A Large Kindred with Autosomal Dominant Parkmson’s Disease Lawrence I. Golbe, MD,* Giuseppe Di Iorio, MD,? Vincenzo Bonavita, MD,? Douglas C. Miller, MD, PhD,$ and Roger C . Duvoisin, MDX ~~

~~

We report two large kindreds with Parkinson’s disease (PD) apparently inherited in autosoqal dominant fashion. Forty-one persons in four generations have been affected; we have examined 7 of them. The two kindreds originated in a single small town in southern Italy and therefore are probably related. The illness was typical for PD except for early onset at a mean age of 46.5 years and a rapid course that averaged 9.7 years from onset to death. Clinical appearance and response to levodopa were typical for PD. Only one instance of definite nonpenetrance is known. Autopsy of 2 patients in one kindred showed the pathological changes typical of PD with Lewy bodies. Disease duration among affected persons who spent most of their lives in Italy was longer than for their affected US relatives, suggesting that exogenous agents may influence the course of this genetic illness. We conclude that what is probably a single gene without an additional environmental insult can cause the pathological changes typical of PD. Our findings therefore enhance the likelihood of a significant genetic component in the cause of sporadic PD. By identifying a toxic gene product, future molecular genetic studies in our kindred(s) may provide insight into the pathogenesis of sporadic PD. Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A large kindred with autosomal dominant Parkinson’s disease. Ann Neurol 1990;27:276-282

A century ago Gowers {I) concluded that in Parkinson’s disease (PD) “in some instances . . . hereditary influences may be powerful.” Until the 1 9 8 0 ~it ~was generally accepted that there is a significant genetic component in the cause of idiopathic PD. This opinion was supported by anecdotal reports of small P D pedigrees (none with autopsy confirmation) 12-51, by factor analysis that indicated a multifactorial cause [bl, and by tallies of patients’ allegations of secondary familial cases [77. In the 1 9 8 0 ~however, ~ came reports of acute parkinsonism after inadvertent exposure to a nigrotoxic pyridine derivative chemically similar to many environmental substances f81. Epidemiological data that showed a rural predilection for PD [9, 101 supported the environmental hypothesis. Concurrently, three twin studies showed that the P D concordance rate for monozygotic ‘twins was no greater than that for dizygotic twins [ll-131. These studies were prompted, in part, by an earlier report of personal examination of alleged secondary familial cases [ 141. In this report, the authors verified secondary cases no more frequently among relatives of patients than among those of control subjects. All these data turned opinion strongly against a significant genetic component in the cause of

We now report two large, probably related, kindreds with autopsy-confirmed PD with apparent autosomal dominant inheritance. We believe this represents important new evidence for a significant genetic component in the cause of sporadic PD. Patients and Methods Description of Kindreds

PD riri.

W e have identified a total of 41 affected individuals in two kindreds (Fig l), 31 from kindred 1 (Kl) and 10 from kindred 2 (=). Both kindreds immigrated to the New Jersey/ New York area between 1890 and 1920 from Contursi, a village in the hills of Salerno province in southern Italy. Fourteen affected members o f K 1 and one affected member of K2 spent their entire lives in Contursi or environs. Each kindred was identified via probands who were being followed by the authors (L.I.G. and R.C.D.) at the Robert Wood Johnson Medical School, New Brunswick, NJ (Kl: VII-25 and 26, K2: IV-57). Italian branches of the pedigree were ascertained by tracing the descendants of nonimmigrating antecedents named by the individuals in the United States. Genealogical data on US-born individuals were obtained from family members or medical records, or both, and on Italian-born individuals from civil and church records as well. Our investigations in Italy revealed no affected members of K2 there subsequent to generation 11. There were 23 men and 18 women among the affected

From the “Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ; t Istituto di Scienze Neurologiche, Universita degli studi di Napoli, Naples, Italy; and $Department of Pathology (Neuropathology),New York University-Bellevue Medical Center, New York, NY.

Received Mar 28, 1989, and in revised form Aug 9 and Aug 23. Accepted for publication Aug 25, 1989. Address correspondence to Dr Golbe, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, CN-19, New Brunswick, NJ 08903.

276 Copyright 0 1990 by the American Neurological Association

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individuals. Symptoms began at a mean age of 46.5 years (standard deviation, 10.8; range, 28-68; n = 33 for whom we deemed this data reliable), and death occurred, usually from complications of immobility, at a mean age of 53.5 years (standard deviation, 9.2; range, 42-74; n = 32). Of the 41 affected persons, only 2 (both in K1) were said to have had tremor as a prominent or early feature and only 8 were reported to have had tremor at all. None of the patients we examined had tremor. The course was otherwise typical of idiopathic PD. Dementia was said to be unusual, mild, late, or all three in its appearance and this was the case in the affected patients we examined. Depression was present in the minority and was never severe. The initial sign that members of both kindreds learned to recognize as premonitory was a parkinsonian wide-eyed stare. One or more authors have examined 5 affected members of K1 and 2 affected members of K2. (These are represented by a double symbol in Fig 1.) All of the open symbols without question marks in the pedigrees represent individuals who have been positively identified as being unaffected to date. We examined 15 unaffected individuals, none of whom had been considered by relatives to be affected. Assurances of absence of P D in an unavailable individual were confirmed by interviewing multiple family members whenever possible. One reportedly affected living individual (Kl: VII-47) refused to participate in this study. H e r clinical appearance was confirmed by 2 relatives. Another individual (K2: IV-GO), suspected by a relative of being affected, denied symptoms and refused examination. He is indicated as being affected in Figure 1 but was not considered as affected in our statistics. Three obligate heterozygotes have been positively identified by their descendants as being unaffected: K1: V-9 represents the only definite instance of nonpenetrance. He died at age 96 (1885-1981) of “old age” and was vigorous until his last few years. His wife lived to age 85. Her father lived into his 90s but her mother died “young,” reportedly without parkinsonism. K2: 11-7 lived to age 57 (1868-1925), when he died of complications of diabetes. PD, therefore, might have appeared later o r its signs may have been masked by neurological complications of diabetes. Thus, he cannot be definitely considered unaffected. K1: IV-4 died at age 65. No reliable medical history is available except that his relatives deny that he had PD. W e have no data on his wife or her family. The phenotypic homogeneity of the illness in the two kindreds is illustrated in the Table. No significant difference between the two kindreds was seen with respect to duration of P D or age at death of the affected individuals. These observations, together with the paucity of tremor in either kindred and the common origin of both kindreds in a single small town, constitute strong evidence that the two kindreds suffer from the same illness. Unfortunately, our genealogical work extending to the mid-I 700s failed to reveal a common ancestor of affected members of the two kindreds. W e investigated the possibility that, as in Huntington’s disease, younger age at onset is associated with inheritance of the gene from the father. W e found that for the patients for whom these data were available, neither age at symptom onset nor age at death differed according to the sex of the parent who had passed on the gene. W e considered the possibility that the illness was environ-

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Duration of Illness and Age at Death of AffectedIndividuals in the Two Kindreds” ~

Variable

Kindred 1

Kmdred 2

Mean duration of illness 2 SD

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“The similarity between kindreds 1 and 2 suggests that they share a common abnormal gene. The survival difference between US and Italian individuals suggests that an environmental factor contributes to this apparently genetic illness. bSignificant difference ( p = 0.007, 2-tailed t test). Other K1-K2 and USItalian differences were not significant.

SD = standard deviation; N = number of individuals for whom reliable information is available.

mentally acquired. However, no one occupation was common to all the affected individuals (although K1: VII-28 and 29 were fire fighters), and none of the affected US individuals for whom travel history is available had ever visited Contursi. W e were unable to identify any cooking practice or hobby common to several generations of the two families in two countries. Conversely, we were unable to identify any unique dietary or health practice of any of the unaffected obligate heterozygotes that could have protected against P D symptom development.

Autopsied Cases ~ 1VII-28. : The patient was a male fire chief who at age 38 noted stiffness and slowness of the left hand that may have been present since age 32. He had no history of specific episodes of carbon monoxide intoxication, excessive smoke inhalation, or head trauma. A neurologist found diffuse mild rigidity and bradykinesia and prescribed levodopdcarbidopa (Sinemet), which gave considerable relief. At no time was there tremor. He was referred to the Movement Disorder Center at Robert Wood Johnson Medical School at age 48 because of dose-related fluctuations with peak-dose chorea not responding to a regimen of Sinemet every 2 hours. Addition of bromocriptine, up to 30 mg a day, had provided no benefit and produced nightmares. Salient neurological findings during the “off” state were severe bradyphrenia with mild dementia, diffuse 3 + (Columbia Scale) rigidity, 3 + bradykinesia, inability to arise without help, and inability to walk o r recover from retrodisplacement. When “on,” his rigidity was 2 with diffuse mild chorea, 1+ postural instability, and a stable but festinating gait. Examination revealed no orthostatic hypotension, supranuclear gaze deficits, cerebellar deficits, pyramidal tract signs, or amyotrophy. Addition of pergolide gave no improvement. Addition of deprenyl gave mild improvement in the proportion of the day spent “on.” At age 49 the patient was found drowned in a swimming pool. Abnormalities seen at autopsy were severe neuronal loss in the substantia nigra (Fig 2A), with Lewy bodies in some of the remaining neurons and in cell ghosts (Fig 2B). Neuromelanin was present in macrophages and there was marked

+

A Fig 3. Locus ceruleus from Patient K l : VII-28.A large pigment-bearing neuron contains a large Lewy body with a center region stained by Luxol fast blue. The background is gliotic. (Luxolfast blue, hematoxylin-eosin, x 50.)

B

C

Fig 2. Substantia nigra from Patient K l : VII-28. There is marked depletion of the pars compacta (Aj with both intracellular (B), extracellular, or axonal (C, arrow) Lpwr bodies. (Luxol fast blue, hematoxylin-eosin, x 50 before 2% reducti0n.j

gliosis in the substantia nigra. In addition, Lewy body-like structures were seen outside of any visible cells, perhaps in axons (Fig 2C). The locus ceruleus (Fig 3) and dorsal motor nucleus of the vagus also showed mild to moderate cell loss with Lewy bodies. Sections of the substantia innominata revealed mild cell loss, moderate gliosis, and numerous Lewy bodies in the nucleus basalis of Meynert (Fig 4),as well as extracellular (or axonal) Lewy body-like structures. The hippocampus at the level of the lateral geniculate showed loss of pyramidal neurons with gliosis in the Sommer sector and subiculum. The remainder of the brain was normal. A specific search for neurofibrillary tangles, granulovacuolar degeneration, and neuritic plaques produced negative results. ~ 1 VI-10. : This patient, the maternal uncle of K1:VII-28, noted onset of shuffling gait at age 60 (in 1962); no medical records from that period are available. Gait difficulty progressed, and he was recognized by his family as having the typical familial illness. The family reports that tremor never occurred but depression was a problem. H e was still ambulatory when he was admitted to a hospital in 1966 with “bleeding ulcers.” H e became bedbound while in the hospital, where he remained for 3 months until his death. Postmortem examination of the brain included sections only of the cerebral cortex, basal ganglia (including parts of the caudate, globus pallidus, and putamen), pons, cerebellum, and cervical cord. The original report makes no comment on the macroscopic appearance of any of the pigmented nuclei. The original sections had been lost, but the blocks were available for sectioning and examination by author D.C.M. The only abnormalities were in the locus ceruleus, which showed marked depletion of pigmented neurons, fragments of neuromelanin in the neuropil and in macrophages, gliosis, 2 Lewy bodies in pigmented neurons (Fig >A), and Lewy body-like structures in the neuropil (Fig 5B).

Golbe et al: AutosomalDorninant PD 279

A Fig 4.Nucleus basalis of Meynert (nbM)from Patient K l : VII-28. There is some decreased density of large neurons in the nbM. In the center and inset, a large nbM neuron contains 2 moderate-sized Lewy bodies. (Luxolfast blue, hematoxylin-eosin, x 50; Inset, x 100 before 2% reduction.)

Laboratory lnvestigations We have thus far performed karyotyping of red cell and HLA antigens for 3 affected individuals: K1: VII-29 and 55 and K2: IV-59. Karyotyping revealed no abnormalities, and no HLA types were found in common. Red blood cell antigens in common among the 3 patients, with chromosomal loci, were Rh, RhC, RhE (lp); Lewis a, b ( 1 9 ~ ) Kell ; (locus unknown); Duffy (lq); Kidd a, b (2p); Lutheran b ( 1 4 ) ; Lewis a (19p); M, N , S (4q); and P1 (22q). As most of these antigens occur in the majority of persons of Italian descent, they are of limited use in guiding further

B

genetic analysis. Red blood cell antigens not held in common among the 3 patients are ABO (9q, though the possibility of linkage with the 0 allele exists); Rhc (lp); and s (4q). These loci can therefore be excluded from close linkage with the abnormal gene in our kindred.

Fig 5 . Locus ceruleus from Patient KI: VI-10. There are intracellular (A, arrow) and extracellular (B, arrowhead) Lewy bodies in a depleted locus ceruleus. (Luxolfast blue, hematoxylineosin. A, x 100; B, x 50 before 2% reduction.)

Discussion To our knowledge this is the first report of apparently hereditary occurrence of pathologically typical Lewy body parkinsonism (i.e., Parkinson’s disease as usually defined). The genetic pattern strongly supports a Mendelian autosomal dominant mode of transmission. The clinical illness in these kindreds is atypical in its early onset, aggressive course, and low incidence of tremor, but typical in its dopa-responsiveness and constellation of clinical signs. The two kindreds presented appear to have the same genetic illness, as they share origin in a single small town and display the same combination of typical and atypical parkinsonian traits. We must recognize the remote possibility that an environmental agent may be the cause of PD in our

lundred. Our failure thus far to find a genetic link between K1 and K2 enhances this possibility slightly. However, the prevalence within each sibship was close to 50% (compatible with autosomal dominant inheritance), nearly all cases proved to have an affected parent, affected conjugal pairs did not exist, no nonsib affected members of a generation shared a household, and these two families are apparently unique in Contursi. These points are all strongly against an environmental explanation in this kindred. The difference in duration of disease course between Italian and US individuals (see Table) suggests that an environmental agent may have affected the aggressiveness of the disease. We were unable to identify

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such an agent by informal interviews. We must admit the possibility that this difference is an artifact of nonstandardization of interview methods. (Author L.I.G. interviewed the US individuals and author G.D.I. interviewed the Italians.) Parkinsonism as an autosomal dominant heritable trait can be seen in some types of olivopontocerebellar atrophy 1161, juvenile-onset Huntington’s disease 1171, Joseph disease [18), depression with taurine deficiency 1191, depression with alveolar hypoventilation 1201, and a form of Charcot-Marie-Tooth disease 121). None of these is compatible with the pathological findings in our two autopsied cases. Moreover, the clinical course and degree of dopa-responsiveness in our patients would be highly unusual for any of these entities. Diseases inherited in autosomal dominant fashion that can display intraneuronal eosinophilic structures similar or identical to Lewy bodies include Joseph disease 1221, cerebello-pallido-luysio-nigral atrophy 1231, ataxia-telangiectasia 124, 251, and amyotrophic lateral sclerosis 126,271. In addition, 1 of 4 autopsied cases of hereditary dysphasic dementia had a single Lewy body 1281. Our patients’ clinical appearance and the overall pathological picture in our adequately autopsied case suggest none of these entities. Muenter and colleagues [291 have recently presented a lundred with 12 individuals affected by PD starting in the teens or 20s and ending in death within 10 years. Transmission, as in our kindred, was autosomal dominant, but dementia was a salient and constant feature, and autopsy showed severe affection with Lewy bodies of limbic areas as well as of nigra. While this is clearly a different disease from that of our kindred, it provides additional precedent for a genetic cause of Lewy body nigral degeneration. Further precedent for a genetic theory of PD is provided by studies in mice that revealed genetic control of number of dopamine neurons at birth 130). The dopamine cell number correlates with exploratory behavior in these animals. A similar mechanism in humans could confer vulnerability to an exogenous nigrotoxic substance and explain the lifelong “parkinson personality” 111, 3 11. The major conclusion offered by the present report is that the pathoanatomical picture of typical sporadic PD can be produced by what is probably a single gene acting without an additional nonheritable insult. We must raise the possibility that some cases of sporadic PD may be the result of the same or a similar gene acting with lower penetrance than is the case in our lundreds. The agent lowering the penetrance may be other gene(s) or an environmental protective agent. As an example, recent epidemiological data suggest that lifelong intake of foods rich in vitamin E may be such a protective agent 1321 and other antioxidants have

also been proposed for this role. Furthermore, even if sporadic PD is of purely environmental origin, the possibility now arises that the causative agent may be an analogue or fragment (or analogue of a fragment) of the toxic peptide product of our kindred’s abnormal gene. The next logical step, now in progress, is linkage analysis of the defective gene. Identification of a marker may allow presymptomatic identification of heterozygotes, who may then benefit from prophylaxis by monoamine oxidase inhibition or antioxidant therapy. The former recently proved effective in symptomatic persons 133, 341. A more distant result of linkage analysis is identification and sequencing of the PD gene itself, followed by in vitro production of its peptide product, as has recently been performed for Duchenne muscular dystrophy. If, as we deem likely, PD is caused by the combination of a genetic defect and an exogenous toxin (or insufficient exposure to an exogenous protective agent), and if the exogenous agent eludes detection, inactivation of the culprit gene or its peptide product could then offer hope for prevention of the disease.

Addendum We recently discovered a common origin of lundreds 1 and 2, in a couple born about 1700. Their daughter, born in 1722, was the mother of K1: 1-2. Their son, born in 1724, was the great-great grandfather of K2: 1-2. Health data for kindred members born before about 1860 remain unavailable, so any conclusion that the “Parlunson gene” was transmitted through these individuals must remain conjectural.

We are grateful to the United Parkinson Foundation, Chicago, for financial support for the biochemical linkage analysis and to MingLiang Lee, MD, for helpful advice. Most important, we thank the many members of the kindreds for their assistance in this research.

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