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Figure 1.
A, Pedigree of a patient (No. 17) and his brother (No. 18) with Hirayama disease. B, Spinal magnetic resonance sagittal image on T1 sequence showing cord atrophy at the lower cervical region in a patient with Hirayama disease.

A, Pedigree of a patient (No. 17) and his brother (No. 18) with Hirayama disease. B, Spinal magnetic resonance sagittal image on T1 sequence showing cord atrophy at the lower cervical region in a patient with Hirayama disease.

Figure 2.
Absence of the SMN gene deletion in a patient with Hirayama disease. Exon 7 polymerase chain reaction (PCR)–restriction fragment length polymorphism with Dra 1 Lanes 1 and 3, patient’s undigested PCR product; lanes 2 and 4, patient’s sample without SMN1 deletion; lane 5, 50–base pair marker.

Absence of the SMN gene deletion in a patient with Hirayama disease. Exon 7 polymerase chain reaction (PCR)–restriction fragment length polymorphism with Dra 1 Lanes 1 and 3, patient’s undigested PCR product; lanes 2 and 4, patient’s sample without SMN1 deletion; lane 5, 50–base pair marker.

Table. 
Clinical Features, Electromyography, and Magnetic Resonance Imaging Findings of Patients With Hirayama Disease
Clinical Features, Electromyography, and Magnetic Resonance Imaging Findings of Patients With Hirayama Disease
1.
Hirayama  K Juvenile nonprogressive muscular atrophy localised in hand and forearm observation in 38 cases. Rinsho Shinkeigaku 1972;12313- 324
2.
Hirayama  K Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama’s disease).  In: De  Jong JMBV, ed. Handbook of Clinical Neurology. Vol 15. Amsterdam, the Netherlands: Elsevier Science; 1991:107-120
3.
Sobue  ISaito  NLida  MAndo  K Juvenile type of distal and segmental muscular atrophy of upper extremities. Ann Neurol 1978;3429- 432
PubMedArticle
4.
Misra  UKKalita  J Central motor conduction in Hirayama disease. Electroencephalogr Clin Neurophysiol 1995;9773- 76Article
5.
Gourie-Devi  MNalini  A Long-term follow-up of 44 patients with brachial monomelic amyotrophy. Acta Neurol Scand 2003;107215- 220
PubMedArticle
6.
Cobben  JMvan der Steege  GGrootscholten  Pde Visser  MScheffer  HBuys  CH Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy. Am J Hum Genet 1995;57805- 808
PubMed
7.
Gillaim  TCBrzustowicz  LMCastilla  LH  et al.  Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 1990;345823- 825
PubMedArticle
8.
Lefebvre  SBurglen  LReboullet  S  et al.  Identification and characterization of a spinal muscular atrophy–determining gene. Cell 1995;80155- 165
PubMedArticle
9.
Hirayama  KTokumar  Y Cervical dural sac and spinal cord in juvenile muscular atrophy of distal upper extremity. Neurology 2000;541922- 1926
PubMedArticle
10.
Donofrio  PD Monomelic amyotrophy. Muscle Nerve 1994;171129- 1134Article
11.
Kira  JOchi  H Juvenile muscular atrophy of the distal upper limb (Hirayama disease) associated with atrophy. J Neurol Neurosurg Psychiatry 2001;70798- 801
PubMedArticle
12.
Robberecht  WAgnirre  TVan den Bosch  L  et al.  Familial juvenile focal amyotrophy of the upper extremity (Hirayama disease): superoxide dismutase 1 genotype and activity. Arch Neurol 1997;5446- 50
PubMedArticle
13.
Schlegel  UJerusalem  FTackmann  WCordt  ATsuda  Y Benign juvenile focal muscular atrophy of upper extremities: a familial case. J Neurol Sci 1987;80351- 353
PubMedArticle
14.
Peiris  JBSeneviratne  KNWickremasinghe  HRGunatilake  SBGamage  R Nonfamilial juvenile distal spinal muscular atrophy of upper extremity. J Neurol Neurosurg Psychiatry 1989;52314- 319Article
15.
Somerville  MJHunter  AGWAubry  HLKorneluk  RGMackenzie  AESurh  LC Clinical application of the molecular diagnosis of spinal muscular atrophy. Am J Med Genet 1997;69159- 165
PubMedArticle
16.
Guglielmo  GDBrahe  CDi Muzio  AUncini  A Benign monomelic amyotrophies of upper and lower limb are not associated to deletions of survival motor neuron gene. J Neurol Sci 1996;141111- 113
PubMedArticle
17.
Blin  NStafford  DW A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acid Res 1976;32303- 2308Article
18.
Chang  JGJong  YJLin  SP  et al.  Molecular analysis of survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes of spinal muscular atrophy patients and their parents. Hum Genet 1997;100557- 581Article
19.
Hirayama  KTomonaga  MKitano  KYamada  TKojima  SArai  K Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg Psychiatry 1987;50285- 290
PubMedArticle
20.
Schroder  RKeller  EFlacke  S  et al.  MRI findings in Hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease? J Neurol 1999;2461069- 1074
PubMedArticle
21.
Scheffer  HCobben  JMMatthijs  GWirth  B Best practice guidelines for molecular analysis in spinal muscular atrophy. Eur J Hum Genet 2001;9484- 491
PubMedArticle
22.
Zerres  KRudnik-Schoneborn  S Spinal muscular atrophies.  In: Rimoin  DL, Connor  JM, Pyeritz  RE, Korf  B, eds. Emery and Rimoin’s Principle and Practice of Medical Genetics. 4th ed. London, England: Churchill Livingstone; 2002;3:3349-3372
23.
Tandan  RSharma  KRBradley  WG  et al.  Chronic segmental spinal muscular atrophy of upper extremities in identical twins. Neurology 1990;40236- 239
PubMedArticle
Original Contribution
January 2005

A Clinical, Magnetic Resonance Imaging, and Survival Motor Neuron Gene Deletion Study of Hirayama Disease

Author Affiliations

Author Affiliations: Departments of Neurology (Drs Misra, Kalita, and Mishra) and Genetics (Ms Kesari and Dr Mittal), Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.

Arch Neurol. 2005;62(1):120-123. doi:10.1001/archneur.62.1.120
Abstract

Background  Hirayama disease (HD) is a segmental nonprogressive spinal muscular atrophy found in male patients.

Objective  To report the results of a comprehensive evaluation of clinical, magnetic resonance imaging (MRI), electromyography (EMG), and survival motor neuron (SMN) gene analysis of HD.

Design  Clinical, MRI, and SMN gene deletion study.

Setting  Tertiary care teaching hospital.

Patients  Patients with HD diagnosed according to defined criteria were included in the study.

Interventions  Patients underwent a neurologic evaluation and pedigree charting. Concentric needle EMG was performed on a number of muscles. Motor nerve conduction study of the median, ulnar, and peroneal nerves and sensory conduction study of the median, ulnar, and sural nerves were also performed. Spinal MRI of the cervical region was performed with the 2-T scanner operating at 1.5 T. Gene deletion study of SMN1 and SMN2 was performed in all patients.

Main Outcome Measures  History of trauma, occupation, exercise, associated medical disease, and cold paresis and muscle wasting, power, reflex changes, and tone.

Results  Fifteen male patients with HD from 14 families participated in the study (mean age at the onset of disease, 18 years; range, 15-23 years). Muscle weakness and wasting were noted in the right upper limb in 12 and the left upper limb in 3, which became bilateral in 8 patients. Cold paresis was present in 6 patients and polyminimyoclonus in all patients. The EMG revealed fibrillations in 10, fasciculations in 15, and neurogenic motor unit potentials in C7, C8, and T1 myotomes in all patients. The EMG abnormalities were unilateral in 5, bilateral in 10, and subclinical in 2 patients. Spinal MRI revealed cord atrophy in 3 of 11 patients. Although family history was present in 1 brother only, the results of both SMN1 and SMN2 gene deletion studies were negative in all patients.

Conclusions  The SMN gene deletion is not found in HD. Exclusive occurrence in male patients and the presence of this disease in 2 brothers suggest a possible role of the X chromosome, which needs further evaluation.

Nonprogressive juvenile spinal muscular atrophy (SMA), also known as Hirayama disease (HD), is characterized by insidious onset of unilateral or asymmetric oblique amyotrophy that affects the C7, C8, and T1 myotomes. It usually affects young men and is characteristically associated with aggravation of weakness on exposure to cold, known as cold paresis. The onset is insidious and characterized by muscle weakness and atrophy in the hand and forearm with sparing of brachioradialis, giving the characteristic appearance of oblique amyotrophy. The amyotrophy is unilateral in most patients and asymmetrically bilateral in some. Although there are no fasciculations at rest, finger extension causes fascicular twitching or polyminimyoclonus. The initial progressive course of HD is followed by spontaneous arrest within several years after onset. The patients with HD have been reported mainly from Japan but also from Denmark, Holland, Singapore, the United States, India, Malaysia, Sri Lanka, and France.15 Spinal muscular atrophies are clinically and genetically heterogeneous, and their primary cause remains unknown.6 Using linkage analysis, the locus was mapped to chromosome 5q11.2-13.3, which was shown to be associated with SMA.7 Recent studies have shown that the deletion of the small subregion of 5q13 is associated with phenotypic expression of the SMA. These findings have resulted in the identification of 2 candidate genes: the survival motor neuron (SMN) gene and the neuronal apoptotic inhibitory protein (NAIP) gene.8 Hirayama disease has been attributed to several factors, including trauma, ischemia,9,10 autoimmune basis,11 familial or hereditary occurrence,3,4,12,13 and toxins and infection.14

In SMA types 1, 2, and 3, variable frequency of the SMN gene deletion has been reported.15 Absence of the SMN gene deletion has been reported in 2 patients with upper limb distal SMA (HD) from Italy.16 A comprehensive evaluation of clinical, magnetic resonance imaging (MRI), electromyography (EMG), and genetic analysis may help in understanding HD better. Although different aspects have been reported in various studies,1,4,5 a comprehensive evaluation is lacking. This article reports the results of clinical, neurophysiologic, MRI, and SMN gene analysis of 15 patients with HD.

METHODS

This study was conducted in a tertiary care teaching hospital in India. The basis of diagnosis of HD was as follows: (1) occurrence between 15 and 25 years of age; (2) insidious onset of unilateral or asymmetric oblique amyotrophy often associated with cold paresis; (3) association with fine tremulous irregular involuntary movements of the fingers on moderate extension or fasciculations in the extensors of forearm; (4) absence of sensory findings, reflex changes in arms, little if any pyramidal signs in the legs, and absence of ocular or sphincter disturbances; (5) nonprogressive course and arrest of disease within a few years after the onset; and (6) laboratory data that indicate neurogenic changes in EMG restricted to C7, C8, and T1 myotomes and normal nerve conduction study results.

A detailed history and clinical examination were performed with recording of the family history and pedigree charting. History of trauma, occupation, exercise, associated medical disease, and cold paresis were noted. Muscle wasting, power, reflex changes, and tone were recorded. Sense of pinprick, temperature, joint position, and vibration were measured in all patients. Evidence of Horner syndrome, sweating of palms, and postural hypotension were also recorded.

Spinal MRI was performed in all the patients who could afford the procedure. Sagittal and axial sections were performed using T1, T2, and proton density sequence using a 2-T scanner operating at 1.5 T (Magnetome SP, Siemens, Germany). The nerve conduction studies included motor nerve conduction velocity studies of the median, ulnar, and peroneal nerves and sensory nerve conduction studies of the median, ulnar, and sural nerves using a standard technique (Neuromatic 2000; Dantec, Scovlunde, Denmark). The results of the nerve conduction studies were compared with our laboratory reference ranges, which were determined from 32 healthy adult volunteers.7

For the SMN1 and SMN2 gene deletion study, DNA was extracted from peripheral leukocytes of the patients.17 The presence or absence of exons 7 and 8 of the SMN1 and SMN2 genes was determined by polymerase chain reaction (PCR)–restriction fragment length polymorphism. The PCR for exon 7 (amplified with RIII and mismatch primer X7-Dra or reverse primer18) and exon 8 (amplified with 541C960 and 541C1120 primers) was performed with an initial denaturation at 96°C for 7 minutes followed by 35 cycles (94°C, 62°C, and 72°C for 1 minute each). The PCR products were digested by restriction enzymes DraI and DdeI, respectively, for exons 7 and 8 and separated on 10% polyacrylamide gel electrode visualized in UV and photographed by a documentation and analysis system (Alpha Imager 1220; Alpha Innotech Corporation, San Leandro, Calif).

RESULTS

Our results are based on 15 patients from 14 families. In one family, 2 brothers were affected (Figure 1A). There was no family history of similar disease in the remaining families, including 10 first-degree relatives who were personally examined. The age of the patients ranged from 15 to 30 years (mean age, 21 years). The mean duration of symptoms was 2.9 years (range, 1-10 years). All the patients were Hindu except one, who was Muslim. There was no consanguinity, and all the patients were male. Two patients had a history of trauma; one each had head injury (15 years ago) and mild cervical trauma (10 years ago). After the injury, the patients were asymptomatic for several years (range, 7.5-13 years). Two patients had a history of pulmonary tuberculosis, and 1 had hyperhidrosis of the palms. In one patient with a positive family history, the brother developed HD at the age of 17 years; this patient was included in the study group.

The mean age at the time of onset of disease was 18 years (range, 15-23 years). The symptoms started in the right upper limb in 12 patients and the left upper limb in 3. The disease progressed to involve the other side in 8 patients for a mean duration of 1.4 years (range, 0.5- 2.0 years). Cold paresis was present in 6 patients and Horner syndrome in none. Polyminimyoclonus was present in all the patients. Biceps, triceps, and supinator reflexes were present in all, whereas knee and ankle reflexes were brisk in 4 patients. Plantar response was flexor and sensations were normal in all the patients.

The nerve conduction velocity of the median and ulnar nerves was normal in 13 patients. (The median motor nerve conduction in 1 patient and the ulnar motor nerve in 2 were unrecordable.) Median compound muscle action potential was reduced in 7 patients. Sensory conduction velocity, however, was normal. Concentric needle EMG revealed fibrillations in 10 patients, fasciculations in 15 patients, and neurogenic changes in the C7, C8, and T1 myotomes in all patients. The EMG findings were unilateral in 5 and bilateral in 10, and subclinical changes were present in the other upper limb in 2 patients. The EMG findings of other muscles beyond the C7, C8, and T1 myotomes, such as the brachioradialis, deltoid, vastus lateralis, tibialis anterior, and gastrocnemius muscles, were normal.

Spinal MRI of the cervical region was performed in 11 patients and revealed cord atrophy in 7, which was restricted to the C6 through C8 vertebral level (Figure 1B) and dilated venous plexus in 3 patients. The clinical, EMG, and MRI findings are summarized in the Table. None of the patients had signal alteration in the cervical cord. The results of MRI were normal in 3 patients. The results of both SMN1 and SMN2 gene deletion studies were negative in all 15 patients (Figure 2).

COMMENT

Our study on HD is the first study, to our knowledge, that reports comprehensive evaluation of clinical, neurophysiologic, MRI, and gene deletion analysis. The patients presented with a homogeneous clinical picture characterized by weakness and wasting of the C7, C8, and T1 myotomes, which started unilaterally but eventually progressed to the other limb in 8 patients. The EMG and nerve conduction velocity findings helped not only in documenting the restricted segmental involvement but also in ruling out a number of other conditions, such as brachial neuritis, multifocal motor block, and mononeuritis multiplex. From South India, brachial monomelic amyotrophy has been reported. These patients, however, also had wasting of the biceps and deltoid, unlike ours in whom wasting was restricted to the C7, C8, and T1 myotomes. In addition, progression of neurologic deficit was seen for up to 5 years in most patients followed by a stationary phase without any evidence of fresh neurologic deficit, supporting a benign nature of illness. In this study, however, none of the patients had familial occurrence, and MRI or genetic studies were not conducted.5

Japanese investigators have suggested that HD may be due to microvascular changes following chronic trauma to the spinal cord during flexion and extension of the neck, especially during adolescence when there is rapid growth.9 In our MRI study, cord atrophy was present in 7 patients and dilated venous plexus in 3, although we did not perform MRI in flexion and extension. Anterior horn cell susceptibility to ischemia might account for the atrophy of the anterior horn cells following a microcirculatory disturbance in the anterior spinal artery territory. In such a situation, corticospinal tracts are likely to be affected because of their strategic location in the border zone. Four of our patients had lower limb hyperreflexia, but tone and power were normal in the lower limb muscles. In an earlier study,4 we evaluated the lower limb hyperreflexia in HD using H reflex studies and concluded that hyperreflexia is not pathologic in view of vibratory inhibition, which is regarded as a specific test of pyramidal dysfunction. Ischemic theory of HD has been disproved in an autopsy study.19 An alternative hypothesis of HD is a benign focal variant of SMA.20

In the present study, both SMN1 and SMN2 gene deletions were found to be negative in all patients. The SMN1 and SMN2 gene deletion study has been advocated for carrier detection, prenatal analysis, and patient diagnosis.21 Deletion of the SMN1 gene has been reported in 95% of patients with SMA, especially types 1 and 2.22 Because most of our patients were adults, the likelihood of finding an SMN1 gene deletion was low. Occurrence of HD in the brother of a patient was of interest. A similar family history has been reported in an earlier study, by Hirayama himself,1 as well as in male twins who developed HD at the same age.23 The SMN1 and SMN2 gene deletion studies evaluate the centromeric and telomeric SMN gene deletion; the results of these studies were negative in our patients. Presence of the homozygous SMN1 and SMN2 genes in all the patients with HD, occurrence exclusively in male patients, and occasional occurrence in brothers point toward a role of the X chromosome in the genesis of HD, although this needs further evaluation.

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Article Information

Correspondence: U. K. Misra, DM, Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareily Road, Lucknow 226014, India (ukmisra@sgpgi.ac.in, ukmisra@indiatimes.com).

Accepted for Publication: April 13, 2004.

Author Contributions:Study concept and design: Misra, Kalita. Acquisition of data: Kalita, Mishra. Analysis and interpretation of data: Misra, Kalita, Kesari, Mittal. Drafting of the manuscript: Misra, Kalita, Kesari. Critical revision of the manuscript for important intellectual content: Misra, Kalita, Mishra, Mittal. Statistical analysis: Kalita. Administrative, technical, and material support: Misra.

Acknowledgment: We gratefully acknowledge Rakesh Kumar Nigam, BSc, for secretarial help.

References
1.
Hirayama  K Juvenile nonprogressive muscular atrophy localised in hand and forearm observation in 38 cases. Rinsho Shinkeigaku 1972;12313- 324
2.
Hirayama  K Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama’s disease).  In: De  Jong JMBV, ed. Handbook of Clinical Neurology. Vol 15. Amsterdam, the Netherlands: Elsevier Science; 1991:107-120
3.
Sobue  ISaito  NLida  MAndo  K Juvenile type of distal and segmental muscular atrophy of upper extremities. Ann Neurol 1978;3429- 432
PubMedArticle
4.
Misra  UKKalita  J Central motor conduction in Hirayama disease. Electroencephalogr Clin Neurophysiol 1995;9773- 76Article
5.
Gourie-Devi  MNalini  A Long-term follow-up of 44 patients with brachial monomelic amyotrophy. Acta Neurol Scand 2003;107215- 220
PubMedArticle
6.
Cobben  JMvan der Steege  GGrootscholten  Pde Visser  MScheffer  HBuys  CH Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy. Am J Hum Genet 1995;57805- 808
PubMed
7.
Gillaim  TCBrzustowicz  LMCastilla  LH  et al.  Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 1990;345823- 825
PubMedArticle
8.
Lefebvre  SBurglen  LReboullet  S  et al.  Identification and characterization of a spinal muscular atrophy–determining gene. Cell 1995;80155- 165
PubMedArticle
9.
Hirayama  KTokumar  Y Cervical dural sac and spinal cord in juvenile muscular atrophy of distal upper extremity. Neurology 2000;541922- 1926
PubMedArticle
10.
Donofrio  PD Monomelic amyotrophy. Muscle Nerve 1994;171129- 1134Article
11.
Kira  JOchi  H Juvenile muscular atrophy of the distal upper limb (Hirayama disease) associated with atrophy. J Neurol Neurosurg Psychiatry 2001;70798- 801
PubMedArticle
12.
Robberecht  WAgnirre  TVan den Bosch  L  et al.  Familial juvenile focal amyotrophy of the upper extremity (Hirayama disease): superoxide dismutase 1 genotype and activity. Arch Neurol 1997;5446- 50
PubMedArticle
13.
Schlegel  UJerusalem  FTackmann  WCordt  ATsuda  Y Benign juvenile focal muscular atrophy of upper extremities: a familial case. J Neurol Sci 1987;80351- 353
PubMedArticle
14.
Peiris  JBSeneviratne  KNWickremasinghe  HRGunatilake  SBGamage  R Nonfamilial juvenile distal spinal muscular atrophy of upper extremity. J Neurol Neurosurg Psychiatry 1989;52314- 319Article
15.
Somerville  MJHunter  AGWAubry  HLKorneluk  RGMackenzie  AESurh  LC Clinical application of the molecular diagnosis of spinal muscular atrophy. Am J Med Genet 1997;69159- 165
PubMedArticle
16.
Guglielmo  GDBrahe  CDi Muzio  AUncini  A Benign monomelic amyotrophies of upper and lower limb are not associated to deletions of survival motor neuron gene. J Neurol Sci 1996;141111- 113
PubMedArticle
17.
Blin  NStafford  DW A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acid Res 1976;32303- 2308Article
18.
Chang  JGJong  YJLin  SP  et al.  Molecular analysis of survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes of spinal muscular atrophy patients and their parents. Hum Genet 1997;100557- 581Article
19.
Hirayama  KTomonaga  MKitano  KYamada  TKojima  SArai  K Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg Psychiatry 1987;50285- 290
PubMedArticle
20.
Schroder  RKeller  EFlacke  S  et al.  MRI findings in Hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease? J Neurol 1999;2461069- 1074
PubMedArticle
21.
Scheffer  HCobben  JMMatthijs  GWirth  B Best practice guidelines for molecular analysis in spinal muscular atrophy. Eur J Hum Genet 2001;9484- 491
PubMedArticle
22.
Zerres  KRudnik-Schoneborn  S Spinal muscular atrophies.  In: Rimoin  DL, Connor  JM, Pyeritz  RE, Korf  B, eds. Emery and Rimoin’s Principle and Practice of Medical Genetics. 4th ed. London, England: Churchill Livingstone; 2002;3:3349-3372
23.
Tandan  RSharma  KRBradley  WG  et al.  Chronic segmental spinal muscular atrophy of upper extremities in identical twins. Neurology 1990;40236- 239
PubMedArticle
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