Clinical Diagnosis

Perry syndrome should be suspected in individuals with early-onset familial parkinsonism, particularly when associated with mood / personality changes (depression, apathy, withdrawal, disinhibition) and weight loss.

Central hypoventilation, if present, strongly supports the diagnosis. Sleep studies are recommended to detect hypoventilation.

Definitive diagnosis relies on identification of a disease-causing mutation in the gene DCTN1.

Molecular Genetic Testing

Gene. DCTN1 is the only gene known to be associated with Perry syndrome.

Clinical testing

• Sequence analysis. All 20 individuals with Perry syndrome who have been tested and reported so far harbor one of five mutations in exon 2 of DCTN1 (Table 2) [Farrer et al 2009, Newsway et al 2010]. Therefore, mutation detection frequency using sequence analysis is 100%. However, given the rarity of the disease and the limited number of families tested so far, it is likely that additional mutations will be identified in subsequent families.

Table 1. Summary of Molecular Genetic Testing Used in Perry Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
DCTN1	Sequence analysis	Sequence variants 2	20/20 (100%)	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Sequence analysis of DCTN1 is recommended to confirm the diagnosis in a proband. Given that all known mutations cluster in exon 2, it may be reasonable to sequence this exon first.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Distal hereditary motor neuropathy type VIIB (HMN7B) is the only other phenotype known to be associated with a mutation in DCTN1 [Puls et al 2003, Puls et al 2005]. No clinical or pathologic overlap was observed between HMN7B and Perry syndrome [Wider et al 2010]. In HMN7B, age of onset is 34 years (range: 23-44 years); affected individuals present with a lower motor neuron syndrome involving mainly the larynx, face, and upper limbs [Puls et al 2005]. In contrast with Perry syndrome in which death occurs within ten years, progression in HMN7B is very slow (>30 years in some individuals). Inheritance is autosomal dominant.

Natural History

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 48 years (range: 35-61) and the mean disease duration is five years (range: 2-10). 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, i.e., 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 genetically proven 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 “athymormia” 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 might in fact reflect psychiatric changes; however, mechanisms involving central modification of hunger sensation or an increase in metabolic rate cannot be excluded.

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, however to a lesser extent than in persons with Parkinson disease [Perry et al 1990].

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 brainstem 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 pathology predominates 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), however with distinct regional distributions.

Genotype-Phenotype Correlations

Five mutations in DCTN1 have been associated with Perry syndrome (Table 2) [Farrer et al 2009]. No clear genotype-phenotype correlation exists, in that families/individuals with the same mutation in DCTN1 do not necessarily share the same phenotype.

Persons with Perry syndrome do 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.

Anticipation

Anticipation is not observed in Perry syndrome.

Nomenclature

Perry syndrome was named after Professor Thomas L Perry, who reported with colleagues a large Canadian family with autosomal dominantly inherited parkinsonism, central hypoventilation, depression, weight loss, and sleep difficulties [Perry et al 1975, Perry et al 1990].

Some authors refer to Perry syndrome as “Parkinsonism with alveolar hypoventilation and mental depression,” however, this designation does not include all the cardinal findings.

Prevalence

Since the original reports of Perry et al [1975] and Perry et al [1990], nine additional families have been reported from Canada, the US, the UK, Japan, France, and Turkey [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, Saka et al 2010, Wider et al 2010].

Mutations in DCTN1 appear to be rare in neurodegenerative diseases: no pathogenic mutation was identified in a thorough sequencing study of 286 persons with familial Parkinson disease, TDP-43-positive FTLD, and ALS [Vilariño-Guell et al 2009].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of 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, as well as neuropsychological examination if needed

Treatment of Manifestations

Parkinsonism. Dopaminergic therapy (particularly levodopa/carbidopa) 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]. Recently, however, large doses (>2g) of levodopa/carbidopa have been used successfully to reduce rigidity, tremor, and other symptoms in two patients, 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 non-invasive) 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].

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 are appropriate.

Agents/Circumstances to Avoid

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

Testing 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 for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Perry syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Individuals diagnosed with Perry syndrome usually have an affected parent.

• A proband with Perry syndrome may have the disorder as the result of a new gene mutation. Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the mutation was de novo, the proportion of Perry syndrome caused by de novo mutations is unknown.

• If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are: (1) germline mosaicism in a parent or (2) a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical and genetic evaluations. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with Perry syndrome have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, alternate paternity, donated egg transplanted to the mother, or undisclosed adaption.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• The sibs of a proband with clinically unaffected parents are still at increased risk for Perry syndrome because of the possibility of reduced penetrance in a parent.

• If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with Perry syndrome has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of Perry syndrome caused by mutation of DCTN1 are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

DCTN1 encodes p150^(glued), the major subunit of the dynactin protein [Farrer et al 2009]. The dynactin protein complex plays a major role in retrograde axonal and cytoplasmic transport of vesicles, organelles, and other cargoes. Its complex structure allows dynactin to bind microtubules, the motor dynein, and various cargoes. In vitro experiments have shown that DCTN1 mutations that cause Perry syndrome or HMN7B alter the ability of dynactin to bind microtubules, thereby impairing its function as a transport protein [Puls et al 2003, Levy et al 2006, Farrer et al 2009]. However, the link between DCTN1 mutations and neuronal dysfunction/death remains to be elucidated. In particular, the fact that mutations located close to each other on the same gene cause completely different diseases (Perry syndrome and HMN7B) with distinct regional specificity constitutes a challenging puzzle [Wider et al 2010].

Normal allelic variants. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. The reference sequence NM_004082.3 is known as isoform 1; details of other isoforms are available at Entrez Gene.

Pathologic allelic variants. See Table 2.

Normal gene product. The DCTN1 gene encodes p150^(glued), the major subunit of the dynactin protein complex, which plays an important role in axonal and cytoplasmic transport.

Abnormal gene product. DCTN1 harboring point mutations that cause Perry syndrome and HMN7B encode a truncated form of p150^(glued), which alters the affinity of dynactin for microtubules.

Literature Cited

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9. Puls I, Oh SJ, Sumner CJ, Wallace KE, Floeter MK, Mann EA, Kennedy WR, Wendelschafer-Crabb G, Vortmeyer A, Powers R, Finnegan K, Holzbaur EL, Fischbeck KH, Ludlow CL. Distal spinal and bulbar muscular atrophy caused by dynactin mutation. Ann Neurol. 2005;57:687–94. [PMC free article: PMC1351270] [PubMed: 15852399]
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14. Tsuboi Y, Wszolek ZK, Kusuhara T, Doh-ura K, Yamada T. Japanese family with parkinsonism, depression, weight loss, and central hypoventilation. Neurology. 2002;58:1025–30. [PubMed: 11940687]
15. Vilariño-Güell C, Wider C, Soto-Ortolaza AI, Cobb SA, Kachergus JM, Keeling BH, Dachsel JC, Hulihan MM, Dickson DW, Wszolek ZK, Uitti RJ, Graff-Radford NR, Boeve BF, Josephs KA, Miller B, Boylan KB, Gwinn K, Adler CH, Aasly JO, Hentati F, Destée A, Krygowska-Wajs A, Chartier-Harlin MC, Ross OA, Rademakers R, Farrer MJ. Characterization of DCTN1 genetic variability in neurodegeneration. Neurology. 2009;72(23):2024–8. [PMC free article: PMC2692178] [PubMed: 19506225]
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17. Wider C, Dickson DW, Stoessl AJ, Tsuboi Y, Chapon F, Gutmann L, Lechevalier B, Calne DB, Personett DA, Hulihan M, Kachergus J, Rademakers R, Baker MC, Grantier LL, Sujith OK, Brown L, Calne S, Farrer MJ, Wszolek ZK. Pallidonigral TDP-43 pathology in Perry syndrome. Parkinsonism Relat Disord. 2009;15:281–6. [PMC free article: PMC2693935] [PubMed: 18723384]
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Acknowledgments

Dr. Wszolek is supported by NIH/NINDS 1P50NS072187-01, 1RC2NS070276-01, 1R01NS057567-01A2; Carl Edward Bolch, Jr. and Susan Bass Bolch Gift, and Mayo Clinic Florida Research Committee.

Dr. Wider is supported by the Swiss Parkinson’s Disease Foundation.

Author History

• 30 September 2010 (me) Review posted live

• 3 May 2010 (cw) Original submission