The Natural History of Machado-Joseph Disease

We have examined 138 cases of a disorder previously described in people of Portuguese origin and which has received many names. By computer analysis of 46 different items of a standardized neurological examination carried out in each patient, we have been able to delineate the main components of the clinical presentation, to conclude that the marked variability in clinical expressions does not negate the homogeneity of the disorder, and to describe the natural history of this entity which should be called, for historical reasons, "Machado-Joseph Disease". This hereditary disease has an autosomal dominant pattern of inheritance, presenting as a progressive ataxia with external ophthalmoplegia, and should be classified within the group of "Ataxic multisystem degenerations". When the disease starts before the age of 20, it may present with marked spasticity, of a non progressive nature but often so severe that it can be accompanied by "Gegenhalten" countermovements and dystonic postures but little frank dystonia. There are few true extrapyramidal symptoms except akinesia. When the disease starts after the age of 50, the clinical spectrum is mostly that of an amyotrophic polyneuropathy with fasciculations accompanying the ataxia. For all the other cases the clinical picture is a c.ontinuum between these two extremes, the main determinant of the clinical phenotype being the age of onset and a secondary factor, the place of origin of the given kindred. The ataxic and amyotrophic components are clearly progressive with time in contrast to the spasticity component. Although the majority of known cases are of Portuguese origin, this is not obligatory. The next research endeavour should be a search for the chromosomal site of the gene, using molecular biology technology such as those for recombinant DNA. RESUME: Nous avons examine 138 cas d'une maladie decrite prealablement chez des sujets d'origine portugaise et qui a recu plusieurs noms. Une analyse sur ordinateur de 46 items differents d'un examen neurologique uniformise fait sur chaque patient nous a permis de delimiter les principales composantes du tableau clinique, de conclure que la grande variability d'expression ne contredit pas l'homog6neite de la maladie et de decrire I'histoire naturelle de cette entity que Ton devrait appeler "LaMaladiedeMachado-Joseph". Cette maladie heYeditaire se transmet de fa?on autosomale dominante et se presente comme une ataxie progressive avec ophtalmoplegie externe. Elle devrait etre incluse parmi les "Degenerescences multisystemiques ataxiques". Lorsque la maladie debute avant Page de 20 ans, elle peut se presenter sous la forme d'une importante spasticity, non progressive, mais souvent si severe qu'elle peut s'accompagner du phenomene de "Gegenhalten" et de postures dystoniques sans dystonie franche. II existe peu, dans cette entity, de symptomes que l'on peut qualifier d'extrapyramidaux, sauf pour l'akin6sie. Par contre, lorsque la maladie debute apres l'age de 50 ans, le tableau clinique est surtout celui d'une polyneuropathie amyotrophique avec fasciculations associees a l'ataxie. Pour tous les autres cas, le tableau est le resultat d'un continuum entre ces deux ph£notypes extremes, dont le determinant principal est l'age de d6but et le facteur secondaire, le lieu d'origine de la famille sous etude. Les composantes ataxiques et amyotrophiques de la maladie sont nettement progressives, a l'encontre de la composante spastique. Meme si la majorite des cas connus sont d'origine portugaise, cette appartenance ethnique n'est pas obligatoire. Les recherches futures devraient se concentrer sur I'identification du site cnromosomique du gene de la maladie, a l'aide des nouvelles technologies de biologie moleculaire. Can. J. Neurol. Sci. 1984; 11:510-525 A Histories) Review the Portuguese Azores, and whose children emigrated to The first report of the entity we will analyze was made in 1972 Massachusetts in the late nineteenth and early twentieth century. by Nakano and collaborators (1972) from Boston, who studied The authors described the hereditary ataxic signs and stated 51 affected members of a family descending from one William that the syndrome, which appeared to be transmitted in an Machado, a native of Bretanha on the Island of Sao Miguel in autosomaldominantfashion,alsoincludednystagmusonlateral From the Clinical Research Institute of Montreal, The University of Coimbra, Portugal, The University of Texas, Dallas, The University of California at Los Angeles, Queens University. Kingston, Canada, The University of Lyon, France, Stanford University CA, Boston University and the University of Porto. Portugal. Reprint requests for the complete supplement (Phase 3, Part 3) to: Prof. A. Barbeau, Clinical Research Institute of Montreal. 110 Pine Avenue West. Montreal, Quebec. Canada H2W IR7. 510 https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100034983 Downloaded from https://www.cambridge.org/core. IP address: 54.70.40.11, on 31 Oct 2017 at 01:58:38, subject to the Cambridge Core terms of use, available at LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES gaze, mild dysarthria, depressed or absent tendon reflexes, equivocal plantar responses, distal muscle atrophy and, in some patients, contraction fasciculations. A distal blunting of vibratory and position sense was also noted. It is of interest that in the patients examined by the authors, the ataxia of gait was said to appear late in life and to be slowly progressive. The disease, they said, did not correspond to olivo-ponto-cerebellar atrophy nor to the ataxic variations of familial spastic paraplegia. They therefore named it Machado disease, implying the description of a new entity (Nakano et al., 1972). The same year Woods and Schaumburg (1972) also described what they thought was a new disorder which they termed "nigro-spinodentatal degeneration with nuclear ophthalmoplegia". Again this family (the "Thomas" family) was of Portuguese origin and had migrated to Massachusetts where 12 cases were examined, one at post-mortem. In the typical picture as reported by these authors there is gait ataxia, nystagmus, extrapyramidal rigidity, and hyperreflexia. Spasticity and extensor plantars were more variable findings while mild weakness and distal muscular atrophy were present in more advanced cases. In contrast to the first paper, the authors noted that posterior column sensation had remained intact. The disease, as seen by Woods and Schaumburg (1972) has more features of spastic ataxia than the Machado form. In a subsequent chapter for the Handbook of Clinical Neurology (Woods and Schaumburg, 1975), the same authors confirmed and expanded their findings. They also described a second post-mortem case and listed the main physical findings in II family members they examined, emphasing the gait ataxia (10/11 cases), spasticity (3/11), hyperreflexia (9/11), and extrapyramidal rigidity (7/11). A few years later, Rosenberg et al. (1976) independently described an autosomal dominant disorder in a family of Portuguese ancestry living in California, whose illness begins in the second, third or fourth decade, progresses for about 15 years with parkinsonian rigidity, spasticity, spastic dysarthria and abnormalities of eye movements. Facial fasciculations, facial myokymia and lingual fasciculations without atrophy were common and early manifestations. The authors state that the spasticity is the main problem responsible for the gait imbalance, speech difficulty, and dysphagia. Their patients had some rigidity, dystonia or athetosis, but these features were not prominent. Based on the neuropathological examination of one case demonstrating severe neuronal loss and astrocytic gliosis of the corpus striatum and substantia nigra, and a moderate neuronal loss in the dentate nucleus and red nucleus, the authors conclude to a new form of striatonigral degeneration. Although they cite the previous authors, they state categorically that this entity is distinct from nigro-spino-dentatal degeneration, olivoponto-cerebellar degeneration, dystonia musculorum deformans, Machado disease and Huntington's disease. The original ancestor of this California family was Antdnio Jose (Joseph) Bastiana, hence the name proposed: Joseph disease. Shortly thereafter, Nielsen (1977) challenged the pathological conclusions, particularly the caudate and putamen involvment, and stressed the similarities with the report of Woods and Schaumburg (1972). In 1976, Portuguese neurologists, aware of the previous descriptions, travelled to the Azores and identified 40 cases of a similar disorder (in 15 families) which was called "Doenga da Ponta Ruiva" from a village on the Island of Flores (Coutinho et al., 1977). This preliminary report was followed by a more complete description of these cases (Coutinho and Andrade, .1978) in which the authors argue for a system degeneration involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions. They also give a thorough description of the clinical features as seen in all cases including the "Freitas" family from the Island of Flores. For the first time three separate but interrelated subtypes of the disease are identified: Type I, in which pyramidal and extrapyramidal abnormalities predominate; Type II with mainly cerebellar deficits and Type III with mainly distal muscle atrophy. In all types cerebellar signs and PEO are present. The authors conclude to a continuum of clinical expression in this dominantly inherited neurologic disease. Meanwhile in Boston, Romanul et al. (1977) studied another Portuguese family from the Azores who suffered a progressive neurologic disease characterized by gait ataxia, features similar to Parkinson's disease in some patients, limitation of eye movements, widespread fasciculations of muscles, loss of reflexes in the lower limbs, followed by nystagmus, mild cerebellar tremor and extensor plantar responses. Two post-mortem studies were carried out. The presence of considerable variability in the clinical expression of the disease in individual members of their family, led the authors to conclude that this kinship had the same disease as those previously reported and that they represented a single genetic entity with variable expression. For the first time Machado disease and Joseph disease were united in what the authors proposed to call the "Azorean disease of the nervous system". This report prompted a number of exchanges and field trips to the Azores (Dawson, 1977; Rosenberg, 1977a; Fowler etal., 1977; Romanul, 1977) which again confirmed the existence of similar cases on the Islands. Initially Rosenberg (1977) maintained that the type III cases were a different entity while Romanul (1977) was for "lumping", but objected to the term striatonigral degeneration. However, in his subsequent report on his 1977 field trip to the Azores, Rosenberg (Rosenberg et al., 1978) stated "it seemed likely that all reported families of similar ancestry represented a single genetic entity with variable expression". Rosenberg used the term "Joseph disease" to describe all cases he examined which, may cause ambiguity since it was first used to describe one type of the illness and was not the initial description of the entity. The Freitas family originally described by Coutinho and Andrade (1978) is now called the Sousa family, from the name of the earliest known ancestor. Rosenberg et al. (1978) also state that on the Island of Flores, they did not encounter a single example of type III, or the Machado form, with evidence of peripheral neuropathy, distal atrophy, and cerebellar findings. [In subsequent field trips, the present authors as well as Coutinho were able to observe at least 6 cases (nos 3, 6, 10, 16, 76, and 98 in our files) of this type on the Island of Flores]. Rosenberg and his group then launched the search for a molecular marker of "Joseph disease" (Rosenberg et al., 1979; 1981; Morrison and Rosenberg, 1983). Using two-dimensional acrylamide gels they examined proteins from skin fibroblast cultures and brain homogenates. They reported increases in certain proteins (possibly representing gliosis) in the putamen and cerebellum. They subsequently reported that the same proteins were increased in the brains of Huntington's disease patients and proposed a common primary deficit of glial-neuronal interaction in these disorders. Meanwhile, Lima and Coutinho (1980) had discovered and described a new family residing in the village of Freixo-deVolume II, No. 4 (Supplement) — November 1984 511 https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100034983 Downloaded from https://www.cambridge.org/core. IP address: 54.70.40.11, on 31 Oct 2017 at 01:58:38, subject to the Cambridge Core terms of use, available at THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Espada-a-Cinta, in northern Portugal, with no known relationship to the Azores or North America. Because this makes the term " Azorean disease" obsolete and incorrect, the authors propose the use of the eponym "Machado-Joseph disease", since the Machado family was the first to be described and the Joseph represent the largest and most comprehensively described family. The authors also propose some definite criteria for the disease: "(1) An autosomal dominant mode on inheritance. (2) Major neurologic picture including cerebellar ataxia and pyramidal signs (Type II), associated in variable degree with a dystonic-rigid extrapyramidal syndrome (Type I) or peripheral amyotrophy (Type III). (3) Minor, but more specific, clinical signs such as progressive external ophthalmoplegia (PEO), dystonia, intention facial and lingual fasciculation-like movements, and bulging eyes." This last feature had been recognized in the 1976 and 1977 field trips to the Azores. These clinical criteria have been accepted by Rosenberg and Fowler in their 1981 review, which summarizes the First International Symposium on this disorder held in June 1980 in Lisboa. The genetic aspects of the disorder were also reviewed by Sequeiros and Coutinho (1981), while Sachdev et al. (1982) concluded, from the neuropathological study of two patients from different families, that the disease represents a single entity. It should be noted that in both these cases, the neostriatum appeared normal. Finally Dawson et al. (1982) have studied electro-oculographic recordings in 26 patients with Machado-Joseph disease. All patients with clinically apparent disease had abnormal eye movements, with abnormal calorics, sinusoidal tracking, opticokinetic nystagmus, refixation saccades and gaze paretic nystagmus in that order of frequency. The interest in this strange disorder in patients of Portuguese descent has prompted reevaluation of the presence of similar clinical complexes in non-Portuguese families. The first such kindred, American black in origin, was reported from Harlem Hospital in New York by Healton et al. (1980). The patients from this kindred have mostly the Type II phenotype. Sakai et al. (1983) also recently reported 4 cases from a non-Portuguese Japanese family, with neuropathologic confirmation in one case (degeneration of the substantia nigra, dentate nuclei, Clarke column and anterior horn cells of the spinal cord). There were two clinical types in the family. One was characterized by pyramidal and cerebellar signs with or without extrapyramidal signs; the other by cerebellar signs, loss of tendon reflexes, and peripheral sensory loss. Again there was autosomal-dominant inheritance. A second black family originating in the West Indies and living in California was recently described (Cooper et al., 1983) as well as a family from France originating from near the Spanish border and presenting with marked peripheral signs (Chazot et al., 1983). A brain scan in two patients showed cerebellar atrophy. A similar clinical presentation was described by Goto et al. (1982) in a Japanese family, but the pathological examination showed a dentato-rubro-pallido-luy sian degeneration. B. Unanswered Questions As is obvious from the above historical review, there is still a considerable degree of uncertainty concerning many aspects of the disorder called Machado-Joseph disease. The unanswered questions are listed in Table 1. Table 1: Machado-Joseph Disease In the last two years the two senior authors had the opportunity to personally study 138 cases of this disorder from various regions of the world. The present paper will summarize our experience and attempt to answer some of the above questions through analysis of the objective neurological examination results. SUBJECTS AND METHODS In 1979, the senior author was asked to examine a patient from South Africa who presented with the symptom complex previously described by Nakano et al. (1972) and by Rosenberg et al. (1976). It turned out that the patient was born in Lisboa and was a member of a second, previously unreported, mainland Portuguese family with Machado-Joseh disease. Subsequently we were able to examine three Canadians of Azorean origin with the same disease. This was the trigger to our interest in this disorder. In May 1982, thanks to the kindness of the neurological team from the University of Coimbra (Professor A .N. de Vincente) under the direction of Professor L. Cunha, we travelled to Terceira, Sao Miguel and Flores in the Portuguese Azores where we examined a total of 43 cases of Machado-Joseph disease including the large Sousa-Freitas family. Shortly afterwards, a further 11 cases (including cases reported by Lima and Coutinho, 1980) were examined in Coimbra and the region of Freixo-de-Espada-a-Cinta in northeastern Portugal, near the border of Spain and two cases were seen in Lyon, France with Dr. G. Chazot. In the fall of 1982, both of us attended' 'Joseph Disease" Clinics in Los Angeles, and the San Jose area of the San Francisco Bay in California. This was made possible through the courtesy of Dr. Roger Rosenberg and of Mrs. Rose Marie Sil va of the Joseph Diseases Foundation, Inc.. At these clinics a total of 40 cases (mostly from the Joseph family) were personally examined. Finally, 38 further cases were examined in the spring of 1983 at similar clinics of the Joseph Diseases Foundation in the Fall River area of Massachusetts again through the courtesy of Drs. R. Rosenberg and D.M. Dawson and of Mrs. Silva. The latter cases included patients from the families reported by Nakano et al. (1972), Woods and Schaumburg (1972), and Romanul et al. (1977). The protocol followed for each of the 138 cases seen in the course of this study was always the same. After a clinical and genetic questionnaire to identify the individual within the large UNANSWERED QUESTIONS 1. ARE the various phenotypes indications of genetic heterogeneity or of a continuum of clinical expressivity in the same disease? 2. WHAT is the typical clinical presentation of the disease if it is a single entity? 3. WHAT are the modifyers of the clinical phenotype? What are the respective roles of sex, age of onset, sex of affected parent, genetic drift and place of origin? 4. IS the noted phenomenon of anticipation an observer bias? 5. WHAT is the natural history of this disease? 6. WHAT is the nosological place of Machado-Joseph disease within degenerative disorders of the CNS? 512 Machado-Joseph Disease — Barbeau et al. https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100034983 Downloaded from https://www.cambridge.org/core. IP address: 54.70.40.11, on 31 Oct 2017 at 01:58:38, subject to the Cambridge Core terms of use, available at LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES pedigrees available and establish his age of onset and personal data, each patient was carefully examined following a strict protocol developped for ataxia by Pourcher and Barbeau (1980). In this protocol 48 items are objectively calibrated on a scale of 0 to 3: 0 is normal; 1: mild; 2: moderate; 3: severe disability or deviation from normal. These items are grouped into 6 categories: cranial nerves (max. score 18); incoordination (42); tone (18); reflexes (24); peripheral signs (24); muscle strength (12, distal; 12, proximal). For computer analysis (Vax 750 Computer) using the statistical package for the social sciences (SPSS) program of the University of Montreal, scores for the measurement of individual signs were utilized. In addition "symptom complex" scores were calculated for "Periphery" (P),"Incoordination" (C), and "Spasticity" (S): the "Periphery Score" (max. 45) included items 27 to 32 if negative (decrease in reflexes), items 35 to 37 (atrophy and fasciculations), 41 and 42 (vibration sense), and 43 to 48 (decrease muscle strength); the "Incoordination Score" (max. 42) included items 7 to 20 (gait, Romberg, finger to nose, heel to knee, adiadocokinesia, postural tremor, tapping and drawing a spiral with each hand); finally the "Spasticity Score" (max. 42) included items 21 to 24, if increased (tone), 27 to 34 (reflexes if increased, plantars), and 47,48 (clonus). Each of these symptom-complex scores was normalized to 100%. For each patient a P/S Ratio was calculated from the scores for "Periphery" and "Spasticity". From the P, C and S scores for each patient a clinical phenotype was determined according to the following rules: the highest of the three scores determined the major axis, while the second highest determined the minor axis, i.e. the direction for subtyping (see Figs 1 and 2 and legends). For example if the scores were thus: C (52), P (35), S (12), the patient would be classified as phenotype II B. In this way a total of 6 phenotypes can be defined (with scores in order of magnitude): IA (SPC), IB (SCP), IIA (CSP), IIB (CPS), III A (PCS), and III B (PSC). The total spectrum is illustrated in Fig. 1. MACHADO-JOSEPH DISEASE SYMPTOM-TYPE DISTRIBUTION