References 1. Mullis KB, Faloona FA. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol 1987; 155:335-350 2. Godec MS, Asher DM, Swoveland IT, et al. Detection of measles virus genomic sequences in SSPE brain tissue by the polymerase chain reaction. J Med Virol 1990;30:237-244 3. Devereux J, Haeberli P, Smithies 0. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res 1984;12:387-395 4. Ho-Terry L, Terry GM, hndesborough P. Dienosis of foetal rubella virus infection by polymerase chain reaction. J Gen Virol 1990~71:1607-1611 5. McConlogue L, Brow MAD, Innis MA. Structure-independent DNA amplification by PCR using 7-deaza-2’-deoxyguanosine. Nucleic Acids Res 1988;16:9869 6. Kwok S, Higuchi R. Avoiding false positives with PCR. Nature 1989;339:237-238 7. Marie P. Sclerose en plaques et maladies infectieuses. Prog Med (Paris) 1884;12:287-289 8. Ehrlich GD, Glaser JB, Bryz-Gornia V, et al. Multiple sclerosis, retroviruses, and PCR. Neurology 1991;41:335-343 9. Sever JL, Madden DL. Viruses that do not cause multiple sclerosis. In: Boese A, ed. Search for the cause of multiple sclerosis and other chronic diseases of the central nervous system. Weinheim: Verlag Chemie, 1980:414-424 10. Gershon AA. Measles virus (rubeola). In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3rd ed. New York Churchill Livingstone, 1990: 1279- 1286 11. Baum SG, Litman N. Mumps virus. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3rd ed. New York Churchill Livingstone, 1990:1260-1265 12. Gershon AA. Rubella virus (German measles). In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990: 1242-1247 13. Stroop WG, Baringer JR. Persistent, slow and latent viral infections. Prog Med Virol 1982;28:1-43 14. Cosby SL, McQuaid S, Taylor MJ, et al. Examination of eight cases of multiple sclerosis and 56 neurological and nonneurological controls for genomic sequences of measles virus, canine distemper virus, simian virus 5 and rubella virus. J Gen Virol 1989;70:2027-2036 15. Greenham LW, Hicks D, Smith S. Detection of DNA transcripts of measles genes in multiple sclerosis brain tissue by transfection. J Neurol Sci 198885:55-65 16. Nath A, Wolinsky JS. Antibody response to rubella virus structural proteins in multiple sclerosis. Ann Neurol 1990;27:533 17. Tourtellotte WW, Pick PW. Current concepts about multiple sclerosis. Mayo Clin Proc 1989;64:592-596 18. Li H, Gyllensten UB, Cui X, et al. Amplification and analysis of DNA sequences in single human sperm and diploid cells. Nature 1988;335:4 14-417 19. Rozenblatt S, Eizenberg 0,Ben-Levy R, et al. Sequence homology within the morbilliviruses. J Virol 1985;53:684-690 20. Buckland R, Gerald C, Barker R, Wild TF. Fusion glycoprotein of measles virus: nucleotide sequence of the gene and cornparison with other paramyxoviruses. J Gen Virol 1987;68:1695 21. Waxman MN, Aronowski J, Server AC, et al. Sequence determination of the mumps virus H N gene. Virology 1988;164: 318-325 22. Waxham MN, Server AC, Goodman HM, Wolinsky JS. Cloning and sequencing of the mumps virus fusion protein gene. Virology 198735 9 3 8 1-388 23. Nakhasi HL, Meyer BC, Liu T-Y. Rubella virus cDNA: Sequence and expression of E l envelope protein. J Biol Chem 1986;261:16616-16621
Werdnig-Hoffmann Disease and Chronic Distal Spinal Muscular Atrophy with Apparent Autosomal Dominant Inheritance Kevin B. Boyla, MD,* and David R. Cornblath, MD?
We report on a family in which both Werdnig-Hoffmann disease (severe infantile-onset spinal muscular atrophy) and chronic distal spinal muscular atrophy OCcurred, with apparent autosomal dominant inheritance. The female proband clinically had Werdnig-Hoffmann disease and died at 10 months. In their second decade of life, the probands father and his 2 brothers developed bilateral progressive atrophy and weakness of the hands and mild weakness in the distal parts of the legs. Their mother had no symptoms or signs of motor neuron disease but electromyography revealed distal denervation of the limbs. While the family studies suggest autosomal dominant inheritance, it is possible that the probands condition was influenced by a maternally derived dlelic or modifying trait. Boylan KB, Cornblath DR. Werdnig-Hoffmann disease and chronic distal spinal muscular atrophy with apparent autosomal dominant inheritance. Ann Neurol 1992;32:404-407
The Werdnig-Hoffmann (severe infantile-onset) form of spinal muscle atrophy (SMA) generally is regarded as an autosomal recessive disorder in which most patients appear to show linkage to chromosome 5q11.213.3 (SMA 5q) [I, 2). Infantile-onset SMA not linked to chromosome 5qll.2-13.3 has also been reported, however, suggesting that genetic heterogeneity may exist [3}. Distal SMA is a chronic lower-motor-neuron disorder clinically distinct from Werdnig-Hoffmann disease, presenting as weakness and atrophy of the distal aspects of the limbs with onset from the first through sixth decades of life [4-10). Motor involvement may predominate in either the upper or the lower limbs. Bulbar function is normal and strength in the proximal parts of the limbs is affected mildly, if at all. Sporadic occurrence as well as autosomal dominant and reces-
From the *Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, and the tDepartment of Neurology,Johns Hopkins University School of Medicine, Baltimore, MD. Received Oct 28, 1991, and in revised form Mar 23, 1992. Accepted for publication Mar 30, 1992. Address correspondence to Dr Boylan, Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224.
404 Copyright 0 1992 by the American Neurological Association
sive inheritance have been reported, suggesting genetic heterogeneity. No linkage data have been published on distal SMA, and its molecular basis is unknown. Dominant inheritance of childhood-onset SMA is rare [2). We report on an unusual family in which both severe infantile-onset SMA and distal SMA occurred, with apparent autosomd dominant inheritance.
lUl
0
Male Female Distal SMA
@
a
Family Evaluation The family was white, of English and German extraction (Fig I). There was no known consanguinity. There was no history of neuromuscular disease other than as indicated in Figure 1. Clinical and laboratory findings in affected persons are summarized in the Table. The proband’s sister (111 OZ), age 3% years, mother (I1 03), age 37, and paternal grandfather (I 03), age 73, had no symptoms or signs of neuromuscular disease. Results of median and ulnar nerve conduction studies and electromyography (EMG) of intrinsic hand muscles of Subject I 03 were normal. The female proband showed decreased movement in utero and delivery was by forceps at term. Hypotonia was recognized by 2 months. At 5 months, social and language development was normal. Findings on general examination were unremarkable. Cranial nerves were normal except for tongue fasciculations. There was diffuse hypotonia and marked quadriparesis, especially in the lower limbs and worse proximally. Tendon reflexes were absent; plantar responses were flexor. Sensory responses were normal. Right median and ulnar compound muscle action potential (CMAP) amplitudes were less than 10% of the lower limit of normal, and motor conduction velocities and sensory nerve action potentials were normal. EMG of the rectus abdominus and proximal and distal muscles of the upper and lower limbs showed signs of denervation 1117. Examination of a quadriceps femoris biopsy specimen showed a mixture of normal and small-diameter fibers without inflammation or inclusions,
Werdnig-Hoffmann Disease Deceased Person
I
II
111 Fig 1. Pedigree of the family. The proband is Patient III 01. Subject I 03 died a f m months aftw being eualuatedfor this study. The ancestry of Subjects I 02 and I 03 is German; Subjects I 01 and I 04 were of English descent. Family members with pedigree numbers underlined were examined by us.
Features of Spinal Muscular Atrophy in the Aflected Family Members
Age at examination Age at onset Neurological symptoms
Neurological findings
Electrophysiology Additional studies
Patient I11 01
Patient I1 04
Patient I1 05
Patient I1 06
Patient I 0 3
5 mo 3 wk Delayed motor milestones
36 and 42 yr
34 and 39 yr
24 and 29 yr 12 yr
67 yr
12 yr Progressive (R>L) hand Progressive (R>L) hand weakness; mild proweakness gressive footdrop BIL; tremor Intrinsic hand muscle Tongue fasciculation; hy- Intrinsic hand muscle wastingiweakness BIL; porn& quadriparesis wasting/weakness mild to moderate wast(R>L); mild (R)weak(mainly proximal); abness in distal anterior ingiweakness B/L in sent reflexes distal leg; foot-slap leg gait; action tremor; brisk patellar jerks; flexor plantar responses Widespread denervation Distal upper-limb dener- Distal upper- and lowerlimb denervation BIL vation BIL Cervical spine and chest Cervical spine and chest Quadriceps biopsyx-rays, NL; very-longx-rays, NL denervation atrophy chain fatty acids, NL
15 yr
Progressive (R= L) hand weakness
Unknown Stroke-related left hemiparesis; tremor
Intrinsic hand muscle wasting/weakness; mild weakness BIL in distal anterior leg; brisk lower-limb reflexes; flexor plantar responses
Mild left hemiparesis; action tremor
Distal upper- and lowerlimb denervation B/L
Distal upper- and lowerlimb denervation B/L
Cervical spine and chest None x-rays, NL; hexosaminidase, N L very longchain fatty acids, NL
R = right; L = left; B/L = bilateral; NL = normal.
Brief Communication: Boylan and Cornblath: Werdnig-Hoffmann and Distal SMA
405
Fig 2. Hands of Patient I1 04, photographed during attempted spreading of thejngers. There is essentially no lateral movement ofthe second and third digits bilaterally. There is marked wasting bilaterally of the (A)first dorsal interosseous muscle and (B) right thenar eminence, and moderate leji thenar and right hypothenar wasting. compatible with denervation atrophy. There was no fibertype disproportion or fiber hypertrophy. Progressive weakness led to death from pneumonia at 10 months. Neurological findings in the proband’s father (I1 04) and his 2 brothers (I1 05 and I1 06) were similar (see Table). Slowly progressive hand weakness developed between ages 12 and 15, followed by leg weakness at age 20. The initial examination was performed at age 36 years for Patient I1 04, 34 years for Patient I1 05, and 24 years for Patient I1 06. Thenar and interosseous muscles showed marked weakness (MRC grade 0-2) and wasting; hypothenar involvement was less severe (Fig 2). Leg weakness was mild in 2 brothers (11 04 and I1 06),but moderate and associated with an abnormal gait in 1 (I1 05). Findings were asymmetrical in Patients I1 04 and I1 06. Lower limb reflexes in 2 brothers (I1 05 and I1 06) were moderately brisk and 1 (I1 06) showed a few beats of ankle clonus bilaterally. Fasciculations were not seen. Patient I1 05 had pes cavus and Patient I1 06 had pes planus. Patient I1 05 also had an upper-limb action tremor. Otherwise, limb strength, reflexes, plantar responses, and sensory findings were normal. Evoked CMAP amplitudes were decreased in the involved hand muscles in the 3 brothers. Distal peroneal CMAP amplitude was decreased as well in Patient I1 05. Conduction velocities and sensory nerve action potentials were normal. EMG showed devervation in intrinsic hand muscles in all 3, and in the distal part of the lower extremities in 2 (I1 05 and I1 06). Cervical spine and chest x-ray films were noncontributory. Values for hexosaminidase and very-long-chain fatty acids were normal. Repeat examinations after 6 to 7 years showed mild to moderate progression of the hand findings in Patient I1 04 and slightly more impaired gait in Patient I1 05; Patient I1 06 was unchanged. Patient I 04, grandmother of the proband (see Fig I), had no neuromuscular symptoms. Examination at age 67 showed mild spastic left hemiparesis, hyperreflexia, and Babinski sign
related to a remote stroke. An upper-limb action tremor of many years’ duration was present bilaterally. Other neurological findings were normal. There was no foot deformity. Median conduction studies showed mild carpal tunnel entrapment bilaterally. Bilateral ulnar, peroneal, and left sural conduction studies were normal. EMG revealed chronic denervation in first dorsal interosseous and anterior tibial muscles bilaterally, and in the left abductor pollicis brevis and extensor indicis proprius. EMG findings of the left deltoideus, pronator teres, and right abductor pollicis brevis were normal.
Discussion The female proband’s (111 01) disorder is compatible with the Werdnig-Hoffmann form of SMA, whereas her father and his 2 brothers showed signs of distal SMA affecting mainly the hands. The paternal grandmother (I 04) was asymptomatic, but showed EMG evidence of distal SMA. We believe that this represents autosomal dominant inheritance of distal SMA, although X-linked transmission is also possible. Clinically, two other neurological features were present in addition to the distal SMA. First, brisk lowerlimb reflexes were present in Patients I1 05 and I1 06, and may represent upper-motor-neuron involvement. We think this is uncertain, as other upper-motorneuron signs were absent. A similar family with hand atrophy and hyperreflexia has been reported [61. Second, tremor clinically resembling essential tremor was present in Patients I 04 and I1 05, but whether this is part of the neurological disorder producing the distal SMA is unknown; we found no reports of this association. Abnormal movements widely referred to as tremor are found in patients with distal SMA E12, 131, but from clinical descriptions and our own observations of one such affected patient (not a member of the present family) the movements are irregular and coarse, unlike the tremor seen in our patients. The term “minipolymyoclonus” has been applied to these irregular movements by some authors 1141, to distinguish them from a centrally mediated movement disorder.
406 Annals of Neurology Vol 32 N o 3 September 1992
The paternal history of distal SMA in the present family raises the possibility that Werdnig-Hoffmann disease in the proband represents severe expression of the distal SMA gene. Familial concordance of the SMA phenotype within families usually is high [Z, 41, suggesting that the proband's condition was influenced by a maternally derived gene or genes. The two seemingly different motor neuron disorders seen in this family could be allelic, or could be related to a nonallelic modification of disease expression by unlinked genes (l5}, one of which presumably would be the paternal distal SMA gene. Familial association of distal SMA and WerdnigHoffmann disease apparently is rare. We found only two reported cases in which adult-onset limb SMA occurred in association with Werdnig-Hoffmann disease in a first- or second-degree relative (161. It is not known whether distal SMA in a parent is a risk factor for having offspring with Werdnig-Hoffmann disease, but the present family and the two reported elsewhere {l6] suggest that it may be. Identification of SMA 5q carriers currently requires DNA-linked marker analysis { 2 , 31, which was not feasible in our family. Hence, the possibility of 5q linkage of the proband's disorder is unresolved. When the SMA 5q gene (or genes) is identified, direct D N A analysis in this family should be helpful in clarifying the relationship, if any, between Werdnig-Hoffmann disease in the proband and the paternal distal SMA. This work was supported in part by a Dana Foundation Fellowship (to K. B. B.) and The James P. Dunn Fund for Neuromuscular Disease. We thank Dr Pamela Talalay for critically reviewing the manuscript, and Rod Graham for preparing the manuscript. Presented in part at the 116th Annual Meeting of the American Neurological Association, Seattle, WA, October 1, 1991.
References 1. Brooke MM. A clinician's view of neuromuscular diseases. Baltimore: Williams & Wilkins, 1986 2. Munsat TL, Skerry L, Korf B, et al. Phenotype heterogeneity of spinal muscular atrophy. Mapping to chromosome 5qll.2-13.3 (SMA 5s).Neurology 1990;40:1831-1836 3. Gilliam TC, Brzustowicz LM, Castilla LH, et al. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 1990345:823-825 Meadows JC, Marsden CD, Harriman DGF. Chronic spinal muscular atrophy in adults. Part 2: other forms. J Neurol Sci
1969;9:551-566 McLeod JG, Prineas JW. Distal type of chronic distal spinal muscular atrophy: clinical, electrophysiological,and pathological studies. Brain 1971;94:703-714 Lander CM, Eadie MJ, Tyrer JM. Hereditary motor peripheral neuropathy predominantly affecting the arms. J Neurol Sci 1976;28:389-394 Vignaendra V, Thiam Ghee L. A family with neurogenic atrophy of the distal muscles of the upper arms: clinical and elecrrophysiological studies. Med J Aust 1976;2:639-641
8. OSullivan DJ, McLeod JG. Distal spinal muscular atrophy involving the hands. J Neurol Neurosurg Psychiatry 1978;41:653 9. Pearn J, Hudgson P. Distal spinal muscular atrophy, a clinical and genetic study of 8 kindreds. J Neurol Sci 1979;43:183-191 10. Harding AE, Thomas PK. Hereditary distal spinal muscular atrophy, a report of 34 cases and a review of the literature. J Neurol Sci 1980;45:337-348 11. Cornblath DR, Kuncl RW, Rechthand E, et al. The value of rectus abdominal muscle electromyography. Muscle Nerve
1987;10:376 12. Tandan R, Sharma KR, Bradley WG, er al. Chronic segmental spinal muscular atrophy of upper extremities in identical twins. Neurology 199O;40:236-2 39 13. Peiris JB, Seneviratne KN, Wickremasinghe HR, et al. Nonfamilial juvenile distal spinal muscular atrophy of upper extremity. J Neurol Neurosurg Psychiatry 1989;52:314-319 14. Singh N, Sachdev KK, Susheela AK. Juvenile muscular atrophy localized to arms. Arch Neurol 1980;37:297-299 15. Hausmanowa-Petrusewicz I. Spinal muscular atrophies: how many types? In: Rowland LP, ed. Amyotrophic lateral sclerosis and other motor neuron diseases. New York: Raven, 1991: 157-168 16. Harding AE, Bradbury PG, Murray NMF. Chronic asymmetrical spinal muscular atrophy. J Neurol Sci 1983;59:69-83
Recurrent 'I'ransverse Myelitis, Myasthenia Gravis, and -Autoantibodies J. W. Lindsey, MD,' G. W. Albers, MD,? and L. Steinman, MD'
A 45-year-old man with a longstanding diagnosis of myasthenia gravis presented with four episodes of transverse myelitis in 5 years. Each episode improved after treatment with steroids. Laboratory studies revealed no evidence of multiple sclerosis or a structural spinal lesion. He had antinuclear and anti-DNA antibodies and the HLA-A1, B8, DR3 haplotype known to be associated with certain autoimmune diseases. We propose an autoimmune cause for the recurrent episodes of myelitis. Albers GW, Steinman L. Recurrent Lindsey JW, transverse myelitis, myasthenia gravis, and autoantibodies.Ann Neurol 1992;32:407-409 Transverse myelitis is an inflammatory disease of unknown cause that usually has a monophasic course. Recurrence is rare, but can occur with collagen vascular ~~
~
~
~~
~
From the *Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, and ?Department of Neurology, Palo Alto Veterans' Affairs Medical Center, Palo Alto, CA. Received Jan 21, 1992, and in revised form Mar 18. Accepted for publication Mar 22, 1992. Address correspondence to Dr Lindsey, Department of Neurology, Stanford University Medical Center, Stanford, CA 94305-5235.
Copyright 0 1992 by the American Neurological Association 407
Werdnig-Hoffmann Disease and Chronic Distal Spinal Muscular Atrophy with Apparent Autosomal Dominant Inheritance Kevin B. Boyla, MD,* and David R. Cornblath, MD?
We report on a family in which both Werdnig-Hoffmann disease (severe infantile-onset spinal muscular atrophy) and chronic distal spinal muscular atrophy OCcurred, with apparent autosomal dominant inheritance. The female proband clinically had Werdnig-Hoffmann disease and died at 10 months. In their second decade of life, the probands father and his 2 brothers developed bilateral progressive atrophy and weakness of the hands and mild weakness in the distal parts of the legs. Their mother had no symptoms or signs of motor neuron disease but electromyography revealed distal denervation of the limbs. While the family studies suggest autosomal dominant inheritance, it is possible that the probands condition was influenced by a maternally derived dlelic or modifying trait. Boylan KB, Cornblath DR. Werdnig-Hoffmann disease and chronic distal spinal muscular atrophy with apparent autosomal dominant inheritance. Ann Neurol 1992;32:404-407
The Werdnig-Hoffmann (severe infantile-onset) form of spinal muscle atrophy (SMA) generally is regarded as an autosomal recessive disorder in which most patients appear to show linkage to chromosome 5q11.213.3 (SMA 5q) [I, 2). Infantile-onset SMA not linked to chromosome 5qll.2-13.3 has also been reported, however, suggesting that genetic heterogeneity may exist [3}. Distal SMA is a chronic lower-motor-neuron disorder clinically distinct from Werdnig-Hoffmann disease, presenting as weakness and atrophy of the distal aspects of the limbs with onset from the first through sixth decades of life [4-10). Motor involvement may predominate in either the upper or the lower limbs. Bulbar function is normal and strength in the proximal parts of the limbs is affected mildly, if at all. Sporadic occurrence as well as autosomal dominant and reces-
From the *Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, and the tDepartment of Neurology,Johns Hopkins University School of Medicine, Baltimore, MD. Received Oct 28, 1991, and in revised form Mar 23, 1992. Accepted for publication Mar 30, 1992. Address correspondence to Dr Boylan, Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224.
404 Copyright 0 1992 by the American Neurological Association
sive inheritance have been reported, suggesting genetic heterogeneity. No linkage data have been published on distal SMA, and its molecular basis is unknown. Dominant inheritance of childhood-onset SMA is rare [2). We report on an unusual family in which both severe infantile-onset SMA and distal SMA occurred, with apparent autosomd dominant inheritance.
lUl
0
Male Female Distal SMA
@
a
Family Evaluation The family was white, of English and German extraction (Fig I). There was no known consanguinity. There was no history of neuromuscular disease other than as indicated in Figure 1. Clinical and laboratory findings in affected persons are summarized in the Table. The proband’s sister (111 OZ), age 3% years, mother (I1 03), age 37, and paternal grandfather (I 03), age 73, had no symptoms or signs of neuromuscular disease. Results of median and ulnar nerve conduction studies and electromyography (EMG) of intrinsic hand muscles of Subject I 03 were normal. The female proband showed decreased movement in utero and delivery was by forceps at term. Hypotonia was recognized by 2 months. At 5 months, social and language development was normal. Findings on general examination were unremarkable. Cranial nerves were normal except for tongue fasciculations. There was diffuse hypotonia and marked quadriparesis, especially in the lower limbs and worse proximally. Tendon reflexes were absent; plantar responses were flexor. Sensory responses were normal. Right median and ulnar compound muscle action potential (CMAP) amplitudes were less than 10% of the lower limit of normal, and motor conduction velocities and sensory nerve action potentials were normal. EMG of the rectus abdominus and proximal and distal muscles of the upper and lower limbs showed signs of denervation 1117. Examination of a quadriceps femoris biopsy specimen showed a mixture of normal and small-diameter fibers without inflammation or inclusions,
Werdnig-Hoffmann Disease Deceased Person
I
II
111 Fig 1. Pedigree of the family. The proband is Patient III 01. Subject I 03 died a f m months aftw being eualuatedfor this study. The ancestry of Subjects I 02 and I 03 is German; Subjects I 01 and I 04 were of English descent. Family members with pedigree numbers underlined were examined by us.
Features of Spinal Muscular Atrophy in the Aflected Family Members
Age at examination Age at onset Neurological symptoms
Neurological findings
Electrophysiology Additional studies
Patient I11 01
Patient I1 04
Patient I1 05
Patient I1 06
Patient I 0 3
5 mo 3 wk Delayed motor milestones
36 and 42 yr
34 and 39 yr
24 and 29 yr 12 yr
67 yr
12 yr Progressive (R>L) hand Progressive (R>L) hand weakness; mild proweakness gressive footdrop BIL; tremor Intrinsic hand muscle Tongue fasciculation; hy- Intrinsic hand muscle wastingiweakness BIL; porn& quadriparesis wasting/weakness mild to moderate wast(R>L); mild (R)weak(mainly proximal); abness in distal anterior ingiweakness B/L in sent reflexes distal leg; foot-slap leg gait; action tremor; brisk patellar jerks; flexor plantar responses Widespread denervation Distal upper-limb dener- Distal upper- and lowerlimb denervation BIL vation BIL Cervical spine and chest Cervical spine and chest Quadriceps biopsyx-rays, NL; very-longx-rays, NL denervation atrophy chain fatty acids, NL
15 yr
Progressive (R= L) hand weakness
Unknown Stroke-related left hemiparesis; tremor
Intrinsic hand muscle wasting/weakness; mild weakness BIL in distal anterior leg; brisk lower-limb reflexes; flexor plantar responses
Mild left hemiparesis; action tremor
Distal upper- and lowerlimb denervation B/L
Distal upper- and lowerlimb denervation B/L
Cervical spine and chest None x-rays, NL; hexosaminidase, N L very longchain fatty acids, NL
R = right; L = left; B/L = bilateral; NL = normal.
Brief Communication: Boylan and Cornblath: Werdnig-Hoffmann and Distal SMA
405
Fig 2. Hands of Patient I1 04, photographed during attempted spreading of thejngers. There is essentially no lateral movement ofthe second and third digits bilaterally. There is marked wasting bilaterally of the (A)first dorsal interosseous muscle and (B) right thenar eminence, and moderate leji thenar and right hypothenar wasting. compatible with denervation atrophy. There was no fibertype disproportion or fiber hypertrophy. Progressive weakness led to death from pneumonia at 10 months. Neurological findings in the proband’s father (I1 04) and his 2 brothers (I1 05 and I1 06) were similar (see Table). Slowly progressive hand weakness developed between ages 12 and 15, followed by leg weakness at age 20. The initial examination was performed at age 36 years for Patient I1 04, 34 years for Patient I1 05, and 24 years for Patient I1 06. Thenar and interosseous muscles showed marked weakness (MRC grade 0-2) and wasting; hypothenar involvement was less severe (Fig 2). Leg weakness was mild in 2 brothers (11 04 and I1 06),but moderate and associated with an abnormal gait in 1 (I1 05). Findings were asymmetrical in Patients I1 04 and I1 06. Lower limb reflexes in 2 brothers (I1 05 and I1 06) were moderately brisk and 1 (I1 06) showed a few beats of ankle clonus bilaterally. Fasciculations were not seen. Patient I1 05 had pes cavus and Patient I1 06 had pes planus. Patient I1 05 also had an upper-limb action tremor. Otherwise, limb strength, reflexes, plantar responses, and sensory findings were normal. Evoked CMAP amplitudes were decreased in the involved hand muscles in the 3 brothers. Distal peroneal CMAP amplitude was decreased as well in Patient I1 05. Conduction velocities and sensory nerve action potentials were normal. EMG showed devervation in intrinsic hand muscles in all 3, and in the distal part of the lower extremities in 2 (I1 05 and I1 06). Cervical spine and chest x-ray films were noncontributory. Values for hexosaminidase and very-long-chain fatty acids were normal. Repeat examinations after 6 to 7 years showed mild to moderate progression of the hand findings in Patient I1 04 and slightly more impaired gait in Patient I1 05; Patient I1 06 was unchanged. Patient I 04, grandmother of the proband (see Fig I), had no neuromuscular symptoms. Examination at age 67 showed mild spastic left hemiparesis, hyperreflexia, and Babinski sign
related to a remote stroke. An upper-limb action tremor of many years’ duration was present bilaterally. Other neurological findings were normal. There was no foot deformity. Median conduction studies showed mild carpal tunnel entrapment bilaterally. Bilateral ulnar, peroneal, and left sural conduction studies were normal. EMG revealed chronic denervation in first dorsal interosseous and anterior tibial muscles bilaterally, and in the left abductor pollicis brevis and extensor indicis proprius. EMG findings of the left deltoideus, pronator teres, and right abductor pollicis brevis were normal.
Discussion The female proband’s (111 01) disorder is compatible with the Werdnig-Hoffmann form of SMA, whereas her father and his 2 brothers showed signs of distal SMA affecting mainly the hands. The paternal grandmother (I 04) was asymptomatic, but showed EMG evidence of distal SMA. We believe that this represents autosomal dominant inheritance of distal SMA, although X-linked transmission is also possible. Clinically, two other neurological features were present in addition to the distal SMA. First, brisk lowerlimb reflexes were present in Patients I1 05 and I1 06, and may represent upper-motor-neuron involvement. We think this is uncertain, as other upper-motorneuron signs were absent. A similar family with hand atrophy and hyperreflexia has been reported [61. Second, tremor clinically resembling essential tremor was present in Patients I 04 and I1 05, but whether this is part of the neurological disorder producing the distal SMA is unknown; we found no reports of this association. Abnormal movements widely referred to as tremor are found in patients with distal SMA E12, 131, but from clinical descriptions and our own observations of one such affected patient (not a member of the present family) the movements are irregular and coarse, unlike the tremor seen in our patients. The term “minipolymyoclonus” has been applied to these irregular movements by some authors 1141, to distinguish them from a centrally mediated movement disorder.
406 Annals of Neurology Vol 32 N o 3 September 1992
The paternal history of distal SMA in the present family raises the possibility that Werdnig-Hoffmann disease in the proband represents severe expression of the distal SMA gene. Familial concordance of the SMA phenotype within families usually is high [Z, 41, suggesting that the proband's condition was influenced by a maternally derived gene or genes. The two seemingly different motor neuron disorders seen in this family could be allelic, or could be related to a nonallelic modification of disease expression by unlinked genes (l5}, one of which presumably would be the paternal distal SMA gene. Familial association of distal SMA and WerdnigHoffmann disease apparently is rare. We found only two reported cases in which adult-onset limb SMA occurred in association with Werdnig-Hoffmann disease in a first- or second-degree relative (161. It is not known whether distal SMA in a parent is a risk factor for having offspring with Werdnig-Hoffmann disease, but the present family and the two reported elsewhere {l6] suggest that it may be. Identification of SMA 5q carriers currently requires DNA-linked marker analysis { 2 , 31, which was not feasible in our family. Hence, the possibility of 5q linkage of the proband's disorder is unresolved. When the SMA 5q gene (or genes) is identified, direct D N A analysis in this family should be helpful in clarifying the relationship, if any, between Werdnig-Hoffmann disease in the proband and the paternal distal SMA. This work was supported in part by a Dana Foundation Fellowship (to K. B. B.) and The James P. Dunn Fund for Neuromuscular Disease. We thank Dr Pamela Talalay for critically reviewing the manuscript, and Rod Graham for preparing the manuscript. Presented in part at the 116th Annual Meeting of the American Neurological Association, Seattle, WA, October 1, 1991.
References 1. Brooke MM. A clinician's view of neuromuscular diseases. Baltimore: Williams & Wilkins, 1986 2. Munsat TL, Skerry L, Korf B, et al. Phenotype heterogeneity of spinal muscular atrophy. Mapping to chromosome 5qll.2-13.3 (SMA 5s).Neurology 1990;40:1831-1836 3. Gilliam TC, Brzustowicz LM, Castilla LH, et al. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 1990345:823-825 Meadows JC, Marsden CD, Harriman DGF. Chronic spinal muscular atrophy in adults. Part 2: other forms. J Neurol Sci
1969;9:551-566 McLeod JG, Prineas JW. Distal type of chronic distal spinal muscular atrophy: clinical, electrophysiological,and pathological studies. Brain 1971;94:703-714 Lander CM, Eadie MJ, Tyrer JM. Hereditary motor peripheral neuropathy predominantly affecting the arms. J Neurol Sci 1976;28:389-394 Vignaendra V, Thiam Ghee L. A family with neurogenic atrophy of the distal muscles of the upper arms: clinical and elecrrophysiological studies. Med J Aust 1976;2:639-641
8. OSullivan DJ, McLeod JG. Distal spinal muscular atrophy involving the hands. J Neurol Neurosurg Psychiatry 1978;41:653 9. Pearn J, Hudgson P. Distal spinal muscular atrophy, a clinical and genetic study of 8 kindreds. J Neurol Sci 1979;43:183-191 10. Harding AE, Thomas PK. Hereditary distal spinal muscular atrophy, a report of 34 cases and a review of the literature. J Neurol Sci 1980;45:337-348 11. Cornblath DR, Kuncl RW, Rechthand E, et al. The value of rectus abdominal muscle electromyography. Muscle Nerve
1987;10:376 12. Tandan R, Sharma KR, Bradley WG, er al. Chronic segmental spinal muscular atrophy of upper extremities in identical twins. Neurology 199O;40:236-2 39 13. Peiris JB, Seneviratne KN, Wickremasinghe HR, et al. Nonfamilial juvenile distal spinal muscular atrophy of upper extremity. J Neurol Neurosurg Psychiatry 1989;52:314-319 14. Singh N, Sachdev KK, Susheela AK. Juvenile muscular atrophy localized to arms. Arch Neurol 1980;37:297-299 15. Hausmanowa-Petrusewicz I. Spinal muscular atrophies: how many types? In: Rowland LP, ed. Amyotrophic lateral sclerosis and other motor neuron diseases. New York: Raven, 1991: 157-168 16. Harding AE, Bradbury PG, Murray NMF. Chronic asymmetrical spinal muscular atrophy. J Neurol Sci 1983;59:69-83
Recurrent 'I'ransverse Myelitis, Myasthenia Gravis, and -Autoantibodies J. W. Lindsey, MD,' G. W. Albers, MD,? and L. Steinman, MD'
A 45-year-old man with a longstanding diagnosis of myasthenia gravis presented with four episodes of transverse myelitis in 5 years. Each episode improved after treatment with steroids. Laboratory studies revealed no evidence of multiple sclerosis or a structural spinal lesion. He had antinuclear and anti-DNA antibodies and the HLA-A1, B8, DR3 haplotype known to be associated with certain autoimmune diseases. We propose an autoimmune cause for the recurrent episodes of myelitis. Albers GW, Steinman L. Recurrent Lindsey JW, transverse myelitis, myasthenia gravis, and autoantibodies.Ann Neurol 1992;32:407-409 Transverse myelitis is an inflammatory disease of unknown cause that usually has a monophasic course. Recurrence is rare, but can occur with collagen vascular ~~
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From the *Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, and ?Department of Neurology, Palo Alto Veterans' Affairs Medical Center, Palo Alto, CA. Received Jan 21, 1992, and in revised form Mar 18. Accepted for publication Mar 22, 1992. Address correspondence to Dr Lindsey, Department of Neurology, Stanford University Medical Center, Stanford, CA 94305-5235.
Copyright 0 1992 by the American Neurological Association 407
