Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome

Acre ,Yeitrol Scofid 1994 89- 347-352 Printed 111 Belgruni - [ I / / righrr reseried

Coovriehhr 0 Muribeuard 1994

ACTA NEUROLOGICA SCANDINAYICA

ISSN 0001-6314

Pallido-p yrami supranuclear u

.dal Pga

degenerat 0

.ze paresis ion, and

Kufor-Rakeb syndrome

Najim Al-Din AS, Wriekat A, Mubaidin A, Dasouki M, Hiari M. Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurol Scand 1994: 89: 347-352. 0 Munksgaard 1994.

An unusual neurological syndrome in an Arab family with five affected siblings, is reported. Autosomal recessive inheritance is suggested by having multiplc affected siblings born to phenotypically normal consanguineous parents. Similar to Davison's Pallido-pyramidal syndrome, they presented with the clinical signs and symptoms of severe parkinsonism as well as evidence of cortico-spinal tract disease. In addition, they had dementia and supranuclear upgaze paresis. MRI studies showed significant atrophy of the globus pallidus and the pyramids, as well as generalized brain atrophy in later stages. Therapy with levodopa resulted in significant improvement in the extrapyramidal dysfunction. We suggest that this probably represents a new syndrome which is closely related but not identical to the pallido-pyramidal syndrome.

dementia:

A. S. Najim Al-Din ', A. Wriekat2, A. Mubaidin', M. Dasouki', M. Hiari2 ' Jordan University Hospital, Medical Centre, Amman, Jordan

King Hussein

Key words: pallido-pyramidal syndrome: Parkinson's disease; dementia: upgaze paralysis; autosomal recessive inheritance

Amir S. Najim Al-Din, Jordan University Hospital, P.O. Box 13046, Amman, Jordan

Accepted for publication September 2 1, 1993

An autosomally recessive inherited syndrome, characterized by paralysis agitans and pyramidal tract signs was first recognized by Davison in 1954 (1). A total of 3 families and 2 sporodic cases with the pallido-pyramidal syndrome (PPS) have been reported (1-3).

We report on a closely related, but not identical, syndrome in a consanguineous Jordanian family originating from a small community (Kufor-Rakeb) located in the north of the country.

Results

Information was available on 99 members of the family (Fig. 1). There were 48 men and 51 women. Over several visits to the community 87 living family members, were examined clinically by ASN, AW and AM, five were known to have neurological symptoms. N o new cases were discovered other than

Patients and methods

Following the identification of the proband (V-49) in November 1992, several visits to the village were made and the available members of the family were identified and examined by ASN, AW and AM.

Affected members were evaluated as in-patients. They had detailed haematologic and biochemical profiles as well as estimation for serum copper and caeruloplasmin and urinary copper excretion. All affected individuals had electrocardiograms, and some had MRI of the brain and electromyography and nerve conduction studies.

Fig. I . Family pedigree symbols used: O/u normal female/male; O/. affected female/male; 0/@ deceased; 010 heterozygous female/male; double bar indicates consangiuinety and arrow indicates proband.

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originally reported by the family. All individuals in generation VI were considered to be too young to show the clinical features (less than 10 years). Those who died prior to this study were reported to have been free. The dead family members (Fig. 1) were reported to have lived in the same village community. Elderly family members (111-3 and 111-7) were interviewed and reported that none of the dead family members were known to have a similar illness. No similarly affected individuals in the same community were reported.

Details of the syndrome

All affected members were normal at birth and were reported to have had normal milestones, and later had average progress at school (at least to 6th grade) until the disease onset around the age of 13 years (16, 12, 13, 12 and 12 years for V-42, V-44, V-48, V-49 and V-53, respectively).

A summary of the neurologic features is shown in Table 1. Onset of symptoms was gradual in all affected members. They were noted to develop vague facies and progressively become slower in all motor activities. Walking becomes slow, they become less inclined to participate in sports and it would take them longer to dress and bathe.

Within an average of 6-12 months they would stop attending school, and all, with long enough duration, except V-44 and V-53 (1-yr duration) dete- riorated over another 6-12 months to the point of non-productive existence. Constant drooling of

Table 1. Neurological featrures in the family with pallido-pyramidal degeneration

saliva was a major problem particularly when the disease had progressed.

No skeletal abnormalities were detected. Exami- nation of the cardiovascular system, chest and ab- domen showed no abnormalities. ECG and chest X-rays were normal in all.

Those more severely affected (V-42, V-48 and V-49) were confined to bed in a generalized flexed posture; V-42 had moderately severe flexion con- tractures of the knees. All patients had expression- less faces with varying degrees of widening of the palpebral fissures giving a staring look. Blinking was infrequent and patients had a monotonous almost whispering speech. Intellectual functions were impossible to assess at that stage because of the grossly impaired limb functions and speech. Lack of habituation upon tapping over the bridge of the nose (Meyerson’s sign) was present in all.

Hypokinesia was a fairly marked feature; patients had extreme poverty of movement. Automatic habitual movements were absent, even in those less severely affected (V-44 and V-53). All possible movements were slow to initiate and execute. Those who were still able to walk (V-44 and V-53) walked in a shuffle, in a festinate fashion with faulty rightening reactions. Their upright posture was that of involuntary flexion of the trunk, limbs and head. Severe lead-pipe rigidity, in all muscle groups, was a prominent feature. There was no tremor nor other associated involuntary movements.

Only a mild paresis of the antigravity muscles of the lower limbs was noted in V-44, V-48, V-49 and

Age Response to Number (duration years) Sex Mentation Extrapyramidal Pyramidal Ocular L-Dopa therapy

v-42 36 M Demented Severe akinesia, MRC grade Upgaze and Can stand but not (201 and rigidty 3 paraparesis covergence walk, could speak

Beedridden paralysis and feed himself Anartheric

v -44 26 M Normal Hypokinesia Mild paraparesis Upgaze and Normal walking (14) Mobile, festinate gait, convergence

loss of associated limitation movements

v-48 22 M Demented Severe akinesia Mild paraparesis Upgaze and Walked slowly, 191 and rigidty convergence festinate gait,

Bedridden limitation loss of associated Anartheric movements

v-49

v-53

15 M Mild dementia Severe akinesia Mild paraparesis Normal Almost normal (3) and rigidty

Bedridden Anartheric

12 F Normal Hypokinesia Mild paraparesis Normal Almost normal (1) Mobile, festinate

gait, loss of associated movements

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V-53, but an almost MRC grade 3 paraparesis was brisk in all patients, with extensor plantar responses. found in V-42. No muscle wasting was detected. The Evaluation of the different sensory modalities re- jaw jerk, as well as the limb myotatic reflexes, were vealed no abnormalities. Electromyography and

Fig. 2. MRI of the brain for V-49 (I) V- 48 (11) and V-42 (111) AT the ages of 19, 28 and 31 years respectively. A, Tz weighted image (trite: 2200/80) at the level of the pyramieds showing widening of the subarachnoid space in V-49 but more significant atrophy in the other two. B and C, T , weighted images (tr/te:2200/80) showing atrophy of the globus pallidurn, clostrum and insula more marked in V-48 and V-42.

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motor and sensory conduction studies were per- formed in V-47 and V-53, and were normal in both, including studies of the late responses. No significant incoordination was detected.

Three patients (V-42, V-44 and V-48) had abnor- mal eye signs, however, they were unaware of any visual symptoms. Visual acuity was normal in all. The pupils were normal and the ocular media were clear in all. Fundoscopy revealed no retinal abnormalities and the optic discs were normal. In V-44 and V-48 upgaze and convergence were limited but lost in V-42. Bell’s phenomenon and oculocephalic manuveurs increased the range of upward eye movements. Active lid retraction was noted on attempted upgaze. The rest of eye movements were normal.

Four of the 5 patients (V-42, V-44, V-48 and V-49) had MRI studies of the brain. As they had different disease duration (20, 14,9 and 3 years, respectively), and all except V-44 had severe disability (before L-dopa therapy), it was possible to view the MRI changes in different stages of the disease (Fig. 2). V-49, who had severe disability which responded, almost to full normality to L-dopa therapy; had a mild generalized atrophy. V-42 and V-48, with more dementia, pyramidal dysfunction and less dramatic response to L-dopa; had a more prominent generalized cerebral, cerebellar and brainstem atrophy. Furthermore, a fairly selective atrophy of the lentiform nuclei and of the pyramids (Fig. 2) was noted.

Normal laboratory investigations included haema- tological and biochemical profiles, in particular acan- thocytosis was not detected, and the serum copper, caeruloplasmin and urinary copper excretion were normal. The cerebrospinal fluid (CSF) was studied in V-44 and V-49, and was normal.

Response to L-dopa therapy

L-dopa + carbidopa therapy was initiated in all, in a gradually increasing dose. A variable but dramatic improvement was noted within 48 h in all, this being limited to the extrapyramidal manifestations. All, except V-42, were able to walk. V-44, V-49 and V-53 did so almost normally but V-48 walked slowly and did not have associated limb movements. V-42 was able to stand but not walk, he could now speak and feed himself. The pyramidal dysfunction and upgaze paralysis were not influenced. Bromocreptin was added (initially 2.5 mg/day and then increased to 5 mg/day) was given to V-42 and V-48 after a dose of 250 mg of L-dopa + 25 mg carbidopa 4 times daily was reached in both. In both, particularly V-48, further significant improvement was noted. Again this was limited to the extrapyramidal dysfunction.

All patients were reported to have attended school, at least to 6th grade, and to have had average

progress. Initially the severity of the akinesia made formal IQ testing difficult to be interpreted. Thus, IQ was formally tested in V-48 and V-49 after the initiation of treatment. At the ages of 23 and 19 years, respectively. V-48 with a 9 year disease duration had a verbal IQ of 68 whereas the performance IQ was 45. V-49 with a 3 year disease duration had a verbal IQ of 86 and a performance IQ of 64. The young- est affected individual (V-53), was able to resume normal schooling, with normal performance after being stabilized on L-dopa therapy.

Disease progression

Prior to the initiation of L-dopa therapy and except for V-44, the disease proved to be severely disabling within 2 years of onset, rendering them bed-bound and totally dependent on their relatives, even for the most basic needs. This proved to be largely due to the extrapyramidal dysfunction which was respon- sive to a significant, though variable degree, in all siblings to L-dopa therapy. The other features of the syndrome; pyramidal dysfunction, dementia and supranuclear vertical gaze paresis, were slower to evolve and were not altered by L-dopa. The pyramidal dysfunction proved to be severely disabling in V-42 with a 20 year disease duration.

Genetic analysis

Autosomal inheritance is suggested by having mul- tiple affected siblings born to phenotypically normal consanguineous parents (Fig. 1). The offsprings of individuals V-37 and V-44 have a significant risk of being affected depending on whether or not the parent (V-37) is a carrier for this trait.

Discussion

A spectrum of inherited diseases in which parkinsonism is a prominent feature exists (1, 4-1 1). In some, parkinson disease is either the only manifes- tation (4) or is associated with some other extrapyramidal manifestations (5 ) . Other associations in- clude retinitis pigmentosa (6), ophthalmoparesis (7), pyramidal dysfunction (8), mental retardation (9), and slow refixational eye movements (1 1). The mode of inheritance is variable; some are autosomal dominant (4, 5), some are autosomal recessive (1,6,7, 10, 11) or X-linked recessive (8,9). Response to L-dopa therapy is variable but a significant response was reported in some of these diseases (2-5).

The kindred presented bears close resemblance to the 3 families and 2 sporadic cases with the pallido- pyramidal syndrome (1-3). PPS was originally recognized as a separate syndrome following the de- scription of 5 affected cases in 3 families by Davison

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(1). One of Davison’s cases had been reported by Ramsy Hunt (12). PPS as described by Davison as well as in later reports, is an autosonial recessive disease with onset in the second or early third decade with the picture of paralysis agitans and pyramidal tract signs (1-3). Autopsy in one of Davison’s patients showed pallor of the pallidal segments, thin- ning of the ansa lenticularis, slight shrinkage and cellular change in the substantia nigra and early de- myelination of the pyramids and crossed pyramidal tracts (1). Horowitz & Greenberg (1975) were the first to report the dramatic reversibility, after L-dopa therapy, of the picture of paralysis agitans in PPS whereas the pyramidal tract signs did not (2). Sig- nificant differences exist between PPS and the syndrome of progressive pallidum atrophy as the latter is characterized by dystonia with pyramidal dysfunction (13, 14). In addition to the features of PPS, affected members in this kindred had dementia and supranuclear paresis of upgaze. Furthermore, unlike Davison’s cases, tremor was remarkably absent despite having an otherwise classical picture of parkinson’s disease. The features of paralysis agitans were remarkable in their rate of development ren- deringthe patients bed-ridden within less than 2 years of onset.

The other features; pyramidal tract signs, dementia and upgaze paresis were slower to develop, but had contributed significantly to the disability in V-42 (the patient with longest duration). Although a dramatic response to levodopa therapy was noted in all patients, only those with the shortest disease duration (V-49 and V-53) were rendered almost normal regarding the extrapyramidal manifestations.

The variability of response to levodopa therapy depending on the disease duration probably suggests that, in the early stages a significant dysfunction or degeneration of the dopaminergic neurons in the substantia nigra exists. The factors that result in this relentless progression are not clear. It is possible that at a later stage a severe depletion of the dopaminergic neurons and probably a more severe striatonigral degeneration develops. Yet, the degenerative process in PPS is less wide spread than what is seen in the Shy-Drager syndrome (1 5 ) or the con- genital dopamine beta-hydroxylase deficiency syndrome (16), as none of our patients had features of autonomic failure.

The biochemical basis of PPS is not clear. It is possible that, like in Parkinson’s disease, there is degeneration of dopaminergic nigral neurous result- ing in a decrease in the nigrostriatal activity of tyrosine hydroxylase. Alternatively the basis for paralysis agitans in PPS might be a mutation in the tyrosine hydroxylase gene. Yet, the degenerative process in PPS is more extensive and is not limited to nigrostriatal system. The MRI studies at different

stages of the disease, in this kindred, show both generalized and selective degenerative changes. In V-49, despite being bedridden for 3 years with severe paralysis agitans he had only mild atrophic changes (Fig. 2 I). That patient responded almost fully to le- vedopa therapy. Those with longer duration and thus more severe extensive dysfunction (V-42 and V-48); a more severe and generalized atrophy was evident (Fig. 211 and 111).

Differences exist between the syndrome described in this kindred and most of the diseases collectively described as Parkinson plus syndrome. Progressive supranuclear palsy is a non-familial disease that pre- sents between the sixth and seventh decade of life. The supranuclear gaze palsy usually affects down- ward more than upward gaze. Furthermore, treatment with L-dopa is largely unrewarding (17, 18). Straiatonignal degeneration bears little difference from Parkinson’s disease other than presenting with a predominately akinetic-rigid syndrome with poor resposivness to anti-parkinsonian therapy ( 19, 20). A less common syndrome, progressive pallidal atrophy, is characterized by the onset, usually in childhood, of parkinsonism and dystonia, with gradual progression to death over the course of 20 or more years (21).

Described here is an unusual and rare syndrome with some resemblance though not identical to PPS. It is important to be aware of this syndrome as it represents one of the very few inherited neurological diseases in which pharmacological therapy can effectively control some of the neurological dysfunction. Furthermore, elaborate studies of the genetics and neuropathologic aspects might shed some light on the aetiology of the Parkinson’s disease.

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Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome