Perry 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 ... Perry 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. Neuropathologically, both 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.
In 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 ... In 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.
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. ...
DiagnosisClinical 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. Autonomic dysfunction has been reported in one family and may support the diagnosis.Definitive diagnosis relies on identification of a disease-causing mutation in DCTN1.Molecular Genetic TestingGene. DCTN1 is the only gene in which mutations are known to cause Perry syndrome.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Perry Syndrome View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityDCTN1Sequence analysis of select exonsSequence variants in exon 2 2, 3UnknownClinicalSequence analysisSequence variants 324/24 (100%) 4Deletion/duplication analysis 5Unknown 6Unknown, none reported 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Exons tested may vary between laboratories.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. All 24 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, Ohshima 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.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. No deletions or duplications involving DCTN1 have been reported to cause Perry syndrome.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).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. If no mutation is identified by sequence analysis, deletion/duplication analysis may be considered, although the diagnostic yield is unknown.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.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, the mean age at 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.
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]....
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 “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 mutation, 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, however to a lesser extent than in persons with Parkinson disease [Perry et al 1990].In four affected individuals in one family from Japan, decreased cardiac uptake with [123]I-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 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), although with distinct regional distributions.
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....
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].
Other forms of familial early-onset parkinsonism that need to be distinguished from Perry syndrome include those types caused by mutations in PARK2 (see Parkin Type of Early-Onset Parkinson Disease), PINK1 (see PINK1 Type of Young-Onset Parkinson Disease), PARK7 (formerly DJ-1), or LRRK2 (see LRRK2-Related Parkinson Disease). The findings of personality changes, weight loss, and hypoventilation in Perry syndrome tend to distinguish it from other forms of early-onset Parkinson disease (see Parkinson Disease Overview). Additionally, response to standard doses of levodopa is usually poorer or of shorter duration in Perry syndrome than in other forms of early-onset Parkinson disease....
Differential DiagnosisOther forms of familial early-onset parkinsonism that need to be distinguished from Perry syndrome include those types caused by mutations in PARK2 (see Parkin Type of Early-Onset Parkinson Disease), PINK1 (see PINK1 Type of Young-Onset Parkinson Disease), PARK7 (formerly DJ-1), or LRRK2 (see LRRK2-Related Parkinson Disease). The findings of personality changes, weight loss, and hypoventilation in Perry syndrome tend to distinguish it from other forms of early-onset Parkinson disease (see Parkinson Disease Overview). Additionally, response to standard doses of levodopa is usually poorer or of shorter duration in Perry syndrome than in other forms of early-onset Parkinson disease.Mood/personality changes in Perry syndrome may suggest frontotemporal dementia, which has similar age at onset and often associates with levodopa-resistant parkinsonism. Perry syndrome needs to be distinguished from frontotemporal dementia caused by mutations in MAPT (see MAPT-Related Disorders or in GRN (see GRN-Related Frontotemporal Dementia). Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with Perry syndrome the following evaluations are recommended:...
ManagementEvaluations 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 functionSleep study and evaluation by a pulmonologist or sleep disorders consultant for ventilation support if requiredPsychiatric evaluation, as well as neuropsychological examination if neededMedical genetics consultationTreatment of ManifestationsParkinsonism. 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]. More 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 ComplicationsAdequate caloric intake must be ensured to prevent weight loss. SurveillanceRoutine 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 AvoidUse of central respiratory depressants (e.g., benzodiazepines, alcohol, narcotics) should be minimized.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Perry Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDCTN12p13.1Dynactin subunit 1IPN Mutations, DCTN1 alsod/DCTN1 genetic mutations ALS mutation database DCTN1 homepage - Leiden Muscular Dystrophy pagesDCTN1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Perry Syndrome (View All in OMIM) View in own window 168605PERRY SYNDROME 601143DYNACTIN 1; DCTN1Molecular Genetic PathogenesisDCTN1 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.Table 2. DCTN1 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.175G>Ap.Gly59SerNM_004082.4 NP_004073.2c.211G>Ap.Gly71Argc.212G>Ap.Gly71Gluc.212G>Cp.Gly71Alac.214A>Cp.Thr72Proc.221A>Cp.Gln74ProSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. DCTN1 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.