TAR DNA-binding protein 43 pathology in a case clinically diagnosed with facial-onset sensory and motor neuronopathy syndrome: An autopsied case report and a review of the literature

Abstract

We report an autopsy case of a 48-year-old female clinically diagnosed with facial-onset sensory and motor neuronopathy (FOSMN) syndrome with TAR DNA-binding protein 43 (TDP-43) pathology. She developed paresthesia involving her whole face, right upper extremity and the right side of her upper trunk, followed by dysphagia, dysarthria, muscle atrophy and weakness with fasciculation in both upper extremities. Her symptoms showed a marked cranial and right-sided dominancy. She had anti-sulfoglucuronyl paragloboside (SGPG) IgG and anti-myelin-associated glycoprotein (MAG) IgG, and repeatedly showed limited response to immunotherapies. Her disease was essentially progressive, culminating in death due to respiratory failure three and a half years after onset. The autopsy revealed severe degeneration of the nuclei of the right trigeminal nerve and right facial nerve and widespread TDP-43-positive glial inclusions in the brainstem tegmentum. Neurons in the hypoglossal nerve nuclei were also shrunken and lost, with TDP-43-positive neuronal inclusions. Neuronal loss and gliosis in the anterior horn, predominantly in the cervical cord, were prominent with TDP-43-positive skein-like inclusions. Bilateral ventral roots were obviously atrophic. Spinal tract degeneration was also prominent in the ventral columns, essentially sparing the anterior corticospinal tracts at the cervical cord level. Additionally there was severe myelin pallor in the right spinal trigeminal tract and right fasciculus cuneatus of the cervical cord. The right spinal root ganglion showed numerous Nageotte's nodules and focal lymphocytic infiltration. The present case manifested FOSMN syndrome clinically, while the pathological findings suggested a motor neuron disease like TDP-43 proteinopathy and a possible involvement of immune-mediated neuropathy.

Introduction

FOSMN syndrome is an extremely rare disease which was first described by Vucic et al. in 2006 [1]. Since then, only 15 cases including two autopsy cases have been reported [1], [2], [3], [4], [5]. FOSMN syndrome is heralded by facial paresthesia and sensory deficits, slowly spreading to the scalp, neck, upper trunk and upper extremities in a rostral–caudal direction [1]. Later or concurrently, lower motor neuron signs, such as dysphagia, dysarthria, fasciculation, muscle atrophy and weakness develop in the affected parts. The disease slowly progresses over years until death.

Neuropathological studies on two autopsied cases of FOSMN syndrome revealed loss of neurons in the trigeminal sensory nuclei, facial nerve nuclei, nuclei of the solitary tracts, hypoglossal nerve nuclei, anterior horns and dorsal root ganglia (DRG), suggesting a neurodegenerative nature of the disease [1], [5]. However, there have been several case reports implicating an involvement of immune-mediated or inflammatory processes; that is, the coexistence of anti-sulfatide IgG in three patients [1], [5], and partial response to immunotherapies, such as intravenous immunoglobulin (IVIg) infusion and plasma exchange [2], [4]. Therefore, the underlying mechanism in FOSMN syndrome remains to be elucidated.

Recently, Vucic et al reported that neither evidence of inflammation nor intraneuronal inclusions were present in two autopsied cases and proposed the disease to be a primary neurodegenerative disorder of sensory and motor neurons, arguing against any association with amyotrophic lateral sclerosis (ALS) [1], [5]. Here, we report unique clinicopathological findings of an autopsy case clinically diagnosed as having FOSMN syndrome.

A previously healthy right-handed woman first felt paresthesia in her right peri-oral area and the fingers of her right hand at the age of 45 years. Her paresthesia gradually extended to the right side on her face, and she felt photophobia within one year. At the age of 46, her paresthesia spread further to her right upper extremity, and she subsequently reported atrophy and loss of power in the same area. She also developed dysarthria and dysphagia. At the age of 47, she was first admitted to our hospital. She had no familial history of any neurological disorders, and was diagnosed with FOSMN syndrome based on the characteristic symptoms and signs. IVIg treatment (400 mg/kg for five consecutive days) resulted in improvements in her facial muscle powers and right hemi-facial paresthesia. However, one month later, she felt a recurrence of right hemi-facial paresthesia, and worsening of dysarthria, dysphagia and weakness of her right upper limb muscles. At her second admission, she was again treated with IVIg; however, only her right hemi-facial paresthesia improved. She was subjected to percutaneous endoscopic gastrostomy for dysphagia. After discharge, she developed proximal dominant weakness of her left upper extremity. At the age of 48, home oxygen therapy was commenced for dyspnea, but because of difficulty caring for her at home, she was admitted to our hospital a third time.

On admission, she was 147 cm tall and weighed 26 kg. Her body mass index was 12.1. She was alert. She had bilateral facial paresthesia and hypalgesia and hypesthesia on the right side of her face, especially in the ophthalmic nerve area, facial weakness, absent gag reflex, soft palate paralysis, dysphagia, dysarthria, tongue weakness and atrophy with fasciculation, and atrophy and weakness of both upper limb muscles with generalized fasciculation (power: neck 2–3/5; upper limbs, right proximal 1/5, distal 3/5, left proximal 2–3/5, distal 4–5/5; both lower limbs 5/5). Her gait was normal. Deep tendon reflexes were absent in the right upper extremity and decreased in her left upper extremity, but brisk in both lower extremities with right-side dominance. Babinski and Chaddock reflexes were equivocal bilaterally. Rossolimo and Mendel-Bechterew reflexes were positive bilaterally. She had paresthesia in her right C2–Th10 dermatomes, but sensations of touch, pain and position were normal. Vibration sense was slightly impaired in all four limbs.

The peripheral blood and cerebrospinal fluid test findings in the present case are summarized in Table 1. Anti-SGPG IgG and anti-MAG IgG were positive. A pulmonary function test showed that her vital capacity (VC) was 0.85 L (%VC 34.1%). A genetic test for Kennedy–Alter–Sung disease was negative, and no other genetic tests were performed. The edrophonium test was negative. Brain magnetic resonance imaging (MRI) was normal. Cervical MRI revealed a mild degree of canal stenosis with a spondylotic ridge at C5/6, but spinal cord compression, intramedullary lesion and spinal cord atrophy were absent. Body computed tomography disclosed uterine myoma and a Nabothian cyst without any findings of malignancy.

The results of nerve conduction studies (NCS) of her lower extremities were normal. In her upper extremities, sensory nerve action potentials were not evoked in the right median and ulnar nerves. Sensory nerve conduction velocities (SCV) in the left median and ulnar nerves were slightly delayed. Motor nerve conduction velocities (MCV) were also slightly delayed and distal latencies (DL) were prolonged in the bilateral median and ulnar nerves. F-waves were not evoked in the left median nerve (see details in Table 2 and Fig. 1). Needle electromyography revealed chronic neurogenic patterns (giant motor unit potentials, polyphasic motor unit potentials, and a reduced interference pattern) and fasciculation in the tongue, left masseter, bilateral biceps brachii, left first dorsal interosseous and bilateral quadriceps femoris muscles. Blink reflexes were absent bilaterally.

After admission, she was subjected to percutaneous tracheostomy. For the weakness in her left upper extremity, she was again treated with methylprednisolone pulse therapy (1000 mg/day for three consecutive days) followed by oral prednisolone (30 mg/day) with gradual taper. She improved partially in terms of her weakness and sensory impairment, clinically as well as electrophysiologically (see details in Table 2 and Fig. 1). However, thereafter, her dyspnea was exacerbated, culminating in carbon dioxide narcosis and death. A full autopsy was performed about 3 h post-mortem.