Parkinson disease

Summary

Parkinson disease (PD) is the second most common neurodegenerative disorders in elder population and it affects more than 6 milions of people worldwide. The exact pathogenic mechanism is still elusive, but it arises from a complex interaction of multiple genetic and nongenetic factors, that results in degeneration of dopaminergic neurons in the substantia nigra and other brain areas. The landscape of genetic forms of Parkinson's diseases (PD) has grown exponentially in recent years, so that we can now distinguish a 10% of genetic forms of PD cases caused by pathogenic variants in single genes (monogenic PD) from the majority of idiopathic Parkinson disease (iPD) cases.

 

Detailed clinical description

PD is characterized by specific movement anomalies: resting tremor, rigidity, bradykinesia, postural instability, and gait instability, due to the loss of pigmented neurons in the substantia nigra and other brain areas. Onset is typically unilateral and may include other abnormal movements such as postural or action tremor as well as limb dystonia. Together with motor symptoms PD is also characterized by non-motor symptoms (NMS), which include cognitive decline, autonomic dysfunctions (i.e.: drooling, constipation), sleep disorder, anxiety, depression, and olfactory impairment. The NMS often precede motor symptoms by several years. That’s why the identification of NMS in PD is important for the early management of the disease, as prompt treatment of these NMS may improve patients’ quality of life.

The diagnosis of Parkinson disease relies on clinical findings of bradykinesia and rest tremor with or without rigidity. An useful evidence supporting the diagnosis of PD is a noticeable response to pharmacological therapy with dopamina. However, specific sets of diagnostic criteria are increasingly being used in establishing the diagnosis in different countries (e.g.: Movement Disorder Society clinical diagnostic criteria for PD).

The most common onset of PD is around age 60 years but it can vary. According to the age of onset, we can distinguish three different forms of PD: juvenile-onset PD (< 20 yrs), early-onset PD (20-50 yrs), late-onset PD (>50 yrs).

The pathological hallmark of PD is Lewy bodies, which are aggregates of misfolded α-synuclein protein, encoded by the SNCA gene, in nerve cells. These aggregates are related to the loss of midbrain dopamine-producing neurons.

Prevalence

Parkinson disease affects approximately 1% of individuals older than 60 years, with an approximated incidence of 8:100,000 per year, and an approximated prevalence of around 120:100,000 individuals. Some studies report that the prevalence is expected to double in the next 20 years. Age is a risk factor and it is related to decline in midbrain neurons that produces dopamina.

Molecular genetics

Around 15% of individuals with PD have a positive family history for the disease. Around 5%-10% of PD cases are caused by mutations in single genes. In 2018 at least 23 loci and 19 disease-causing genes for monogenic forms of PD have been identified. In 2020 more than 90 susceptibility loci have been described, making the genetics of PD very complex. We now list only those genes related to the most important forms of monogenic forms of PD, in accordance with their mode of inheritance.

Autosomal dominant
SNCA (associated loci: PARK1/PARK4) was the first causative gene identified, although mutations in this gene are very rare. Patients with SCNA-related PD are characterized by early-onset (but usually after 40 years) and rapid progression. The most common motor symptoms are bradykinesia and rigidity, while only 30% of affected individuals report resting tremor and postural instability. The NMS are evident and cognitive decline is the most common symptom, followed by depression, autonomic dysfunction, and other psychotic manifestations (including visual and auditory hallucinations). There is a good response to pharmacological therapy with levodopa. Pathogenic multiplications of the whole gene (duplications and triplications) are often reported, but intragenic missense mutations have also been described.

LRRK2 (associated locus: PARK8). LRRK2 mutations are the most common cause of monogenic PD, accounting for 1%-2% of all PD cases, and reaches up to 13%-30% of adult PD cases in Ashkenazi population. Patients with LRRK2-related PD are characterized by late onset and progression similar to idiopathic PD. The most prominent motor symptoms are usually postural instability gait difficulty, whereas NMS are less common and patients have better performance in attention, executive functions, emotion, and language, but dementia has been reported. There is a good response to pharmacological therapy with levodopa. The penetrance of this monogenic PD is variable and is related to the type of mutation, age and ethnicity. More than 40 mutations have been reported and the most studied variant is G2019S, with a penetrance ranging from 28% at the age of 59 to 74% at the age of 79.

VPS35 (associated locus: PARK17). Mutations in the VPS35 gene cause a rare form of PD with low penetrance, accounting for approximately 0.4% of PD cases. The onset is around 50 years. Progression and phenotype are very similar to iPD. The most prominent motor symptom is tremor, while non-motor symptoms are similar to iPD and include hyposmia, autonomic manifestations (orthostatic hypotension and constipation), rare mild cognitive impairment, and neuropsychiatric features. There is a good response to pharmacological therapy with levodopa.

GBA. Bi-allelic mutations in this gene cause Gaucher disease and it was first considered for PD because patients with Gaucher disease were noted to develop high levels of parkinsonian features. Now, this gene is becoming the most important genetic susceptibility factor for PD. Because of its low age-related penetrance, there is some disagreement as whether this gene should be considered a PD risk factor or a causative gene. However, the estimated penetrance of some GBA pathogenic variants is similar to those ones of LRRK2 variants. Many studies showed that PD cases with GBA mutations are around 5 years younger than iPD and the progression is more severe. NMS are more prominent than iPD and primarily impact cognitive functions, working memory, executive functions, and visual-spatial ability. The incidence of autonomic dysfunctions, anxiety, and depression is similar to iPD.

Autosomal recessive
PRKN (associated locus: PARK2), previously called Parkin, is one of the biggest gene in the human genome and it is related to the most common cause of autosomal recessive PD, accounting for 4.6%-10.5% of early-onset PD and around 1% of PD cases. The age of onset is around 31 years with a slow progression. Motor symptoms are similar to iPD, hyperreflexia is common and lower-limb dystonia may be a presenting sign. NMS are less severe than in iPD. Cognitive impairment is uncommon, psychosis and dementia are rarely reported, but the patients may have more serious impulse control disorders, while the sense of smell is preserved. There is a good response to pharmacological therapy with levodopa (but usually complicated by dystonia and freezing of gait). In many cases of PRKN-related PD a peculiar feature is the absence of Lewy bodies. The related monogenic PD form is caused by bi-allelic mutations, however, several studies reported that heterozygous mutations represent a risk factor for developing PD. Pathogenic variants include intragenic loss-of-function variants and structural variants (SVs) not detectable by sequencing, as large deletions and duplications. As SVs account for more than 50% of the mutations in the PRKN gene, large deletion/duplication testing (such as MLPA) can be taken into account as first-tier genetic testing for PRKN-related PD, before proceeding with the sequencing of the PRKN coding regions.

PINK1 (associated locus: PARK6). PINK1 mutations are the second most common cause of autosomal recessive PD. The onset is around 32 years with a slow progression. The main motor symptom is rigidity and NMS include anxiety, depression, cognitive dysfunction. Executive functions and attention are usually most affected. There is a good response to pharmacological therapy with levodopa.

DJ-1 (associated locus: PARK7). DJ-1 mutations account for less than 1% of early-onset PD cases. The clinical manifestations and progression are very similar to PRKN- or PINK1-related PD, and dystonia is particularly common. However, NMS are more evident and include mental disorders and cognitive decline.

DNAJC6 (PARK19). DNAJC6 mutations are rare among PD patients, and they can cause two different subtypes of the disease. The most frequent subtype is a juvenile-onset PD with onset around 21 years with rapid progression and neuroregression. Motor symptoms also include seizures and other movement disorders as spasticity or dystonia. NMS include developmental delay, intellectual disability, and neuropsychiatric features which are common features among these patients. Pharmacological therapy with levodopa is not very helpful to treat parkinsonian symptoms.
The less common subtype is a early-onset PD with slow progression, typical motor symptoms, and absence of additional neurologic features. In these cases, there is some response to pharmacological therapy with levodopa.

ATP13A2 (associated locus: PARK9). Bi-allelic mutations in this gene can cause autosomal recessive spastic paraplegia 78 or Kufor-Rakeb syndrome. The latter is a rare form of juvenile-onset atypical PD, with onset in adolescence and characterized by supranuclear gaze palsy, spasticity, dementia and hallucinations. In some patients, it is possible to observe iron deposition in the basal ganglia, and for that the disease can be also considered among the syndromes of neurodegeneration with brain iron accumulation.

X-linked
ATP6AP2. In five family members affected by X-linked parkinsonian syndrome with variably penetrant spasticity, a synonymous variant in the ATP6AP2 gene, which should lead to inefficient splicing of the exon, was suggested as causative mutation. Another study described a second indipendent family with two individuals affected by X-linked mental retardation, epilepsy and parkinsonism, and singled out an intronic variant in a splice site region of exon 2 as causative mutation.

Differential diagnosis

Multiple system atrophy (MSA) is another α-synucleinopathy, although much rarer than PD. There are a range of associated clinical features, which include parkinsonism, cerebellar ataxia, autonomic failure, urogenital dysfunction, and corticospinal involvement. There is a relative preservation of cognition. In this context the parkinsonism tends to be rapidly progressive and poorly responsive to levodopa.

Progressive supranuclear palsy. This neurodegenerative disorder is a tauopathy which usually has a distinct presentation from PD. Patients usually present in their 60s with walking difficulties, unsteadiness, falls, and visual symptoms.

Corticobasal syndrome (CBS) is another tauopathy which is both clinically and pathologically heterogenous. The diagnosis of CBS is clinical and based primarily on its motor features. It causes asymmetric limb rigidity or akinesia, which may resemble the parkinsonism of PD. However, this is frequently associated with dystonia and myoclonus, and the parkinsonism is typically levodopa-resistant and may also involve the axial musculature. Tremor may also be a feature, although it is not the typical rest tremor of PD.

Genetic testing strategy

A multigene panel that includes all the known genes related to monogenic forms of PD is most likely to identify a genetic cause of Parkinson disease at the most reasonable cost. Striking evidences about the onset of the disease and mode of inheritance can steer genetic testing to a subset of PD genes. In case of suspect of autosomal recessive Parkinson disease large deletion/duplications analysis can be considered as the first tier test, as more than 50% of mutations in the PRKN, which is the most common cause of autosomal recessive PD, are SVs not detectable by sequencing.

Panel testing recommended at Breda Genetics for this condition:

Parkinsons disease (ADH1C, ATP13A2, ATP1A3, ATP6AP2, ARSD, CHCHD2, CSF1R, DCTN1, DNAJC6, EIF4G1, FBXO7, FTL, GBA, GCH1, GIGYF2, HTRA2, LRRK2, MAPT, PARK2, PARK7, PDXK, PINK1, PLA2G6, POLG, PRKRA, SLC6A3, SNCA, SNCAIP, SNCB, SYNJ1, TAF1, TH, UCHL1, VPS13C, VPS35)

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References

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Korvatska et al. Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS). Hum Mol Genet 2013 Aug; 22(16):3259-68. PMID: 23595882

Gupta et al. A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism. Parkinsonism Relat Disord 2015 Dec;21(12):1473-5. PMID: 26467484

Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: https://omim.org/

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