Finger Extension Weakness and Downbeat Nystagmus Motor Neuron Disease Syndrome: A Series of Two Cases

Eye movement abnormalities are rare in motor neuron disease (MND). Ophthalmoparesis is eventually found in patients with amyotrophic lateral sclerosis (ALS) who chose invasive ventilation, but is otherwise typically not observed. There are a few case reports documenting slowing of vertical saccades, gaze-evoked horizontal or rotatory nystagmus, impairment of smooth pursuit, and progressive ophthalmoplegia and eyelid apraxia (1–4). These eye movement abnormalities are typically seen in ALS patients with bulbar onset or frontal lobe impairment. In 2006, Thakore et al (5) reported 3 cases of a novel MND with early and disproportionately severe involvement of finger and wrist extensors, downbeat nystagmus (DBN), relative sparing of bulbar and respiratory musculature, prolonged survival, and lack of family history. In 2016, they described an additional 3 patients with the same clinical phenotype, and designated the disorder as Finger Extension Weakness and Downbeat Nystagmus Motor Neuron Disease Syndrome with an acronym of FEWDON-MND (6). We document 2 patients with FEWDON-MND adding clinical and genetic insights into this novel entity. A 31-year-old woman reported an eleven-year history of slowly progressive left hand weakness years after the onset of left hand weakness, she experienced oscillopsia worse with downgaze, and 3 years after that cramping in her calves and left forearm muscles with generalized intermittent fasciculations. There were no associated sensory symptoms. Her medical history was significant for anxiety, and she was on sertraline and oral contraceptive pill. There was no family history of neurological or neuromuscular disorders. On examination, visual acuity was 20/20 in each eye with intact pupillary responses and color vision. Ocular motility showed full versions and ductions with DBN in primary gaze, which worsened with lateral gaze (See Supplemental Digital Content, video, https://links.lww.com/WNO/A358) and downgaze. Pursuit was interrupted by DBN, which did not dampen with convergence. Automated visual fields and the appearance of the anterior and posterior segments of both eyes were normal. Neurological examination revealed tongue fasciculations and atrophy without slowing of speech or dysarthria. There were both upper and lower motor neuron signs present in the limbs with predominant finger extensor weakness bilaterally. Nerve conduction studies (NCS) showed a reduced right peroneal motor amplitude, and needle electromyography (EMG) revealed large motor units and reduced recruitment in the left cervical and lumbosacral myotomes with fibrillations. MRI brain showed a Chiari I malformation without cerebellar atrophy, and MRI of the cervical spine was unremarkable. A 39-year-old woman experienced oscillopsia at the age of 18 years. Nine years later, after her second pregnancy, she developed persistent fatigue. At age 32 years, the patient presented to our clinic with slowly progressive weakness. She had no significant medical history and was not taking any medications. There was no family history of neurological or neuromuscular disorders. On examination, visual acuity was 20/20 in the right eye and 20/30 in the left eye. Pupillary responses and color vision were normal. Ocular motility showed full versions and ductions with DBN in primary gaze, worsened with lateral gaze and downgaze, and slightly decreased in upgaze. Pursuit was interrupted by the DBN, which did not dampen with convergence. Automated perimetry, slit-lamp examination, and funduscopy were normal. Neurological examination revealed both upper and lower motor neuron signs in the limbs with predominant finger extensor weakness bilaterally. NCS were normal and needle EMG showed very large motor units with reduced recruitment typical of a very longstanding slowly progressive neurogenic process. Brain MRI was normal. A trial of 3, 4-diaminopyridine had resulted in some symptomatic relief. However, she independently stopped this medication. Evaluation of both patients included venous blood gas, ammonia, beta-hexosaminidase A plasma amino acids, urine organic acids, anti-glutamic acid decarboxylase, and transglutaminase, all of which were negative/normal. Cerebrospinal fluid analysis was unremarkable in both patients. Genetic testing for spinal muscular atrophy (SMA) 4, Kennedy carrier, spinocerebellar atrophy Types 3 and 4, and survival motor neuron were all normal. Molecular analysis in our first patient showed that she was heterozygous in a variant of the vesicle-associated membrane protein–associated protein B (VAPB gene) (neutral amino acid substitution of an isoleucine for methionine), which has been identified in a small number of individuals diagnosed with classic ALS, atypical ALS, or late-onset SMA (SMA-Finkel type). Both patients were given a diagnosis of atypical slowly progressive ALS and have only mildly worsened over time. MND, particularly ALS, is a progressive and incurable neurodegenerative disorder with a median survival of 2–5 years from symptom onset (7). We describe 2 female patients with clinical and electrodiagnostic evidence of a diffuse MND. However, their phenotype also included early and disproportionate weakness of finger and wrist extensors, DBN, lack of bulbar involvement, negative family history, and prolonged survival. Combining the 6 previously reported cases of FEWDON-MND with our 2 patients, there seems to be a female predominance with 6 of the 8 patients being women. The range of age at onset is between 16 and 40 years, compared with the mean age of onset of ALS, which is 62 years (8). The duration of disease is uncharacteristic of MND, with 1 of the 8 patients having the disease for greater than 43 years. Both of our patients fit this phenotype as they are both in their third decades with a slowly progressive disease course. A comprehensive panel of investigations including lumbar puncture and genetic analysis has excluded other potential disorders that may have a similar phenotype. Unique features of our 2 patients include one with tongue fasciculations (also described in one patient by Delva et al [6]), and genetic testing with a variant of the VAPB gene. This variant has not been documented previously. Family history was noncontributory in all patients. A genetic basis is still possible in an autosomal recessive inheritance pattern with sporadic or de novo mutations. Further genetic sequencing efforts are underway. Another plausible etiology is an immune-mediated process. Supporting this mechanism was the presence of elevated antinuclear antibody titers in 3 of the 6 previously reported patients and anti-GAD antibodies in one patient (5,6). Intravenous immunoglobulin and plasma exchange have not been reported to be effective treatment, arguing against an autoimmune process. Both of our patients had a normal autoimmune work-up. DBN has not been previously reported in the setting of MND (9). It typically results from damage to the cerebellar flocculus (or its projections) or, less often, from damage to the brainstem paramedian tracts. Brain MRI in one of our patients showed a Chiari I malformation, which is known to be associated with DBN. However, if all clinical symptoms and signs are to be explained by one disease process, the Chiari malformation is likely an incidental finding, given the topographical distribution of weakness and the electrodiagnostic studies confirming a diffuse MND. In conclusion, FEWDON-MND is a unique clinical entity characterized by early and disproportionately severe involvement of finger and wrist extensors, DBN, relative sparing of bulbar and respiratory musculature, prolonged survival, and lack of family history. Increased awareness of this disorder and whole-genome sequencing may provide further insight into its pathogenesis. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Micieli and A. N. E. Sundaram; b. Acquisition of data: A. Micieli, L. Zinman, P. Ashby, and A. N. E. Sundaram; c. Analysis and interpretation of data: A. Micieli, L. Zinman, P. Ashby, and A. N. E. Sundaram. Category 2: a. Drafting the manuscript: A. Micieli, L. Zinman, P. Ashby, and A. N. E. Sundaram; b. Revising it for intellectual content: A. Micieli, L. Zinman, P. Ashby, and A. N. E. Sundaram. Category 3: a. Final approval of the completed manuscript: A. Micieli, L. Zinman, P. Ashby, and A. N. E. Sundaram.

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