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Autosomal Recessive Juvenile Parkinson Disease


The term autosomal recessive juvenile Parkinson's disease refers to hereditary forms of Parkinson's disease that manifest before adulthood. This applies to Parkinson's disease types 2, 15, and 19A (PD2, PD15, and PD19A, respectively). It is very difficult to clinically distinguish PD2, PD15, and PD19A from the classical sporadic disease, but symptom onset occurs much earlier, namely in adolescence or early adulthood, and affected individuals have a positive family history of Parkinson's disease.


Insidious-onset muscle rigidity, tremor, bradykinesia and postural instability - the clinical hallmarks of sporadic Parkinson's disease - are also present in patients suffering from PD2, PD15, and PD19A. And while these disorders are characterized by particular features regarding symptom onset, disease progression, and comorbidities, the distinction of single types of Parkinson's disease based on clinical findings alone poses a major challenge.

With regard to PD2, the most common presenting symptoms are lower-extremity dystonia and hyperreflexia, leading to gait disorders [1]. Some patients describe their symptoms to improve after sleep, although diurnal fluctuations seem to level out as the disease progresses. PD2 may be accompanied by mental illness, but affected individuals don't usually show dementia. Disease progression is generally slow but has been reported to be accelerated in patients carrying missense mutations of PRKN instead of truncating mutations. Missense mutations are also known to reduce the age at symptom onset. Thus, juvenile onset is frequently associated with a more rapid progression and a poorer prognosis than onset in early adulthood [2].

PD15 patients suffer from parkinsonism associated with atypical features [2]. Similar to PD2, dystonia is common in early stages of the disease, as are tremor and bradykinesia, but advanced PD15 is further characterized by pyramidal signs [3]. The latter result from corticospinal tract involvement and give rise to a so-called pallido-pyramidal or Parkinsonian-pyramidal syndrome. Dysarthria and dysphagia may be developed and significantly affect the patients' quality of life, but the disease progresses slowly.

PD19A is a rapidly progressive variant of juvenile-onset Parkinson's disease that typically manifests in the first or second decade of life. It may be accompanied by mental retardation and seizures, and some patients eventually develop pyramidal signs [4] [5].

  • MyBioSource and its authorized distributors reserve the right to refuse to process any order where we reasonably believe that the intended use will fall outside of our acceptable guidelines.[mybiosource.com]
  • Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.[invitae.com]
Skin Lesion
  • An individual was regarded as having leprosy if he or she showed skin lesion consistent with leprosy and with definite sensory loss, with or without thickened nerves and positive skin smears test.[bmjopen.bmj.com]
  • Diagnosis of Leprosy was made by at least 2 independent leprologists after a physical examination of each patient and standard histological and pathological examination of the affected skin lesions.[journals.plos.org]
Postural Instability
  • Insidious-onset muscle rigidity, tremor, bradykinesia and postural instability - the clinical hallmarks of sporadic Parkinson's disease - are also present in patients suffering from PD2, PD15, and PD19A.[symptoma.com]
  • Parkinson disease (PARK) [MIM:168600]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability.[genecards.org]
  • It may be accompanied by mental retardation and seizures, and some patients eventually develop pyramidal signs. First and foremost, the diagnosis of autosomal recessive juvenile Parkinson's disease requires a thorough anamnesis.[symptoma.com]
  • He suffered from the first attack of absence seizure at his age of 2.5 years old but no anti-epileptic drug was used.[molecularautism.biomedcentral.com]


First and foremost, the diagnosis of autosomal recessive juvenile Parkinson's disease requires a thorough anamnesis. Young age at symptom onset and familial clustering are valuable hints on PD2, PD15, and PD19A, and thus, it is essential to assess the patient's medical and family history [6]. It may be necessary to carry out a genealogical analysis to recognize the pattern of inheritance of familial Parkinson's disease.

Parkinson's disease itself is diagnosed clinically. The vast majority of patients presents at least two out of the three cardinal symptoms, namely rigidity, resting tremor, and bradykinesia. In the absence of these symptoms, the diagnosis of Parkinson's disease poses a major challenge unless there is a concrete suspicion as to a causal gene defect. In any case, genetic studies have to be performed to identify the underlying mutation in genes PRKN, FBXO7, or DNAJC6.

The employment of additional diagnostic tools may support but not replace the clinical diagnosis of this neurodegenerative disorder: Magnetic resonance imaging may not yield pathological findings, but positron emission tomography often reveals reduced fluorodopa uptake [3] [7]. Results obtained by means of electroencephalography are often in agreement with diffuse encephalopathy and cognitive decline, and they may hint at the presence of epileptic foci in PD19A patients [4]. Muscle biopsies are not helpful for diagnosing Parkinson's disease although they may allow the exclusion of differential diagnoses. Neither of these findings is specific.

  • Histological hallmarks of Parkinson's disease comprise the selective loss of dopaminergic neurons in the pars compacta of the substantia nigra, which is accompanied by depigmentation and gliosis.[symptoma.com]
Diffuse Encephalopathy
  • Results obtained by means of electroencephalography are often in agreement with diffuse encephalopathy and cognitive decline, and they may hint at the presence of epileptic foci in PD19A patients.[symptoma.com]


Specific recommendations for the management of PD2, PD15, and PD19A have not yet been published, so affected individuals are essentially treated like those suffering from the classical sporadic disease. Dopamine replacement is the mainstay of therapy; it may alleviate the symptoms of Parkinson's disease, but can't halt its progression. Furthermore, an individual patient's responsiveness to such therapy depends on the specific type of the disease: PD2 is a levodopa-responsive form of Parkinson's disease, but levodopa-induced dyskinesias occur frequently [8]. By contrast, levodopa-responsiveness varies considerably among PD15 patients [3]. PD19A patients usually respond to levodopa. Besides levodopa, which is a dopamine precursor, dopamine agonists may be employed in the treatment of Parkinson's disease. Additionally, patients may benefit from the administration of anticholinergics, COMT inhibitors, MAO-B inhibitors, and NMDA receptor antagonists. They should also be offered physical therapy and psychological support.


Specific data regarding the life expectancy of patients diagnosed with PD2, PD15, or PD19A are not available. A review of the literature reveals that individuals affected by slowly progressive juvenile-onset Parkinson's disease often survive over decades. Still, their quality of life may be significantly reduced, especially if they don't respond to levodopa or suffer from severe motor and psychiatric side effects [3]. PD19A tends to render affected subjects wheelchair-dependent within ten years after symptom onset [5] [7].


PD2, PD15, and PD19A have all been identified as monogenic forms of autosomal recessive juvenile Parkinson's disease [2].

  • PD2 has been related to mutations in the PRKN gene. PRKN mutations are carried by about 50% of patients developing Parkinson's disease before the age of 25, rendering PD2 the most common form of juvenile Parkinson's disease [2]. PRKN is a protein-coding gene whose product, parkin, is required for the formation of the E3 ubiquitin ligase complex. Pathogenic mutations in this gene hinder E3 ubiquitin ligase complex function and interfere with the attachment of ubiquitin to proteins that should be degraded.
  • PD15 is caused by FBXO7 mutations [3]. This gene encodes for F-box protein 7, another component of the ubiquitin ligase complex. Similarly to what has been described for PD2, PD15 is assumed to develop due to dysfunctional protein degradation. Clinical differences between PD2 and PD15 may possibly be explained by expression patterns or additional functions fulfilled by parkin and F-box protein 7, but further research is required to this end.
  • PD19A may be diagnosed in patients carrying DNAJC6 mutations [7]. DNAJC6 encodes for DnaJ heat-shock-protein family member C6, a protein also referred to as auxilin that is involved in the regulation of chaperone activity and clathrin-mediated endocytosis.

Of note, for Parkinson's disease to be inherited, it must be caused by germline mutations. Patients suffering from autosomal recessive juvenile Parkinson's disease are homozygous for pathogenic mutations in either of the genes described above and whether heterozygous germline mutations increase the individual risk of developing Parkinson's disease could not yet be clarified. But mutations in genes PRKN, FBXO7, and DNAJC6 may also be acquired and may thus be identified in patients suffering from the sporadic disease. Therefore, age at symptom onset, family history, and the results of genetic studies should all be considered before diagnosing autosomal recessive juvenile Parkinson's disease.


Sporadic Parkinson's disease is the second most common neurodegenerative disorder, second only to Alzheimer's disease [9]. The annual incidence of Parkinson's disease ranges between 10 and 20 per 100,000 inhabitants [10]. While it has been estimated that Parkinson's disease affects 1-2% of people aged >65 years and up to 4% of individuals aged >85 years, early onset is uncommon and accounts for <3% of all cases [10]. Onset before the age of 20 is exceedingly rare [2]. PD2 may manifest in childhood, adolescence, or young adulthood, and is diagnosed at a mean age of approximately 30 years [2] [8]. PD15 is generally diagnosed in the second decade of life and PD19A manifests around the tenth year of life [3] [4] [5] [7].

Sex distribution
Age distribution


While the triggers of neurodegeneration remain largely unknown, it is the key process in the pathogenesis of Parkinson's disease. Histological hallmarks of Parkinson's disease comprise the selective loss of dopaminergic neurons in the pars compacta of the substantia nigra, which is accompanied by depigmentation and gliosis. Neuronal loss may also be observed in the locus ceruleus, pedunculopontine nucleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulb, parasympathetic as well as sympathetic post-ganglionic neurons, Mynert nucleus, amygdaloid nucleus and cerebral cortex [9]. These histological features can, however, only be confirmed at autopsy.

With regard to PD2, it has been hypothesized that the accumulation of parkin substrates like α-synuclein leads to nigral degeneration [9] [11]. It may be speculated that the onset of PD15 is caused by similar pathophysiological events, but this assumption can neither be confirmed nor refuted as long as the precise role of F-box protein 7 remains unclear.

Accumulated protein may or may not form Lewy bodies, which are typical of classical sporadic Parkinson's disease. However, Lewy bodies are generally absent in samples obtained from PD2 patients. Lewy bodies are known to interfere with neuronal function. For instance, Lewy body infiltration in the olfactory bulb adversely affects the sense of smell. Thus, people with Parkinson's disease frequently suffer from olfactory impairment. By contrast, PD2 patients have a normal olfactory perception [12].


Affected families may benefit from genetic counseling. Consanguineous marriage and reproduction greatly enhance the likelihood of homozygosity for pathogenic variants of genes PRKN, FBXO7, and DNAJC [3] [5] [8], and people should be advised against them. Pregnant women from affected families may be recommended pre- or postnatal analysis to see whether their child is homozygous or compound heterozygous for pathogenic mutations related to PD2, PD15, or PD19A.


Parkinson's disease is a neurodegenerative disorder associated with muscle rigidity, tremor, and bradykinesia. The majority of cases is deemed sporadic, but familial clustering and Mendelian inheritance of phenotypic traits is occasionally been observed. Parkinson's disease has been shown to be inherited in autosomal dominant and autosomal recessive patterns, with the underlying gene defect having been identified in some of the families affected, but remaining unknown in others [2].

The following variants of hereditary Parkinson's disease are inherited in an autosomal recessive manner:

  • Parkinson's disease type 2, also referred to as autosomal recessive juvenile Parkinson's disease
  • Parkinson's disease type 6, also referred to as autosomal recessive early-onset Parkinson's disease 6
  • Parkinson's disease type 7, also referred to as autosomal recessive early-onset Parkinson's disease 7
  • Parkinson's disease type 14, also referred to as autosomal recessive early-onset Parkinson's disease 14
  • Parkinson's disease type 15, also referred to as autosomal recessive juvenile-onset Parkinson's disease 15
  • Parkinson's disease type 19, including autosomal recessive juvenile-onset Parkinson's disease 19A (PD19A) and autosomal recessive early-onset Parkinson's disease 19B
  • Parkinson's disease type 23, also referred to as or autosomal recessive early-onset Parkinson's disease 23

Sporadic Parkinson's disease is most frequently diagnosed beyond the age of 60 and thus, patients presenting first symptoms more than ten years earlier are generally diagnosed with "early-onset Parkinson's disease" [10]. By contrast, the term "juvenile Parkinson's disease" is usually reserved for those patients who develop clinical disease in their second decade of life [6]. Juvenile Parkinson's disease may indeed be understood as a subtype of early-onset Parkinson's disease. However, distinct definitions can be found in literature and the attributes "early-onset" and "juvenile" are often used interchangeably. This is partially due to the fact that familial cases of Parkinson's disease have initially been classified according to the average age at symptom onset, but have been related to determined mutations later on. PD6, for instance, is a type of autosomal recessive Parkinson's disease that is distributed worldwide and has been associated with mutations in the PINK1 gene [14]. PD6 patients are diagnosed at a mean age of 36 years but may present symptoms in adolescence [13] [14], suggesting an overlap between early-onset and juvenile disease.

This article will focus on PD2, PD15, and PD19A, which commonly manifest before adulthood.

Patient Information

Parkinson's disease is the second most common neurodegenerative disorder, second only to Alzheimer's disease. It is generally diagnosed in the elder adult, but may occasionally occur in young adults, adolescents, and even children. The clinical hallmarks remain the same and comprise muscle rigidity, tremor, and slowness of movements. Juvenile-onset Parkinson's disease is often caused by genetic defects that have been inherited from the parents. In case of autosomal recessive juvenile Parkinson's disease, a defective allele has been passed on to the child by both their mother and their father. This is much more likely to happen if the parents are closely related.



  1. Takahashi H, Ohama E, Suzuki S, et al. Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology. 1994; 44(3 Pt 1):437-441.
  2. Schulte C, Gasser T. Genetic basis of Parkinson's disease: inheritance, penetrance, and expression. Appl Clin Genet. 2011; 4:67-80.
  3. Di Fonzo A, Dekker MC, Montagna P, et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology. 2009; 72(3):240-245.
  4. Elsayed LE, Drouet V, Usenko T, et al. A Novel Nonsense Mutation in DNAJC6 Expands the Phenotype of Autosomal-Recessive Juvenile-Onset Parkinson's Disease. Ann Neurol. 2016; 79(2):335-337.
  5. Köroğlu C, Baysal L, Cetinkaya M, Karasoy H, Tolun A. DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability. Parkinsonism Relat Disord. 2013; 19(3):320-324.
  6. Klein C, Schlossmacher MG. The genetics of Parkinson disease: Implications for neurological care. Nat Clin Pract Neurol. 2006; 2(3):136-146.
  7. Edvardson S, Cinnamon Y, Ta-Shma A, et al. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS One. 2012; 7(5):e36458.
  8. Ishikawa A, Tsuji S. Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology. 1996; 47(1):160-166.
  9. Hatano T, Kubo S, Sato S, Hattori N. Pathogenesis of familial Parkinson's disease: new insights based on monogenic forms of Parkinson's disease. J Neurochem. 2009; 111(5):1075-1093.
  10. Tysnes OB, Storstein A. Epidemiology of Parkinson's disease. J Neural Transm (Vienna). 2017; 124(8):901-905.
  11. Huynh DP, Scoles DR, Nguyen D, Pulst SM. The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI. Hum Mol Genet. 2003; 12(20):2587-2597.
  12. Alcalay RN, Siderowf A, Ottman R, et al. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study. Neurology. 2011; 76(4):319-326.
  13. Bentivoglio AR, Cortelli P, Valente EM, et al. Phenotypic characterisation of autosomal recessive PARK6-linked parkinsonism in three unrelated Italian families. Mov Disord. 2001; 16(6):999-1006.
  14. Hatano Y, Sato K, Elibol B, et al. PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations. Neurology. 2004; 63(8):1482-1485.

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Last updated: 2019-07-11 19:55