, as both affect myelinated nerve fibers of the trigeminal nerve. Clinically, it is difficult to distinguish the two diseases at the onset. In our case, the clinical features and electrophysiological findings were suggestive of involvement of multiple cranial nerve nuclei, including trigeminal, facial, vagal, and hypoglossal, along with dorsal root ganglion at the cervical level and anterior horn cell involvement at multiple levels of the spinal cord. The onset and progression were similar to the cases previously reported. Though the imaging had findings of cranio-vertebral junction (CVJ) anomaly, there were no significant changes in the spinal cord or brainstem to establish CVJ anomaly as the cause of this clinical presentation. So far, there are no international diagnostic criteria for FOSMN. The only available diagnostic criterion is the one proposed by Zheng et al.[7] in 2016. This criterion grossly mentions the features of FOSMN, but does not mention the characteristic onset and pattern of progression of symptoms. This criterion needs validation and further modification. In 2023 Hu et al.[3] proposed the key diagnostic features of FOSMN, based on the findings in 71 cases [Table 1].Table 1: Key diagnostic features in FOSMN, proposed by Hu et al.[ 3 ]Accordingly, the diagnosis of FOSMN can be made only after ruling out all the other possible etiologies. Genetic analysis is essential to rule out genetic diseases like Kennedy’s disease, oculopharyngeal muscular dystrophy, Fazio–Lunde syndrome, Tangier disease, familial amyloidosis neuropathy, etc., and also to look for the presence of any of the previously reported genes in the FTD–ALS spectrum or other neurodegenerative diseases as FOSMN is so far considered to be a variant in the FTD–ALS spectrum of diseases. Mutations reported as of now in FOSMN cases include those of SOD1,[9]TARDBP,[10,11] SQSTM1,[12]VCP, CHCHD10 genes.[10]SETX gene mutation is so far not reported in cases of FOSMN. Heterozygous missense mutation of SETX gene causes juvenile ALS, inherited in an autosomal dominant pattern. The mutations in SETX gene may cause neuronal degeneration through dysfunction of helicase activity or other steps in RNA processing (Chen et al.),[11] possibly causing a neurodegenerative disease like FOSMN. Hence, heterozygous single base pair deletion in exon 10 of the SETX gene (c. 4082del) may be considered as a novel genotype for FOSMN phenotype. The fact that SETX gene mutation is previously known to cause juvenile ALS reinstates the possibility of FOSMN being a part of the FTD–ALS spectrum. Immunotherapy can be considered in the treatment of FOSMN in view of the presence of autoantibodies and partial improvement of symptoms reported in some cases.[8,13-15] In the case series reported by de Boer et al.,[2] 20% of the patients treated with intravenous immunoglobulin (IVIg) had clinical improvement. Steroids and plasma exchange have also been tried in some patients, with very few patients showing improvement in symptoms (one out of 15 patients treated with steroids and one out of six patients treated with plasmapheresis). To find out the actual response to immunotherapy, randomized controlled trials should be performed with a placebo arm. As in ALS, the most common cause of death in FOSMN is by aspiration, with a mean disease duration of 7.5 years.[2] In a nationwide survey conducted in Japan from June 2020 to September 2021 with 20 cases of FOSMN, it was found that those patients with motor-predominant presentation had worse prognosis compared to those in the sensory-predominant group.[16] In the motor-predominant group, the rate of progression of the disease was faster, gait disturbance was worse, the need for gastrostomy was more frequent, and the revised ALS rating scale scores were less. Conclusion FOSMN is a new clinical entity. It is unique from other motor neuron diseases because of the presence of characteristic sensory deficits. It is a neurodegenerative disease that can be included in the FTD–ALS spectrum, which has predominant lower motor neuron involvement along with characteristic sensory deficits. Heterozygous single base pair deletion in exon 10 of the SETX gene (c. 4082del) may be considered as a novel pathogenic variant for FOSMN. More studies need to be conducted on the disease to figure out the pathogenesis and to test the response to various treatment options after randomization with a placebo arm. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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