182 CALDWELL ET AL: FAMILIAL RING (9) CHROMOSOME familial cases than to find severely affected parents 5. ZDANSKY R, BUHLER EM, YEST M, ET AL: Familiiires Mosaik with normal children. mit G-ring. Humangenetik 7:275-286, 1969. REFERENCES 6. MOORHEAD PS, NOWELL PC, MELLMAN WJ, ET AL: Chromo­ I. KJSTENMACHER ML, PUNNETT HH: Comparative behavior of some preparations of leukocytes cultured from human periph­ ring chromosomes. Am J Hum Genet 22:304-318, 1970. eral blood. Exp/ Cell Res 20:613-'616, 1960. 2. BURDEN M, LUPASCU E, MARGINEANU L: A familial case of 7. SEABRIGHT M: A rapid banding technique for human chromo­ I 7R ring shaped chromosome of group E with transmission somes. Lancet 2:971-972, 1971. from father to son. Revista Medico-Chirurgicala a Societatii de Medici si Naturalisti din Ia§i 77:353-357, 1973. 8. BERGSMA D (exec ed): Birth Defects: Original Article Series. Number 7: Paris Conference ( 1971 ): Standardization in Human 3. CHRISTENSEN KR, FRIEDRICH U, JACOBSEN P, ET AL: Ring Cytogenetics, · vol 8.· New York, The National Founpatjon­ chromosome 18 in mother and daughter. J Ment Defic Res March of Dimes, 1972. 14:49-67, 1970. 4. PALMER CG, HODES ME, REED T, ET AL: Four new cases of ring 9. FRAISSE J, LAURAS B, OOGHE MJ, ET AL: Apropos d'un cas de 21 and 22 including familial transmission of ring 21. J Med chromosome 9 en anneau. Ic!entification par denaturation Genet 14:54-60, 1977. menagee. Ann Genet 17:175-180, 1974. Dominantly Inherited Amyotrophic Lateral Sclerosis (Motor Neuron Disease) LOUISE E. WILKINS, Graduate Assistant, Department ofHuman Genetics ROBIN M. WINTER, M.B., M.R.C.P., Postdoctoral Fellow, Departt.nent ofHuman Genetics EDWIN C. MYER, M.D., Assistant Professor, Department of Pediatric Neurology WALTER E. NANCE, M.D., Ph.D., Professor, Department ofHuman Genetics, Pediatrics and Medicine The term amyotrophic lateral sclerosis (ALS) sensory impairment.1 Later, th~ syndromes of pro­ was first introduced by Charcot to describe cases with gressive bulbar palsy (PBP) and progressive muscular mixed upper and lower motor neuron signs without atrophy (PMA) were recognized to be variations of the same pathological process, and ALS was used as an inclusive term to refer to these syndromes as well. This is paper #46 from the Department of Human Genetics of Although some authors reserve the term ALS for the the Medical College of Virginia and was supported in part by Grant #C-187 from the National Foundation-March of Dimes. specific syndrome of mixed upper. and lower motor Correspondence and reprint requests to Lpuise E. Wilki!)s, neuron lesions and use the term "motor neuron dis­ Box 33, Medical College of Virginia, Richmond, Virginia 23298. ease" to refer to the constellation of syndromes, most MCY QUARTERLY 13(4): 182-186, 1977 WILKINS ET AL: MOTOR NEURON DISEASE 183 e Affected () Passlllly lfflCtltl Fig I-Pedigree of proband and family members. * = Age at diagnosis • = Present age + = Age at death of the literature on familial cases uses ALS as a aunt (11-4), cousin (III-10), niece (IV-2), and two brothers generic title. We will adhere to this convention. (III-I, III-8) have all been diagnosed as having ALS. The Initially, the disease was thought to be sporadic, age a.t onset has been variable, as has the duration of the disease in the different family members. with a stable incidence of 1 in 100,000 population per The offspring of the proband are presently under inves­ year. In the early 1950s, reports appeared of a high tigation. The eldest son (IV-3) has definite upper motor incidence of ALS in the Chamorro Micronesians of neuron signs in the legs with brisk reflexes and bilateral Guam and on the Kii Peninsula in Japan.2 - 5 Studies Babinski responses which, combined with the family his­ suggested that at least some of the cases of ALS tory, are highly suggestive of ALS. Two offspring (IV-4 and IV-5) show minimal signs of muscle wasting and slightly among Chamorros might be familial, and at about brisk reflexes. The diagnosis of ALS here is less certain, but the same time familial cases began to be reported in the possibility exists that these two brothers are also af­ Caucasian populations. fected. The two youngest children (IV-6 and IV-7) show no sign of the disease. EMO studies may help establish a Case Report definite diagnosis in those family members at risk. Prohand: The proband (Fig I, III-2) is a 55-year-old white female with known maturity-onset diabetes, hypothy­ Discussion roidism, hypertension, and hepatosplenomegaly diagnosed Evidence for Heterogeneity in ALS as cirrhosis with fatty infiltration on liver biopsy, who pre­ There are three recognizable clinical forms of sented with a three-year history of progressive weakness in her legs, causing difficulty in walking upstairs and rising classical, sporadic ALS. In progressive bulbar palsy from a chair. For one year, weakness increasingly impaired (PBP), muscles innervated by the medulla are pri­ her ability to pick up objects, and her writing had become marily affected. The presenting symptoms are dysar­ illegible. There had been no episodes of acute exacerbation thria and dysphagia of insidious onset. The tongue or remissions. atrophies and shows conspicuous fasciculations. Pa­ On examination, wasting and fasciculations of the tongue were noted, and her speech was slow and slurred, latal involvement is indicated by progressive speech and the jaw jerk was hyperactive. There was weakness and difficulties and regurgitation of food through the wasting in the legs, and all reflexes were brisk with sustained nose. Whereas PBP is the result of a lower motor ankle clonus, bilateral Hoffman signs, and bilateral positive neuron (LMN) lesion, it is frequently accompanied Babinski responses. Sensation was normal in all modalities. by upper motor neuron (UMN) involvement of the VDRL, serum B12, cerebrospinal fluid (CSF), myelogram, and computerized axial tomography (CT) scans were all cranial nerves leading to "pseudobulbar palsy." Here normal. An electromyogram (EMO) showed changes con­ the tongue is again small but tends to be spastic, and sistent with ALS, especially in the C, and T, nerve root the jaw, palatal, and pharyngeal reflexes are exagger­ distributions. ated. In addition, there is marked emotional )ability Other Family Members: It can be seen from the ped­ with attacks of inappropriate laughing or crying. igree (Fig I) that the pro band's mother (II-3), maternal In a second form of the disease, muscles in- 184 WILKINS ET AL: MOTOR NEURON DISEASE nervated by the spinal nerves are primarily affected pyramidal cells of Ammon horn where eosinophilic and U MN signs accompany those resulting from the crystaloid inclusion bodies are also seen.6 lesions of the LMNs. Isolated UMN lesions are in­ Although reports of familiai adult-onset ALS dicated by spasticity and brisk reflexes with bilateral constitute only about 5% to 10% of the reported Babinski responses, whereas isolated LMN lesions cases,7 at least 30 Caucasian families have been de­ present with muscle wasting, weakness, and fascicula­ scribed in which ther:! appears to have been a domi­ tions with depressed or absent reflexes. The actual nant mode of inheritance.8 - 16 physical signs depend on the relative preponderance Among the Chamorros, nearly 50% of all re­ of UMN or LMN degeneration. ported cases are familial; 17 however, extensive studies In a third form, LMN lesions predominate re­ have failed to define a clear pattern of inheritance.7 It sulting in progressive muscular atrophy, but UMN is possible that there may be a genetic predisposition lesions may occasionally be present. The symptoms to an environmental agent. and signs of LMN lesions are as described above and It is still uncertain whether these three entities, usually start in the hands and forearms. sporadic, Guamanian, and familial ALS, represent Although these three clinical presentations can one or several etiologically different diseases. All be distinguished, all are thought to be variations of three present with indistinguishable symptoms of the same process. Sensory impairment is not found, muscular atrophy, lateral sclerosis, and bulbar palsy. although patients may complain of muscle cramps or Dementia, often seen in affected Chamorros, also abnormal sensations resulting from muscle fascicula­ occurs in both familial and sporadic cases.18 In­ tions. volvement of the posterior columns has been de­ The diagnosis is usually made on clinical scribed in a small number of inherited ALS cases19 grounds, although the EM G shows characteristic but not with enough consistency to be distinctive. patterns of denervation with fibrillation, fascicula­ Other parameters may permit a clear distinction tion, and giant action potentials indicating spontane­ of the three types (Table 1 ). ous activity. Sporadic ALS typically has a late onset in the Pathologically, extensive neuronal loss is evident early 50s; the first signs usually appear in the upper with astrocytic gliosis of the UMNs and LMNs as extremities, and the disease has a short duration lead­ well as the lower cranial nuclei. Cytoplasmic and ing to death within five years. In contrast, a review of nuclear shrinkage occurs with excessive accumulation 30 published Caucasian pedigrees indicates that fa­ of lipofuscin. In Guamanian cases, additional fea­ milial cases more often have an onset in the early tures include neurofibrillary degeneration of the or­ forties beginning in the lower extremities with a bital gyrus, Ammon horn, and basal ganglia. Gran­ longer duration. Chamorro cases resemble familial ulovascular bodies are almost a lways present in the ALS in onset and duration but are similar to sporadic TABLE I Comparison of Sporadic, Guamanian , and Familial ALS Sporadic Guamanian Familial Number of Number of Number of Based on Parameter value cases Parameter value cases Parameter value cases Age of onset, yrs 52.7 ± 2.7 JOO 46.1 ± 13.