facial onset sensory and motor neuronopathy ( fosmn ) is a slowly progressive disorder characterised by facial sensory deficits which may spread to affect the neck , the upper trunk and the limbs , with the development later in the course of the disease of bulbar symptoms such as dysarthria and dysphagia , muscle weakness , cramps and fasciculation . because of these latter features
, parallels between fosmn and motor neurone disease ( mnd ) have been drawn , although sensory features are not a feature of mnd and the onset and progression of fosmn appear to be slower than those of mnd .
based on the limited currently available clinical and investigative evidence [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] and the lack of therapeutic response to immunosuppressive agents in most ( but not all )   cases , an underlying neurodegenerative process has been suggested in fosmn , although cases with neuropathological examinations are very few [ 2 , 6 , 9 ] .
we report 3 further cases of fosmn , one with a post - mortem examination , suggesting that at least some of these cases fall within the spectrum of the transactive response dna binding protein 43 ( tdp-43 ) proteinopathies .
a 62-year - old man presented with a 3-year history of perioral numbness and paraesthesia progressing to involve all divisions of the trigeminal nerve bilaterally . over a similar interval
twelve months prior to presentation , he described progressive slurring of speech , dysphagia and weight loss of 7 kg as well as complete loss of taste and smell .
a neurological examination showed a decreased sensation to pinprick and light touch in all divisions of the trigeminal nerve bilaterally .
there was wasting of the periscapular muscles bilaterally , with widespread fasciculation in the upper limbs and occasional fasciculation in the quadriceps bilaterally .
reflexes were globally brisk with bilateral flexor plantar responses . normal or negative investigations included an autoantibody screen , anti - ganglioside antibodies , serum immunoglobulins , cerebrospinal fluid ( csf ) analysis ( opening pressure , cell count , protein , glucose ) , and mri of the brain and the cervical spine .
needle electromyography and nerve conduction studies ( emg / ncs ) showed widespread neurogenic changes without evidence of a neuropathy .
the patient died at the age of 64 , approximately 6 years after symptom onset .
a neuropathological examination exhibited that the number of cervical , thoracic , and lumbar spinal motor neurones was reduced by approximately 40% .
some of the remaining spinal cord motor neurones displayed characteristic intracytoplasmic extranuclear inclusions that stained positive for tdp-43 ( fig .
1b ) ; tdp-43 inclusions were also seen in hypoglossal nucleus motor neurones ( fig .
in addition , p62 and tdp-43-positive inclusions could be detected in neurones of the trigeminal nuclei ( not shown ) .
a 38-year - old woman presented with a 3-month history of right lower facial and oral cavity numbness . over the next 3 years , she developed sensory loss involving the upper and lower limbs as well as a wasting of the small muscles of the hand .
she described decreased upper limb strength , and it progressed to a point when she was unable to wash her hair or dress without help .
there was a progressive spread of sensory loss to her arms , neck and trunk . over the next 8 years , she developed lower limb weakness , more prominent distally than proximally ; she mobilised with a frame .
there was fasciculation , global muscle wasting and flaccid weakness with finger drop of the ring finger and little finger on the right . in the lower limbs ,
there was a reduced pinprick and temperature sensation to the knees and elbows and over the trunk , with preserved joint position and vibration sensation .
normal or negative investigations included autoantibody screen , anti - neuronal and anti - gm1 antibodies , serum protein electrophoresis , lysosomal storage enzymes , hiv and syphilis serology , csf examination , mri of the brain , and neurogenetic tests ( pmp-22 , p0 , cmt - x , mitofusin , sca 1 , 2 , 3 , 6 , 7 , 17 , and frataxin ) .
an mri of the spinal cord showed an atrophy of the cervical and thoracic cord with no evidence of a syrinx . a muscle biopsy ( left quadriceps ) showed denervation changes only , with no evidence of cox negative or abnormal nadh staining and no polyglucosan bodies .
there was no clinical response to 3 monthly intravenous immunoglobulin ( ivig ) infusions given over 12 months .
a 69-year - old man presented with a 4-month history of numbness affecting his left cheek , gradually progressing to involve the right cheek , tongue , jaw , and forehead , associated with difficulty swallowing .
a neurological examination showed a reduced sensation to pinprick and light touch throughout the distribution of the trigeminal nerve bilaterally , and also over the tongue .
an initial examination was otherwise normal , but over the following year , he developed wasting and fasciculation of the tongue and widespread wasting of the upper limbs .
his dysphagia deteriorated over the same interval , causing a weight loss of 19 kg , requiring a percutaneous endoscopic gastrostomy insertion for nutritional support .
normal or negative investigations included autoantibody screen , thyroid autoantibodies , onconeural and anti - glutamic acid decarboxylase antibodies , serum electrophoresis , serum angiotensin - converting enzyme , complement , hiv and lyme serology , brain mri , ct of the chest / abdomen / pelvis , bronchoscopy , and csf analysis .
emg / ncs showed no neurogenic changes 1 year after symptom onset ; further electrophysiological examination after onset of the tongue and upper limb fasciculation was declined .
there was no response to treatment with steroids and ivig ; treatment with riluzole was subsequently commenced .
we have presented 3 cases with clinical and investigation features consistent with the syndrome of fosmn first described by vucic et al . in 2006 , namely trigeminal sensory symptoms followed by a lower motor neurone disorder with bulbar onset ( table 1 ) .
the characteristic features in the limited number of cases reported to date [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] are those of a sensory and motor neurone disorder , with sensory loss in the trigeminal nerve distribution , with subsequent peripheral facial weakness which may spread to affect other bulbar muscles , neck , upper and lower limbs .
the disease is , with exceptions , usually slowly progressive ( but with exceptions ) .
neurophysiological findings in fosmn syndrome include diminished sensory nerve action potential amplitudes in the upper limbs .
blink reflexes have also been noted to be abnormal in the majority of patients identified with fosmn ( not examined in our cases ) . a selective loss of myelinated trigeminal nerve fibres with sparing of unmyelinated fibres has been reported .
sensory impairment is detected in some patients with familial mnd associated with sod1 gene mutations [ 13 , 14 ] . a case with the clinical and neurophysiological features of fosmn with a heterozygous d90a - sod1 mutation
one case reported in the abstract by bosch et al .   had neuronal loss and gliosis with tdp-43-positive cytoplasmic neuronal and glial inclusions in the hypoglossal nucleus and cervical motor neurones , as well as incidental changes of lewy body disease .
the case presented by sonoda et al .   showed a severe degeneration of the nuclei of the right trigeminal nerve and the right facial nerve as well as widespread tdp-43-positive glial inclusions in the brainstem tegmentum .
neurones in the hypoglossal nerve nuclei were also shrunken and lost , with tdp-43-positive neuronal inclusions .
neuronal loss and gliosis were prominent in the anterior horns , predominantly in the cervical cord , with tdp-43-positive skein - like inclusions .
however , in contrast , vucic et al .   found a widespread degeneration of sensory and motor neurones in 5 cases , but with no evidence of intraneuronal inclusions such as tdp-43 , bunina bodies or ubiquitin inclusions , nor inflammation or amyloid deposition , and felt that novel mechanisms , unrelated to mnd , were involved .
the neuropathological findings in our case 1 are similar to those reported by sonoda et al .
, with a widespread loss of spinal motor neurones and characteristic tdp-43 inclusions in some motor neurones , which also stained positive for p62 antibodies .
in addition , tdp-43-and p62-positive inclusions could be detected in some neurones of the trigeminal nuclei .
these data suggest that at least some fosmn cases fall within the spectrum of the tdp-43 proteinopathies , which encompasses mnd and some forms of frontotemporal dementia with or without mnd .
fosmn may therefore represent a focal form of mnd ( progressive course , affecting contiguous regions , fasciculation and denervation ) , but with slow onset and progression and a relatively good prognosis with the appropriate supportive care . to pursue this potential nosology , it might be of interest to examine cognitive function in fosmn cases , specifically looking for subtle subclinical signs of frontal dysfunction as found in some mnd cases
. however , since fosmn has rightly been described as a syndrome , this does not exclude the possibility that other examples of fosmn may have a different pathogenesis , including possibly inflammatory disorders which may on occasion respond to immunotherapy .
anti - ganglioside antibodies were checked in 2 of our patients ( cases 1 and 2 ) and were negative .
nevertheless , an assay of anti - ganglioside antibodies , especially those associated with facial and bulbar weakness ( gd1a and gt1a respectively ) , might be reasonable in fosmn cases , although unlike fosmn , the associated clinical syndromes are not chronic progressive disorders .
further neuropathological studies are critical to clarify disease mechanisms . we suggest that this might be facilitated by identifying possible cases of fosmn , for example cases currently being followed up with a diagnostic label of  atypical or 
the possibility of identifying a subpopulation of patients with a better prognosis mandates searching mnd clinic databases for such patients as well as a careful review of the history for sensory symptoms in each new  bulbar mnd case .
 three patients with the clinical and investigation features of facial onset sensory and motor neuronopathy ( fosmn ) syndrome are presented , one of whom came to a post - mortem examination . 
 this showed tdp-43-positive inclusions in the bulbar and spinal motor neurones as well as in the trigeminal nerve nuclei , consistent with a neurodegenerative pathogenesis . 
 these data support the idea that at least some fosmn cases fall within the spectrum of the tdp-43 proteinopathies , and represent a focal form of this pathology . 
Introduction
Case 1
Case 2
Case 3
Discussion
Disclosure Statement