Donald W. Mulder

Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity

BACKGROUND Amyotrophic lateral sclerosis is a progressive neurologic disorder that commonly results in paralysis and death. Despite more than a century of research, no cause of, cure for, or means of preventing this disorder has been found. In a minority of cases, it is familial and inherited as an autosomal dominant trait with age-dependent penetrance. In contrast to the sporadic form of amyotrophic lateral sclerosis, the familial form provides the opportunity to use molecular genetic techniques to localize an inherited defect. Furthermore, such studies have the potential to discover the basic molecular defect causing motor-neuron degeneration. METHODS AND RESULTS We evaluated 23 families with familial amyotrophic lateral sclerosis for linkage of the gene causing this disease to four DNA markers on the long arm of chromosome 21. Multipoint linkage analyses demonstrated linkage between the gene and these markers. The maximum lod score--5.03--was obtained 10 centimorgans distal (telomeric) to the DNA marker D21S58. There was a significant probability (P less than 0.0001) of genetic-locus heterogeneity in the families. CONCLUSIONS The localization of a gene causing familial amyotrophic lateral sclerosis provides a means of isolating this gene and studying its function. Insight gained from understanding the function of this gene may be applicable to the design of rational therapy for both the familial and sporadic forms of the disease.

Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis.

Lewy body-like hyaline inclusions in the soma and swollen, cord-like cell processes are characteristic alterations of the anterior horn cells in familial amyotrophic lateral sclerosis (ALS) with posterior column and spinocerebellar tract involvement. A fine structural analysis of these two structures has been performed in two brothers from a family (“C” family) previously described by Kurland and Mulder in 1955. The perikaryal hyaline inclusions consisted of accumulations of randomly oriented neurofilaments interspersed with thick linear densities associated with granular material. Some of the accumulations showed a central condensation. Cord-like, swollen neuronal processes were composed, for the most part, of numerous neurofilaments arranged parallel to the long axes. Dense structures were sometimes observed within the large bundles of filaments. They were composed of ill-defined dense, granular and fibrillar material associated with scattered vesicles and mitochondria. These dense areas were sometimes surrounded by various amounts of fine filaments, approximately 5 nm in diameter.

Epidemiologic Investigations of Amyotrophic Lateral Sclerosis: 1. Preliminary Report on Geographic Distribution, with Special Reference to the Mariana Islands, Including Clinical and Pathologic Observations

NUMEROUS HYPOTHESES of the etiology of amyotrophic lateral sclerosis have been suggested since Charcot described the disorder more than 75 years ago, but the etiology and the pathogenesis remain unknown. It has often been reported that the classic form of the disease is nonfamilial and nonhereditary,14 although reports of familial occurrence have been forthcoming at intervals since 1850. In this paper the familial incidence of amyotrophic lateral sclerosis will be reviewed in detail, with a description of those cases found in the literature and of several additional pedigrees and other data which we have obtained. References to familial aggregations of amyotrophic lateral sclerosis are widely scattered in the literature, and no recent attempt has been made to our knowledge to collect and classify such material clinically. We shall also attempt to analyze by statistical means some of the genetic characteristics of the collected pedigrees. These studies were initiated by the reports of the high incidence of a classic form of amyotrophic lateral sclerosis on Guam by Arnold and associates’ and by Koerner8 and our subsequent experience in the Manana and the Caroline Islands. The prevalence rate for amyotrophic lateral sclerosis on Guam and Rota is about 420 per 100,000 population as compared to about four per 100,OOO population for various North American and European countries. No external etiologic agent has yet been detected to explain this high prevalence, but a marked familial aggregation of cases has been n ~ t e d . ~ , ~ Although familial aggregation of cases might be due to a common environmental factor as well as to a genetic influence, the distribution of cases among the various peoples in the area is more suggestive of a genetic influence than of an environmental f a c t ~ r . ~ Koerner reported a “positive family history” in 40 per cent of the cases that he observed on Guam, and in our pre-

Frequency of nerve fiber degeneration of peripheral motor and sensory neurons in amyotrophic lateral sclerosis Morphometry of deep and superficial peroneal nerves

Among 10 patients with amyotrophic lateral sclerosis who had combined biopsy of muscle and cutaneous nerves, two had a history of paresthesia that suggested involvement of peripheral afferent neurons. Of four patients without paresthesia, two had unequivocal abnormalities of touch-pressure sensation of the toe. On morphometric evaluations of lateral fascicles of deep peroneal nerve, one nerve had an abnormally low myelinated fiber density and seven of 10 had abnormally high frequencies of teased-fiber abnormalities. Teased fibers in which myelin was degenerating into linear rows of myelin ovoids and balls occurred in 10.5 percent of fibers in amyotrophic lateral sclerosis nerves as compared with 1.7 percent in control nerves (0.01 <p <0.025). Estimates of density of myelinated fibers were less sensitive than estimates of the frequency of various changes in teased fibers for detecting abnormality.

Myasthenic syndrome in patients with amyotrophic lateral sclerosis.

DURING THE COURSE of their illness, patients with amyotrophic lateral sclerosis may have complaints of, and may demonstrate on clinical and laboratory examination, unusual puscle fatigability resembling that of myasthenia gravis. Other features of amyotrophic lateral sclerosis usually are sufficient to differentiate it from myasthenia gravis. However, it is important to recognize this occurrence of a myasthenic syndrome in amyotrophic lateral sclerosis to avoid confusion and uncertainty in diagnosis. The presence of a significant defect of neuromuscular conduction in patients with diseases affecting the lower motor neurons has been suggested by others. Hamill and Walker1 reported improvement of muscular strength after injection of neostigmine (Prostigmin) in patients with a variety of diseases of the motor system. In poliomyelitis, Buchthal and Honckez observed unusual fatigability of motor units manifested in electromyographic studies by a gradual decrease in amplitude of their action potentials as seen during a sustained contraction. This was observed frequently in poliomyelitis by Pinelli and Buchthal,3 but it was found only exceptionally in other diseases of the lower motor neurons. It was observed as early as the first ten days after onset of paresis in poliomyelitis. Hodes4 concluded that this abnormality was explained best by the presence of a defect of neuromuscular conduction; this view was supported by the demonstration that use of neostigmine restored the amplitude of the action potential. A similar fatigue of motor units has been observed in syringomyelia,5 amyotrophic lateral sclerosis6 (Fig. l), and other neurogenic atrophies. A myasthenic syndrome associated with neuromyopathy in carcinomatosis has been reported.? It has become increasingly apparent that patients who have unusual sensitivity to curare or neostigmine and related drugs do not necessarily have myasthenia gravis. Rowland* concluded that it was not necessary to assume that all syndromes responsive to neostigmine have the same cabse. Eaton and Lambert? stated that they no longer thought that positive results to tests for myasthenia gravis with neostigmine, edrophonium chloride, and curare are

ALS in Rochester, Minnesota, 1925–1977

The incidence, trend, and survivorship of ALS in the population of Rochester, Minnesota, was determined for the years 1925 through 1977. The average annual incidence was 1.76 per 100,000 population. There was a small but nonsignificant increase in the rate during the 53-year period. The male:female ratio was 1.1, and the male:female ratio of incidence rates was 1.6. The median age at onset was 66 years; the incidence rates increased with increasing age. Median survivorship was 22.5 months, and was longer for younger patients than for patients with an advanced age at onset. The demographic characteristics in this total community experience are believed to reflect the pattern of ALS more accurately than previously reported clinical series.

Epidemiologic Investigations of Amyotrophic Lateral Sclerosis 2. Familial Aggregations Indicative of Dominant Inheritance Part II.

THE first part of this article was published in the preceding number of this journal. The observation of considerable familial aggregation of cases of amyotrophic lateral sclerosis on Guam has led to the present study. The review of the literature for the past 100 years revealed 18 extensive pedigrees compatible with dominant inheritance. The view held by most neurologists and recent investigators to the effect that amyotrophic lateral sclerosis is not hereditary was also presented.

Follow-Up Study on Amyotrophic Lateral Sclerosis in Rochester, Minn., 1925 through 1984

The incidence, secular trend and survivorship of amyotrophic lateral sclerosis in the Rochester, Minn., population has been investigated over a 60-year period, 1925 through 1984. The crude average annual incidence rate was 2.0 per 100,000 population. The rate, age- and sex-adjusted to the US 1970 white population, was 2.4 per 100,000 population (3.0 for men and 2.0 for women), with a male to female ratio of 1.5:1. Incidence rates after 1955 showed a small but nonsignificant increase compared to those of the former 30-year period. Median age at onset was 67.5 years; the incidence rates increased significantly with advancing age, but without a peak. Median survivorship was 23.8 months, and younger patients had a better prognosis than patients with an advanced age at onset. No change in duration of survivorship was observed over the period studied. Two of the 44 patients (4.5%) had a family history of amyotrophic lateral sclerosis.

Charcot‐Marie‐Tooth disease: nerve conduction and clinical studies of a large kinship

CHARCOT-MARIE-TOOTH disease is a familial disorder which usually begins with atrophy and weakness of the peroneal muscles and may advance insidiously to involve other distal muscles of the leg and arm. The deep tendon reflexes are usually diminished or absent in this disease, and, commonly, pes cavus deformity is found. Some authors,13 but not others,4-g have considered enlarged peripheral nerves characteristic of the disease. England and Denny-Brown5 preferred to classify cases in which the nerves were enlarged, especially when associated with miosis, nystagmus, and sensory alterations, as more typical of the chronic hypertrophic interstitial polyneuritis of Dhjerine and Sottas. Charcot-Marie-Tooth disease was found by Bell1 to be inherited most commonly as a dominant trait and less frequently as a recessive and as a sex-linked trait. LambertloJ1 drew attention to the low conduction velocities of peripheral nerves seen in chronic familial polyneuropathies. Similar observations were reported by Gilliatt and his Lambert, Bastron, and Mulderlz suggested that low conduction velocities might be an indication of early or minimal involvement. In addition, they said that low conduction velocity gave evidence of this disease in some patients, even in the presence of normal neurologic findings. They stated: “Study of conduction velocity of peripheral nerves may aid in determining which individual in an affected family may later show clinical manifestations of disease or transmit the disease.” The present report concerns the study of a large kinship (157 members) with CharcotMarie-Tooth disease. (The kinship is depicted in figure 1.) Neurologic examination of 110 members of this family and measurement of the conduction velocity of peripheral nerves

History of standard scoring, notation, and summation of neuromuscular signs. A current survey and recommendation.

Abstract  In this article, we trace the history of scoring, notation, and summation of the neuromuscular signs of muscle weakness and decrease of tendon reflexes and sensation. We recommend a standard system to promote consistency in the effort introduced by Mitchell and Lewis to ‘represent systems and force by their signs.’ The scoring of neuromuscular signs began with Mitchell and Lewis in the 19th century who used pluses, minuses, and N (for normal) to express the activity of muscle stretch reflexes. Henry Plummer introduced an ordinal scoring approach for muscle weakness, reflex decrease and increase, and sensation loss. In 1919, he and Walter Sheldon and Henry Woltman introduced standard pre‐printed examination forms with written instructions for notation and scoring. Robert Lovett, a Boston orthopedist, scored weak muscles of poliomyelitis patients from 2 (mild weakness) to 6 (paralyzed), 1 being normal. Lovetts approach was used, after reversing the order of the grades and decreasing each grade by 1, by a Committee of the Medical Research Council for evaluating return of muscle weakness after nerve injury. Despite dissimilarity to existing reflex and sensation scores and uneven width of grades, this approach was widely adopted for use in neurologic practice. We introduced the Neuropathy Impairment Score using a combination of the Mitchell, Plummer, and Lovett approaches, summing all individual scores of a standard set of neuromuscular examinations. In a non‐representative survey of 19 neuromuscular physicians from different countries, we find that there is a considerable variability in the approaches used for grading. Assuming that scoring is useful, we herein suggest (a) impairments should be scored separately from hyperfunction and (b) for the scoring of impairments (muscle weakness, reflex decrease, and sensation loss), the same ordinal scoring approach should be used with 0 as normal and 1, 2, … representing increasing impairment based on the judgment of percentage abnormality with corrections made for age, sex, physical fitness, and physical characteristics.