Prognosis in Familial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results in progressive degeneration of motor neurons. The incidence rate (1-2/100,000) is constant among different ethnic groups with the exception of some areas of high incidence in the western Pacific, including Guam, western New Guinea, and the Kii Peninsula in Japan. ^[1]

There are three major types of ALS, which are clinically indistinguishable: (1) the sporadic form, (2) the familial form, and (3) the western Pacific form. Approximately 5 to 10% of ALS patients have a family history with an autosomal dominant inheritance pattern. Ninety to 95% of ALS cases are sporadic and have no known etiologic basis. Disease onset usually occurs during the fourth or fifth decade of life, resulting in death within 2 to 5 years. ^[2] There is also an autosomal recessive form that has a much earlier onset, usually in the second decade of life. ^[3]

The familial form of ALS provided a genetic model to which genetic linkage studies could be applied. Using this model, Siddique et al. ^[4] mapped one of the familial ALS (FALS) genes to 21q22.1 in proximity to the gene encoding cytosolic Cu,Zn superoxide dismutase (SOD1). Fifteen percent of FALS families have mutations in SOD1 (T. Siddique, unpublished). Deng et al. ^[5] predict that these mutations destabilize the protein and result in reduced steady state SOD1 activity. They observed reduced SOD1 activity in red blood cell lysates from affected patients with mutations in SOD1.

There are three forms of superoxide dismutase present in the cytosol (Cu,ZnSOD, SOD1), mitochondria (MnSOD, SOD2), and the extracellular fluid (ECSOD, SOD3). The Cu,Zn superoxide dismutase is an enzyme present in aerobic organisms and is a critical participant in free radical homeostasis. It is a homodimeric copper- and zinc-containing metalloenzyme that catalyzes the reaction of the superoxide anion (O₂ sup.-) to hydrogen peroxide (H₂ O₂) and molecular oxygen (O₂).

A transgenic mouse model overexpressing human mutant SOD1 (gly93ala) developed paralysis caused by the degeneration of motor neurons. On the contrary, a transgenic mouse overexpressing wild type SOD1 displayed no clinical signs of motor neuron disease. ^[6] The mechanism of the disease is yet to be fully understood. In this study we investigated the relationship between the genotype and onset of symptoms as well as the duration of disease after onset of clinical symptoms.

Methods.

After obtaining informed consent, we studied 158 patients from 27 FALS pedigrees with known mutations in SOD1. All families were of Caucasian descent and displayed an autosomal dominant pattern of inheritance. Clinical records of patients affected with FALS from these families were examined for phenotype information such as age of onset of symptoms, duration of disease, and other clinical features. Additional information was obtained from patients and family members who had closely participated in the patients' care. Age of onset was defined by the onset of weakness, presence of atrophy, or clinical symptoms indicative of upper or lower motor neuron disease.

Any patient who received artificial respiration and hence lived an extended period of time was not included in the survival analysis. Also, patients with a history of polio infection were excluded from the study. Autopsy records where available were examined for the extent of neuropathology. All the statistical functions were performed using SPSS for Windows 6.1; Advanced Statistics. ^[7]

Results.

This study clearly demonstrates the existence of subgroups in families with a missense mutation in SOD1 based on the specific point mutation found. We analyzed 158 FALS patients from 27 families with identified mutations in SOD1. We constructed a table of the various mutations studied and the duration and age of onset associated with each subgroup (Table 1). The mean age of onset was 45.5 +/- 8.9 years, with a mean duration of disease of 3.4 +/- 4.5 years. Age of onset of symptoms had a range of 15 to 81 years.

Survival curves.

Kaplan-Meier curves were constructed for three groups of patients having mutations in SOD1: (1) ala4val; (2) glu100gly; and (3) ala4val, gly37arg, his43arg, gly85arg, gly93ala, glu100gly, leu106val, ile113thr, leu144phe, and val148gly. Both the probability for age of onset and survival of illness were analyzed. Figure 1 Table 2 represents all three groups and demonstrates both the duration and onset associated with each respective group.

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Figure 1. Kaplan-Meier survival function for patients with point mutations in SOD1 (in years). Age of onset and cumulative survival of FALS patients with different mutations (ala4val, gly37arg, his43arg, gly85arg, gly93ala, glu100gly, leu106val, ile113thr, leu144phe, and val148gly; n = 158; green) graphed with patients with the ala4val (n = 75; red) and patients with glu100gly mutations (n = 23; blue). Age of onset was found to be almost identical among the three groups (A). (B) Seventy-five percent of patients with the glu100gly mutation were alive 2 years after onset of symptoms, whereas virtually all patients with the ala4val mutation died within 2 years of symptoms (mean, 1.0 years). The 25th, 50th, and 75th percentiles are given for the three groups and provide the cumulative survival for the designated groups as a function of time:

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Table 2.

Discussion.

Because of the lack of therapy to modify the cause of the disease, a major concern to patients with ALS and their physicians is the expected length of survival. The clinical management of the disease involves discussion of critical issues such as course of prognosis, ventilatory support, control of bodily functions, and patient safety.

Previously, investigators studying survival prediction utilized different characteristic findings in ALS patients such as age of onset, electrophysiologic findings, and site of initial clinical involvement as predictors of disease progression. ^[8,9] Eisen et al. ^[10] described a group of 246 sporadic ALS patients supporting an inverse, exponential relationship between age of onset and duration of the disease. Iijima et al. ^[11] suggested that the motor nerve fibers regenerate more in younger patients in the early stages of the disease. The disadvantage with these methods for survival prediction was that they required the patient to have had the disease for some time.

Strong et al. ^[12] conducted a statistical analysis of world literature reviewing all FALS cases; he showed the probability of survival to be age-dependent, with younger patients having a significantly slower progression than older patients. In the Strong et al. study, it was not possible to distinguish various subgroups of FALS. Not only does our study define subgroups in FALS, but it also describes a method of survival prediction in SOD1-associated FALS. This method is easily applicable and provides a more accurate model than previously described.

Our data clearly establish a relationship between some mutations in SOD1 and the duration of disease after onset of symptoms. The duration for patients with the ala4val mutation was significantly shorter when compared with glu100gly as well as all other FALS patients. Other FALS studies have reported the age of onset to be 46.8 ^[13] and 45.1 years. ^[14] In our study, the mean age of onset was 47.6 years.

Families with mutations associated with a longer duration or a shorter duration may be true representations of disease duration seen in these FALS families even though the test population is not large enough to conduct independent comparison tests. The overall analysis of the 158 FALS patients provides the basis for a model to predict survival time for patients with mutations in SOD1.