An autosomal recessive form of familial juvenile parkinsonism, defined as onset before age 40 years, was described in a Japanese family by Takahashi et al. (1994). Juvenile-onset Parkinson disease is symptomatically different in several aspects from classic late-onset ... An autosomal recessive form of familial juvenile parkinsonism, defined as onset before age 40 years, was described in a Japanese family by Takahashi et al. (1994). Juvenile-onset Parkinson disease is symptomatically different in several aspects from classic late-onset Parkinson disease (PD; 168600), although classic symptoms of PD, such as bradykinesia, rigidity, and tremor, are present. Takahashi et al. (1994) commented that the familial occurrence in Japanese PDJ patients with cases was approximately 40 to 50% and that the inheritance pattern appeared to be mostly autosomal recessive. They reported a family in which 4 of 5 sibs were affected and the parents were first cousins. A full pathologic examination of 1 of the sibs, a 67-year-old woman, was presented. The substantia nigra (SN) showed obvious neuronal loss and gliosis in the medial and ventrolateral regions. In the remainder of that region and in the locus ceruleus, the population of neurons was reduced and there was low melanin content in most of the neurons but no detectable gliosis or extraneuronal free melanin pigment suggestive of a neurodegenerative process. There were no Lewy bodies. The entire pathologic picture was different from that of Lewy body Parkinson disease (168601). This patient had been well until about the age of 10 years when gait disturbance appeared. By age 14, she was unable to walk long distances. By her forties, she was unable to walk without assistance. There was no evidence of dementia. She had been slow-moving and had shown frozen gait and tremor, more evident on motion, in the head and upper and lower limbs. She showed improvement of the movement disorder after waking up in the morning. When she was young, the improvement lasted until evening, but as she aged it became progressively shorter, eventually lasting only about 10 minutes. In the other sibs, gait disturbance began at the age of 8 or 9 years. One sister had died at age 42 years and a brother at the age of 27 years, both in a bedridden state. Ishikawa and Tsuji (1996) described the clinical features of 17 patients from 12 Japanese families with familial juvenile parkinsonism. In 11 of these families affected members were products of consanguineous matings. All 12 families resided within the same geographic area, raising the possibility of founder effect. The mean age of onset was 27 years, with a range from 9 to 43. The most prominent symptoms were retropulsion, dystonia of the feet, and hyperreflexia with classic parkinsonism. Symptoms of tremor, rigidity, and bradykinesia were mild. Patients responded to levodopa but dopa-induced dyskinesias and wearing-off phenomena occurred frequently. Bonifati et al. (1994) reported a man who presented with Parkinson disease at age 28. He was born of a consanguineous mating between a man who developed Parkinson disease at age 74 and his first cousin, who apparently was not affected with parkinsonian symptoms; however, the maternal grandfather developed Parkinson disease at age 65. Bonifati et al. (1994) speculated that the proband may have been homozygous for a defective Parkinson disease gene, which in heterozygous form gave rise to late-onset Parkinson disease in the affected father and maternal grandfather. Mitsui et al. (1994) described a sister and a brother, the only offspring of a first-cousin mating, with atypical juvenile parkinsonism. They presented at age 38 and 40, respectively, with bradykinesia, cogwheel rigidity, and mild pyramidal and cerebellar signs. They were unresponsive to levodopa but responded very well to trihexyphenidyl, an anticholinergic drug. Mitsui et al. (1994) proposed that this was a new hereditary variant of early-onset Parkinson disease, distinct from the levodopa-sensitive form of juvenile Parkinson disease. They commented that responsiveness to anticholinergics but not levodopa may also be seen in Joseph disease (SCA3; 109150). MRI studies demonstrated atrophy of the cerebellar hemisphere and vermis, as well as high intensity areas in both pyramidal tracts. This juxtaposition of extrapyramidal and cerebellar signs usually results in classification of a disease as a multisystem atrophy or an olivopontocerebellar degeneration and is characteristic of many adult-onset spinocerebellar atrophies, most of which are transmitted as autosomal dominant traits. Yamamura et al. (1973) reported familial cases of juvenile parkinsonism with marked diurnal fluctuation in symptoms. The disorder was found to show nigral cell loss and occurred in a setting of inbreeding; it undoubtedly represented a subtype of autosomal recessive juvenile parkinsonism (Nygaard, 1993). Matsumine et al. (1998) noted that early-onset parkinsonism with diurnal fluctuation (EPDF) is also a dopa-responsive form of parkinsonism and is associated with selective degeneration in the zona compacta of the substantia nigra without Lewy body formation. A distinguishing feature of this phenotype is a benefit from sleep with lessening of parkinsonian symptoms after awakening. Portman et al. (2001) performed PET scans on 2 brothers with early-onset parkinsonism caused by mutations in the parkin gene and found marked reduction of fluorodopa (FDOPA) uptake in the caudate and putamen. Portman et al. (2001) noted that this was a different nigrostriatal dopaminergic pattern than that found in sporadic PD, thus suggesting a different pathophysiology for the early-onset disease. Ohsawa et al. (2005) found that 8 of 9 patients with PARK2 mutations had significantly reduced sural sensory nerve action potential (SNAP) amplitude compared to 8 patients with idiopathic Parkinson disease. However, 6 PARK2 carriers had absence of decreased vibration sense in the foot, and only 2 had subjective sensory symptoms. Two patients with a presumptive diagnosis of idiopathic PD who showed a reduced SNAP amplitude were subsequently diagnosed with PARK2 as a result of DNA analysis. Ohsawa et al. (2005) suggested that reduced SNAP amplitude in patients with PD under 60 years of age may be a diagnostic indicator of PARK2 mutations, and concluded that sensory axonal neuropathy may be a common feature of the disorder. - Pathologic Findings Mori et al. (1998) reported neuropathologic findings in a patient with PARK2 confirmed by genetic analysis. The patient had disease onset at age 24 years and died from unrelated complications at age 62. Grossly, the substantia nigra showed marked depigmentation. Melanin-containing neurons in the pars compacta were moderately decreased, and neuronal loss and gliosis were especially marked in the ventrolateral and medial regions. Most of the remaining nigral neurons contained melanin pigments. The pars reticulata was spared. Lewy bodies were not identified. Neurofibrillary tangles and argyrophilic astrocytes were identified in the SN, the locus ceruleus, posterior hypothalamus, the hippocampus, and various cortical areas. However, the pattern was not consistent with Alzheimer disease. Tyrosine hydroxylase (191290) activity was markedly reduced in the caudate and putamen, and modestly reduced in the SN. Hayashi et al. (2000) reported neuropathologic findings in a Japanese patient with a mutation in the PARK2 gene (602544.0002) who had previously been reported by Ishikawa and Miyatake (1995). Loss of pigmented neurons and gliosis were most pronounced in the medial and ventrolateral regions of the substantia nigra pars compacta and in the locus ceruleus. Remaining neurons had low amounts of melanin. There was mild neuronal loss and gliosis in the substantia nigra pars reticulata. No Lewy bodies were identified. Some neurofibrillary tangles and senile plaques were observed in the cerebral cortex, although there was no clinical evidence of dementia. Van de Warrenburg et al. (2001) reported a Dutch family with PARK2 confirmed by genetic analysis. Neuropathologic examination of the proband showed depigmentation of the substantia nigra, with severe loss of pigmented neurons in the pars compacta, deposition of extraneuronal melanin, and mild gliosis. No Lewy bodies or neurofibrillary tangles were seen. However, there was a diffuse spread of tau (MAPT; 157140)-positive thorn-shaped astrocytes in the caudate, putamen, and subthalamic nucleus, and a few tau-positive astrocytes in the SN. Farrer et al. (2001) reported a patient who was compound heterozygous for 2 mutations in the PARK2 gene. At autopsy, Lewy body pathology typical of idiopathic Parkinson disease was found, which was noted to be unusual for this form of parkinsonism. Sasaki et al. (2004) reported neuropathologic examination of a patient with Parkinson disease due to homozygous exon 3 deletion in the PARK2 gene (602544.0005). The patient had disease onset at age 33 years and died of respiratory failure at age 70. The substantia nigra showed marked depigmentation, and melanin-containing neurons of the pars compacta were moderately to severely depleted, particularly in the ventrolateral group and medial part. Some dopaminergic neurons remained, but most were atrophic, and free melanin was observed. The pars reticulata of the SN was spared. In the locus ceruleus, neurons were mildly decreased, and free melanin was seen. Lewy bodies were not observed in the SN or locus ceruleus. There were alpha-synuclein-positive and ubiquitin-positive, round or donut-shaped inclusions in the neuropils of the pedunculopontine nucleus, but no such inclusions were seen in the SN, locus ceruleus, or subthalamic nucleus. The inclusions were somewhat basophilic, distinguishing them from Lewy bodies, which show an eosinophilic tint. No immunoreactivity to phosphorylated tau was seen in any region of the brain. Sasaki et al. (2004) suggested that a functioning parkin protein may be required for Lewy body formation.
Foroud et al. (2003) identified 25 different parkin mutations in 103 affected individuals from 47 families with PD, including 41 individuals with mutations in both alleles and 62 individuals with a single mutation in only 1 allele. Individuals ... Foroud et al. (2003) identified 25 different parkin mutations in 103 affected individuals from 47 families with PD, including 41 individuals with mutations in both alleles and 62 individuals with a single mutation in only 1 allele. Individuals with 2 parkin mutations had an earlier age at disease onset and longer disease duration than those with 1 mutation. Thirty-five subjects (35%) with a parkin mutation had an age at onset of 60 years or above, with 30 of these 35 having only 1 mutant allele. The authors concluded that mutations in the parkin gene occur among individuals with PD with an older age at onset (greater than 60 years) who have a positive family history of the disease. In 16 of 307 (5%) families with PD, Oliveira et al. (2003) identified mutations in the parkin gene, which included 18% of all early-onset and 2% of all late-onset families. Three families were homozygous, 3 families were compound heterozygous, and in 10 families, all the patients had heterozygous mutations. The results showed that mutations in exon 7 were observed primarily in heterozygous PD patients with a later age at onset. Oliveira et al. (2003) concluded that mutations in the parkin gene contribute to the common form of PD, and that heterozygous mutations act as susceptibility alleles for the late-onset form of PD. Lohmann et al. (2003) compared 146 PD patients with parkin mutations to 250 PD patients without parkin mutations; they found that patients with the parkin mutations had a significantly earlier and more symmetric onset, a slower progression of disease, and a tendency toward greater response to L-DOPA despite lower doses. However, both groups had a similar wide range for age at onset (7 to 70 years and 12 to 76 years, respectively). In families with autosomal recessive parkinsonism, more than 80% of patients with an age at onset of 20 years or younger had parkin mutations, compared to 28% of those between the ages of 46 and 55 years. Carriers of at least 1 parkin missense mutation had a more severe phenotype than those with 2 truncating mutations, suggesting that missense mutations result in more than a loss of function. Patients with a single heterozygous parkin mutation had significantly later and more asymmetric onset and more frequent L-DOPA-induced difficulties than those with 2 parkin mutations. Poorkaj et al. (2004) undertook a study to determine whether patients with early-onset PD should be screened for parkin mutations as part of their clinical workup. Patients with a diagnosis of PD and onset at or before 40 years of age were selected for genotyping by sequence and dosage analysis for all 12 exons. Mutations were found in 7 of 39 patients. Two of these were compound heterozygous; 5 were heterozygous. Early-onset PD accounted for 10% of PD patients, and 18% of the early-onset patients had parkin mutations. Assuming a strictly recessive inheritance, only 5% of early-onset cases had a pathogenic parkin genotype. The remaining 13% were heterozygous, and whether heterozygous parkin mutations were the cause of early-onset PD in these patients was unclear. Using PET scan, Khan et al. (2005) found that 13 asymptomatic heterozygous carriers of a PARK2 mutation had significantly decreased fluorodopa uptake in the caudate, putamen, and ventral and dorsal midbrain compared to controls. Four of the heterozygous carriers had subtle extrapyramidal signs. Khan et al. (2005) concluded that parkin heterozygosity is a risk factor for nigrostriatal dysfunction and suggested that parkin heterozygosity may contribute to late-onset PD. Klein et al. (2000) reported a large kindred from a remote village in the Western Alps of South Tyrol in northern Italy affected with adult-onset Parkinson disease inherited in an autosomal dominant pattern. The clinical features were indistinguishable from idiopathic Parkinson disease, and none of the patients demonstrated typical features of PARK2, such as diurnal fluctuation, sleep benefit, foot dystonia, hyperreflexia, or early susceptibility to levodopa-induced dyskinesias. Haplotype analysis implicated the parkin locus on chromosome 6q. Molecular analysis showed that 4 affected male sibs were compound heterozygous for 2 deletions in the PARK2 gene: a large deletion, which was later determined by Hedrich et al. (2001) to be a deletion of only exon 7 (602544.0010), and a 1-bp deletion in exon 9 (602544.0019). Two affected females were heterozygous for the 1-bp deletion. Klein et al. (2000) concluded that the phenotypic spectrum associated with mutations in the PARK2 gene are broad and that PARK2 may play a role in the etiology of late-onset typical PD. Pramstaller et al. (2005) provided detailed clinical and molecular follow-up of the family reported by Klein et al. (2000). Ancestors could be traced back to the year 1657; relevant clinical data were obtained from 196 individuals spanning 7 generations. The mean age at onset was 52.8 years, but ranged from 20 to 76 years. Five of 25 definitely affected individuals were found to be compound heterozygous for the 2 previously identified PARK2 deletions; 8 patients had only 1 of these deletions; the mutational status of 5 deceased patients was unknown; and 7 patients had no PARK2 mutations. Patients who were compound heterozygous had earlier onset than those with heterozygous mutations. Pramstaller et al. (2005) concluded that heterozygous mutations in the PARK2 gene contribute to idiopathic PD. Postmortem analysis of 1 of the patients reported by Pramstaller et al. (2005) with both PARK2 mutations showed SNCA-positive Lewy bodies.
In several patients with PDJ, Kitada et al. (1998) identified deletions in the PARK2 gene (see, e.g., 602544.0001).
Hoenicka et al. (2002) found 5 different mutations in the PARK2 gene in 5 of 13 Spanish families ... In several patients with PDJ, Kitada et al. (1998) identified deletions in the PARK2 gene (see, e.g., 602544.0001). Hoenicka et al. (2002) found 5 different mutations in the PARK2 gene in 5 of 13 Spanish families with recessive inheritance. Two of the mutations were novel (602544.0013 and 602544.0012). Hoenicka et al. (2002) found 2 simple heterozygous PARK2 mutation carriers who developed clinical symptoms, either in late adulthood or after brief exposure to parkinsonizing agents. The authors suggested that heterozygosity may be a risk factor for PD. In 14 other Spanish kindreds with familial PD, 8 autosomal recessive, 4 autosomal dominant and 2 of uncertain inheritance, Hoenicka et al. (2002) found no mutations in the alpha-synuclein (SNCA; 163890) or UCHL1 (14312) genes related to PARK1 (168601) and PARK5 (191342), respectively. Lucking et al. (2001) described an Italian family in which parkinsonism was associated with mutations in the PARK2 gene in a pseudodominant pattern of inheritance. The father (with disease onset at age 57 years) was homozygous for a triplication of exon 2, a previously undescribed mutation. The unaffected mother was heterozygous for deletions of exons 3 and 4, and the son (with disease onset at age 31 years) was a compound heterozygote carrying both mutations. In 10 affected members of a consanguineous Brazilian family with early-onset parkinsonism, Chien et al. (2006) identified a homozygous splice site mutation in the PARK2 gene (602544.0020). The family was from an isolated region in northeastern Brazil, and their ancestors had originated from Portugal. One individual who was heterozygous for the mutation developed neuroleptic-induced parkinsonism, suggesting that haploinsufficiency was a predisposing factor. Kay et al. (2007) found that heterozygous parkin mutations were as common in 301 controls as in 302 PD patients, and they replicated the finding in an independent set of 1,260 PD patients and 1,657 controls. Thirty-four variants, including 21 novel variants, were identified. Kay et al. (2007) concluded that heterozygous mutations in the parkin gene are not likely to contribute to the development of Parkinson disease. Quantitative gene dosage was not examined. Alcalay et al. (2010) identified mutations in the PARK2 gene in 64 (6.7%) of 953 patients with early-onset PD before age 51, including 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Thirty-three patients had a heterozygous PARK2 mutation, and 27 had homozygous or compound heterozygous mutations. Four of 64 patients had a PARK2 mutation and another mutation in the LRRK2 (609007) or GBA (606463) genes. Hispanic individuals were more likely to be PARK2 mutation carriers than non-Hispanic individuals (15.6% vs 5.9%; p = 0.003). Marder et al. (2010) examined the same dataset reported by Alcalay et al. (2010), with specific focus on PARK2 mutation carriers. Of the 64 patients with parkin mutations, 37 were heterozygous (including 4 with mutations in other genes), 6 homozygous, and 21 compound heterozygous. Compound heterozygous and homozygous carriers had a significantly younger age at onset compared to heterozygous carriers. Significant associations were found between parkin mutation carrier status and Hispanic origin (odds ratio (OR) of 2.7), younger age at onset (less than 40 years) (OR of 5.0), and family history of PD in a first-degree relative (OR of 2.8). Deletions in exons 3 and 4 and 255delA (602544.0014) were common among Hispanics, specifically Puerto Ricans. In addition, those with heterozygous parkin mutations had younger age at onset compared to PD patients without parkin mutations, suggesting that heterozygosity is a susceptibility factor for disease development. Kay et al. (2010) identified heterozygous copy number variations (CNV) in the parkin gene in 0.95% of 1,686 controls and 0.86% of 2,091 PD patients, suggesting that heterozygous PARK2 CNV mutations are not associated with PD risk.
Parkin type of early-onset Parkinson disease is often clinically indistinguishable from idiopathic Parkinson disease [Lücking et al 2000]. Rigidity, bradykinesia, and resting tremor are variably combined in both disorders....
DiagnosisClinical DiagnosisParkin type of early-onset Parkinson disease is often clinically indistinguishable from idiopathic Parkinson disease [Lücking et al 2000]. Rigidity, bradykinesia, and resting tremor are variably combined in both disorders.The following findings suggest parkin type of early-onset Parkinson disease: Early onset (age <40 years) or, rarely, juvenile onset (age <20 years). Most affected individuals appear to have onset before age 40 years. Lower-limb dystonia, which may be a presenting sign or occurs during disease progression. This finding can sometimes be present in isolation for years.Hyperreflexia of the lower extremitiesWell-preserved sense of smellMarked and sustained response to oral administration of levodopa, which is frequently associated with levodopa-induced motor fluctuations and dyskinesias (abnormal involuntary movements) Slow disease progression Absence of dementia in most cases (prevalence <3%)Family history consistent with autosomal recessive inheritance TestingNo clinical investigations distinguish individuals with parkin type of early-onset Parkinson disease from those with idiopathic Parkinson disease. Molecular Genetic Testing Gene. PARK2 is the only gene in which mutations are known to cause parkin type of early-onset Parkinson disease. Clinical testing Note: The detection frequency of all mutation types varies by population and depends mostly on the presence of a positive family history and the age at onset [Abbas et al 1999, Lücking et al 2000, Periquet et al 2001, Hedrich et al 2002, West et al 2002, Lohmann et al 2003, Periquet et al 2003, Poorkaj et al 2004, Wiley et al 2004, Wu et al 2005, Marder et al 2010, Kilarski et al 2012]. The detection frequency of all types of mutations is as high as 80%-90% in familial cases with onset before age 20 years, and lower than 10% in individuals with no family history and onset around age 40 years. Otherwise, only 18%-26% of cases with a reported mutation had a juvenile onset, whereas 70% manifested the disease between the ages of 20 to 40 years, and 12% at 41 years or older (Table 2) [Periquet et al 2003, Kasten et al 2010]. A major caveat is that more than 50% of all published studies restricted their recruitment to those with young-onset disease [Grünewald et al, in press].Table 1. Summary of Molecular Genetic Testing Used in Parkin Type of Early-Onset Parkinson DiseaseView in own windowGene SymbolTest Method Mutations DetectedMutation Detection Frequency 1Test Availability Family History Positive Negative PARK2Sequence / mutation scanning analysis 2Sequence variants 3≤80%-90% 4See Table 2 Clinical Deletion / duplication analysis 5Heterozygous deletions / duplications / triplications 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.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. Sequencing of the12 coding exons permits identification of the missense and nonsense mutations described so far, as well as small exonic rearrangements (1- or 2-base pair deletions or insertions) [Hattori et al 1998a, Hattori et al 1998b, Kitada et al 1998, Leroy et al 1998, Lücking et al 1998, Abbas et al 1999, Nisipeanu et al 1999, Maruyama et al 2000, Munoz et al 2000, Hedrich et al 2004].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 (alias array comparative genomic hybridization (aGCH).6. Exon rearrangements (i.e. deletions, duplications, and rarely, triplications of single or multiple exons) account for more than 50% of mutations [Hedrich et al 2004, Marder et al 2010]. The frequency of exon rearrangements is likely even underestimated given that early mutation screening studies did not include methods that aimed at identifying these types of mutations. Deletions or duplications are frequently found in the heterozygous state [Lücking et al 2000].Table 2. Frequency of PARK2 Mutations by Age at Onset in Individuals with Early-Onset Parkinson Disease and No Family HistoryView in own windowAge at Onset Individuals with PARK2 Mutations Total 1 Mutation Detection Frequency 95% Confidence Interval <20 yrs10 15 67% 38-88 20-24 yrs4 15 27% 8-55 25-29 yrs9 38 24% 11-40 30-34 yrs4 53 8% 2-18 35-39 yrs4 71 6% 2-14 40-45 yrs5 51 9% 3-21 Total 38 2 246 2 15% 11-20 Adapted from Periquet et al [2003] with permission 1. Including 100 cases from Lücking et al [2000] 2. Age at onset was not known for two affected individuals with PARK2 mutations and for one affected individual without a mutation; all three were younger than age 45 years when examined.Interpretation of test results For issues to consider in interpretation of sequence analysis results, click here. The diagnosis of parkin type of early-onset Parkinson disease can only be confirmed when disease-causing mutations are identified on both PARK2 alleles (i.e., the individual is homozygous for the same disease-causing allele or a compound heterozygote for two different disease-causing alleles). The finding of a single disease-causing mutation is only suggestive (i.e., not diagnostic) of parkin type of early-onset Parkinson disease; the affected individual may truly be a heterozygote and have parkinsonism from some other cause. In some series, even with individuals with early-onset Parkinson disease, the proportion of individuals with a single (heterozygous) mutation is very high, up to 70% of parkin cases [Poorkaj et al 2004]. Those affected individuals with a single heterozygous PARK2 mutation have on average about a nine year higher age at onset (39.9±13.3 years, n=232) than affected individuals with homozygous or compound heterozygous mutations in PARK2 (30.9±11.2 years, n=378) [Grünewald et al, in press].A better understanding of the mode of inheritance, penetrance, and carrier frequency is needed to interpret the significance of single (heterozygous) mutations. The absence of a PARK2 mutation on one or both alleles cannot completely exclude the diagnosis of parkin type of early-onset Parkinson disease. Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband identification of disease-causing mutations on both PARK2 alleles (i.e., the individual is homozygous for the same disease-causing allele or a compound heterozygote for two different disease-causing alleles) is required. Single gene testing. One strategy for molecular diagnosis of a proband suspected of having parkin type of early-onset Parkinson disease is molecular genetic testing of PARK2. Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having parkin type of early-onset Parkinson disease is use of a multi-gene panel. The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest. See Differential Diagnosis. Note: Testing for mutations in PARK2, PINK1, and DJ-1 is recommended in families with a recessive mode of inheritance or in sporadic cases in which an affected individual has an early age at onset (<35 years [Harbo et al 2009] or <40 years [Klein & Schlossmacher 2006]). Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersHeterozygous PARK2 mutations have been detected in a large number of individuals with Parkinson disease, raising the question of whether heterozygous mutations may contribute to the development of parkinsonism [Klein et al 2000, West et al 2002, Oliveira et al 2003, Klein et al 2007]. Case-control studies revealed a frequency of 0 to 7.9% in people with Parkinson disease and 0 to 3.7% of neurologically healthy control subjects [Grünewald & Klein 2012]. The frequency of heterozygous exon rearrangements was the same among affected persons and control subjects in a comprehensive case-control study [Kay et al 2010]. Notably, however, the frequency of PARK2 mutations in public exome databases is only 0.17% in presumably healthy individuals. Multimodal neuroimaging and electrophysiologic studies disclosed latent nigrostriatal impairment in asymptomatic individuals with heterozygous PARK2 mutations, supporting the assumption that heterozygous mutations are a genetic susceptibility factor for Parkinson disease [van der Vegt et al 2009]. In addition, pseudo-dominant inheritance (i.e., one of the parents is also affected) has been reported in some families with autosomal recessive PARK2 mutations [Maruyama et al 2000, Bonifati et al 2001, Lücking et al 2001, Kobayashi et al 2003]. However, based on the currently available data (and lack of prospective evaluations), the role of heterozygous PARK2 mutations cannot be determined conclusively.Mutations in PARK2 have also been associated with cancer [Veeriah et al 2010], leprosy [Mira et al 2004], and autism [Glessner et al 2009]. The involvement of PARK2 mutations in oncogenesis is, however, ambiguous, as the association with cancer could not be replicated in a population-based study [Alcalay et al 2012].
Unlike in idiopathic Parkinson disease, women and men are affected with equal frequency. Age at onset is highly variable, even in individuals with the same mutation [Chien et al 2006]; onset is usually before age 40 years, but some individuals may not develop disease until age 60 or 70 years [Klein et al 2000, Lohmann et al 2003]....
Natural HistoryUnlike in idiopathic Parkinson disease, women and men are affected with equal frequency. Age at onset is highly variable, even in individuals with the same mutation [Chien et al 2006]; onset is usually before age 40 years, but some individuals may not develop disease until age 60 or 70 years [Klein et al 2000, Lohmann et al 2003].Clinical signs vary; however, bradykinesia and tremor are the most common presenting signs. Dystonia is observed in 42% of affected individuals. Almost half of affected individuals present with hyperreflexia. A prolongation of the central motor conduction time points to involvement of the corticospinal tract [De Rosa et al 2006, Schneider et al 2008, Perretti et al 2011] corresponding to the clinically observed hyperreflexia. On average, the response to low doses of levodopa is excellent and sustained. The likelihood of developing levodopa-induced dyskinesias is higher than in individuals with parkinsonism resulting from other etiologies. Parkin type of early-onset Parkinson disease is not associated with specific behavioral, neuropsychological, or psychiatric symptoms [Caccappolo et al 2011, Srivastava et al 2011]. Cognitive impairment is uncommon, and dementia is observed very rarely [Benbunan et al 2004; Grünewald et al, in press]. In contrast to idiopathic Parkinson disease, the sense of smell does not appear to be impaired in affected individuals with compound heterozygous mutations, whereas individuals with Parkinson disease and a heterozygous PARK2 mutation demonstrate typical hyposmia [Alcalay et al 2011]. The disease is slowly progressive and disease duration of longer than 50 years has been reported. Neuroimaging. Routine cranial CT and MRI scans are usually normal.PET/SPECT studies have revealed a reduced striatal 18F-DOPA uptake and a reduced presynaptic dopamine transporter density in individuals with parkin type of early-onset Parkinson disease [van der Vegt et al 2009]. The putamen is predominantly affected, consistent with the findings in idiopathic Parkinson disease. Unlike the idiopathic form, however, the loss of dopaminergic striatal innervation is rather symmetric and the progression rate is considerably slower. The postsynaptic D2 receptor density as assessed with 11C-raclopride PET has been shown to be upregulated in untreated affected individuals and downregulated in affected individuals who receive dopaminergic medication.Asymptomatic individuals who have a heterozygous mutation show a slight and subclinical impairment of dopaminergic neurotransmission. A longitudinal PET study demonstrated a very subtle progression rate, indicating that only a marginal number of asymptomatic individuals with a heterozygous mutation may develop clinically overt parkinsonism if no other risk factors are present [Pavese et al 2009].Voxel-based morphometry revealed a decrease of putaminal gray matter volume and a slight increase of gray matter in the right pallidum in affected individuals (those with two mutated alleles), whereas asymptomatic individuals with a single heterozygous mutation demonstrated an increase of both putaminal and pallidal gray matter volume.Using functional MRI, asymptomatic individuals with a single heterozygous mutation showed an increased activation of motor-related brain regions when they performed repetitive finger movements [van Nuenen et al 2009]. The same mechanism of an increased neuronal recruitment has been illustrated for a facial emotion recognition task [Anders et al 2012].Neuropathology. To date, detailed post mortem studies of nine individuals with homozygous and compound heterozygous PARK2 mutations have been published [Poulopoulos et al 2012]. The most prominent and most common feature was the finding of neuronal loss in pigmented nuclei of the brain stem. Unlike idiopathic Parkinson disease, the neuronal loss was stronger in the substantia nigra pars compacta than in the locus coeruleus (see Parkinson Disease Overview). Typical alpha-synuclein-containing Lewy bodies were identified in only two affected individuals, whereas one affected individual had basophilic Lewy body-like pathology of the pedunculopontine nucleus. Tau-containing neurofibrillary tangles were observed in two affected individuals. In conclusion, the spectrum of post mortem findings is broad and thus reminiscent of the situation in LRRK2-related Parkinson disease.
Exon rearrangements of PARK2 appear to have greater pathogenicity than point mutations or small insertions/deletions, resulting in an association with an earlier age at onset [Pankratz et al 2009; Grünewald et al, in press]. No correlation between missense or truncating PARK2 mutations and age at onset, clinical presentation, or disease progression has been observed [Lücking et al 2000; Grünewald et al, in press]. Missense mutations in known functional domains do not result in an earlier onset than missense mutations in other regions of the protein [Grünewald et al, in press]....
Genotype-Phenotype CorrelationsExon rearrangements of PARK2 appear to have greater pathogenicity than point mutations or small insertions/deletions, resulting in an association with an earlier age at onset [Pankratz et al 2009; Grünewald et al, in press]. No correlation between missense or truncating PARK2 mutations and age at onset, clinical presentation, or disease progression has been observed [Lücking et al 2000; Grünewald et al, in press]. Missense mutations in known functional domains do not result in an earlier onset than missense mutations in other regions of the protein [Grünewald et al, in press].
Parkinson disease multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. ...
Differential DiagnosisParkinson disease multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. Parkin type of early-onset Parkinson disease and idiopathic Parkinson disease are difficult to distinguish by clinical examination (see Parkinson Disease Overview). More than 80% of individuals with Parkinson disease have no family history of the disorder. Several monogenic forms account for a number of cases with a positive family history.Mutations in PINK1 are the second most common cause of early-onset Parkinson disease, after PARK2. Cases associated with mutations in PARK2 and PINK1 are clinically indistinguishable on an individual basis [Ibanez et al 2006] (see PINK1 Type of Young-Onset Parkinson Disease).Another disorder in the differential diagnosis is the DJ1- type of early-onset Parkinson disease, which also presents as an early-onset disorder with an overall similar phenotype to that of the parkin type of early-onset Parkinson disease [Bonifati et al 2003].For individuals with juvenile-onset Parkinson disease, especially those with prominent dystonia, dopa-responsive dystonia should be considered; for example, GTP cyclohydrolase 1-deficient dopa-responsive dystonia, caused by mutations in GCH1.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 in an individual diagnosed with parkin type of early-onset Parkinson disease, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with parkin type of early-onset Parkinson disease, the following evaluations are recommended:Assess the presence and the severity of parkinsonian signs, non-motor features and treatment-related complications using the Unified Parkinson’s disease rating scale (UPDRS) [Fahn & Elton 1987] or the Movement Disorder Society (MDS) UPDRS [Goetz et al 2008]. Assess the presence of atypical signs, such as hyperreflexia and dystonia.Evaluate the degree of response to treatment. Assess for cognitive or behavioral problems. Consider medical genetics consultation.Treatment of ManifestationsTo date, the treatment of parkin type of early-onset Parkinson disease is not different from that of idiopathic Parkinson disease. No specific guidelines are currently available.The motor impairment usually responds very well to low doses of dopaminergic medication and is typically sustained even after long disease duration. The most relevant treatment-related problem is the early occurrence of levodopa-induced dyskinesias (abnormal involuntary movements) and motor fluctuations. The management of treatment-related complications is not different from the strategies applied in idiopathic Parkinson disease and includes deep brain stimulation in selected cases [Moro et al 2008].Prevention of Secondary ComplicationsTo reduce or delay side effects, levodopa doses should not exceed the levels required for satisfactory clinical response.SurveillanceNeurologic follow-up every six to 12 months to modify treatment as needed is appropriate.Agents/Circumstances to AvoidNeuroleptic treatment may exacerbate parkinsonism.Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Pregnancy in women with Parkinson disease is a rare event. Only one case of a successful pregnancy in a woman with parkin type of early-onset Parkinson disease has been reported [Serikawa et al 2011]. The 27-year old woman successfully gave birth to spontaneously conceived dichorionic/diamnionic male twins. Exacerbation of her motor disabilities was noted during late pregnancy. She was treated with levodopa/carbidopa only during the period of organogenesis. Both babies were born healthy, without any evidence of psychomotor impairment two years after birth. Worsening of parkinsonian symptoms could in part be explained by the reduction of dopaminergic replacement therapy. If possible, dopaminergic medication should be limited to levodopa/decarboxylase inhibitor to minimize the potential risk for teratogenicity at least over the course of the embryonic phase.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. Parkin Type of Early-Onset Parkinson Disease: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPARK2PARK26q26E3 ubiquitin-protein ligase parkinParkinson's disease Mutation Database PD mutation databasePARK2Data 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 Parkin Type of Early-Onset Parkinson Disease (View All in OMIM) View in own window 600116PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE; PARK2 602544PARKIN; PARK2Normal allelic variants. PARK2 is the second largest human gene spanning approximately 1.35 Mb. It consists of 12 coding exons separated by large intronic regions. Many exonic and intronic variants have been detected; four of them cause amino acid changes (Table 3). The frequency of the particular normal allelic variants varies by geographic location [Abbas et al 1999, Wang et al 1999, Lincoln et al 2003, Lücking et al 2003]. Pathologic allelic variants. More than 180 pathologic allelic variants of PARK2 have been described with half of them being situated in the region spanning exons 2 to 4 [Corti et al 2011; Grünewald et al, in press]. Several of the mutations are recurrent [Hattori et al 1998a, Hattori et al 1998b, Leroy et al 1998, Lücking et al 1998, Abbas et al 1999, Nisipeanu et al 1999, Klein et al 2000, Maruyama et al 2000, Munoz et al 2000, Hedrich et al 2002, Periquet et al 2003, Rawal et al 2003, Grünewald & Klein 2012]. Different types of PARK2 mutations are found at variable frequencies. Changes have been identified in the homozygous, compound heterozygous, and heterozygous state.PARK2 exon rearrangements (deletions or duplications; rarely triplications) of single or multiple exons account for more than 50% of all PARK2 mutations [Hedrich et al 2004; Marder et al 2010; Grünewald et al, in press]. The frequency of exon rearrangements is likely even underestimated given that early mutation screening studies did not include methods that aimed at identifying these types of mutations. Gene dosage alterations lead to internal deletions or premature protein truncation [Lücking et al 2000]. The deletion of exon 3 is the most frequent mutation in PARK2. Importantly, heterozygous exon rearrangements cannot be detected by conventional sequencing.Most of the PARK2 point mutations are missense mutations. The most common point mutation is the c.924C>T single nucleotide mutation in exon 7. Nonsense mutations, one- or two-base pair deletions, or small insertions result in a frameshift that either predicts or is known to cause truncated parkin. Table 3. PARK2 Normal Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.500G>Ap.Ser167Asn NM_004562.1 NP_004553.1c.1096C>Tp.Arg366Trp c.1138G>Cp.Val380Leuc.1182G>Ap.Asp394AsnSee 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. The normal gene product, parkin, is a 465-amino acid protein, which contains a ubiquitin-like domain at the N terminus and a RING (Really Interesting New Gene) domain composed of three RING finger motifs (RING0, 1, and 2). RING1 and 2 are separated by a sequence without any recognizable domain structure (in between-RING (IBR). Parkin is mainly localized in the cytoplasm under basal conditions. Like other RING finger proteins, parkin exhibits E3 ubiquitin ligase activity [Imai et al 2000, Shimura et al 2000, Zhang et al 2000] and mediates the ubiquitination of a number of proteins, thus targeting them for proteasomal degradation. Parkin can additionally mediate non-degradative modes of ubiquitination, which appear to be required for the survival of nigrostriatal dopaminergic neurons [Moore 2006]. More than twenty of its substrates have yet been identified. In addition to its role as E3 ligase, parkin is also involved in the maintenance of mitochondrial function and integrity, and protection from multiple stressors, hence acting as neuroprotectant. In the context of its role in mitochondrial metabolism, parkin interacts with PINK1, another protein linked to autosomal recessive, early-onset parkinsonism [Valente et al 2004]. PINK1 promotes the mitochondrial translocation of parkin, thus enabling parkin to ubiquinate mitochondrial proteins, to selectively identify impaired mitochondria, and to trigger their degradation by mitophagy [Narendra et al 2012, Rakovic et al 2013]. Abnormal gene product. It is postulated that the vast majority of PARK2 mutations produce a loss of function of normal E3 ubiquitin ligase activity by the absence of the protein (truncating mutations) or its inactivation (missense mutations). PARK2 mutations impair the ubiquitination of mitofusins, which are highly relevant mitochondrial fusion and fission factors [Rakovic et al 2011]. The mutations could also result in the accumulation of its substrates because they are no longer appropriately targeted to the proteasome system for their degradation. However, this hypothesis has not been confirmed in appropriate experimental models. As an example, degeneration does not occur in the substantia nigra of different lines of mice with inactivation of PARK2. In addition, in vitro studies have shown that the consequences of mutations may vary according to their nature and their location (e.g., decreased expression, abnormal aggregation, decreased interaction with substrates and/or E2 ubiquitin transferases). According to their involvement in mitochondrial integrity, PARK2 mutations were demonstrated to result in reduction of mitochondrial complex I activity, disruption of the mitochondrial morphology, and impairment of protection of mitochondrial genomic integrity from oxidative stress.