DNAJC6 Parkinson Disease

Synonym: PARK-DNAJC6

Kurian MA, Abela L.

Publication Details

Estimated reading time: 25 minutes

Summary

Clinical characteristics.

DNAJC6 Parkinson disease is a complex early-onset neurologic disorder whose core features are typical parkinsonian symptoms including bradykinesia, resting tremor, rigidity, and postural instability.

The majority of individuals have juvenile onset and develop symptoms before age 21 years. Developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features occur in the majority of individuals with juvenile onset and often precede parkinsonism. The onset of parkinsonian features usually occurs toward the end of the first or beginning of the second decade and the disease course is rapidly progressive with loss of ambulation in mid-adolescence in the majority of individuals. Additional features include gastrointestinal manifestations and bulbar dysfunction.

A minority of individuals with DNAJC6 Parkinson disease develop early-onset parkinsonism with symptom onset in the third to fourth decade and absence of additional neurologic features.

Diagnosis/testing.

The diagnosis of DNAJC6 Parkinson disease is established in a proband with suggestive phenotypic findings and biallelic pathogenic variants in DNAJC6 identified by molecular genetic testing.

Management.

Treatment of manifestations: Levodopa, dopaminergic agonists, and/or anticholinergics. Medications and/or surgical interventions for dystonia and spasticity. Medications (e.g., sodium valproate, clonazepam, levetiracetam, piracetam) as needed for myoclonus. Multidisciplinary management including physical and occupational therapy, speech and language therapy, and special education services as indicated for developmental delay and intellectual disability. Seizures are treated with anti-seizure medication. Psychiatric disorders are treated as per neuropsychiatry. Sleep aids (e.g., sleep system, conservative measures, melatonin, sedative medications) as needed for sleep disorder. Feeding support and medications as needed for constipation, sialorrhea, and reflux. Supportive rehabilitation devices and equipment for orthopedic manifestations. Surgical interventions as needed for hip dislocation or kyphoscoliosis. Low-vision therapy, glasses, and surgical intervention as needed for strabismus and/or vision deficits.

Surveillance: Physical therapy, occupational therapy, and speech and language therapy evaluations every six months or as needed. Assess for new manifestations such as seizures, changes in tone, and movement disorders at each visit. Repeat electroencephalogram as needed. Monitor those with seizures as clinically indicated. Psychiatric assessment as needed. Sleep study/polysomnography as needed. Growth assessment at each visit in children. Assessment of nutritional status at each visit. Swallowing assessment to evaluate risk of aspiration as needed. Gastroenterology evaluation and gastroscopy as needed. Hip and spine radigraphs every six months in individuals older than age two years who are nonambulatory and in individuals with signs and symptoms concerning for spinal deformity. Follow-up ophthalmology evaluation for those with vision concerns.

Agents/circumstances to avoid: Dopamine antagonists and vesicular monoamine transporter 2 (VMAT2) inhibitors should be avoided as they could aggravate dopamine deficiency.

Genetic counseling.

DNAJC6 Parkinson disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DNAJC6 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither DNAJC6 pathogenic variant. (Note: The risk to heterozygotes of developing manifestations is not yet determined.) Once the DNAJC6 pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

GeneReview Scope

Table Icon

Table

DNAJC6 juvenile Parkinson disease DNAJC6 type of early-onset Parkinson disease

Diagnosis

Suggestive Findings

DNAJC6 Parkinson disease should be considered in individuals with the following findings.

Juvenile-onset presentation (onset age <21 years)

  • Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) usually at the end of the first or beginning of the second decade
  • Rapid disease progression and neurologic regression after onset of parkinsonism
  • Loss of ambulation often in mid-adolescence
  • Parkinsonian symptoms often difficult to treat with common medications used for Parkinson disease (e.g., levodopa)
  • Additional features that often precede the parkinsonian features: developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features (anxiety, psychosis, behavior disorders, sleep disorders)

Early-onset presentation (onset age 21- 44 years)

  • Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) in the third to fourth decade
  • Slower disease progression than juvenile-onset presentation
  • Some response to dopaminergic medications

Establishing the Diagnosis

The diagnosis of DNAJC6 Parkinson disease is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in DNAJC6 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic DNAJC6 variants of uncertain significance (or of one known DNAJC6 pathogenic variant and one DNAJC6 variant of uncertain significance) does not establish or rule out the diagnosis.

Because the phenotype of DNAJC6 Parkinson disease is indistinguishable from many other inherited causes of Parkinson disease, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of DNAJC6, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

  • A Parkinson disease multigene panel that includes DNAJC6 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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.
  • Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table Icon

Table 1.

Molecular Genetic Testing Used in DNAJC6 Parkinson Disease

Clinical Characteristics

Clinical Description

DNAJC6 Parkinson disease is a complex early-onset neurologic disorder characterized by typical parkinsonian symptoms including bradykinesia, resting tremor, rigidity, and postural instability. To date, 20 individuals with biallelic DNAJC6 pathogenic variants have been identified, 19 of whom have prominent motor features [Edvardson et al 2012, Vauthier et al 2012, Köroğlu et al 2013, Elsayed et al 2016, Olgiati et al 2016, Mittal 2020, Ng et al 2020]. One additional individual with early-onset parkinsonism and other findings consistent with DNAJC6 Parkinson disease was compound heterozygous, with one DNAJC6 variant predicted to be pathogenic and one DNAJC6 variant that may potentially be associated with disease manifestations; further study is needed to determine if this variant is benign or pathogenic [Li et al 2020].

The following description of the phenotypic features associated with this condition is based on reports of the 20 individuals with biallelic DNAJC6 pathogenic variants.

Table Icon

Table 2.

DNAJC6 Parkinson Disease: Frequency of Select Features

Parkinsonism is the predominant motor phenotype in individuals with DNAJC6 Parkinson disease. Bradykinesia and resting tremor were the motor features at the time of presentation, followed by rigidity and gait abnormalities. Hypomimia and postural instability often occurred later in the disease course.

Juvenile-Onset Parkinsonism

The majority of individuals reported to date (14/21) developed symptoms before age 21 years [Edvardson et al 2012, Vauthier et al 2012, Köroğlu et al 2013, Elsayed et al 2016, Mittal 2020, Ng et al 2020]. The onset of parkinsonian features usually occurred toward the end of the first or beginning of the second decade (median age of onset 10 years, range 7-14 years) and the disease course was then rapidly progressive with loss of ambulation in mid-adolescence in the majority of individuals. Loss of ambulation is likely due to multiple factors including developmental motor regression, progressive bradykinesia leading to akinesia, and also limb rigidity and postural instability.

Developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features are observed in the majority of individuals with juvenile onset and often precede the movement disorder [Edvardson et al 2012, Vauthier et al 2012, Köroğlu et al 2013, Elsayed et al 2016, Mittal 2020, Ng et al 2020].

Detailed developmental history was available for six individuals with juvenile-onset parkinsonism. They showed delay in motor and language development but ultimately reached independent walking and achieved spoken language between ages three and four years. These individuals had slow developmental progress over time and manifested learning difficulties requiring special educational support. Three individuals suffered cognitive decline; of these, two became nonverbal in the second decade of life in tandem with progression of the movement disorder. The remaining three individuals were reported to have mild-to-moderate intellectual disability (IQ range 40-63).

Seizures were classified as generalized (5/7) and/or atypical absences (4/7), when specified [Köroğlu et al 2013, Elsayed et al 2016, Ng et al 2020, Mittal 2020]. Seizure onset was reported to occur in the first decade of life. Seizures were treated with lamotrigine, zonisamide, or sodium valproate, which led to clinical improvement in four individuals.

Additional movement disorders often occurred as the disease progressed, with dystonia being the most frequent feature, followed by spasticity and myoclonus. Dystonia and spasticity also increased the risk of secondary complications such as limb contractures, hip dislocation, and kyphoscoliosis. To date, eye movement abnormalities have only been reported in one individual, who had hypometric saccades [Edvardson et al 2012]; given that this feature often correlates with hypokinesia (and is eventually present in almost all individuals with Parkinson disease), it is possible that it is underrecognized in this condition.

Neuropsychiatric features included anxiety disorder, behavior disorders (e.g., emotional lability, aggressive behavior, perseveration behavior, attention-deficit disorder), and psychosis. Behavioral features and psychosis emerged after levodopa therapy in two individuals. Disrupted sleep pattern in tandem with neuropsychiatric features was observed in three individuals.

Systemic features, in particular gastrointestinal (neonatal/infantile feeding difficulties, recurrent vomiting, sialorrhea) and bulbar dysfunction (dysphagia, dysarthria, drooling), were associated with a more severe disease course [Ng et al 2020].

CSF neurotransmitter analysis showed low CSF homovanillic acid (HVA) in three individuals and borderline CSF HVA in one individual. A reduced CSF HVA:5-HIAA ratio was identified in four individuals with juvenile-onset parkinsonism. Other CSF neurotransmitter metabolites (pterins species, 5-methyltetrahydrofolate) were normal in these four individuals [Ng et al 2020].

Treatment with levodopa showed a moderate-to-good response in six of fourteen individuals – although in two individuals, levodopa had to be discontinued due to intolerable motor and neuropsychiatric side effects.

Other

  • Scoliosis (1 individual)
  • Pes cavus (1 individual)
  • Primary non-progressive microcephaly (3 sibs from a consanguineous family); the possibility of a second condition causing microcephaly cannot be fully excluded.

Early-Onset Parkinsonism

Six individuals from four families have been reported with symptom onset in the third to fourth decade. The median age of onset was 32 years (range 21-44 years). Additional neurologic features were not observed in this group, although psychosis was described in one individual. In this group, there appears to be slower disease progression [Olgiati et al 2016] with better clinical response to dopaminergic treatments [Olgiati et al 2016]. Three individuals underwent surgical procedures with good outcome (bilateral subthalamic nucleus deep brain stimulation in two individuals and pallidotomy in the other) [Olgiati et al 2016, Li et al 2020].

Neuroradiographic Features

Fourteen individuals had a normal brain MRI. Mild-to-moderate generalized cerebral atrophy was reported in five individuals with juvenile-onset disease, and two of these five individuals also had cerebellar atrophy [Edvardson et al 2012, Köroğlu et al 2013, Elsayed et al 2016, Olgiati et al 2016, Mittal 2020, Ng et al 2020.

123I-FP-CIT SPECT (DaTScanTM) imaging performed in three individuals with juvenile-onset parkinsonism showed reduced or absent tracer uptake in the basal ganglia [Ng et al 2020].

F-DOPA-PET performed in two individuals with early-onset parkinsonism showed striatonigral abnormalities [Olgiati et al 2016].

Heterozygotes

Five individuals with Parkinson disease (representing both simplex and multiplex cases) have been reported with heterozygous DNAJC6 variants (mean age of onset 33 years, range 29-58 years) [Olgiati et al 2016]. There are no further details of the disease presentation and course. Although these variants were classified as pathogenic by several variant prediction programs, their clinical relevance and contribution to disease needs to be further investigated. It is possible that these rare variants may confer risk of Parkinson disease, similar to other Parkinson disease-related genes (LRRK2, SNCA, GBA1 [GBA]) [Blauwendraat et al 2020]. Of note, obligate carrier parents of individuals with biallelic DNAJC6 variants have not been reported to develop Parkinson disease.

Genotype-Phenotype Correlations

Though data are limited, there is some evidence of a genotype-phenotype correlation.

Nonsense variants throughout the gene (e.g., c.2410C>T, c.2365C>T, c.766C>T, c.2416C>T) and splice site variants located toward the 5' end (e.g., c.801-2A>G in intron 6). Individuals homozygous for these variants predicted to cause complete protein deficiency or a nonfunctional protein, showed a rapidly progressive, juvenile-onset parkinsonism with a complex neurologic phenotype [Edvardson et al 2012, Köroğlu et al 2013, Elsayed et al 2016, Mittal 2020, Ng et al 2020]. Treatment proved difficult in these individuals: only a few demonstrated a mild-to-moderate clinical response to levodopa (6/14). Also, a rapidly developing sensitivity to levodopa was evident in this group.

Missense variants located throughout the gene (e.g., c.2779A>G) and splice site variants located toward the 3' end (e.g., c.2223A>T in exon 15, c.2038+3A>G in intron 13). Individuals homozygous for these variants showed later disease onset, with early-onset parkinsonism with a milder disease course [Olgiati et al 2016]. All had a good clinical response to levodopa, though the dose had to be frequently adjusted due to intolerable side effects. Two individuals underwent surgical procedures – subthalamic nucleus deep brain stimulation and pallidotomy – with marked improvement of motor manifestations.

Nomenclature

Other terms used to refer to DNAJC6 Parkinson disease:

Prevalence

The prevalence of DNAJC6 Parkinson disease is not yet established. To date, 20 individuals with biallelic DNAJC6 pathogenic variants have been reported.

Differential Diagnosis

Early-Onset Parkinson Disease

DNAJC6 Parkinson disease is often clinically indistinguishable from early-onset Parkinson disease and parkinsonism of other etiologies (see Parkinson Disease Overview and Table 3). Rigidity, bradykinesia, and resting tremor are variably combined in these disorders.

Table Icon

Table 3.

Genes Associated with Early-Onset Autosomal Recessive Parkinson Disease and Parkinsonism in the Differential Diagnosis of DNAJC6 Parkinson Disease

Juvenile-Onset Parkinsonism with Prominent Dystonia

For individuals with juvenile-onset parkinsonism, especially those with prominent dystonia, dystonia-parkinsonism phenotypes should be considered (see Table 4 and the Hereditary Dystonia Overview).

Table Icon

Table 4.

Genes Associated with Dystonia-Parkinsonism in the Differential Diagnosis of DNAJC6 Parkinson Disease

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DNAJC6 Parkinson disease, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table Icon

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with DNAJC6 Parkinson Disease

Treatment of Manifestations

Table Icon

Table 6.

Treatment of Manifestations in Individuals with DNAJC6 Parkinson Disease

Surveillance

Table Icon

Table 7.

Recommended Surveillance for Individuals with DNAJC6 Parkinson Disease

Agents/Circumstances to Avoid

Though there are no data available to date, dopamine antagonists and vesicular monoamine transporter 2 (VMAT2) inhibitors should be avoided as they could aggravate dopamine deficiency. VMAT2 inhibitors prevent reuptake and storage of neurotransmitters into synaptic vesicles and thus could theoretically cause further depletion of presynaptic dopamine.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DNAJC6 Parkinson disease is inherited in an autosomal recessive manner.

Note: The identification of heterozygous DNAJC6 variants in five individuals with Parkinson disease has raised the question of whether heterozygous DNAJC6 variants may contribute to the development of parkinsonism [Olgiati et al 2016]. Further studies are needed to determine if these variants confer Parkinson disease risk.

Risk to Family Members (Autosomal Recessive Inheritance)

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one DNAJC6 pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a DNAJC6 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
    • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
    • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
  • The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, Heterozygotes).

Sibs of a proband

  • If both parents are known to be heterozygous for a DNAJC6 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither DNAJC6 pathogenic variant.
  • In sibs who inherit biallelic DNAJC6 variants, the range in onset of Parkinson disease reported to date is:
  • The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, Heterozygotes).

Offspring of a proband. The offspring of an individual with DNAJC6 Parkinson disease are obligate heterozygotes (carriers) for a pathogenic variant in DNAJC6.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a DNAJC6 pathogenic variant.

Heterozygote Detection

Heterozygote testing for at-risk relatives requires prior identification of the DNAJC6 pathogenic variants in the family.

Related Genetic Counseling Issues

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, heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the DNAJC6 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing 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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table Icon

Table A.

DNAJC6 Parkinson Disease: Genes and Databases

Table Icon

Table B.

OMIM Entries for DNAJC6 Parkinson Disease (View All in OMIM)

Molecular Pathogenesis

DNAJC6 encodes for the protein auxilin 1, which is a co-chaperone protein involved in clathrin-mediated synaptic vesicle endocytosis. It specifically recruits the molecular chaperone protein heat shock cognate (Hsc70) to the nascent clathrin-coated vesicle. Auxilin induces Hsc70-mediated ATP hydrolysis, which leads to subsequent uncoating of the clathrin lattice and release of cargo [Kaksonen & Roux 2018, Milosevic 2018]. Clathrin-mediated endocytosis is involved in a variety of cellular processes including synaptic neurotransmission, regulation of surface protein expression, and plasma membrane homeostasis, as well as developmental and synaptic signaling [Kaksonen & Roux 2018].

Auxilin deficiency has been investigated in several animal models. The auxilin knockout mouse model demonstrated increased early postnatal mortality and a significantly reduced body weight in one-week old mice [Yim et al 2010]. In cortical and hippocampal neurons, synaptic vesicle endocytosis was impaired, most likely due to accumulation of clathrin-coated vesicles (CCVs) and empty clathrin cages. The mice also showed upregulation of the ubiquitously expressed homolog protein cyclin-G-associated kinase (GAK) in brain lysates, probably as a compensatory mechanism for auxilin deficiency. The auxilin knockdown Drosophila model showed reduced locomotion and longevity [Song et al 2017]. The flies exhibited an age-dependent, α-synuclein-mediated loss of dopaminergic neurons and showed increased sensitivity to paraquat, a toxin widely used to induce parkinsonism in animal and cell models.

Altogether, these findings suggest that auxilin deficiency leads to impaired synaptic vesicle endocytosis, which in turn negatively impacts synaptic neurotransmission, synaptic homeostasis, and signaling. However, the exact pathogenic mechanisms by which auxilin deficiency leads to dopaminergic neurodegeneration and a complex neurologic phenotype still remain to be fully elucidated.

Mechanism of disease causation. DNAJC6 Parkinson disease is caused by loss-of-function variants including nonsense, missense, and splice site variants.

Table Icon

Table 8.

Notable DNAJC6 Pathogenic Variants

Chapter Notes

Author Notes

Dr Lucia Abela
Developmental Neurosciences
Zayed Centre for Research into Rare Diseases in Children
UCL Great Ormond Street-Institute of Child Health, London

Dr Abela is a senior resident in pediatric neurology and currently a research fellow in Dr Kurian’s research group with a special interest in childhood movement disorders.

Professor Manju Ann Kurian
Developmental Neurosciences
Zayed Centre for Research into Rare Diseases in Children
UCL Great Ormond Street-Institute of Child Health, London
Prof Kurian's web page

Prof Kurian is a pediatric neurologist and clinician-scientist with a clinical and research interest in childhood movement disorders.

Revision History

  • 13 May 2021 (sw) Review posted live
  • 10 September 2020 (mak) Original submission

References

Literature Cited

  • Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson’s disease. Lancet Neurol. 2020;19:170–8. [PMC free article: PMC8972299] [PubMed: 31521533]

  • Edvardson S, Cinnamon Y, Ta-Shma A, Shaag A, Yim YI, Zenvirt S, Jalas C, Lesage S, Brice A, Taraboulos A, Kaestner KH, Greene LE, Elpeleg O. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS One. 2012;7:e36458. [PMC free article: PMC3341348] [PubMed: 22563501]

  • Elsayed LE, Drouet V, Usenko T, Mohammed IN, Hamed AA, Elseed MA, Salih MA, Koko ME, Mohamed AY, Siddig RA, Elbashir MI, Ibrahim ME, Durr A, Stevanin G, Lesage S, Ahmed AE, Brice A. A Novel Nonsense Mutation in DNAJC6 Expands the Phenotype of Autosomal-Recessive Juvenile-Onset Parkinson's Disease. Ann Neurol. 2016;79:335-7. [PubMed: 26703368]

  • Fahn S, Elton R. UPDRS Development Committee. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease. Vol 2. Florham Park, NJ: Macmillan Health Care Information. 1987;153–63.

  • Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23:2129-70. [PubMed: 19025984]

  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017; 549: 519-22. [PubMed: 28959963]

  • Kaksonen M, Roux A. Mechanisms of clathrin-mediated endocytosis. Nat. Rev. Mol. Cell Biol. 2018;19:313–26. [PubMed: 29410531]

  • Köroğlu Ç, Baysal L, Cetinkaya M, Karasoy H, Tolun A. DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability. Parkinsonism Relat Disord. 2013;19:320-4. [PubMed: 23211418]

  • Li C, Ou R, Chen Y, Gu X, Wei Q, Cao B, Zhang L, Hou Y, Liu K, Chen X, Song W, Zhao B, Wu Y, Shang H. Mutation analysis of DNAJC family for early-onset Parkinson's disease in a Chinese cohort. Mov Disord. 2020;35:2068-76 [PubMed: 32662538]

  • Malek N, Weil RS, Bresner C, Lawton MA, Grosset KA, Tan M, Bajaj N, Barker RA, Burn DJ, Foltynie T, Hardy J, Wood NW, Ben-Shlomo Y, Williams NW, Grosset DG, Morris HR; PRoBaND clinical consortium. Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study. J Neurol Neurosurg Psychiatry. 2018;89:702-9. [PMC free article: PMC6031283] [PubMed: 29378790]

  • Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, Mercimek-Mahmutoglu S, Ebrahimi-Fakhari D, Warner TT, Durr A, Assmann B, Lohmann K, Kostic V, Klein C. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society task force. Mov Disord. 2016;31:436–57. [PubMed: 27079681]

  • Milosevic I. Revisiting the role of clathrin-mediated endoytosis in synaptic vesicle recycling. Front Cell Neurosci. 2018;12:27. [PMC free article: PMC5807904] [PubMed: 29467622]

  • Mittal SO. Levodopa responsive-generalized dystonic spells and moaning in DNAJC6 related juvenile Parkinson's disease. Parkinsonism Relat Disord. 2020;81:188-9. [PubMed: 33181391]

  • Ng J, Cortès-Saladelafont E, Abela L, Termsarasab P, Mankad K, Sudhakar S, Gorman KM, Heales SJR, Pope S, Biassoni L, Csányi B, Cain J, Rakshi K, Coutts H, Jayawant S, Jefferson R, Hughes D, García-Cazorla À, Grozeva D, Raymond FL, Pérez-Dueñas B, De Goede C, Pearson TS, Meyer E, Kurian MA. DNAJC6 mutations disrupt dopamine homeostasis in juvenile parkinsonism-dystonia. Mov Disord. 2020;35:1357-68. [PMC free article: PMC8425408] [PubMed: 32472658]

  • Olgiati S, Quadri M, Fang M, Rood JP, Saute JA, Chien HF, Bouwkamp CG, Graafland J, Minneboo M, Breedveld GJ, Zhang J; International Parkinsonism Genetics Network, Verheijen FW, Boon AJ, Kievit AJ, Jardim LB, Mandemakers W, Barbosa ER, Rieder CR, Leenders KL, Wang J, Bonifati V. DNAJC6 mutations associated with early-onset Parkinson's disease. Ann Neurol. 2016;79:244-56. [PubMed: 26528954]

  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]

  • Song L, He Y, Ou J, Zhao Y, Li R, Cheng J, Lin CH, Ho MS. Auxilin underlies progressive locomotor deficits and dopaminergic neuron loss in a drosophila model of Parkinson's disease. Cell Rep. 2017;18:1132-43. [PubMed: 28147270]

  • Vauthier V, Jaillard S, Journel H, Dubourg C, Jockers R, Dam J. Homozygous deletion of an 80 kb region comprising part of DNAJC6 and LEPR genes on chromosome 1P31.3 is associated with early onset obesity, mental retardation and epilepsy. Mol Genet Metab. 2012;106:345-50. [PubMed: 22647716]

  • Yim YI, Sun T, Wu LG, Raimondi A, De Camilli P, Eisenberg E, Greene LE. Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice. Proc Natl Acad Sci U S A. 2010;107:4412-7. [PMC free article: PMC2840126] [PubMed: 20160091]