Perry Syndrome
A number sign (#) is used with this entry because Perry syndrome is caused by heterozygous mutation in the DCTN1 gene (601143) on chromosome 2p13.
DescriptionPerry syndrome is an autosomal dominant neurodegenerative disorder classically characterized by adult-onset parkinsonism and depression, followed by weight loss and respiratory hypoventilation (Perry et al., 1975). The phenotype has subsequently been expanded to include features that overlap with other neurodegenerative conditions, including frontotemporal dementia (see, e.g., 600274) and progressive supranuclear palsy (PSP; 601104). There is intrafamilial variation in the manifestations of the disorder (summary by Caroppo et al., 2014; review by Wider et al., 2010).
Mutation in the DCTN1 gene can also cause distal motor neuronopathy type VIIB (HMN7B; 607641) and confer increased susceptibility to amyotrophic lateral sclerosis (ALS; see 105400).
Clinical FeaturesPerry et al. (1975) described an unusual neuropsychiatric disorder inherited in an autosomal dominant fashion through 3 generations of a family. Symptoms began late in the fifth decade in 6 affected persons and death occurred after 4 to 6 years. The earliest and most prominent symptom was mental depression not responsive to antidepressant drugs or electroconvulsive therapy. Sleep disturbances, exhaustion and marked weight loss were features. Parkinsonism developed later, and respiratory failure occurred terminally. Perry et al. (1975) found greatly diminished taurine in plasma and cerebrospinal fluid, and at autopsy all regions of the brain showed markedly reduced taurine content. Taurine is a putative inhibitory synaptic transmitter.
Perry et al. (1990) described 2 additional affected persons in this kindred. Neuropathologic studies showed showed severe neuronal loss and reactive gliosis in the substantia nigra. Neurochemical studies showed a marked depletion of dopamine in the substantia nigra, putamen, and caudate nucleus, as well as reduction in serotonin content in the substantia nigra. In both patients, glutamate contents were low in frontal cortex and thalamus, and GABA contents were low in thalamus and substantia nigra. In addition, phosphoethanolamine contents were reduced in all brain regions of both patients, especially in the substantia nigra. One patient with severe symptoms had low levels of homovanillic acid, 5-hydroxyindoleacetic acid, and GABA in his CSF repeatedly for 3 years before death at age 58. The second patient died at the age of 51 of an unrelated cause before developing symptoms of the familial disorder.
Between the times of the 2 reports by Perry et al. (1975, 1990), 2 additional unrelated families affected with the same disorder were reported (Purdy et al., 1979; Roy et al., 1988). Brain content of taurine was normal in the patients reported by Purdy et al. (1979). Both Purdy et al. (1979) and Roy et al. (1988) emphasized alveolar hypoventilation as a feature. Apathy and progressive weight loss were also emphasized as early symptoms. Sudden death, presumably from failure of central respiratory control, was a characteristic feature. Roy et al. (1988) described a patient who after multiple episodes of respiratory arrest was 'successfully managed with aggressive pulmonary care, tracheostomy, and intermittent home mechanical ventilation, which, combined with carbidopa/levodopa, allowed for a functional lifestyle with improvement in apathy, mobility, and nutritional status.'
Lechevalier et al. (1992) described 5 cases in 1 family. Death caused by central respiratory disorders occurred after 6 to 8 years of progressive course. Autopsies in 2 cases were reported.
Tsuboi et al. (2002) reported a Japanese family in which 5 affected members presented in the third and fourth decades with parkinsonism and depression. Three affected members were studied in detail. Weight loss and central hypoventilation developed in the later stages, leading to death in at least 1 member. The disorder showed autosomal dominant inheritance. Tsuboi et al. (2002) noted that hypoventilation is the most critical feature of the disorder and suggested that altered neurotransmitter levels may be causative.
Wider et al. (2010) reported 2 unrelated families of Japanese origin with Perry syndrome. Two affected individuals in 1 family presented at age 47 years with parkinsonism and respiratory symptoms; neither had depression or weight loss. In the second family, 2 sibs presented with resting tremor and weight loss, respectively. Both developed levodopa-responsive parkinsonism, weight loss, and hypoventilation. Neither developed depression or apathy.
Newsway et al. (2010) reported a man with Perry syndrome who developed progressive symptoms in his mid-forties. In addition to parkinsonism, psychiatric disturbances, and weight loss, he also showed signs of frontotemporal dementia as well as slowing of vertical downgaze and midbrain atrophy, reminiscent of progressive supranuclear palsy. Genetic analysis identified a heterozygous mutation in the DCTN1 gene (G71R; 601143.0006). The findings expanded the phenotype associated with DCTN1 mutations.
Caroppo et al. (2014) reported a large 3-generation French family in which 4 individuals had variable manifestations of an adult-onset neurodegenerative disorder associated with a heterozygous missense mutation in the DCTN1 gene (G71E; 601143.0008). The age at symptom onset ranged from 39 to 59 years, and the age of death from 43 to 64 years. The duration of disease was 4 to 5 years in all patients except 1 who survived for 14 years after onset. One patient presented with parkinsonism, 1 with gait imbalance, and 2 with depression or apathy. All eventually developed parkinsonism and frontal signs, leading to a diagnosis of behavioral variant of frontotemporal dementia in 2 patients. One patient developed oculomotor abnormalities consistent with progressive supranuclear palsy, and another had respiratory arrest, consistent with Perry syndrome. The features of 4 affected individuals from the previous generation were also reported. All had parkinsonism, and 1 also had psychiatric symptoms and respiratory failure, leading to a diagnosis of Perry syndrome. Another had oculomotor abnormalities, consistent with PSP. Overall, the clinical diagnoses were Parkinson disease in 4 patients, Perry syndrome in 1, progressive supranuclear palsy in 2, and frontotemporal dementia in 2. None of the patients had symptoms of amyotrophic lateral sclerosis.
Neuropathologic Features
By neuropathologic examination of 8 affected individuals, Wider et al. (2010) demonstrated that Perry syndrome is a TDP43 (605078)-related proteinopathy. There was severe neuronal loss in the substantia nigra and locus ceruleus without Lewy bodies. Surviving neurons contained intranuclear and cytoplasmic TDP43-positive inclusions as well as dystrophic neurites, axonal spheroids, and glial cytoplasmic inclusions. Immunohistochemistry for MAPT (157140) and SNCA (163890) was negative. Most of the pathology in Perry syndrome showed pallidonigral predominance, which could explain the parkinsonism, with sparing of the cortex, hippocampus, and motor neurons, consistent with the lack of dementia and motor neuron disease in most patients. Putative loss of neurons in the brainstem may account for central hypoventilation.
Molecular GeneticsIn affected members of 8 families with Perry syndrome, Farrer et al. (2009) identified 5 different heterozygous mutations in the DCTN1 gene (see, e.g., 601143.0006-601143.0007). In vitro functional expression studies indicated that the mutations resulted in decreased microtubule binding and intracytoplasmic inclusions.