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Difficulties in distinguishing sporadic from familial amyotrophic lateral sclerosis.

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2. Bicknell JM. Familial cavernous angioma of the brain stem
dominantly inherited in Hispanics. Neurosurgery 1989;24:
3. Gangemi M, Maiuri F, Donati P, et al. Familial cerebral cavernous angiomas. Neurol Res 1990;12:131-136
4. Steiger HJ, Markwalder TM, Reulen HJ. Clinicopathological
correlations of cerebral cavernous angiomas: observation in
eleven cases. Neurosurgery 1987:21:879-884
5. Zabramski JM, Wascher TM, Spetzler RF, et al. The natural
history of familial cavernous malformations: results of an ongoing study. J Neurosurg 1994;80:422-432
6. Pozzati E, Guiuliani G, Nuzzo G, Poppi M. The growth of
cerebral cavernous angiomas. Neurosurgery 1989;25:92-97
7. Sanvar M, McCormick WF. Inrracerebral venous angioma.
Arch Neurol 1978;35:323-325
8. Berry RG, Alpers BJ, White JC. The site, structure and frequency of intracranial aneurysms, angiomas and arteriovenous
abnormalities. In: Millikan CH, ed. Research publications, association for research in nervous and mental disease. Baltimore:
Williams & Wilkins, 1966:40-72
9. Simard JM, Garcia-Bengoechea F, Ballinger WE, et al. Cavernous angioma: a review of 126 collected and 12 new clinical
cases. Neurosurgery 1986;18:162-172
10. Hayman LA, Evans RA, Ferrell RE, et al. Familial cavernous
angiomas: natural history and genetic study over a 5-year period. Am J Med Genet 1982;11:147-160
11. Dubovsky J , Zabramski JM, Kurth J, et al. A gene responsible
for cavernous malformations of the brain maps to chromosome
7q. Hum Mol Genet 1995;4:453-458
12. Gil-Nagel A, Wilcox KJ, Stewart JM, et al. Familial cerebral
caverous angioma: clinical analysis of a family and phenotypic
classification. Epilepsy Res 1995;21:27-36
13. Weber JL, Wang Z, Hansen K, et al. Evidence for human
meiotic recombination interference obtained through construction of a short tandem repeat-polymorphism linkage map of
chromosome 19. Am J Hum Genet 1993;53:1079-1095
14. Lathrop GM, Lalouel JM, Julier C, Ott J. Strategies for
multilocus linkage analysis in humans. Proc Natl Acad Sci USA
1984;81 :3443-3446
Difficulties in
Distinguishing Sporadic
from P amilial
Amvot r oDhic Latera1
Richard W. Orrell, MRCP,*T James Habgood, BSc,*
Peter Rudge, FRO,$ Russell J. M. Lane, FRCP,?
and Jackie S. de Belleroche, PhD*
Mutations of the copperlzinc superoxide dismutase
(SOD-1) gene are present in around 20% of patients
with a family history of amyotrophiclateral sclerosis. The
finding of these mutations in patients with sporadic
amyotrophic lateral sclerosis is rare. We describe a family
with amyotrophic lateral sclerosis associated with the
SOD-1 mutation Asp 101 Asn. This mutation was previously described as occurring in a patient with sporadic
disease. We discuss the difficulties in defining truly sporadic amyotrophic lateral sclerosis, and the consequent
implications on the neurogenetic advice given to other
family members.
Orrell RW, Habgood J, Rudge P, Lane RJM,
de Belleroche JS. Difficulties in distinguishing
sporadic from familial amyotrophic lateral
sclerosis. Ann Neurol 1996;39:810-812
Amyotrophic lateral sclerosis (ALS) or motor neuron disease is a progressive neurodegenerative disease, primarily
of upper and lower motor neurons. Around 1 in 1,000
adults die of this condition. A genetic basis to the disease
was suspected over 100 years ago by Aran, bur for many
years a genetic influence on the familial occurrence ofthis
disease was doubted. In 1993 mutations of the gene for
copper-zinc superoxide dismutase, SOD-1, were identified [ 1,2], and subsequently more than 30 different point
mutations and a single 2-bp deletion [3]were identified.
While these mutations are associated with the disease in
families, the causative relationship has yet to be defined,
although transgenic animal models and human pathological studies suggest the possibility of gain of an adverse
function [4,51 or alternatively, reduced enzyme activity
[2, 61.
There has been some debate regarding the finding
From the *Department of Biochemistry, Charing Cross and Westminster Medical School; tNeuromuscular Unit, Charing Cross
Hospital; and $Department of Neurology, National Hospital for
Neurology and Neurosurgery, London, England.
Received Nov 8, 1995.Accepted for publication Dec 27, 1995.
Address correspondence to Dr Orrell, Neuromuscular Unit, Regional Centre and Academic Unit of Neuroscience, Charing Cross
Hospital, Fulham Palace Road, London W6 8RF, England.
Copyright 0 1996 by the American Neurological Association
Fig I . Pedigree of a f a m i 4 with amyotrophic lateral sclerosis. The filled symbols indicate affected individuals. The proband is
marked with an arrow. Squares represent males; circles, females; and oblique lines, deceased individuals.
of mutations of SOD-1 in patients with apparently
sporadic ALS [7,
81. We describe a family with a mutation of SOD-1, previously reported in a patient with
sporadic ALS, and discuss the implication of these
findings in the context of clinical neurogenetics.
Family Details
The proband, 111.2 (Fig l), was born in Pakistan and later
moved to India and subsequently to England. He first noticed difficulty walking with some wasting of the leg muscles
at the age of 46 years. He had weakness of the legs, which
progressed to involve the arms, with cramps in the legs. On
examination he had weakness and wasting of the muscles of
the arms and legs, with widespread fasciculations. Reflexes
were generally depressed, but the plantar responses were extensor. The gag reflex was depressed. Magnetic resonance
images (MRIs) of the spine appeared unremarkable, and
nerve conduction studies and electromyography (EMG) supported the diagnosis of ALS. His condition progressed with
the development of additional bulbar symptoms and signs,
and he died at the age of 48 years, the total disease duration
being almost 3 years.
His brother (111.1) died at age 43 years, after a disease
duration of 2 years, with features of both upper and lower
motor neuron involvement of ALS.
Other affected members of the family include Patient 11.2
who died at age 42 years of presumed ALS commencing in
the legs, then arms, and finally affecting swallowing. Disease
duration was around 2 years. Patient 111.7 died at age 26
years with a similar condition of 2 years' duration. Patient
11.3 died at age 44 years, Patient 1.2 died in her 40s, Patient
11.5 died in his late 40s, and Patient 111.18 died at age 45,
all with a similar condition. At age 53 years, Patient 111.28
died of ALS of 2 years' duration, commencing with cramps
in the right calf, progressing to the right arm, and then affecting all limbs, with brisk reflexes. This progressed to bulbar involvement and death. His father (11.7) died of Alzheimer's disease at age 78 years, and his mother (11.8), in her
70s, was still living at the time of writing.
Molecular Genetics
Blood was obtained from Patients 111.2 and 111.28, and DNA
extracted and investigated for mutation of the SOD-1 gene
as previously described [9], using the primer pairs 5' CATAT
(ilu A
Asp A
A Asn
Fig 2. Sequence of mutation Asp 101 Am. The lanes present
the sequence of the four bases cytosine ( C ) , thymine (T), adenine (A), and guanine (G). The heterozygote point mutation,
with both G and A bands in codon 101 of SOD-I, leads to
the substitution of asparagine ( A n ) for aspartic acid (Asp).
ACTAACAATC. A heterozygote point mutation was identified in codon 101, exon 4, GAT to AAT (Fig 2), leading
to the amino acid substitution of asparagine (Am) for aspartic acid (Asp).
Mutations of SOD-1 appear to be present in around
20% of patients with a family history of ALS. T h e genetic component in the remaining 80% of familial ALS
patients, and the nonfamilial ALS patients is uncertain.
Only around 2% of all ALS patients have SOD-1 mutations [ 101.T h e frequency of SOD-1mutations in patients
with sporadic ALS remains to be determined, but very
few such mutations have been identified.
T h e mutation Asp 101 Asn previously was demon-
Brief Communication: Orrell et al: Distinguishing Sporadic from Familial ALS 811
strated in a patient with sporadic ALS [I 11, and not in
the familial form. Two further mutations, Ile 113 Thr
and Glu 21 Lys, were reported as occurring in sporadic
ALS, in 4 patients from one center in Scotland 1121.The
Ile 113 Thr mutation also was found in patients with familial ALS [ l , 31,including 30% (3/10) of apparently
unrelated families in the same population as the sporadic
ALS patients from Scotland [13].
In the family we describe, Individual 111.28 might
initially appear as a sporadic ALS patient-he
many siblings who are unaffected, and his parents, at
more than 70 years old, did not manifest the disease.
The previous report of the Asp 101 Asn mutation [ 1 11
gave no genealogical information beyond his “aged”
parents, and interestingly the patient was also a 53year-old man of Asian origin. Similarly, the genealogical information of the other 4 patients with sporadic
ALS is limited to the parents (with the details of the
father unknown in one instance) although the grandparents apparently had no similar illness [S].
The penetrance of the manifestation of ALS in families with SOD-1 mutations does appear to be variable.
A family with the Ile 113 Thr mutation (reported as
“sporadic” ALS) and no initial family history of ALS
was described. The father and grandfather were not
affected, although presumably were obligate carriers
given the subsequent finding of the disease in members
of the extended family [ 141.
The findings in the present family emphasize the
importance of obtaining as detailed a family history as
possible before decreeing that a patient with ALS has
truly sporadic disease. Similarly the finding of an SOD1 mutation may lead to a more detailed search of the
family history. This is most readily performed when
the patient is living, as retrospective pursuit of a family
history may be distressing to the family, and at all
times may be inhibited by the potential of generating
anxiety in more distant family members. Unfortunately, it is not clear whether a specific mutation will
accurately predict the degree of disease penetrance or
the severity of disease in terms of age at onset or duration of disease. All these issues make predictive genetic
counseling of unaffected relatives, and diagnostic testing for mutations, of questionable value in the clinical
context [lo, 151. Determining the genetic component
of ALS, and hence further understanding the pathogenesis and developing appropriate and possibly specific treatments [ 5 ] ,may justify genetic analysis of affected families for research purposes.
We gratefdy acknowledge the financial support of the Motor Neurone Disease Association, and the Special Trustees of Charing Cross
and Westminster Hospitals.
We acknowledge the use of the resources of the M R C Human
Genome Mapping Project. W e thank Juliet Greenwood for her
work as a research nurse.
812 Annals of Neurology
VoI 39
No 6 June 1996
1. Rosen DR, Siddique T, Patterson D, et d.Mutations in Cu/
Z n superoxide dismutase gene are associated with familial
amyotrophic lateral sclerosis. Nature 1993;362:59-62
2. Deng H, Hentati A, Tainer J, et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 1993;261:1047-1051
3. Pramatarova A, Goto J, Nanba E, et al. A two base pair deletion in the SOD-1 gene causes familial amyotrophic lateral
sclerosis. Hum Mol Genet 1994;3:2061-2062
4. Gurney ME, Haifeng I’, Chiu A. Motor neuron degeneration
in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994;264:1772-1775
5. Brown RH. Amyotrophic lateral sclerosis: recent insights from
genetics and transgenic mice. Cell 1995;80:687-692
6. Orrell RW, de Belleroche J, Marklund S, et al. A novel SOD
mutant and ALS. Nature 1995;374:504-505
7 . Jones CT, Brock D J H , Chancellor AM, et al. CulZn superoxide dismutase (SOD1) mutations and sporadic amyotrophic
lateral sclerosis. Lancet 1993;342:1050- 105 I
8. Swingler RJ, Jones C, Brock DJH. Superoxide dismutase and
amyotrophic lateral sclerosis. Lancet 1995;345:391
9. Ortell RW, King AW, Hilton DA, et al. Familial amyotrophic
lateral sclerosis with a mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles. J Neurol Neurosurg Psychiatry 1995;59:266-270
10. de Belleroche J, Orrell R, King A. Familial amyotrophic lateral
sclerosis/motor neurone disease (FALS): a review of current
developments. J Med Genet 1995;32:841-847
1 1 . Jones CT, Shaw PJ, Chari G, Brock DJH. Identification of a
novel exon 4 SODl mutation in a sporadic amyotrophic lateral
sclerosis patient. Mol Cell Probes 1994;8:329-330
12. Jones CT, Swinglct RJ, Brock D J H . Identification of a novel
S O D 1 mutation in an apparently sporadic amyotrophic lateral
sclerosis patient and the detection of Ile 113 Thr in three others. H u m Mol Genet 1994;3:649-650
13. Jones CT, Swingier RJ, Simpson SA, Brock DJH. Superoxide
dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients. J Med Genet 1995;32:290292
14 Suthets G , Laing N,Wilton S, et al. “Sporadic” motoneuron
disease due to familial SODl mutation with low penetrance.
Lancet 1994;344:1773
15. Bird TD, Bennett RL. Why do DNA testing? Practical and
ethical implications of new neurogenetic tests. Ann Neurol
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