Monogenic Parkinson's disease and parkinsonism: Clinical phenotypes and frequencies of known mutations.

TL;DR: Clinical features of diseases caused by mutations in SNCA cause cognitive or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-synuclein pathology in the central and peripheral nervous system.

About: This article is published in Parkinsonism & Related Disorders.The article was published on 2013-04-01 and is currently open access. It has received 211 citations till now. The article focuses on the topics: Parkinsonism & Parkin.

Summary

Introduction

• The first mutation causing Parkinson's disease (PD) was discovered in the SNCA gene in 1997 [1] .
• Since then, intensive research efforts have established a total of seven genes containing causal mutations for parkinsonism clinically resembling PD, with autosomal dominant or recessive modes of inheritance.
• For mutations in at least 19 additional genes, a disease-causing role was postulated (Table 1 ), but subsequent studies either could not confirm that mutations in these genes are associated with parkinsonism or PD, or showed that they in most or all cases cause a clinical phenotype that is clearly distinguishable from PD.
• This article reviews the present knowledge on these monogenic disorders, with an emphasis on their clinical phenotype and their frequency.

Dominant PD genes

• Today, there is good evidence that mutations in four dominant PD genes may cause parkinsonism.
• The first two, SNCA and LRRK2, have been studied in detail, whereas EIF4G1 and VPS35 have only been identified recently.

SNCA

• Three pathogenic point mutations as well as genomic duplications and triplications are known in the gene encoding alpha-synuclein (SNCA).
• The family originates from the Basque region in Northern Spain.
• The severity of the clinical symptoms and the response to levodopa were variable [14] , and studies of mutation carriers without PD symptoms revealed sleep abnormalities [16] and cardiac sympathetic denervation [17] .
• The A30P and E46K mutations have not been reported from any other family worldwide.
• The clinical phenotype of PD patients with SNCA mutations (including multiplications) has certain characteristics.

LRRK2

• In 2004, two groups simultaneously reported the discovery of mutations in the leucine-rich repeat kinase 2 (LRRK2, dardarin) gene in PD [26, 27] .
• Nevertheless, the large number of PD patients with the LRRK2 G2019S mutation allowed for a clear description of the clinical phenotype attributed to a single mutation in a PD gene, and for statistical analyses [45] .
• Based on data from 1,045 patients with this mutation, motor symptoms and non-motor symptoms of LRRK2 PD were more benign than those of a control group of patients, for example the risk for dementia was lower [45] .
• These findings remain uncertain [46] and need to be interpreted in light of the fact that that study's control group consisted of PD patients collected in a brain bank, which may not reflect the average idiopathic PD population.

VPS35

• The mutation was present in one family each from the United States and Tunisia, and in one family and one sporadic patient of Yemenite Jewish origin [53] .
• An incomplete neuropathological examination of only parts of the cortex and basal ganglia (but not the brainstem) did not reveal any alphasynuclein immunoreactivity in these areas [54] .
• Penetrance was incomplete with the oldest reported unaffected carrier at 86 years [53] .

EIF4G1

• Five mutations in this gene, encoding eukaryotic translation initiation factor 4-gamma 1, were described in PD patients in 2011 [63] .
• Co-segregation of a mutation with disease could only be demonstrated for the p.R1205H mutation, found initially in a French family and subsequently in patients from the USA, Canada, Ireland, Italy, and Tunisia [63] .
• The clinical phenotype was that of mild PD with a late age of onset (50-80, mean 64 years) and preserved cognition, but this is based on the few patients described.
• Concomitant Alzheimer pathology was present in a family with dementia and parkinsonism who had both G686C and R1197W mutations [66] .

Other dominant and x-linked disorders that may present with parkinsonism

• Trinucleotide expansions in ATXN2 (ataxin-2) or ATXN3 (ataxin-3) usually cause spinocerebellar ataxia that may include parkinsonian features.
• Men with premutations may develop the fragile X tremor/ataxia syndrome , typically characterized by adult-onset tremor, ataxia, neuropathy, autonomic dysfunction, cognitive decline, behavioral changes with apathy, disinhibition or irritability, and depression.
• Some of the individuals with pathogenic MAPT mutations present with parkinsonism; signs of frontotemporal dementia may occur years later [73] .
• The phenotype may resemble PD but there are frequently signs of dystonia as well, such as dystonic tremor [81] .
• Two patients have been reported who had adult onset PD and TH mutations, but the association remains uncertain, although a pathophysiological connection appears reasonable [82] .

Monogenic disorders with various manifestations that may include parkinsonism

• Mutations in mitochondrial DNA polymerase gamma (POLG, POLG1) have been reported from patients with parkinsonism, with loss of dopaminergic cells evidenced in DATscans and at least partial response to dopaminergic medication [85, 86] .
• All these patients also had pronounced additional neurological signs such as progressive external ophthalmoplegia, ataxia, sensory neuropathy or sensorineural hearing loss, or muscle weakness with elevated creatine kinase and mitochondrial myopathy in muscle biopsy, and/or hypogonadism [85] [86] [87] [88] .
• Most patients with hereditary leukoencephalopathy with spheroids, a disorder caused by mutations in the CSF1R gene, develop parkinsonism during the course of their disease, but parkinsonism is neither the initial nor the only symptom [89] [90] [91] .

Recessive PD genes

• Recessive inheritance is suggested in families where several members of one generation are affected, especially siblings, but not their parents or their children.
• Some of these have been published from several groups and have become wellestablished.
• Others have only been found in one or a few patients, and their significance is difficult to ascertain.

PINK1

• Homozygous mutations in phosphatase and tensin homolog-induced putative kinase1 (PINK1, PARK6) are associated with early-onset PD [105] .
• Over 40 point mutations and rarely, large deletions, have been detected [101] .
• The clinical phenotype seems to be similar to that of parkin mutations, but there are some indications that psychiatric symptoms may occur more commonly among patients with PINK1 mutations [101, 106] .
• Mutations in PINK1 are rarer than parkin mutations.

DJ1

• Mutations in oncogene DJ1 (parkinson protein 7, PARK7) are well-established but very rare causes for recessive PD [107] .
• Only a few patients homozygous for DJ1 mutations have been described.

Aspects common to parkin, PINK1, DJ1

• Mutations in these three genes are associated with a similar clinical phenotype, which is distinct from the average patient with idiopathic PD.
• Accompanying non-motor symptoms, if present, remain mild in most cases.
• Apart from the tendency to develop dyskinesias and dystonia common to all patients with early-onset PD irrespective of genetic background [112] , no specific features reliably distinguish these forms.
• An important criterion for the pathogenicity of a mutation is that of co-segregation within families, meaning that mutation carriers develop disease whereas their relatives without mutations remain unaffected.
• Stringent large-scale studies exploring the association of reported mutations with disease have not been performed, and the pathogenicity of a considerable number of mutations in these three genes remains unconfirmed.

Detailed information about clinical characteristics of carriers of certain mutations in parkin,

• PINK1 and DJ1 is also limited: Although a large number of different mutations are known, each one is comparatively rare.
• Grouping together patients with different mutations in the same gene may overcome this problem but has limitations when different biological effects of the various mutations are assumed.
• It has been suggested that certain mutations cause early-onset PD when they are present on both alleles, but cause late-onset PD in heterozygote carriers [115] .
• The overall frequency of mutations in these three genes is lower than previously estimated; a systematic review of publications covering more than 5,800 EOPD patients reported proportions of 8.6% with mutations in parkin, 3.7% in PINK1 and 0.4% in DJ1 [103] .

Recessive disorders that may include parkinsonism

• Mutations in ATPase type 13A2 (ATP13A2; PARK9) were found to cause the rare Kufor-Rakeb syndrome in a Chilean family.
• ATP13A2 mutations appear to be exceedingly rare.
• Both are severe neuro-pediatric disorders that bear no resemblance to PD.
• Three years later, mutations in this gene were reported from patients who also developed what was called adult-onset levodopa-responsive dystonia-parkinsonism [125, 126] .

Conclusions

• The genetic causes of a considerable number of monogenic disorders with parkinsonism are known today.
• In most populations, the known pathogenic mutations are exceptionally rare, and can only explain a very minor part [8, 24, 44, 103, 132] of the estimated 10% of PD patients with one or more affected first-degree relatives [133] .
• In general, the probability to find a pathogenic mutation in a given patient with parkinsonism remains low [44, 103, 132] , but varies widely, depending on factors including the patient's age at onset, family history, origin, and clinical phenotype.
• Table 4 shows which genetic tests may be useful.
• Clinical genetic analysis should only be performed when adequate genetic counseling before, during and after testing can be provided.

Figures

Table 1

Table 2

Table 4

Table 3

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Monogenic parkinson’s disease and parkinsonism: clinical phenotypes and frequencies of known mutations" ?

This review summarizes the clinical features of diseases caused by mutations in 

Q2. How many different parkin mutations have been reported from PD patients?

More than 100 different parkin mutations have been reported from PD patients, including copy number variations (deletions, insertions, multiplications), missense and truncating mutations [101]. 

Q3. What is the common mutation in PD?

In a recently published international multicenter study, only 49 of 8,371 (0.58%) PD patients of European and Asian origin carried a LRRK2 G2019S mutation [44]. 

Q4. How many people with PD have parkin mutations?

Other studies found homozygous or compound heterozygous parkin mutations in a lower percentage of patients with early onset-PD (before 40 or 45 years), ranging from 8.2% in Italy, 2.7% in Korea, 2.5% in Poland, to 1.4% in Australia [8, 98-100]. 

Q5. What are the common causes of parkinsonism?

In rare patients, parkinsonism has been the presenting or predominant clinical manifestation of GRN mutation [77], but mutations in MAPT or GRN are not considered a major cause of familial parkinsonism, especially in the absence of other clinical signs and symptoms. 

Q6. How many siblings have a 25% chance of inheriting the same allele?

In families with recessive patterns of inheritance, cosegregation analysis is often limited to a few siblings, but siblings have a 25% chance probability to have inherited the identical allele. 

Q7. What is the effect of levodopa on PD?

12Puschmann: Review monogenic PDFeatures common to patients with parkin mutations and PD, aside from young or very young age at onset, are probably a good and lasting effect of levodopa, albeit with the occurrence of dyskinesias during the disease course, and a lower risk for non-motor symptoms such as cognitive decline and dysautonomia [102]. 

Q8. What are the phenotypes caused by SNCA or the recessive?

The phenotypes caused by mutations in SNCA or the recessive PD genes (parkin, PINK1, DJ1) represent characteristic subtypes of PD. 

Q9. How many cases of PD have been identified in Belgium?

Given the prevalence of D620N of 0.14% among PD patients in the two initial studies and of 0.4% in the multicentre study [58], and the fact that replication studies in Belgium [61] or China [62] have not identified additional cases, this mutation is rare. 

Q10. What was the earliest reported case of PD in the Austrian family?

Late-onset PD was reported in the Austrian family, one member had only developed depression and tremor with a pathological DATscan indicating incipient PD [55]. 

Q11. what is the probability of finding a pathogenic mutation in a patient with parkinso?

Genetic testing can today be offered to a subset of patients with unusually young onset, dominant inheritance, and/or a clinical phenotype suggesting a defined monogenic form of parkinsonism. 

Q12. What are the common causes of PD?

Carriers of mutations in the other genes may develop parkinsonism with or without additional symptoms, but rarely a disease resembling PD.