Clinical characteristics.

The spectrum of DCTN1-related neurodegeneration includes Perry syndrome, distal hereditary motor neuronopathy type 7B (dHMN7B), frontotemporal dementia (FTD), motor neuron disease / amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy. Some individuals present with overlapping phenotypes (e.g., FTD-ALS, Perry syndrome-dHMN7B).

Perry syndrome (the most common of the phenotypes associated with DCTN1) is characterized by parkinsonism, neuropsychiatric symptoms, hypoventilation, and weight loss. The mean age of onset in those with Perry syndrome is 49 years (range: 35-70 years), and the mean disease duration is five years (range: 2-14 years). In most affected persons, the reported cause/circumstance of death relates to sudden death/hypoventilation or suicide.

Diagnosis/testing.

The diagnosis of DCTN1-related neurodegeneration is established in a proband by identification of a heterozygous DCTN1 pathogenic variant on molecular genetic testing.

Management.

Treatment of manifestations: Dopaminergic therapy in individuals with significant parkinsonism; ventilation support; anti depressants and psychiatric care for depression; high caloric intake for weight loss; feeding tube when needed to prevent aspiration pneumonia and provide adequate caloric intake; arytenoidectomy for vocal cord paralysis to provide a larger airway for respiration; orthosis for neuropathic foot.

Surveillance: Evaluation of weight and calorie intake, respiratory function (particularly at night or during sleep), motor function, and mood/personality changes annually or more frequently as needed.

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

Genetic counseling.

DCTN1-related neurodegeneration is inherited in an autosomal dominant manner. Most individuals diagnosed with DCTN1-related neurodegeneration have an affected parent. Less commonly, individuals diagnosed with DCTN1-related neurodegeneration have the disorder as the result of a de novo pathogenic variant. Each child of an individual with DCTN1-related neurodegeneration has a 50% chance of inheriting the pathogenic variant. Once the DCTN1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for DCTN1-related neurodegeneration are possible.

Suggestive Findings

DCTN1-related neurodegeneration should be suspected in individuals with any combination of the following clinical features, family history of the following features, or neuroimaging findings.

Clinical findings

• Parkinsonism
• Mood/personality/cognitive changes (depression, apathy, withdrawal, disinhibition, dementia)
• Weight loss
• Breathing disturbances (in particular central hypoventilation)
• Muscle atrophy
• Autonomic dysfunction
• Vocal fold paralysis
• Facial weakness

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Neuroimaging and other studies [Felicio et al 2014, Barreto et al 2015, Hwang et al 2016, Konno et al 2017, Mishima et al 2018, Convery et al 2019, Coughlin & Litvan 2020, Masrori & Van Damme 2020, Saka et al 2010, Tian et al 2020, Mishima et al 2021, Tsuboi et al 2021, Zhang et al 2021]

• Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain.
• ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) and single-photon emission CT (SPECT) may demonstrate decreased glucose metabolism and blood perfusion in the frontal, temporal, parietal, and occipital lobes.
• ¹²³I-Ioflupane SPECT (DaTscan) may show reduced tracer uptake in the striatum, reflecting presynaptic dopaminergic dysfunction.
• ¹⁸F-6-fluoro-L-dopa (FDOPA) and ¹¹C-dihydrotetrabenazine (DTBZ) PET may detect a decrease in striatal tracer uptake, reflecting presynaptic dopaminergic dysfunction.
• ¹¹C-raclopride (RAC) PET may find an abnormal striatal tracer uptake, reflecting disturbances of postsynaptic dopaminergic function.
• 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission.
• Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease.
• ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) myocardial scintigraphy may demonstrate reduced cardiac uptake, reflecting autonomic dysfunction.
• Electroneurography may reveal length-dependent predominantly motor neuropathy.
• Electromyography may show evidence of denervation.

Establishing the Diagnosis

The diagnosis of DCTN1-related neurodegeneration is established in a proband with suggestive findings and a heterozygous DCTN1 pathogenic (or likely pathogenic) variant identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous DCTN1 variant of uncertain significance does not establish or rule out this diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Therefore, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with parkinsonism are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The spectrum of DCTN1-related neurodegeneration includes Perry syndrome, distal hereditary motor neuronopathy type 7B (dHMN7B), frontotemporal dementia (FTD), motor neuron disease / amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy. Some individuals present with overlapping phenotypes (e.g., FTD-ALS, Perry syndrome-dHMN7B) [Caroppo et al 2014, Konno et al 2017, Zhang et al 2021]. In most families, the phenotype is consistent among affected family members. However, not infrequently, the same DCTN1 pathogenic variant may manifest with a different clinical phenotype even within the same family.

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been identified. While affected family members often share the same phenotype, intrafamilial variability has also been reported. For example, individuals from one Chinese family with the same DCTN1 pathogenic variant presented with dHMN7B, Perry syndrome, or overlapping features of dHMN7B-Perry syndrome [Zhang et al 2021].

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 age of onset.

Prevalence

Since the discovery of DCTN1-related neurodegeneration [Puls et al 2003], more than 30 families and approximately 200 affected individuals have been reported. The majority of reports included individuals with Perry syndrome (~80%).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DCTN1-related neurodegeneration, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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 [Konno et al 2017, Mishima et al 2018]. However, large doses of carbidopa/levodopa (>2g) have been used successfully to reduce rigidity, tremor, and other symptoms in two individuals [Newsway et al 2010; J Stoessl, personal communication].

Hypoventilation. Ventilation support (invasive or noninvasive) may prolong life expectancy and have a significant effect on quality of life. Several persons without evidence of daytime central hypoventilation or respiratory compromise 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 be helpful for respiratory insufficiency [Konno & Wszolek 2018].

Depression. Psychiatric manifestations may require antidepressants and management by a psychiatrist to reduce the risk of suicide.

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

Dysphagia. Nasogastric or preferably percutaneous endoscopic gastrostomy (PEG) feeding should be considered to prevent aspiration pneumonia and provide adequate caloric intake.

Vocal cold paralysis. Arytenoidectomy should be considered to provide larger airway for respiration.

Neuropathic foot. Orthosis should be considered to improve the function of the foot.

Surveillance

Evaluate weight and calorie intake, respiratory function (particularly at night or during sleep), motor function, and mood/personality changes annually or more frequently as needed.

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.

Mode of Inheritance

DCTN1-related neurodegeneration is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with DCTN1-related neurodegeneration have an affected parent. Affected family members typically have a similar phenotype. However, intrafamilial variability has been reported and family members who are heterozygous for the same DCTN1 pathogenic variant may not infrequently manifest a different clinical phenotype within the spectrum of DCTN1-related neurodegeneration.
• Less commonly, individuals diagnosed with DCTN1-related neurodegeneration have the disorder as the result of a de novo pathogenic variant. The proportion of probands who have a de novo pathogenic variant is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with DCTN1-related neurodegeneration may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the DCTN1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. In most families, heterozygous sibs have a similar phenotype; however, not infrequently, the same DCTN1 pathogenic variant may manifest with a different clinical phenotype within the spectrum of DCTN1-related neurodegeneration.
• If the DCTN1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the DCTN1 pathogenic variant but are clinically unaffected, the risk to sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for DCTN1-related neurodegeneration because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with DCTN1-related neurodegeneration has a 50% chance of inheriting the DCTN1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has a DCTN1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the DCTN1 pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of DCTN1-related neurodegeneration, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the DCTN1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for DCTN1-related neurodegeneration are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

DCTN1 encodes dynactin subunit 1, the major subunit of the dynactin protein complex [Deshimaru et al 2021]. The dynactin protein complex plays a major role in retrograde axonal and cytoplasmic transport of vesicles, organelles, and other cargos through binding to its complex structure. Dynactin subunit 1 contains the cytoskeleton-associated protein glycine-rich (CAP-Gly) domain that is essential for microtubule binding. All DCTN1 variants found in individuals with Perry syndrome and most variants associated with dHMN7B are located in this domain. However, some DCTN1 variants identified in individuals with dHMN7B and motor neuron disease are located in the C-terminal half of the protein [Zhang et al 2021]. In vitro, DCTN1 variants alter the ability of dynactin to bind microtubules, thereby impairing its function as a transport protein [Konno et al 2017, Mishima et al 2018].

Under physiologic conditions, dynactin subunit 1 interacts with TDP-43 and regulates its localization and aggregation. Dysfunction of dynactin subunit 1 may disrupt this process and underlie abnormal TDP-43 aggregation [Deshimaru et al 2021].

The link between DCTN1 pathogenic variants and neuronal dysfunction/death remains to be elucidated. For example, the fact that the same pathogenic variants cause Perry syndrome and dHMN7B constitutes a challenging puzzle.

Mechanism of disease causation. Most reported DCTN1 pathogenic variants are missense variants (26/29). Splicing alterations (2/29) and frameshift changes (1/29) have also been identified. DCTN1 variants alter the ability of dynactin to bind microtubules, thereby impairing its function as a transport protein. The most frequently reported variant, p.Gly71Arg, has a dominant-negative effect on the initiation of retrograde transport [Moughamian & Holzbaur 2012]. Several variants on the C-terminal half have been linked to reduced DCTN1 expression [Tian et al 2020].

DCTN1-specific laboratory technical considerations. Alternative splicing results in multiple transcript variants encoding distinct isoforms. The reference sequence NM_004082.4 is known as isoform 1; details of other isoforms are available at Entrez Gene.

Author Notes

Jaroslaw Dulski, MD, PhD is a specialist in neurology and an assistant professor at the Medical University of Gdansk and St Adalbert Hospital in Gdansk, Poland. His primary interests are neurogenetics and movement disorders. Dr Dulski has been involved in the clinical management of Perry syndrome since 2016.

Takuya Konno, MD, PhD is an assistant professor in the Department of Neurology, Brain Research Institute, Niigata University in Niigata, Japan. He has been involved in the clinical management of neurodegenerative and movement disorders. He has special interest in genetic disorders including DCTN1-related neurodegeneration.

Zbigniew K Wszolek, MD, is a professor of neurology at the Mayo Clinic College of Medicine and Science, and the Haworth Family Professor in Neurodegenerative Diseases. Dr Wszolek has been researching Perry syndrome for 18 years. He has substantially contributed to the understanding of the clinical, pathologic, and genetic aspects of Perry syndrome, and he is a co-discoverer of the causative DCTN1 mutations.

Acknowledgments

We are grateful to the patients and their families for their collaboration.

Dr Dulski received honoraria for lectures and training courses from VM Media Ltd, Radosław Lipiński 90 Consulting, Ipsen.

Dr Wszolek is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, the gifts from The Sol Goldman Charitable Trust, and the Donald G and Jodi P Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc (BHV4157-206 and BHV3241-301), Neuraly, Inc (NLY01-PD-1), and Vigil Neuroscience, Inc (VGL101-01.001) grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc. He is a co-editor-in-chief of the Neurologia I Neurochirurgia Polska (Polish Journal of Neurology and Neurosurgery). The work on this manuscript has been supported by the the Haworth Family Professorship in Neurodegenerative Diseases fund and The Albertson Parkinson's Research Foundation.

Author History

Jaroslaw Dulski, MD, PhD (2021-present
Takuya Konno, MD (2016-present)
Christian Wider, MD; Centre Hospitalier Universitaire Vaudois, Lausanne (2010-2016)
Zbigniew Wszolek, MD (2010-present)

Revision History

• 5 August 2021 (sw) Comprehensive update posted live
• 29 September 2016 (sw) Comprehensive update posted live
• 9 May 2013 (me) Comprehensive update posted live
• 30 September 2010 (me) Review posted live
• 3 May 2010 (cw) Original submission

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