Review
Rapidly progressive familial parkinsonism with central hypoventilation, depression and weight loss (Perry syndrome)—A literature review

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Abstract

Autosomal dominant parkinsonism, hypoventilation, depression and weight loss (Perry syndrome) has been reported in only seven families worldwide. It is a rapidly progressive disease leading to death from respiratory insufficiency within a few years. Parkinsonism is usually mild, with bradykinesia, rigidity, rest and postural tremor, and axial signs. Response to levodopa is poor although transient response has been occasionally observed. The early signs include parkinsonism, depression and weight loss, whereas hypoventilation is a late feature. Neuropathology shows severe neuronal loss in the substantia nigra, less prominent neuronal loss in the locus coeruleus, and no or few Lewy bodies. In this review, we also propose diagnostic criteria for this condition.

Introduction

The association of parkinsonism, hypoventilation and depression was first recognized in two unrelated Canadian families, and reported by Perry et al. in 1975 and then by Purdy et al. in 1979 [1], [2], [3]. Since then, only five additional kindreds have been described in Japan, France, the United Kingdom, the United States (of Irish descent) and Turkey [4], [5], [6], [7], [8], [9], [10]. No sporadic cases have been identified so far. Typical presentation includes moderate parkinsonism, apathy and depression, progressive weight loss, and central respiratory failure. The response to levodopa is usually poor. Although the clinical manifestations may vary, the evolution is relentless, ultimately leading to death within a few years.

In this article, we review the available clinical and pathological data, with the aim of bringing this rare and probably underdiagnosed condition to the parkinsonian community. We hope that studying rare conditions such as Perry syndrome will help us understand more common neurodegenerative diseases. We also propose diagnostic criteria for this condition.

Section snippets

Genealogical studies, known kindreds and mode of inheritance

In the seven families reported so far, the disease follows an autosomal dominant transmission pattern with a high penetrance (close to 50 percent affected subjects among the offspring). The pedigrees are small, with 2, 5, 5, 5, 6, 8 and 10 affected subjects spanning 2–3 generations. Among the 42 patients described, there is a moderate male predominance with 26 males and 16 females (male to female ratio, 1.6). This proportion is comparable to the one found in both sporadic and familial Parkinson

Clinical features

The cardinal symptoms of Perry syndrome consist of:

  • autosomal dominant parkinsonism,

  • hypoventilation,

  • depression, apathy, social withdrawal and suicidal attempts,

  • weight loss.

They will be discussed in the present section, along with the clinical course.

Biochemical studies

In all reports, routine laboratory tests were normal or negative, including serum electrolytes, blood cell count and morphology, and kidney and liver function tests. Serum and urine copper, ceruloplasmin, VDRL, autoantibody screen, lactate, thyroid function tests, protein electrophoresis and vitamin B12 levels were all normal or negative [4], [6], [7]. CSF cell count, glucose and protein content were normal [7], with the exception of one patient in whom protein content was minimally elevated [2]

Pathology

The universal finding is massive cell loss and gliosis in the substantia nigra (SN), more pronounced in the pars compacta, with very few to no Lewy bodies [1], [2], [3], [4], [5], [6], [7], [8]. The SN lesions are more severe than those usually seen in sporadic PD. Other regions displaying cell loss include the locus coeruleus, the caudate nucleus, the putamen and the globus pallidus. Some authors have reported gliosis in the nucleus tractus solitarius, in the dorsal nucleus of the vagus nerve

Parkinsonism

Parkinsonism in Perry syndrome is most certainly due to the substantial neuronal cell loss seen in the SN. However, parkinsonism is often mild, which is in contrast with the severity of the SN cell loss. This raises the possibility of compensatory mechanisms including increased dopaminergic transmission in the remaining neurons [3]. Such hypotheses have been put forward in the early phases of sporadic PD, where partial damage to the nigrostriatal projections may result in a compensatory

Proposed diagnostic criteria

We propose clinico-pathologic criteria for the diagnosis of Perry syndrome (Table 2). It is important to distinguish Perry syndrome from other forms of familial parkinsonism, first because of its poor prognosis, and second in order to take appropriate measures regarding the risks due to hypoventilation, depression and suicidal attempts.

By applying these criteria, all but two of the previously reported families would have a definite diagnosis. In the Turkish family, there is no pathology report

Future prospects

This rapidly progressive and fatal disease remains of undetermined genetic cause. Of all the families reported so far, none is large enough to proceed with linkage analysis. Thorough genetic investigation to uncover the molecular basis of this condition will require the expansion of known families and the identification of additional kindreds. This goal will only be achieved through collaborative studies. Additional insight into the genetic and pathologic bases of Perry syndrome will not only

Acknowledgments

CW received support from the Swiss National Science Foundation, the Swiss Parkinson's disease Foundation, and the Robert and Clarice Smith Fellowship program. ZKW is supported by the Morris K. Udall NIH/NINDS Parkinson Disease Center of Excellence Grant awarded to the Mayo Clinic Jacksonville P50NS40256, by NIH/NIA P01AG017216 and NIH/NIA R01AG015866 Grants, and by the Pacific Alzheimer Research Foundation Centre Grant PARF C06-01.

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