A Practical Approach to Early-Onset Parkinsonism

Genetic forms

Autosomal recessive forms. Autosomal recessive mutations in genes associated with monogenic PD are a frequent cause of EOPD [28, 29]. Among these, mutations in Parkin (PRKN) (missense, nonsense, deletions, insertions, multiplications) are the most common, found in 50% of PD cases with onset before age 40 [30] and in up to 77% of patients with very young-onset parkinsonism before age 20 [31]. Disease onset spans from early childhood to after 50 years in rarer instances [32, 33], with the most common occurrence in the 3rd-4th decade and a median age at onset of 31 [33]. PTEN-induced kinase 1 (PINK1) mutations (point mutations and rarer large deletions) are the second most common cause of autosomal recessive PD [34], found in 4–7% of sporadic EOPD cases [35, 36], with a mean age at onset of 32 years [30]. Patients with mutations in PRKN or PINK1 share a similar phenotype, characterized by slow progression with robust and sustained response to levodopa. More peculiar features include onset with dystonia and symmetrical involvement, hyperreflexia, spasticity, psychiatric symptoms, and diurnal fluctuations with sleep benefit [30, 37]. Patients with PINK1 mutations have less pyramidal signs [30] and more commonly present with psychiatric symptoms [38, 39]. Despite young or very young-onset, disease progression is slow and the incidence of dementia and dysautonomia is low [31, 40–43]. An increased risk for impulse control disorders and early motor fluctuations and dyskinesias in PRKN carriers has been described [44]. Mutations in DJ1 have been found in 0.4–1% of cases of EOPD [45, 46], with a median age of onset of 27 [30]. Despite their rare occurrence, DJ1 mutations are the third most common cause of autosomal recessive EOPD after PRKN and PINK1 mutations. The clinical presentation is similar to that of patients with PRKN or PINK1 mutations, however a higher risk of dementia and psychiatric symptoms (i.e., depression, anxiety, psychosis) has been reported [33, 46]. Brain MRI of EOPD associated with mutations in PRKN, PINK1, or DJ1 is usually normal.

Patients with mutations in FBXO7 present with juvenile parkinsonism typically associated with pyramidal tract signs, thus configuring a “pallido-pyramidal” or “parkinsonian-pyramidal” syndrome [47]. Pyramidal features, comprising spasticity and hyperreflexia predominantly in the lower extremities, Babinski sign, and equinovarus deformities, present in childhood and precede the onset of parkinsonism by 5–20 years [48]. Neuropsychiatric manifestations are often present, and slow vertical saccades have been described in ∼30% of patients [47, 50]. Rare cases with limb myoclonus or chorea have also been reported [51]. Response to levodopa treatment is variable and often limited by dyskinesias and psychiatric complications [52, 53]. However, disease progression is usually slow and there is a low occurrence of dementia or dysautonomia [49, 53]. Mild generalized atrophy can be seen, however brain MRI is often normal [48, 53].

Very rare cases of rapidly progressive parkinsonism with median age at onset of 29 have been associated with mutations in VPS13C [54]. The course of this form is severe and characterized by early and dramatic cognitive decline, pyramidal signs, dysautonomia, and loss of ambulatory capacity within 15 years of onset [54].

Rarer autosomal recessive forms of PD present an early onset and are associated with atypical parkinsonism and complex phenotypes, often with a more severe course and are therefore discussed in the corresponding paragraphs below.

Autosomal dominant forms. Autosomal dominant forms of PD have a wide range of age at onset, from young adulthood to late adulthood, however they represent a rare cause of PD with early onset. Mutations in the LRRK2 gene are the most common variants found in all genetic PD cases [30]. Several missense mutations are considered pathogenic, each exhibiting a characteristic ethnic distribution. The frequency of the recurrent p.Gly2019Ser mutation ranges from 1–5% among European cases to 38–39% among North African populations and 10–28% among Ashkenazi Jews [38, 55]. Mutations at the 1441 site (p.Arg1441Gly, p.Arg1441Cys, and p.Arg1441His) are more common in Spain [56]. The p.Ile2020Thr has been reported in Japanese families [57–59], and the p.Gly2385Arg has been found in kindreds in China, Japan and Korea [60–62]. Although the onset of motor symptoms in carriers of mutations of this gene has been described as early as 28 years, the majority of mutations have been detected in late-onset cases (mean age 58–61 years) [55, 63–68]. The penetrance of LRRK2 mutation is largely incomplete and age-related, ranging from 14% to 90% according to various studies, and thus accounting for several apparently sporadic cases [69]. The clinical phenotype of LRRK2-related PD is that of typical levodopa-responsive PD with a milder disease course characterized by low occurrence of depression, hyposmia, RBD, and cognitive involvement [68, 70–74].

Mutations in SNCA are a highly penetrant and rare cause of PD, accounting for 0.2% of sporadic PD and 1-2% of familial PD cases [38, 76]. The p.Ala53Thr, p.Gly51Asp, and p.Ala53Glu variants are associated with earlier onset PD before age 50 [33, 78], whereas the p.Ala30Pro and p.Glu46Lys mutations cause a form of PD with typical onset in later adulthood [79, 80]. The p.Ala53Thr, p.Ala30Pro, and p.Glu46Lys variants yield a higher risk of cognitive decline, with behavioral changes, hallucinations, and progression to severe dementia and mutism in the later stages [81]. Atypical features can be seen in specific forms: pyramidal signs have been reported in patients with p.Gly51Asp and p.Ala53Glu [82–84], with the latter also presenting with myoclonus [85], while cerebellar signs have been described in patients with the p.Ala30Pro variant [81]. In addition to point mutations, heterozygous duplications and triplications of the SNCA gene have also been described in kindreds with early-onset PD [86]. SNCA multiplications are more common in European and Asian populations, and are linked to a more severe phenotype and a well-established gene dosage effect: triplications have been associated with an earlier onset, a more rapid progression, a higher risk of dementia and dysautonomia, and atypical signs (i.e., myoclonus) [87].

Mutations in VPS35 have a very low frequency (< 1%–1.5% in PD cohorts) [88–91] and represent a very rare cause of PD [123]. The mean age at onset is 51 years [89, 92–94]; however several cases with earlier onset in the 4th-5th decade have been described [90, 95]. The phenotype associated with VPS35 mutations overlaps that of idiopathic PD of the tremor-predominant type with slow progression and good response to levodopa [30]. Atypical features are rare, however cases presenting with learning disabilities, dementia, psychosis, depression, and muscle spasms have been reported [91, 97].

GBA mutations are the most frequent genetic risk factor of PD, found in 5–20% of patients with PD across different populations [98–102]. A recent study screening a large cohort of PD patients identified an enrichment in GBA variants in EOPD [102]. Different variants of this gene have variable frequency across populations [103]. For example, the N370S, 84GG, E326K, and R496H variants are more frequent among Ashkenazi Jews, while the other common variant, L444P, is mostly found in non-Ashkenazi Jewish European subjects [99]. Compared with non-GBA carriers, PD patients with GBA mutations have an earlier onset of PD (median age 58) [98, 104], are more likely to develop PD before 50 years of age [98, 105], and have a higher risk and earlier presentation of non-motor features (i.e., dementia, dysautonomia, psychiatric manifestations) compared with idiopathic PD [99, 107].

Secondary EO parkinsonism

Secondary causes of parkinsonism should be considered as well when assessing patients with EOPD, as they may represent treatable conditions, different from the majority of the degenerative processes. Drug-induced parkinsonism (secondary to the use of dopamine blocking agents, dopamine depletors, or, more rarely, associated with other drugs, such as calcium antagonists), and vascular parkinsonism are the most common forms of secondary parkinsonism [108]. Symmetric presentations and lack of the classical resting tremor are more frequent in these patients [109]. Although these conditions are more common among older subjects, they can be seen also in younger patients. When first evaluating a patient with EOPD, imaging studies of the brain should be considered to rule out rarer causes of secondary parkinsonism, such as vascular malformations (fistula, cavernoma, or arteriovenous malformations), single strategic lesions in the basal ganglia circuitry, supratentorial tumors or metastatic neoplastic lesions, as well as obstructive hydrocephalus [110]. Additional neurological symptoms can be frequently appreciated in secondary forms of EOPD and can help guide the diagnosis.

Systemic diseases that can present with parkinsonism in young age are represented by hepatic insufficiency (associated with bilateral hyperintensities of the basal ganglia on T1-weighted sequences or hyperintensities in the cerebellum and middle cerebellar peduncles on T2-weighted images), systemic lupus erythematosus (where characteristic serological biomarkers and systemic symptoms are crucial for the diagnosis), as well as infectious diseases (such as HIV and possible opportunistic infections) [109]. A high number of cases of secondary parkinsonism were observed during the pandemic of Spanish flu [111].

The use of street drugs (such as amphetamines derivatives or MPTP), as well as exposure to carbon monoxide, manganese - as described in the paragraph “Metals in the brain” -, cyanide and methanol can represent additional causes of secondary parkinsonism in young patients [112].

A recent work also showed a correlation with sport-related head trauma and EO parkinsonism, in subjects where the most common genetic causes of EOPD were excluded [113]. Although more studies will be necessary to further clarify this association, traumatic brain injuries have been already correlated with parkinsonism, thus this trigger may be taken into consideration among the other factors as a causative or precipitating event for EO parkinsonism in predisposed subjects [114].

EO parkinsonism and metals in the brain

Brain metal accumulation can manifest clinically as early-onset parkinsonism in several neurological disorders. Various metals can be accumulated in the brain and other body tissues in these conditions (e.g., copper in Wilson’s disease, iron in neurodegeneration with brain iron accumulation (NBIA), calcium in Fahr’s disease, and manganese in hypermanganesemia). Some of these disorders are genetically inherited, while others are acquired [115–118].

Typically, the clinical suspect for these conditions emerges after brain imaging studies (i.e., brain MRI for Wilson’s disease, NBIA, and hypermanganesemia, and head CT for brain calcifications) [119]. However, associated systemic findings, such as hepatic involvement in Wilson’s disease and hypermanganesemia, can be the first clue to suspect metal accumulation in the brain [115, 120].

Wilson’s disease

Wilson’s disease is distributed worldwide, with an estimated prevalence of 1 case per 30,000 live births in most populations [146]. However, in some isolated populations, such as a small mountain village on the island of Crete, the prevalence is much higher (1 in 15 births), due to high rates of consanguinity [121].

Wilson’s disease is an autosomal recessive disorder caused by loss-of-function mutations of ATP7B gene, which encodes for a copper-transporting ATPase which exports copper out of the cells, with a prominent role in the efflux of hepatic copper into the bile [122, 123]. The defective excretion of copper in the bile leads to hepatic copper overload and consequent damage, up to cirrhosis. Moreover, an impairment of copper incorporation into ceruloplasmin is also observed, resulting in low circulating levels of ceruloplasmin and elevated levels of unbound copper in plasma and urine. This altered copper metabolism leads to copper accumulation also in extrahepatic tissues, particularly in the basal ganglia [124]. In addition to the liver and brain, the cornea is also a characteristic site of copper deposition in Wilson’s disease. Indeed, the pathognomonic sign of this disease is the Kayser-Fleischer ring, an annular deposition of copper in the periphery of the cornea [125].

Copper accumulation is associated with a progressive neurodegeneration of basal ganglia leading to a complex movement disorder often associated with bulbar symptoms. The movement disorder is usually characterized by tremor, dystonia, and/or parkinsonism. Bulbar symptoms consist of dysarthria, drooling and/or dysphagia. In addition, a range of additional neurologic features may be present, including cerebellar ataxia, chorea, hyperreflexia, seizures, cognitive impairment, and psychiatric features [115].

While parkinsonism is rarely found in isolation or as the predominant feature in Wilson’s disease, this is commonly seen in combination with dystonia and/or tremor at presentation. Indeed, isolated parkinsonism occurs in less than 2% of neurologic presentations but parkinsonism in combination with other movement disorders is seen in the majority of the cases [115].

On brain MRI, T2 hyperintensity of the putamina and other deep brain nuclei is the most common abnormality. Involvement of the midbrain tegmentum can appear as a face of the “giant panda” on axial images. Axial T2 at the pons level may also show the face of a “miniature panda”. On T1-weighted images, these same areas show hypointensity. However, patients with severe hepatic dysfunction show areas of T1 hyperintensity, especially in the globus pallidus, similar to that seen in acquired hepatocerebral degeneration attributed to manganese deposition [126].

Neurodegeneration with brain iron accumulation

NBIA is a heterogeneous group of inherited movement disorders characterized by abnormal iron accumulation in basal ganglia and extrapyramidal movement disorders. The clinical features of NBIA range from global neurodevelopmental disorder in infancy to mild parkinsonism associated with minimal cognitive impairment in adulthood [116]. To date, ten NBIA genes have been identified, each associated with a different clinical syndrome and specific brain MRI features [118]. All forms of NBIA combined are considered to be ultra-rare with less than 1/1,000,000 affected world-wide, with the most common form being pantothenate kinase-associated neurodegeneration (PKAN), which accounts for approximately 50% of cases [127].

NBIA disorders presenting with parkinsonism as part of their clinical presentation include PKAN, PLA2G6-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN), mitochondrial-membrane protein-associated neurodegeneration (MPAN), Kufor-Rakeb Syndrome (KRS), Aceruloplasminemia, and Neuroferritinopathy [116]. EOPD is a frequent presentation of PLAN, BPAN, and KRS and typically shows atypical features, such as a poor levodopa response, lack of asymmetry, and the association with dystonia and pyramidal signs [116]. PLAN and KRS present brain iron deposition only in a subgroup of cases [128–130] and, therefore, are also classified in autosomal recessive forms of parkinsonism.

Mutations in ATP13A2 (missense, nonsense, and frameshift) have been found in patients presenting with a form of autosomal recessive hereditary parkinsonism with juvenile onset before age 20, known as Kufor-Rakeb syndrome [131–134]. Cases with onset in adulthood have been described, with a mean age at onset of 24 [129]. The clinical spectrum encompasses severe parkinsonism of the akinetic-rigid type and various atypical manifestations, most characteristically ocular movement abnormalities (i.e., vertical supranuclear gaze palsy, slow vertical saccades), pyramidal signs, and facial-faucial-finger myoclonus [131, 135–138]. Intellectual disability, cognitive decline, hallucinations, dystonia, ataxia, and axonal neuropathy are also common [139]. Parkinsonism in Kufor-Rakeb syndrome has a moderate response to levodopa treatment, however levodopa-induced motor fluctuations occur early in the disease course [49, 135] and response to levodopa is lost with disease progression [133]. Brain MRI findings include diffuse atrophy and a hypointense signal in the striatum and pallidum on T2-weighted images, demonstrating the accumulation of paramagnetic substances [49, 138].

Mutations in PLA2G6 have been associated with a form of parkinsonism-dystonia with onset between 10 and 30 years and with a rapid and severe progression to dementia (PLA2G6-associated Neurodegeneration or PLAN) [49, 141]. Initial symptoms include psychiatric manifestations (i.e., depression, irritability, aggressive behavior, psychosis in some cases), gait changes with dragging of the foot and dysautonomia. Atypical features can include pyramidal signs, eye movement abnormalities (i.e., slow vertical saccades, nystagmus), optic atrophy, neuropathy, ataxia and cerebellar signs [135, 140–142]. Despite a modest response to dopaminergic agents, patients may develop early levodopa-induced dyskinesias. Brain MRI can show iron deposition in the cerebellum or in the pallidum, and cerebellar atrophy [49, 142]. Pontine atrophy with clival prominence can be seen in childhood-onset forms [143].

The clinical differential diagnosis among NBIA disorders is primarily based on the age at onset and on the different brain MRI features. PKAN, BPAN and MPAN typically have an early onset in childhood, PLAN and KRS begin in early adulthood, while neuroferritinopathy and aceruloplasminemia are adult-onset disorders [116]. Notably, BPAN-associated EOPD, due to mutations in WDR45, appears later in the course of the disease after intellectual disability and epilepsy which develop in childhood. MRI iron-sensitive sequences, such as susceptibility weighted imaging (SWI), gradient echo (GRE), and T2^*, are needed to identify the characteristic hypointensity in specific NBIA disorders [144]. Concerning specific brain MRI changes of NBIA syndromes presenting with EOPD, the T1-weighted signal hyperintensity surrounding the substantia nigra is the hallmark of BPAN, the presence of associated cerebellar atrophy suggests a PLAN diagnosis, and marked atrophy and hypointensity of the globus pallidus in the initial phase is typical of KRS [144].

Fahr’s disease

The presence of neurological and psychiatric symptoms associated with bilateral basal ganglia calcifications identifies a clinical syndrome defined as Fahr’s disease [117]. This denomination mainly refers to idiopathic forms where no metabolic or other underlying causes are identified. Fahr’s disease commonly affects people after their 40s; therefore, this disorder is not a frequent cause of EOPD. Patients are usually in good health in their youth and tend to develop symptoms later in adulthood [145]. Calcifications are typically symmetrical and bilateral and involve the caudate, putamen, globus pallidus, thalamus, deep cortex, dentate nucleus, and, less frequently, the white matter [146]. CT scan is considered the gold standard for diagnosis identifying calcifications as hyperdense lesions [146]. Recently, mutations in five different genes (SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG) were found to cause Fahr’s disease, or, more precisely, Familial idiopathic basal ganglia calcification (FBGC). MYORG-related FBGC is the only autosomal-recessively inherited form, while the other four types are transmitted with an autosomal dominant pattern of inheritance [147]. Patients with early onset FBGC present frequently with psychiatric/cognitive symptoms or migraine, while older patients exhibit mostly movement disorders, among which parkinsonism is the most frequent presentation [117]. Parkinsonism can present with both motor and non-motor symptoms [148]. The motor symptoms include the cardinal signs of idiopathic Parkinson’s disease (bradykinesia, rest tremor, rigidity, and postural and gait impairment) that tend to present symmetrically with the presence of coarse postural tremor. Levodopa response is variable from case to case. Parkinsonism can be associated with other movement disorders, such as choreoathetosis, non-parkinsonian tremor, dystonia, and orofacial dyskinesias. Associated neuropsychiatric symptoms consist of apathy, anxiety, depression, psychosis, and cognitive deterioration [117, 148].

Brain manganese accumulation

Manganese brain accumulation can be due to genetic or acquired causes. Genetically-determined brain manganese accumulations are ultra-rare conditions, with less than 100 cases reported world-wide so far [149]. There are two known genetic forms of brain manganese accumulation, associated with recessive mutations of SLC30A10 and SLC39A14 genes, but only the former can present as EOPD [118, 120]. Biallelic SLC30A10 mutations are associated with a clinical syndrome characterized by movement disorders (e.g., dystonia and/or parkinsonism) resulting from manganese accumulation in the basal ganglia, hypermanganesemia, polycythemia, and liver disease (e.g., hepatomegaly with variable degree of hepatic fibrosis). Parkinsonism develops in early adulthood as shuffling gait, rigidity, bradykinesia, hypomimia, and monotone speech, and it is unresponsive to levodopa treatment. Other neurologic findings may manifest in childhood and precede EOPD such as four-limb dystonia, leading to the characteristic “cock-walk gait”, dysarthria, and fine tremor. Hepatic failure, secondary complications of cirrhosis, and the neurologic disorder shorten life expectancy. Brain MRI T1-weighted images show characteristic hyperintensity of the basal ganglia, subthalamic nucleus, and dentate nucleus. Normalization of manganese blood levels with chelating therapies can improve brain MRI findings [120]. Differently, in SLC39A14 deficiency, affected individuals present with hypermanganesemia and rapidly progressive childhood-onset parkinsonism-dystonia due to manganese deposition in the basal ganglia. Brain MRI appearances are the same as for SLC30A10 disease. Distinguishing features are the absence of liver disease and polycythemia due to the lack of hepatic manganese deposition, which can be assessed by liver MRI [118].

Considering non-genetic forms, environmental exposure to high quantities of manganese is known to be neurotoxic and causes manganism, a clinical syndrome characterized by an extrapyramidal movement disorder (e.g., dystonia and/or parkinsonism) associated with T1 hyperintensity of the basal ganglia on brain MRI resulting from manganese accumulation in the basal ganglia. Manganism has been described in workers inhaling manganese-loaded dust or fumes (e.g., mining and welding industries), in individuals drinking manganese-contaminated water, and in drug addicts using intravenous drugs contaminated with potassium permanganate [150]. Brain accumulation of manganese is also observed in subjects with advanced hepatic cirrhosis or portosystemic shunts (acquired hepatocerebral degeneration) in which impaired biliary excretion of manganese results in manganese accumulation in the basal ganglia possibly causing debilitating movement disorders [151].

Dystonia-parkinsonism syndromes

Parkinsonism may be part of the clinical spectrum of syndromes defined as “dystonia-parkinsonisms”. This term applies to rare conditions where the severity of dystonia usually equals that of parkinsonism. Unlike the parkinsonian syndromes with additional dystonia (i.e., PRKN-PARK), these conditions usually have their onset in childhood. The phenotype is often non-specific to a particular form and genetic investigations are required.

DYT-GCH1 typically presents with lower-limb dystonia, causing gait disturbance and a tendency to fall. Clinical features like diurnal fluctuation and sleep benefit are typically associated with this form and can be helpful in differentiating it from other forms of EOPD. The response to levodopa of both dystonic and parkinsonian signs is remarkable with low-doses (i.e., < 300–400 mg/daily) [178] with no development of the levodopa-induced dyskinesias.

Mutations in protein kinase, interferon-inducible double-stranded RNA-dependent activator (DYT-PRKRA) cause an autosomal recessive form of young onset, progressive generalized dystonia and mild parkinsonism [179]. A remarkable involvement of oromandibular and bulbar regions with a sardonic smile, tongue protrusion, significant speech and swallowing disturbances is typical of this form. The axial involvement of the neck and trunk can lead to opisthotonic postures. Parkinsonism is usually not a prominent feature, appears later than dystonia and is characterized by bradykinesia and rigidity, rather than resting tremor. The disorder was initially described in three Brazilian families [179]. In a few cases, bilateral striatal degeneration has been observed on brain MRI [180, 181]. However, the three described cases presented with a very young age of onset, before the age of 20 [180, 181].

Rapid-onset dystonia parkinsonism (RODP) due to mutations in the ATP1A3 gene (DYT-ATP1A3) is characterized by an abrupt onset of dystonia and parkinsonism over minutes to several weeks, usually triggered by febrile illness, physical or emotional stressors, alcoholic binges, or childbirth [182, 183]. The acute onset of symptoms and the autosomal dominant mode of inheritance are distinctive features of DYT-ATP1A3 that can help distinguish this form from other conditions. Age at onset is typically in the second to third decade of life. Initial symptoms rapidly evolve over weeks and then stabilize over time. A possible second abrupt worsening of symptoms after years is possible [184]. The rostrocaudal gradient of involvement with prominent dysarthria and hypophonia, and the asymmetric distribution of both dystonia and parkinsonian features is typical. Tremor is usually absent. Levodopa treatment is ineffective [185].

DYT-TAF1 is an adult-onset X-linked recessive neurodegenerative disorder, affecting predominantly men (male to female ratio of 93:1), described in patients from the island of Panay, Philippines, and very rarely in the general population [186, 187]. Dystonia is usually focal at onset, involving the cranio-cervical region with retrocollis, oromandibular dystonia, blepharospasm, and tongue protrusion, and it has a tendency to generalize as the disease progresses [188]. Deep brain stimulation of the internal pallidum (GPi-DBS) has proven effective with long-lasting benefit, especially when performed in the early stage of the disease [189, 190]. Ten years after the onset there is usually a decrease in the severity of dystonia and parkinsonism becomes gradually more prominent [188, 191]. This temporal pattern is quite unique and helps differentiate this condition from other disorders where there is a progression of both dystonic and parkinsonian features.

Parkinsonism-ataxia

Parkinsonism may be part of the clinical presentation of a range of spino-cerebellar ataxias (SCAs) associated with polyglutamine expansion (SCA1,2,3,6,7,8,10,12,17), other SCAs (19,21,22,28), and Fragile-X tremor ataxia syndrome (FXTAS) [192–194]. Characteristic features of the underlying disease (i.e. mental retardation, physiognomic features (long face, low set ears), action tremor in FXTAS; slow saccades in SCA2; pyramidal signs in SCA3; macular degeneration in SCA7; dementia, psychiatric features, chorea in SCA17; seizures in SCA10; cognitive impairment in SCA21; ophthalmoparesis, ptosis, spasticity in SCA28) can sometimes be overlooked by physicians but they are important to guide the diagnosis [195, 196]. SCA1,2,3 and 17 should be suspected in patients presenting with a phenotype suggestive of multiple system atrophy (MSA), as they can present with prominent parkinsonism and dysautonomia, although the classical “hot cross bun” sign on brain MRI, that is characteristic of MSA, is only rarely present in these forms [197].

Parkinsonism, PEO, or optic atrophy

Parkinsonism preceded by development of progressive external complete ophthalmoplegia (e.g., on both horizontal and vertical plane) has been reported in a few cases of subjects carrying mutations in the mitochondrial-related genes TWNK and POLG1. In these cases, parkinsonism may not be prominent and thus be overlooked. A variable phenotypic presentation and penetrance were present in the reported families. SANDO (sensory ataxic neuropathy, dysarthria, and ophthalmoparesis) syndrome has been reported as well in subjects with parkinsonism due to POLG1 variants [200]. POLG1 mutations can be found also in cases of parkinsonism associated with optic atrophy, manifesting with a gradual vision loss, as well mutations of the SLC25A46 [201].

Parkinsonism and spastic paraplegia

Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary spastic paraplegia (SPG) with thin corpus callosum. Juvenile-onset symmetric parkinsonism has been described, with variable response to dopamine intake [202, 203].

Other SPG syndromes may display parkinsonism as part of the clinical picture, in particular in SPG7 [204–206] and SPG15 [207, 208].

Parkinsonism and intellectual disability

Monogenic forms of early intellectual disability and early or juvenile onset parkinsonism have been described. The combination of early-onset parkinsonism and intellectual disability is a distinctive feature of patients with mutations in RAB39B [209] and PTRHD1 [210, 211]. Intellectual disability develops over a spectrum which encompasses delayed speech initiation, early learning difficulties, and obsessional and ritualistic behavior in childhood [212]. It is non-progressive and can be mild, and therefore is often neglected. Intellectual disability typically precedes the onset of parkinsonism, which has been described to occur as early as age 10 in males with RAB39B mutations [209] and in the 3rd-4th decade in patients with mutations in PTRHD1 [213]. RAB39B mutations (point mutations, deletions, and duplications) are the only known cause of PD with X-linked inheritance [30]. Affected females with mutations in RAB39B have a later onset of parkinsonism and a less severe phenotype [214]. Unaffected females with heterozygous RAB39B mutations have also been reported [214]. The clinical phenotype is that of typical parkinsonism with tremor at rest, bradykinesia and rigidity, and a good response to levodopa. Atypical features have been described in both RAB39B (i.e., postural tremor, seizures, macrocephaly, autism spectrum disorder and strabismus) [215–217] and PTRHD1 (i.e., pyramidal signs, distal muscular atrophy and hyposthenia, axonal sensorimotor polyneuropathy, hypersomnia, hypersexuality) [210, 218]. Basal ganglia calcifications can be seen in RAB39B-related EOPD [209, 219], whereas brain MRI is normal in PTRHD1 mutations.

Phenotypes associated with mutations in WDR45 have already been discussed (“Neurodegeneration with brain iron accumulation” paragraphs).

A dopamine-responsive parkinsonian syndrome has been reported in patients with mutations in the PPP2R5D gene associated with a rare autosomal-dominant disease with developmental delay and mild to severe intellectual disability [220–223].

Interestingly, a recent review found that impaired cognition or neuropsychiatric disorders are also an early presentation in 92% of patients with EOPD associated with mutations in ATP13A2, PLA2G6, or FBXO7, suggesting that these may occur early before parkinsonism develops [224].

Parkinsonism and seizures

Seizures with onset in infancy or childhood are seen in ∼50% [224] of patients with parkinsonism associated with mutations in DNAJC6 [88, 226] and SYNJ1 [227–229]. Onset of parkinsonism, often associated with dystonia, ranges between 7 and 42 years in patients with DNAJC6 mutations [88, 226] and occurs between 20 and 40 years in SYNJ1 carriers [227]. Pyramidal signs and rapid progression to dementia are often seen in DNAJC6 [88, 225], whereas SYNJ1 patients can present with eyelid apraxia and supranuclear gaze palsy [227, 230]. Reports on brain imaging describe generalized atrophy in DNAJC6 and SYNJ1 cases and T2 hyperintensity in the posterior white matter and substantia nigra of few SYNJ1 patients [227, 228].