FOSMN syndrome
Novel insight into disease pathophysiology
Abstract
Objective:
To better define the pathophysiologic mechanisms underlying the development of the novel facial-onset sensory and motor neuronopathy (FOSMN) syndrome and, in particular, to determine whether neurodegenerative processes, mediated by excitotoxicity, or autoimmune mechanisms contribute to the development of FOSMN syndrome.
Methods:
Clinical, laboratory, neurophysiologic, and pathologic assessments were undertaken for 5 patients with FOSMN syndrome (3 male and 2 female), the largest cohort of FOSMN syndrome reported to date. In addition to conventional neurophysiologic studies, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were undertaken to assess for the presence of cortical excitability.
Results:
Clinically, all patients exhibited the typical FOSMN syndrome phenotype, heralded by facial-onset sensory deficits with subsequent development of motor deficits evolving in a rostral-caudal direction. Pathologic studies, including an autopsy, disclosed widespread degeneration of sensory and motor neurons with no evidence of inflammation, amyloid deposition, or intraneuronal inclusions, such as TDP-43, Bunina bodies, or ubiquitin inclusions. Conventional neurophysiologic studies revealed abnormalities of blink reflexes, along with features of motor and sensory neuronopathy. Threshold tracking TMS disclosed normal cortical excitability in patients with FOSMN syndrome, with preserved short-interval intracortical inhibition, resting motor threshold, motor evoked potential amplitude, and cortical silent period duration. Patients with FOSMN syndrome failed to respond to immunomodulatory approaches.
Conclusions:
Findings from the present study suggest that FOSMN syndrome is a primary neurodegenerative disorder of sensory and motor neurons, with distinct pathophysiologic mechanisms. Neurology® 2012;79:73–79
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REFERENCES
1.
Vucic S, Tian D, Chong PS, Cudkowicz ME, Hedley-Whyte ET, Cros D. Facial onset sensory and motor neuronopathy (FOSMN syndrome): a novel syndrome in neurology. Brain 2006; 129: 3384–3390.
2.
Hokonohara T, Shigeto H, Kawano Y, Ohyagi Y, Uehara M, Kira J. Facial onset sensory and motor neuronopathy (FOSMN) syndrome responding to immunotherapies. J Neurol Sci 2008; 275: 157–158.
3.
Fluchere F, Verschueren A, Cintas P, et al. Clinical features and follow-up of four new cases of facial-onset sensory and motor neuronopathy. Muscle Nerve 2011; 43: 136–140.
4.
Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 2008; 131: 1540–1550.
5.
Vucic S, Kiernan MC. Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain 2006; 129: 2436–2446.
6.
Eisen A, Pant B, Stewart H. Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. Can J Neurol Sci 1993; 20: 11–16.
7.
Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet 2011; 377: 942–955.
8.
Vucic S, Howells J, Trevillion L, Kiernan MC. Assessment of cortical excitability using threshold tracking techniques. Muscle Nerve 2006; 33: 477–486.
9.
O'Brien MD. Aid to the Examination of the Peripheral Nervous System, 4th ed. London: WB Saunders; 2004.
10.
Siao P, Cros D, Vucic S. Practical Approach to Electromyography. New York: Demos Medical Publishing; 2011.
11.
Fisher RJ, Nakamura Y, Bestmann S, Rothwell JC, Bostock H. Two phases of intracortical inhibition revealed by transcranial magnetic threshold tracking. Exp Brain Res 2002; 143: 240–248.
12.
Mills KR, Murray NM. Electrical stimulation over the human vertebral column: which neural elements are excited? Electroencephalogr Clin Neurophysiol 1986; 63: 582–589.
13.
Cantello R, Gianelli M, Civardi C, Mutani R. Magnetic brain stimulation: the silent period after the motor evoked potential. Neurology 1992; 42: 1951–1959.
14.
Chen R, Cros D, Curra A, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008; 119: 504–532.
15.
Mori K, Iijima M, Koike H, et al. The wide spectrum of clinical manifestations in Sjögren's syndrome-associated neuropathy. Brain 2005; 128: 2518–2534.
16.
Kaltreider HB, Talal N. The neuropathy of Sjögren's syndrome: trigeminal nerve involvement. Ann Intern Med 1969; 70: 751–762.
17.
Dyck PJ, Ellefson RD, Yao JK, Herbert PN. Adult-onset of Tangier disease: 1: morphometric and pathologic studies suggesting delayed degradation of neutral lipids after fiber degeneration. J Neuropathol Exp Neurol 1978; 37: 119–137.
18.
Zuchner S, Sperfeld AD, Senderek J, Sellhaus B, Hanemann CO, Schroder JM. A novel nonsense mutation in the ABC1 gene causes a severe syringomyelia-like phenotype of Tangier disease. Brain 2003; 126: 920–927.
19.
Lüttmann RJ, Teismann I, Husstedt IW, Ringelstein EB, Kuhlenbäumer G. Hereditary amyloidosis of the Finnish type in a German family: clinical and electrophysiological presentation. Muscle Nerve 2010; 41: 679–684.
20.
Pareyson D. Diagnosis of hereditary neuropathies in adult patients. J Neurol 2003; 250: 148–160.
21.
Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 1968; 18: 671–680.
22.
Victor M, Adams RD. Principles of Neurology. New York: McGraw-Hill; 1993.
23.
Isoardo G, Troni W. Sporadic bulbospinal muscle atrophy with facial-onset sensory neuropathy. Muscle Nerve 2008; 37: 659–662.
24.
Abu-Baker A, Rouleau GA. Oculopharyngeal muscular dystrophy: recent advances in the understanding of the molecular pathogenic mechanisms and treatment strategies. Biochim Biophys Acta 2007; 1772: 173–185.
25.
Dion P, Shanmugam V, Gaspar C, et al. Transgenic expression of an expanded (GCG)13 repeat PABPN1 leads to weakness and coordination defects in mice. Neurobiol Dis 2005; 18: 528–536.
26.
Eisen A, Nakajima M, Weber M. Corticomotorneuronal hyper-excitability in amyotrophic lateral sclerosis. J Neurol Sci 1998; 160 (Suppl 10): S64–S68.
27.
Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W. Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis: evidence from paired transcranial magnetic stimulation. Neurology 1997; 49: 1292–1298.
28.
Vucic S, Cheah BC, Yiannikas C, Kiernan MC. Cortical excitability distinguishes ALS from mimic disorders. Clin Neurophysiol 2011; 122: 1860–1866.
29.
Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362: 59–62.
30.
Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 2008; 319: 1668–1672.
31.
Vance C, Rogelj B, Hortobagyi T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 2009; 323: 1208–1211.
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Copyright © 2012 by AAN Enterprises, Inc.
Publication History
Received: October 24, 2011
Accepted: February 23, 2012
Published online: June 20, 2012
Published in print: July 3, 2012
Disclosure
S. Vucic is a member of the scientific boards for Merck Serono Australia, Novartis, and Bayer Schering and serves as a medical consultant for Merck Serotures from sanofi-aventis. T. Stein reports no disclosures relevant to the manuscript. E.T. Hedley-Whyte reports no disclosures relevant to the manuscript. S. Reddel reports receiving grants and honoraria for lectures by Bayer Schering. S. Tisch, K. Kotschet, and D. Cros report no disclosures relevant to the manuscript. M. Kiernan reports that he is the Editor-in-Chief of the Journal of Neurology, Neurosurgery and Psychiatry (BMJ Group). Go to Neurology.org for full disclosures.
Authors
Author Contributions
S. Vucic recruited patients, performed all studies, performed data analysis, and wrote the manuscript. T. Stein performed autopsy, reported the findings, and edited the manuscript. E.T. Hedley-Whyte performed the autopsy, reported the findings, and edited the manuscript. S. Reddel contributed a patient, assisted with data analysis, and edited the manuscript, providing critical scientific input. S. Tisch contributed a patient, assisted with data analysis, and edited manuscript, providing critical scientific input. K. Kotschet contributed a patient, assisted with data analysis and edited the manuscript, providing critical scientific input. D. Cros provided vital input in the analysis of the neurophysiology, contributed a patient, and edited the manuscript. M. Kiernan provided vital scientific critique, edited the manuscript, and assisted with data analysis.
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