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Cuznsod-associated amyotrophic lateral sclerosis.

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hypothesis that location of a malformation in watershed zone
[5] may indicate a prenatal vascular origin must compete
with the possible role of regionally expressed developmental
Regarding D r Sotrel’s comment on finding no instances of
parietooccipital polymicrogyria in 3,000 autopsies of patients
of all ages, it would be of interest to know how many of
those 3,000 patients had intractable epilepsy or developmental delay in childhood. In all likelihood, Dr Sotrel’s patients
are selected from a very different population than ours. Our
comment about bilateral parietooccipital polymicrogyria being possibly “underdiagnosed referred to the population
that we see in our clinical work, which consists largely of
developmentally delayed children with poorly controlled epilepsy.
The two findings of posterior polymicrogyria mentioned
by Dr Sotrel as incidental autopsy observations are interesting. The first confirms that genetically determined gyral abnormalities are common in congenital muscular dystrophies,
especially in the posterior brain regions [6]. The second observation, concerning thick polymicrogyric cortex overlying a
subtle band of posterior heterotopic cortex in an adult man,
is intriguing. The cortex overlying subcortical laminar heterotopia has been described as either normal [7] or thickened
[8]. The laminar organization of thickened cortex is as yet
unknown, but because of the genetic origin of laminar heterotopia, unlayered polymicrogyria and pachygyria are both
potential causes.
*Institute of ChiU Neurology and Pychiaq, University of
Pisa-IRCCS Stella Maris Foundution, Pisa, Itah; ‘Montreal
Neurological Hospital and Institute, McGill University,
Montreal, Canada; ‘Neuropkdiatrie, H6pital Saint Vincent de
Paul Paris, France; ’Department of Neuroradiology,
University of California, San Francisco, (24; University of
Alabama Epilepsy Center, Birmingham, AL; ‘Neurosciences
Unit, Institute of Child Health, London, UK;.and **National
Hospital for Neurology and Neurosurgery, London, UK
1. Raybaud C, Girard N, Canto-Moreira N, Poncet M. High definition magnetic resonance imaging identification of cortical
dysplasias: micropolygyria versus lissencephaly. In: Guerrini R,
Andermann F, Canapicchi R, et al, eds. Dysplasias of cerebral
cortex and epilepsy. Philadelphia: Lippincott-Raven, 1996: 131143
2. Kuzniecky R, Andermann F, Guerrini R, CBPS Multicenter
Collaborative Study. Congenital bilateral perisylvian syndrome:
study of 31 patients. Lancet 1993;341:608-612
3. Sarnat HB. Disturbances of late neuronal migrations in the perinatal period. Am J Dis Child 1987;141:969-980
4. Lyon G, Robain 0. Etude comparative des enctphalopathies circularoires prtnatales et paranatales. Acra Neuropathol 1967;9:
5. Guerrini R, Dubeau F, Dulac 0 , et al. Bilateral parasagittal
parieto-occipital polymicrogyria and epilepsy. Ann Neurol 1997;
6. Fukuyama Y, Osaka M, Saito K. Congenital muscular dystrophies: an overview. In: Arzimanoglou A, Goutierez F, eds.
Trends in child neurology. Paris: John Libbey Eurotext, 1996:
107- 135
7. Harding B. Gray matter heterotopia. In: Guerrini R, Andermann
F, Canapicchi R, et al, eds. Dysplasias of cerebral cortex and
epilepsy. Philadelphia: Lippincott-Raven, 1996:s 1-88
8. Barkovich AJ, Guerrini R, Battaglia G, et al. Band heterotopia:
correlation of outcome with magnetic resonance imaging parameters. Ann Neurol 1994;36:609-617
CuZnSOD-Associated Amyotrophic
Lateral Sclerosis
Aleksandar Radunovik, MD, PhD,*
Christopher E. Shaw, FRACP,*
Giilgen Akman-Demir, M D , t
H. Idrisoglu, MD,? and P. Nigel Leigh, PhD, FRCP*
W e read with interest the report by Cudkowicz and colleagues [ 11 on the epidemiology of copperlzinc superoxide
dismutase (CuZnSOD) gene mutations in 49 predominantly
North American families with amyotrophic lateral sclerosis
(ALS). The authors concluded that disease phenotype may
be predicted by a particular CuZnSOD genotype. Specifically, they claimed that G37R and L38V conferred a risk for
earlier onset, whereas G37R, G41D, and G93C predicted
longer survival and A4V was associated with shorter survival.
W e have recently collated all available information in the literature on the correlation between genotype and phenotype
in 121 families with ALS and 17 “apparently” sporadic ALS
patients with 46 different CuZnSOD gene mutations [2].
Available evidence suggested that only a few mutations could
be linked to a consistent age of onset or pattern of survival.
Very few data are available on the link between CuZnSOD
gene mutations and other prognostic factors. O f the 49 families reported on by Cudkowicz and associates, 31 were included in our report, although clinical information for some
families was not available at the time of our writing.
One mutation may behave differently to others in a limited selection of mutations, as shown by Cudkowicz and colleagues [I] or by Juneja and co-workers [3]. For example, the
A4V mutation is indeed associated with a rapid progressive
form of ALS, but more than 10 other mutations also have
an aggressive course (survival < 2 years) [2]. It is interesting
that A4V families account for a large proportion of all
CuZnSOD-associated ALS families in North America (e.g.,
50% of all CuZnSOD-associated ALS in the Boston study
[l]) and are thought to be found only there. However, A4V
does occur in ALS patients in other parts of the world and is
associated with a similar short survival but with variable presentation-thar is, not only limb but also bulbar onset [P.
Andersen, personal communication, January, 19971. It is
striking that in 1 1.9% of all CuZnSOD-associated ALS families in the Boston study, symptoms first began in bulbar
musculature b u t were unfortunately nor stratified according
to the specific mutation, and we wonder whether bulbar onset may account for shorter survival in some of their A4V
families. Bulbar onset is known to be an important indicator
of poor prognosis [4]. In addition, we believe that it may be
important to learn the ethnic origin of all A4V families, since
the effect of other disease modifying genes inherited from a
common founder cannot be excluded. We also notice that
the data of Cudkowicz and colleagues from 14118 mutations
are based on single pedigrees, and we are concerned that
prognostic information will be related to patients based on
their mutation.
Annals of Neurology
Vol 42
No 2
August 1997
T o test the hypothesis that genotype influences phenotype, one should study identical mutations in several pedigrees from diverse genetic backgrounds. Cudkowicz and associates reported that G37R is associated with an early onset
and a relatively benign form of ALS (mean survival 18.7
years). We recently identified the same mutation in a Turkish family with 5 affected individuals in three generations.
All had limb onset of symptoms but showed early age of
onset (mean age 34.2 years; range 24-48, years) and variable
survival (2 patients survived only 3 years, whereas 3 patients
are still dive after 2, 6, and 15 years).
We are now aware of 60 different CuZnSOD gene mutations. The number of families has probably risen well
above 250. The number of CuZnSOD gene mutations and
families who carry the mutations must be even larger since
journals cannot keep up with, or will not publish, new single
mutation reports or reports of mutations that are no longer
novel. The number of “apparently” sporadic ALS patients
has also risen steadily in the past year. In a recent study [ 5 ] ,
2.6% of sporadic ALS patients have been found to carry
CuZnSOD gene mutations. This calls for a uniform centralized data base that will record new (and old) mutations and
that, by accumulating clinical and prognostic information,
will enable predictive testing to be carried out with greater
confidence. Until then, one should be cautious when interpreting the genetic influence of a particular CuZnSOD gene
mutation on ALS phenotype, because it is likely that factors
other than the site of the mutation may determine the phenotype of CuZnSOD-associated ALS.
*Department of Clinical Neurosciences, Institute o f Psychiaty
and King? Colbge School of Medicine and Dentisty, London,
U E and ‘Department of Neurology, Istanbul Faculiy of
Medicine, Istanbul, Turkey
1. Cudkowicz ME, McKenna-Yasek D, Sapp PE, et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral
sclerosis. Ann Neurol 1997;41:210-221
2. Radunovit A, Leigh PN. Cu/Zn superoxide dismutase gene mutations in amyotrophic lateral sclerosis: correlation between genotype and clinical features. J Neurol Neurosurg Psychiatry
3. Juneja T, Pericak-Vance MA, Laing NG, et al. Prognosis in familial amyotrophic lateral sclerosis: progression and survival in
patients with glul00gly and ala4val mutations in Cu,Zn superoxide dismutase. Neurology 1997;48:55-57
Annals of Neurology
Vol 42
No 2
August 1997
4. Leigh PN, Ray-Chaudhuri K. Motor neuron disease. J Neurol
Neurosurg Psychiatry 1994;57:886-896
5. Jackson M, A-Chalabi A, Enayat ZE, et al. Mutations in SOD-1
in sporadic ALS. Am J Hum Genet 1996;59(Suppl):A265
Merit E. Cudkowicz, MD,
and Robert H. Brown, MD, PhD
We appreciate the comments of Radunovit and colleagues
and agree that the phenotype of SODl-associated ALS is
mostly likely influenced by the particular mutation as well as
other genetic or biochemical factors. The shorter survival
found in our patients with the A4V mutation was not accounted for by bulbar onset. Site of onset was included in
our regression model and had no significant influence on
survival. Of the 87 patients with the A4V mutation, 40
(48.3%) had limb onset, 20 (23.0%) had bulbar onset, and
the information was not available for 27. Most families with
the A4V mutation in our data base are from North America.
The ethnic origin of these families is not known [l].
We also found a large range of survival in the 8 subjects
from 1 family with the G37R mutation included in our data
base [l]. Mean survival was 18.7 (SD 11.4), with a range of
2 to 36 years. The mean age of onset was 10 years (SD 9.9),
with a range from 24 to 51 years. More generally, the observation that the same mutation (G37R) may have different
survival characteristics in different families is potentially of
importance; this may reveal the influence of other modifying
W e agree that a uniform centralized data base with clinical
and pathological information on subjects with new and old
mutations in the gene for SOD1 would increase our understanding of this form of motor neuron disease and improve
the confidence of predictive testing.
Day Neuromuscuhr Research Laborato y, Massachusetts
General Hospital, Charlestown, MA; and Department of
Neurology, Massachusetts General Hospital, Havvard Medical
School, Boston, MA
1. Cudkowicz M, McKenna-Yasek D, Sapp P, et al. Epidemiology
of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol 1997;41:210-221
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associates, lateral, sclerosis, amyotrophic, cuznsod
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