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Letters to the Editor / Clinical Neurophysiology 126 (2015) 2405–2409
Brais B, Rouleau GA, Bouchard JP, Fardeau M, Tomé FM. Oculopharyngeal muscular dystrophy. Semin Neurol 1999;19:59–66. Hardiman O, Halperin JJ, Farrell MA, Shapiro BE, Wray SH, Brown Jr RH. Neuropathic findings in oculopharyngeal muscular dystrophy. A report of seven cases and a review of the literature. Arch Neurol 1993;50:481–8. Jones Jr LK, Harper CM. Clinical and electrophysiologic features of oculopharyngeal muscular dystrophy: lack of evidence for an associated peripheral neuropathy. Clin Neurophysiol 2010;121:870–3. Mirabella M, Silvestri G, de Rosa G, Di Giovanni S, Di Muzio A, Uncini A, et al. GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy. Neurology 2000;54:608–14.
⇑
Marco Luigetti Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy ⇑ Corresponding author at: Institute of Neurology, Largo F. Vito 1, 00168 Roma, Italy. Tel.: +39 06 30154435; fax: +39 06 35501909. E-mail address: [email protected] Mauro Lo Monaco Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Massimiliano Mirabella Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Guido Primiano Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Matteo Lucchini Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Mauro Monforte Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Serenella Servidei Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Available online 20 March 2015
1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2015.03.005
Familial case reports of stiff-person syndrome
Stiff-person syndrome (SPS) is a rare neurologic disorder of no recognizable cause, typically affecting middle-aged individuals; its prevalence is higher in females than in males, and it is characterized by progressive fluctuating incapacitating axial and proximal limb muscle rigidity with superimposed spasms, and a hypersensitivity to noise, emotional distress, or external stimuli causing intermittent painful muscle spasms. EMG recordings show continuous motor unit potentials (MUPs) at rest to be more prominent in paraspinal muscles and proximal limb muscles. The muscle stiffness in SPS is caused by involuntary discharge of motor neurons in needle EMG recordings. The MUPs have normal morphology and discharge frequency (Gershanik, 2009; Rakocevic and Floeter, 2012). SPS is generally considered to be a sporadic disease, and it is presumably an autoimmune disease. Approximately 80% of SPS is caused by an autoantibody against glutamic acid decarboxylase (GAD). However, several studies have reported familial aggregation in SPS (Klein et al., 1972; Sander et al., 1980; Burns et al., 2003). Although families with congenital SPS have been described, whether SPS is a familial hereditary or a sporadic later-onset disease is still a matter of debate. In the current study, we first report a Chinese family with this disorder, with seven members from four generations of the same family being affected (Fig. 1). The patient’s anonymity was protected in these cases.
The propositus (III2) was a 45-year-old man, who was injured in a car accident and was admitted to the surgery department in October 2014. He related that he began to experience stiffness of the lower limbs, being unable to ambulate about 3 years ago, which then gradually spread upward involving the trunk and upper limbs. He required wheelchair assistance to walk for a year. At times, a transient spasm would arise in his right lower limb due to a sudden sound stimulus; a sudden spasm precipitated by startle caused the car accident, and he visited our hospital. On physical examination, the patient presented a generalized rigidity. He had spasm of the trunk with arching posture and excessive lumbar lordosis; consequently, he cannot lie supine. His abdominal musculature was board-like to palpation with no tenderness and rebound tenderness. Examination of cranial nerves was negative and symmetrical; hypermyotonia and tendon hyperreflexia in both the upper and lower extremities were observed, and the bilateral Babinski sign was positive. The GAD antibody was seronegative. Cerebrospinal fluid examination revealed that protein increased and chloride decreased. EMG examination showed continuous motor unit activity in the bilateral brachioradialis and T11 paraspinal muscles. Brain MRI examination showed subarachnoid hemorrhage. The patient was orally administered a 10-mg tid dose of amantadine and a 5-mg qn dose of diazepam, following which the patient’s symptoms was significantly improved. The patient could stand up by the bedside with his relatives’ help, but his lower back was still rigid, and waist bending and thigh muscle movement was still significantly limited. His sister (III3) was a 40-year-old woman, presenting with a 3-year-long history of progressive stiffness of the neck, trunk, and limb muscles. Physical examination showed that the muscle tone of shoulders, back, and neck muscles increased, and the functions of the shoulder joint and hip joint were limited. EMG revealed continuous MUPs in the biceps and tibialis anterior muscle. The GAD antibody was seropositive. The insular cellular antibody was seropositive, and the insulin autoantibody assay (ELISA method) seronegative. Brain MRI revealed no abnormalities. On November 11, the patient was administered diazepam 5 mg qn. Four days later, the symptoms were improved remarkably, and the patient could walk upstairs without assistance. Pedigree investigation: The propositus’s father (II1), a 67-year-old man who died in 2005, had the same history for about 3 years, and presented with limb and trunk stiffness. Three uncles (II2, II3, and II5) also had the same history, and died as well. The grandmother (I2), maternal grandfather (I3), and maternal uncle (II11) showed a history of movement disorders, and they did not undergo medical examination. Maternal Grandfather Lee (I3) and Grandma Deng (I2) have ties of kinship. We report seven patients (six males and one female) from four generations of the same family, and the patients’ clinical presentation and EMG finding meet the SPS diagnosis criteria proposed by Dalakas (Gershanik, 2009). Neurologic examination is usually normal; all except deep tendon reflexes often increase without other pyramidal tract involvement. In our cases, the propositus’s Babinski sign was positive, and it may be associated with subarachnoid hemorrhage due to the car accident. The patient’s sister tested seropositive for the insular cellular antibody, consistent with the hypothesis that SPS may have a greater relationship with other autoimmune diseases. In this case, SPS showed significant familial aggregation with a male predominance, all adult onset, with a serious impact on their quality of life. The propositus had a yearlong history of wheelchair assistance, which he closely related during this visit. It has been reported, however, that as many as 10% of patients experience sudden death because of autonomic dysfunction. We can speculate this fact as the patient’s father and his three uncles died. The patient’s maternal grandfather and grandmother are cousins, which further
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Letters to the Editor / Clinical Neurophysiology 126 (2015) 2405–2409
Fig. 1. III2 is propositus I2 and I3 have a cousinship.
illustrates the presence of SPS familial aggregation. The inheritance type in this family appeared to be autosomally dominant. We report familial cases of SPS, but the identified susceptibility gene is still unclear. Some studies have shown the human leukocyte antigen (HLA) DQB1⁄0201/DRB1⁄0301 gene and the DYT1 gene to be susceptibility genes for SPS. Burns reports that SPS in a father and daughter was adult onset with the HLA DQB1⁄0201 or DRB1⁄0301 gene, and Klein and Sander report that all cases of SPS in their study were infant onset. We speculate that SPS is a sporadic disease of later onset in our family, and it may be associated with the HLA DQB1 genes. Therefore, the relationship between HLA DR/DQ alleles, DYT1 gene, and SPS is worthy of further study, and more case reports and research are necessary to elucidate the familial inheritance and related susceptibility genes of SPS. Conflict of interest The authors have no financial conflicts of interest.
Sander JE, Layzer RB, Goldsobel AB. Congenital stiff-man syndrome. Ann Neurol 1980;8:195–7.
Zhilong Xiao 1 Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Jian Shan 1 Xiaolin Huang Department of Neurosurgery, Pingxiang HanHe Hospital, Pingxiang, Jiangxi, China Min Yuan Xueli Li Shenjian Chen ⇑ Lijun Xu Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China ⇑ Corresponding author at: No. 1, Minde Road, Nanchang City, China. Tel.: +86 18970907115. E-mail address: [email protected] (L. Xu)
References Burns TM, Jones HR, Phillips LH, Bugawan TL, Erlich HA, Lennon VA. Clinically disparate stiff-person syndrome with GAD65 autoantibody in a father and daughter. Neurology 2003;61:1291–3. Gershanik OS. Stiff-person syndrome. Parkinsonism Relat Disord 2009;15(Suppl. 3):S130–4. Klein R, Haddow JE, DeLuca C. Familial congenital disorder resembling stiff-man syndrome. Am J Dis Child 1972;124:730–1. Rakocevic G, Floeter MK. Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes. Muscle Nerve 2012;45:623–34.
Available online 2 April 2015
1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2015.03.010
1
Zhilong Xiao and Jian Shan is co-first author.
Letters to the Editor / Clinical Neurophysiology 126 (2015) 2405–2409
Brais B, Rouleau GA, Bouchard JP, Fardeau M, Tomé FM. Oculopharyngeal muscular dystrophy. Semin Neurol 1999;19:59–66. Hardiman O, Halperin JJ, Farrell MA, Shapiro BE, Wray SH, Brown Jr RH. Neuropathic findings in oculopharyngeal muscular dystrophy. A report of seven cases and a review of the literature. Arch Neurol 1993;50:481–8. Jones Jr LK, Harper CM. Clinical and electrophysiologic features of oculopharyngeal muscular dystrophy: lack of evidence for an associated peripheral neuropathy. Clin Neurophysiol 2010;121:870–3. Mirabella M, Silvestri G, de Rosa G, Di Giovanni S, Di Muzio A, Uncini A, et al. GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy. Neurology 2000;54:608–14.
⇑
Marco Luigetti Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy ⇑ Corresponding author at: Institute of Neurology, Largo F. Vito 1, 00168 Roma, Italy. Tel.: +39 06 30154435; fax: +39 06 35501909. E-mail address: [email protected] Mauro Lo Monaco Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Massimiliano Mirabella Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Guido Primiano Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Matteo Lucchini Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Mauro Monforte Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Serenella Servidei Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy Available online 20 March 2015
1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2015.03.005
Familial case reports of stiff-person syndrome
Stiff-person syndrome (SPS) is a rare neurologic disorder of no recognizable cause, typically affecting middle-aged individuals; its prevalence is higher in females than in males, and it is characterized by progressive fluctuating incapacitating axial and proximal limb muscle rigidity with superimposed spasms, and a hypersensitivity to noise, emotional distress, or external stimuli causing intermittent painful muscle spasms. EMG recordings show continuous motor unit potentials (MUPs) at rest to be more prominent in paraspinal muscles and proximal limb muscles. The muscle stiffness in SPS is caused by involuntary discharge of motor neurons in needle EMG recordings. The MUPs have normal morphology and discharge frequency (Gershanik, 2009; Rakocevic and Floeter, 2012). SPS is generally considered to be a sporadic disease, and it is presumably an autoimmune disease. Approximately 80% of SPS is caused by an autoantibody against glutamic acid decarboxylase (GAD). However, several studies have reported familial aggregation in SPS (Klein et al., 1972; Sander et al., 1980; Burns et al., 2003). Although families with congenital SPS have been described, whether SPS is a familial hereditary or a sporadic later-onset disease is still a matter of debate. In the current study, we first report a Chinese family with this disorder, with seven members from four generations of the same family being affected (Fig. 1). The patient’s anonymity was protected in these cases.
The propositus (III2) was a 45-year-old man, who was injured in a car accident and was admitted to the surgery department in October 2014. He related that he began to experience stiffness of the lower limbs, being unable to ambulate about 3 years ago, which then gradually spread upward involving the trunk and upper limbs. He required wheelchair assistance to walk for a year. At times, a transient spasm would arise in his right lower limb due to a sudden sound stimulus; a sudden spasm precipitated by startle caused the car accident, and he visited our hospital. On physical examination, the patient presented a generalized rigidity. He had spasm of the trunk with arching posture and excessive lumbar lordosis; consequently, he cannot lie supine. His abdominal musculature was board-like to palpation with no tenderness and rebound tenderness. Examination of cranial nerves was negative and symmetrical; hypermyotonia and tendon hyperreflexia in both the upper and lower extremities were observed, and the bilateral Babinski sign was positive. The GAD antibody was seronegative. Cerebrospinal fluid examination revealed that protein increased and chloride decreased. EMG examination showed continuous motor unit activity in the bilateral brachioradialis and T11 paraspinal muscles. Brain MRI examination showed subarachnoid hemorrhage. The patient was orally administered a 10-mg tid dose of amantadine and a 5-mg qn dose of diazepam, following which the patient’s symptoms was significantly improved. The patient could stand up by the bedside with his relatives’ help, but his lower back was still rigid, and waist bending and thigh muscle movement was still significantly limited. His sister (III3) was a 40-year-old woman, presenting with a 3-year-long history of progressive stiffness of the neck, trunk, and limb muscles. Physical examination showed that the muscle tone of shoulders, back, and neck muscles increased, and the functions of the shoulder joint and hip joint were limited. EMG revealed continuous MUPs in the biceps and tibialis anterior muscle. The GAD antibody was seropositive. The insular cellular antibody was seropositive, and the insulin autoantibody assay (ELISA method) seronegative. Brain MRI revealed no abnormalities. On November 11, the patient was administered diazepam 5 mg qn. Four days later, the symptoms were improved remarkably, and the patient could walk upstairs without assistance. Pedigree investigation: The propositus’s father (II1), a 67-year-old man who died in 2005, had the same history for about 3 years, and presented with limb and trunk stiffness. Three uncles (II2, II3, and II5) also had the same history, and died as well. The grandmother (I2), maternal grandfather (I3), and maternal uncle (II11) showed a history of movement disorders, and they did not undergo medical examination. Maternal Grandfather Lee (I3) and Grandma Deng (I2) have ties of kinship. We report seven patients (six males and one female) from four generations of the same family, and the patients’ clinical presentation and EMG finding meet the SPS diagnosis criteria proposed by Dalakas (Gershanik, 2009). Neurologic examination is usually normal; all except deep tendon reflexes often increase without other pyramidal tract involvement. In our cases, the propositus’s Babinski sign was positive, and it may be associated with subarachnoid hemorrhage due to the car accident. The patient’s sister tested seropositive for the insular cellular antibody, consistent with the hypothesis that SPS may have a greater relationship with other autoimmune diseases. In this case, SPS showed significant familial aggregation with a male predominance, all adult onset, with a serious impact on their quality of life. The propositus had a yearlong history of wheelchair assistance, which he closely related during this visit. It has been reported, however, that as many as 10% of patients experience sudden death because of autonomic dysfunction. We can speculate this fact as the patient’s father and his three uncles died. The patient’s maternal grandfather and grandmother are cousins, which further
2409
Letters to the Editor / Clinical Neurophysiology 126 (2015) 2405–2409
Fig. 1. III2 is propositus I2 and I3 have a cousinship.
illustrates the presence of SPS familial aggregation. The inheritance type in this family appeared to be autosomally dominant. We report familial cases of SPS, but the identified susceptibility gene is still unclear. Some studies have shown the human leukocyte antigen (HLA) DQB1⁄0201/DRB1⁄0301 gene and the DYT1 gene to be susceptibility genes for SPS. Burns reports that SPS in a father and daughter was adult onset with the HLA DQB1⁄0201 or DRB1⁄0301 gene, and Klein and Sander report that all cases of SPS in their study were infant onset. We speculate that SPS is a sporadic disease of later onset in our family, and it may be associated with the HLA DQB1 genes. Therefore, the relationship between HLA DR/DQ alleles, DYT1 gene, and SPS is worthy of further study, and more case reports and research are necessary to elucidate the familial inheritance and related susceptibility genes of SPS. Conflict of interest The authors have no financial conflicts of interest.
Sander JE, Layzer RB, Goldsobel AB. Congenital stiff-man syndrome. Ann Neurol 1980;8:195–7.
Zhilong Xiao 1 Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Jian Shan 1 Xiaolin Huang Department of Neurosurgery, Pingxiang HanHe Hospital, Pingxiang, Jiangxi, China Min Yuan Xueli Li Shenjian Chen ⇑ Lijun Xu Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China ⇑ Corresponding author at: No. 1, Minde Road, Nanchang City, China. Tel.: +86 18970907115. E-mail address: [email protected] (L. Xu)
References Burns TM, Jones HR, Phillips LH, Bugawan TL, Erlich HA, Lennon VA. Clinically disparate stiff-person syndrome with GAD65 autoantibody in a father and daughter. Neurology 2003;61:1291–3. Gershanik OS. Stiff-person syndrome. Parkinsonism Relat Disord 2009;15(Suppl. 3):S130–4. Klein R, Haddow JE, DeLuca C. Familial congenital disorder resembling stiff-man syndrome. Am J Dis Child 1972;124:730–1. Rakocevic G, Floeter MK. Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes. Muscle Nerve 2012;45:623–34.
Available online 2 April 2015
1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2015.03.010
1
Zhilong Xiao and Jian Shan is co-first author.
