Perry syndrome (ORPHA:178509)
A rare inherited neurodegenerative disorder characterized by rapidly progressive early-onset parkinsonism, central hypoventilation, weight loss, insomnia and depression.
Epidemiology
The prevalence is unknown. It has been described in 53 cases from 11 families to date in Canada, U.S., U.K., France, Turkey and Japan.
Clinical description
Perry syndrome has a mean age of onset of 48 years (range 35-61) and presents with parkinsonism (akinetic-rigid and rather symmetric), psychiatric changes manifesting as depression, lethargy, withdrawal, apathy, and changes in character, as well as sleep difficulties. The usual duration of Perry syndrome is about 5 years, with severe weight loss and central hypoventilation being seen late in the disease course. Marked autonomic dysfunction was reported in one family from Japan. Patients are often bedridden or wheelchair bound as motor impairment may be severe at a later stage of the disease.
Etiology
Perry syndrome is caused by mutations (five identified to date) in exon 2 of the dynactin DCTN1 gene coding for p150glued, the major subunit of the dynactin protein complex. Mutations in this gene alter the binding affinity of dynactin for microtubules and consequently this leads to the impairment of this important transport protein. Nigral neurons seem to be more affected by the dysfunction of this protein, explaining their increased cell death and the distinct pathology seen in Perry syndrome.
Diagnostic methods
Diagnosis is based on clinical findings of early-onset parkinsonism combined with depression, weight loss and hypoventilation and is confirmed by a molecular genetic test finding a mutation in the DCTN1 gene. Major histological findings consist of neuronal loss and TAR DNA-binding protein (TDP-43)-positive pathology in the substantia nigra and locus coeruleus, without Lewy bodies. Sleep studies should be performed to detect hypoventilation.
Differential diagnosis
The main differential diagnoses are other forms of familial early-onset parkinsonism (in particular those associated with mutations in the PARK2, PINK1, PARK7 and LRRK2 genes) as well as frontotemporal dementia (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible in laboratories that offer custom prenatal testing for families with a known DCTN1 mutation.
Genetic counseling
Perry syndrome is inherited in an autosomal dominant manner with full penetrance and children of a parent with the disease have a 50% risk of also having the mutation and developing the disease. Pre-symptomatic diagnosis can be offered to at-risk individuals.
Management and treatment
There is no cure for Perry syndrome. Symptomatic treatment requires a multidisciplinary team. Dopaminergic therapy is given to patients to help with parkinsonism, usually using levodopa / carbidopa. Response to levodopa can be erratic or absent but large doses (>2g) have been successful in reducing symptoms in several patients. Patients with hypoventilation require ventilator support (invasive or non-invasive), particularly at night. Respiratory function should be monitored continuously. Psychiatric follow-up along with antidepressant drugs are needed to manage depression and prevent suicide. Weight should be monitored and a high caloric diet should be implemented when weight loss is present. With worsening symptoms hospitalization and major medical assistance is often required.
Prognosis
Perry syndrome progresses rapidly and the prognosis is poor. Death is due to respiratory insufficiency or suicide or, in some cases, can be sudden and unexplained. Ventilation assistance may prolong survival with an acceptable quality of life.

                            Last update: 
                            October 2012


                            - Expert reviewer(s): 
                            Dr Christian WIDER