Perry Syndrome

Clinical characteristics.

Perry syndrome is characterized by parkinsonism, hypoventilation, depression, and weight loss. The mean age at onset is 49 years; the mean disease duration is five years. Parkinsonism and psychiatric changes (depression, apathy, character changes, and withdrawal) tend to occur early; severe weight loss and hypoventilation manifest later.

Diagnosis/testing.

The diagnosis of Perry syndrome is established in a proband with all four of the cardinal features:

• Early-onset familial parkinsonism
• Mood/personality changes
• Weight loss
• Central hypoventilation

Identification of a heterozygous DCTN1 pathogenic variant on molecular genetic testing confirms the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Dopaminergic therapy (particularly carbidopa/levodopa) should be considered in all individuals with significant parkinsonism. Although response to levodopa is often poor, some individuals may have long-term benefit. At times large doses of carbidopa/levodopa are required. Ventilation support may prolong life expectancy and improve quality of life. Those individuals with psychiatric manifestations may benefit from antidepressants and psychiatric care. Weight loss is managed with appropriate dietary changes.

Prevention of secondary complications: Adequate caloric intake to prevent weight loss.

Surveillance: Routine evaluation of weight and calorie intake, respiratory function (particularly at night or during sleep), motor function, and mood/personality changes.

Agents/circumstances to avoid: Central respiratory depressants (e.g., benzodiazepines, alcohol, narcotics).

Genetic counseling.

Perry syndrome is inherited in an autosomal dominant manner. The proportion of cases attributed to a de novo pathogenic variant is unknown. Each child of an individual with Perry syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal and preimplantation genetic testing are possible for families in which the pathogenic variant has been identified.

Suggestive Findings

Perry syndrome should be suspected in individuals with these cardinal clinical features:

• Early-onset familial parkinsonism
• Mood/personality changes (depression, apathy, withdrawal, disinhibition)
• Weight loss
• Central hypoventilation

Diagnostic criteria were previously proposed prior to the availability of molecular and immunohistochemistry testing [Wider & Wszolek 2008]. However, with the availability of molecular genetic testing they are no longer crucial for the diagnosis.

Establishing the Diagnosis

The diagnosis of Perry syndrome can be established in a proband who has ALL of the above cardinal features.

Identification of a heterozygous DCTN1 pathogenic variant on molecular genetic testing confirms the diagnosis if clinical features are inconclusive (see Table 1). Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

• Single-gene testing. Perform sequence analysis of DCTN1.
  Note: Since Perry syndrome occurs through a dominant-negative mechanism (see Molecular Genetics) and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. Detailed genetic studies for intragenic deletions or duplications have not been conducted.
• A multigene panel that includes DCTN1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes DCTN1) fails to confirm a diagnosis in an individual with features of Perry syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The cardinal findings of Perry syndrome are parkinsonism, hypoventilation, depression, and weight loss [Wider & Wszolek 2008, Wider et al 2010]. The mean age at onset is 49 years (range: 35-70 years) and the mean disease duration is five years (range: 2-14 years). Psychiatric (depression, apathy, character changes, withdrawal) and motor (parkinsonism) symptoms tend to occur early, whereas severe weight loss and hypoventilation manifest later. In most affected persons the reported cause/circumstance of death relates to sudden death/hypoventilation or suicide [Wider & Wszolek 2008].

Parkinsonism. Most affected individuals present with akinetic-rigid and rather symmetric parkinsonism that is less severe than that found in Parkinson disease. When present, tremor is often postural; however, typical rest tremor has been reported.

Hypoventilation. Alveolar hypoventilation manifests particularly at night or during sleep with tachypnea alternating with normal respiratory cycles, leading to frequent awakenings. Polysomnographic recordings show that hypoxemia and hypercapnia are of central origin; that is, there is no obstructive or structural respiratory tract abnormality. One detailed autopsy study demonstrated significant neuronal loss in regions critical for respiratory drive (ventrolateral medulla [pre-Bötzinger complex] and dorsal raphe nucleus), which may account for central hypoventilation [Tsuboi et al 2008]. Of note, hypoventilation was not reported in one of the ten families with molecularly confirmed Perry syndrome [Roy et al 1988, Farrer et al 2009].

Sleep difficulties, a common complaint, reflect hypoventilation.

Depression. Psychiatric findings are dominated by apathy, social withdrawal, and "loss of psychic self-activation" (referred to as "athymhormia" in the French literature), although true depression has also been reported.

One affected individual also presented with frontotemporal dementia-type behavioral manifestations, downward gaze abnormalities, and autonomic dysfunction [Newsway et al 2010].

Weight loss. No anatomic substrate has been reported to account for severe weight loss. Additionally, in most affected individuals weight loss cannot be attributed to significant dysphagia. Weight loss may in fact reflect psychiatric changes; however, mechanisms involving central modification of hunger sensation or an increase in metabolic rate cannot be excluded.

Autonomic failure. In one family from Japan with a DCTN1 pathogenic variant, the four affected individuals displayed early and severe autonomic failure [Ohshima et al 2010].

Neuroimaging

• Structural brain imaging is usually normal.
• Functional imaging using 18-fluorodeoxyglucose PET (FDG-PET) showed reduced metabolic rate in the lateral prefrontal and temporal regions in one study [Lechevalier et al 2005].
• Dopaminergic pathway functional imaging using 18-fluorodopa PET (FD-PET) showed reduced striatal tracer uptake [Perry et al 1990, Felicio et al 2014]. The tracer reduction uptake was also observed to a lesser extent in an individual with a DCTN1 pathogenic variant who did not have clinical features of Perry syndrome [Felicio et al 2014].
• Serotonin transporter imaging using ¹¹C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB-PET) showed reduced tracer uptake in cortical and subcortical regions [Felicio et al 2014].
• Transcranial sonography showed hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease [Saka et al 2010].
• In four affected individuals in one family from Japan, decreased cardiac uptake with [123]-metaiodobenzylguanidine scintigram was reported [Ohshima et al 2010].

Neuropathology. Histology shows severe neuronal loss in the substantia nigra, with no Lewy bodies. Lesser degrees of neuronal loss are found in the locus ceruleus, lentiform nucleus, hypothalamus, periaqueductal gray matter, dorsal raphe nucleus, and brain stem reticular formation [Wider et al 2009]. Specific loss of putative respiratory neurons was demonstrated in the ventrolateral medulla and dorsal raphe nucleus [Tsuboi et al 2008].

Immunohistochemistry shows ubiquitin- and transactive response DNA-binding protein 43 (TDP-43)-positive neuronal inclusions, dystrophic neurites, glial cytoplasmic inclusions, and axonal spheroids [Wider et al 2009]. TDP-43-positive inclusions predominate in regions belonging to the extrapyramidal system including the substantia nigra, globus pallidus, striatum, and subthalamic nucleus. Interestingly, TDP-43-positive inclusions in persons with Perry syndrome resemble those found in ubiquitin-positive frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS), although with distinct regional distributions.

Genotype-Phenotype Correlations

Eight pathogenic variants in DCTN1 have been associated with Perry syndrome (see Table 2) [Farrer et al 2009, Aji et al 2013, Araki et al 2014, Chung et al 2014, Tacik et al 2014]. No clear genotype-phenotype correlation exists, in that families/individuals with the same pathogenic variant in DCTN1 do not necessarily share the same phenotype.

Persons with Perry syndrome may not develop all of the cardinal manifestations. For example, individuals from the same family may not have hypoventilation and weight loss, and others may lack psychiatric symptoms [Wider et al 2010].

Penetrance

Although precise estimates have not been calculated given the limited number of families reported, penetrance is age related and high, with all asymptomatic heterozygotes being younger than or within the range of onset age.

Nomenclature

Before Perry syndrome became the prevailing term for the disorder, several terms had been used to describe this condition, including hereditary mental depression and parkinsonism with taurine deficiency [Perry et al 1975], familial fatal parkinsonism with alveolar hypoventilation and mental depression [Purdy et al 1979], familial parkinsonism, apathy, weight loss, and central hypoventilation [Roy et al 1988], dominantly inherited apathy, central hypoventilation, and Parkinson’s syndrome [Perry et al 1990], familial parkinsonism with athymhormia and hypoventilation [Lechevalier et al 1992], familial parkinsonism with depression [Bhatia et al 1993], and familial parkinsonism with apathy, depression, and central hypoventilation [Elibol et al 2002].

"Perry syndrome" has appeared in the literature since 2002 [Elibol et al 2002]; it is named after Professor Thomas L Perry, who reported the first Canadian family with this disease.

Prevalence

Since the original reports of Perry et al [1975] and Perry et al [1990], 21 additional families have been reported from Canada, the United States, the United Kingdom, Japan, France, Turkey, New Zealand, Colombia, Korea, Portugal, and Taiwan [Purdy et al 1979, Roy et al 1988, Lechevalier et al 1992, Tsuboi et al 2002, Lechevalier et al 2005, Wider & Wszolek 2008, Newsway et al 2010, Ohshima et al 2010, Saka et al 2010, Wider et al 2010, Aji et al 2013, Chung et al 2014, Pretelt et al 2014, Tacik et al 2014, Araki et al 2014, Caroppo et al 2014, Barreto et al 2015, Gustavsson et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Perry syndrome the following evaluations are recommended:

• Neurologic evaluation of motor function
• Sleep study and evaluation by a pulmonologist or sleep disorders consultant for ventilation support if required
• Psychiatric evaluation and (if needed) neuropsychological examination
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Parkinsonism. Dopaminergic therapy (particularly carbidopa/levodopa) should be considered in all individuals with significant parkinsonism. Response to levodopa is usually absent, erratic, or transient in Perry syndrome [Tsuboi et al 2002, Wider & Wszolek 2008]. However, large doses of carbidopa/levodopa (>2g) have been used successfully to reduce rigidity, tremor, and other symptoms in two individuals, one from the new British kindred [Newsway et al 2010] and one from the original Canadian family [J Stoessl, personal communication].

Hypoventilation. Ventilation support (invasive or noninvasive) may prolong life expectancy and have a significant impact on quality of life. Several persons without evidence of daytime central hypoventilation or respiratory troubles died suddenly at night most likely as a result of nocturnal hypoventilation. Therefore, ventilation support may be needed only during sleep [Wider & Wszolek, personal observation]. A bilateral diaphragmatic pacemaker may help combat respiratory insufficiency [Pretelt et al 2014].

Depression. Psychiatric manifestations may require antidepressants and psychiatric follow up to help reduce risk of suicide.

Weight loss. Careful weight follow up is indicated and high caloric intake should be considered if weight loss is present.

Prevention of Secondary Complications

Adequate caloric intake must be ensured to prevent weight loss.

Surveillance

Routine evaluation of weight and calorie intake, respiratory function (particularly at night or during sleep), motor function, and mood/personality changes is appropriate.

Agents/Circumstances to Avoid

Use of central respiratory depressants (e.g., benzodiazepines, alcohol, narcotics) should be minimized.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.