anomalies in the superoxide dismutase 1 gene in familial amyotrophic lateral sclerosis: what is the phenotype / genotype correlation and practical implications?

Familial amyotrophic lateral sclerosis (ALS) accounts for 20 percent. 100 of ALS cases. In 15 p. 100 of SLAF, an anomaly of the gene coding for superoxide dismutase 1 (SOD1) has been found. For the majority of them, it is a point mutation, with replacement of one nucleotide by another. Transmission is autosomal dominant for all but two genetic abnormalities, who are recessive. 

To date, more than 100 different genetic abnormalities have been reported. The characteristic clinical profile of SLAF associated with mutations SOD1 is homogeneous when the link between the mutation and the disease is clearly established: mean age from onset to 42 years old, early members, slow evolution. 

Apart from a dominant family character (several subjects affected over several generations), the causation of the mutation is often debatable, not justifying a systematic search for a SOD1 mutation in front of an atypical ALS (very young start, very long evolution, for example). Except in the case of a few frequent and proven causal mutations (less of 15 out of more than 90), the multiplicity of mutations, the variability of their mode of transmission and the often questionable nature of their responsibility for the disease, justify the most complete study possible of a family in order to establish the causality of the genetic anomaly found as well as its transmission.

Mutations in the gene encoding the superoxide dismutase 1 (SOD1) associated with lateral sclerosis amyotrophic familial (SLAF) have represented an significant in knowledge of etiopathogenesis of ALS but raised a number of parallel- bre of problems which it seems useful to underline. We we wanted to present the SOD1 mutations found in France as well as those most frequently listed in the litterature. 

A phenotype / correlation study genotype is presented allowing to propose a clinical profile type of patient with SLAF associated with SOD1 mutation. A number of mutations found vee, both in France and in international literature have a questionable causality. We present the cases French corresponding to such mutations to discuss on the one hand the importance of a global genetic analysis families and on the other hand to show caution necessary in SLAF vis-à-vis any genetic counsel- that and, a fortiori , of any presymptomatic diagnosis


The concept of ALS as a possible inherited disease taire was born from the first descriptions (Aran, 1850). This possibility has long been debated and little invested. ford until 100 years later where Kurland and Mulder (1954) reported 6 families and proposed Mendelian inheritance with autosomal dominant transmission. 

The works on dominant families have led Rosen et al . in 1993 to highlight an association between SLAF and mutations in the gene encoding the enzyme SOD1, located in 21q21. Today the frequency of SLAF is estimated to be 20 p. 100% of ALS, and 15%. 100 the frequency of SOD1 mutations in SLAF. More than 100 different genetic abnormalities have been made to date reported, without always knowing their meaning or their correlation with the clinic. These are mutations occasional for the most part, transmission is autosomal dominant for all but two mutations which are autosomal recessive.


The gene is 15 kb, comprising 5 exons and 4 introns. The SOD1 enzyme is a cytoplasmic metalloenzyme one of the most abundant proteins in eukaryotic cells. Its spatial conformation is globular. It is made up of two sub-units in the form of homo- dimer, each of which consists of 153 amino acids. Within each sub-unit, there is an active site including a copper ion and a zinc ion. 

The two subunits are united by strong hydrophobic bonds, which makes it particularly stable. The enzyme SOD1 plays a key role in protecting neurons and other cells from oxidative stress induced by free radicals. Its function is to catalyze the conversion of the O 2 – anion to H 2 O 2 and to O 2.


The majority of mutations are located on exons 4 and 5, and are point mutations which result in replacing one nucleotide with another (missense). Most of these mutations are involved in integrity structure of the subunit or dimerization. Of mutations in the 5 exons have been reported but exon 3 which code for the active site is rarely affected (Shaw and al ., 1998). Several hypotheses have been explored for determine the pathogenic mechanism of the enzyme SOD1 mutated .

Loss of SOD1 enzyme function

This first hypothesis postulated that the SOD1 mutation leads to a decrease in the detoxifying activity of the teine ​​. Deng et al . (1993) measured SOD1 intraerythrocytic activity in 6 patients. The acti- The average life of the mutated SOD1 was indeed 41 p. 100 that of the control subjects. Other authors have also reported a decrease in SOD1 activity but in a lesser measure. 

On the other hand, Aoki et al . (1993) showed that with the H46R mutation enzyme activity dropped to 80 percent. 100 of normal whereas, in the G37R mutation, the enzymatic activity remained normal. In mice transgenic not expressing SOD1 (“KO” mouse SOD1), no developmental abnormalities were observed and no sign of motor neuron disease. 

However, these animals have a particular vulnerability towards axonal damage, suggesting that SOD1 may have more of a role in axonal repair. These various observations suggest that the mutated SOD1 toxicity is not caused by loss or a reduction in antioxidant activity but rather by a acquisition of new, toxic properties. This last point is more consistent with a dominant genetic model.

Impaired reactivity

This hypothesis follows directly from the biochemicals of mutated SOD1. Indeed, it has been observed that the mutated SOD1 enzyme had a modified reactivity including vis-à-vis H 2 O 2 . Replacement of an acid aminated by another would result in a conforma- the enzyme SOD1 which would then use other substrates like the nitronium ion (ONO 2 -). This would consequence of increasing oxidative stress as well as to induce the nitration of neurofilaments from where an alteration of the cytoskeleton

Metallic toxicity

The mutated SOD1 enzyme seems to interact less with copper and zinc ions, both neurotoxic (Brown, 1995). The H46R mutation directly affects the binding of the copper SOD1 tin. The models have successfully led to the use of D-penicillamine in mice to slow the disease .

Aggregation of cytosolic proteins

Watanabe et al . (2001) identified in the cytoplasm motor neurons of transgenic G37R mice, G93A, G85R, inclusions of proteins Hsp 70, ubiqui- tine and SOD1. These protein aggregates play a role in the cascade leading to motor neuron degeneration. This hypothesis is one of the most studied today.

Although the discovery of abnormalities in the sod1 gene in SLAF and the development of murine models have worked that a valuable step in understanding the mechanics pathogenic nisms of ALS, the exact role of SOD1 mutated in the selective degeneration of motor neurons still remains mysterious. We can however say that the new rotoxicity of mutated SOD1 arises from the acquisition of new properties of the protein.


Transmission of the SOD1 mutation is autosomal dominant for all but two mutations . The existence of people healthy carriers of mutations within certain families suggests that the penetrance is not complete. She however, appears to vary with age and the type of mutation.

On average, 50% 100 of patients develop the disease at 46 years and 90 p. 100 to 70 years. In the A4V mutation, the penetration is 91%. 100 to 70 years against 100% 100 for L38V, E100G and I113T. However, it should be noted that the data from the literature is rarely complete, not allowing, the more often, to analyze the penetrance, the mode of transmission and causation of a mutation.


International literature is flourishing with news mutations but for the majority of them neither causation in the occurrence of the disease, nor the segregation of anomalie are not established. Now, in medical practice, rante the certainty of causation of a genetic anomaly is essential in order to consider genetic counseling ulterior. For a limited number of mutations, mouse models have been developed thus supporting the relationship cause and effect.

The objective here is not to report exhaustively all genetic abnormalities described to date. Current- over 100 different SOD1 mutations have been reported scopes and a website which aims to list all of these mutations exist ( We have retained the most frequent and characteristic mutations ticks of literature and let us report, among them, those found in France  . We present them from “anatomical” way from the first to the last codon. 

They are 13, 11 dominant and 2 recessive. In France, the frequency of SOD1 mutations is 15 p. 100, which is slightly lower than other countries such England, the USA or Japan. We analysed 130 index cases of families and we found 19 with one genetic abnormality. Nine different mutations have been identified. In all cases, this is a mutation ponctuelle.

Transmission is autosomal dominant for 7 mutations. Two mutations are recessive (D90A and D96N). To date, the D96N mutation has not been found just in France. The most frequent mutations in our countries are E21G, G37R and D90A. Among the 19 individuals, we counted 11 men and 8 women. Age average start is 42 years. The average duration of evolution tion is 116 months. A patient had an evolutionary period less than 1 year (G37R). 

The start site is for members lower in 15 cases (79%). There is no interference bulbar. There is a pre-paretic phase that can occur months or even years before the start of the first symptoms, phase during which patients complain intermittent pain in the hips, back, lower limbs, burning sensations, paraesthesia, instability in walking, stiffness in the legs and general fatigue in 9 cases (47%). 

In 5 patients (26%), the clinical picture presented at the beginning is an attack of the isolated peripheral motor neuron. Of sensitive signs such as pain and paraesthesia are present in 7 patients (37%). Urinary problems with urinary urgency were found in patients carrying the homozygous D90A mutation and in carriers of the composite heterozygosity D90A / D96N. In the world, the most frequent dominant mutations quentes are A4V, E21G, G37R, L38R, H46R, G93C, G93D, E100G, I113T, L144F. We can, quite clearly, consider them as causal because of their frequency, their dominant multigenerational transmission and homogeneous- birth of the clinical picture. 

On the other hand, for many of them, experimental data such as functional analysistional mutation and the existence of a transgenic mouse pic presenting a motor neuron disease type ALS support this argument. The clinical picture presented by SLAF associated with a SOD1 mutation is distinct that of sporadic amyotrophic lateral sclerosis (SLAS) and is homogeneous between the different countries, France not departing from the rule. 


We have called questionable causal mutations abnormalities including the association with the disease in families was either inconsistent or rare or never studied due to the very early onset in this patient and a vague suspicion of an ascendant having had a new disease serious rological. 

So in this family, 8 subjects have the mutation of which 7 are completely asymptomatic including the 90 year old grandmother. Two hundred control subjects were analyzed as well as 400 patients with SLAS. The mutation N19S was found in 1 control subject and in 1 other case of SLAS. So out of 10 carriers of the mutation, a total of 2 have ALS. 

The possibility of a suscep- gene flexibility, which alone would not be sufficient to develop the disease seems strong to us. But then, great caution in genetic counseling. The same problem is pre- feeling for the heterozygous D90A mutation. We have identified 2 patients with the mutation who did not family history of ALS. Two hundred control subjects been analyzed. 

None carries the hetero- D90A mutation zygote. In the Scandinavian population, D90A is a poly- morphism whose frequency is 1 in 17 (Sjalander and al ., 1995.) At present, no surrogate families one of the aforementioned SOD1 genetic abnormalities and pre- multigenerational feelings have been reported. Only one complete analysis of families would provide information clear but it is rarely presented in the literature

To conclude

The study of SOD1 mutations in SLAF made it possible to highlight several points: a) the frequency of transfers SOD1 ranges from 15 to 20 percent. 100 depending on the series; b) the role the exact enzyme SOD1 is not known; c) ALS would be caused by more than 100 different mutations on the same gene, but proof of causation is not given for all; d) the clinical picture of patients with family history of ALS and mutation carriers Causal SOD1 is homogeneous: dominant transmission (more than two cases in at least two generations), age of beginning less than 60 years, beginning in the lower limbs, long evolution.

The observed disparity of genetic abnormalities bearing on SOD1 associated with SLAF, the variability of their mode of transmission and the non-exceptional absence of a link of proven causality with the disease allow to suggest the following points:

  1. the need to study and analyze all the members of a family comprising one or several subjects reached in order to clarify the role of anoma- genetic link found, its transmission and its penetrance. However, such a study is not without difficulties because genetic analysis is long and expensive and sometimes refused by family members; 
  2. the uselessness of searching a SOD1 mutation in sporadic cases of ALS; 
  3. the little profitability to seek a SOD1 mutation if only 2 cases of ALS were found in the family tree of a family, a fortiori if their clinical profile diverges from overall profile described above; 
  4. to better understand the pathogenic role of a genetic abnormality found, there not only required studying the correlation pheno- type / genotype but also the functional role of the anomaly genetics found. 

This is to help better resolve unknowns highlighted in this work that we put in places a national network on SLAF, supported by INSERM, AFM and ARS. Better knowledge correlated with systematic management of corphenotype / genotype relationships will allow the design of a adequate information for the patient and his relatives. 

He seems to us more than ever necessary to advance in the family ALS, more cautiously than it has been done in the other hereditary forms of neurological diseases. Unlike the disease of Huntington, for example, in ALS, the genetic abnormality that does not automatically make the diagnosis; the character hereditary or not must be analyzed on a case-by-case basis, likewise for the causal nature of a given mutation. If the well known mutations like homozygous D90A, G37R or A4V, do not raise too many difficulties in terms of advice to patients and families, our work shows that this scenario is not frequently encountered in France.