Parkinsonism in diseases predominantly presenting with dystonia

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Parkinsonism in diseases predominantly presenting with dystonia Alessio Di Fonzoa, Giulia Francoa, Paolo Baroneb and Roberto Errob, * a

Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy; Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy b Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, SA, Italy *Corresponding author: E-mail: [email protected]

Contents 1. Introduction 2. Disorders of dopamine biosynthesis 2.1 DYT-GCH1 2.2 DYT-TH and DYT-SPR 3. Deficit of neurotransmitter transporters 4. Other inherited dystonia- syndromes 4.1 DYT-PRKRA 4.2 DYT-ATP1A3 4.3 DYT-TAF1 4.4 DYT-TUBB4A 5. Disorders of metal metabolism 5.1 Wilson disease 5.2 Neurodegeneration with brain iron accumulation 5.2.1 5.2.2 5.2.3 5.2.4

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PANK2-associated neurodegeneration (PKAN) PLA2G6-associated neurodegeneration (PLAN) Kufor-Rakeb disease Other NBIA syndromes (MPAN, BPAN, CoPAN, Neuroferritinopathy, aceruloplasminemia)

5.3 Hypermanganesemia Supplementary materials References

International Review of Neurobiology, Volume 149 ISSN 0074-7742 https://doi.org/10.1016/bs.irn.2019.10.007

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Abstract If the presence of dystonia is a well-recognized phenomenon in disorders predominantly presenting with parkinsonism, including sporadic Parkinson Disease, the term dystonia-parkinsonism usually refers to rare conditions, often genetic, in which the severity of dystonia usually equates that of parkinsonism. At variance with parkinsonian syndromes with additional dystonia, the conditions reviewed in this chapter have usually their onset in childhood and their diagnostic work-up is different. In fact, the phenotype is not usually specific of the underlying defect and additional investigations are therefore required. Here, we review the diseases predominantly presenting with dystonia where parkinsonism can develop, according to their main pathophysiological mechanism including disorders of dopamine biosynthesis, neurotransmitter transporter disorders, disorder of metal metabolism (i.e., iron, copper and manganese) and other inherited dystonia-parkinsonism conditions.

1. Introduction The term dystonia-parkinsonism obviously refers to the variable combination of dystonia and parkinsonism. However, if the presence of dystonia is a well-recognized phenomenon in disorders predominantly presenting with parkinsonism, including sporadic Parkinson Disease, this term usually applies to rarer conditions where the severity of dystonia usually equates that of parkinsonism. In such cases, the diagnostic work-up often differs from that of both isolated dystonia and parkinsonian syndromes. Although it might be difficult on clinical grounds to identify parkinsonism in cases with severe generalized dystonia, it is important because of treatment, prognostic, and often genetic, implications. In this chapter, we will review the most frequent, albeit rare, dystonic conditions that might present with additional parkinsonism. At variance with parkinsonian syndromes with additional dystonia, the conditions reviewed in this chapter have usually their onset in childhood. In many cases, the phenotype is not specific of the underlying defect and additional investigations are therefore required. If the advent of next-generation sequencing techniques might arguably render some of these investigations (i.e., imaging or CSF examination) superfluous, it is our belief that a pragmatic approach should be pursued, with basic investigation being performed first in order to lead the genetic analysis. The conditions reviewed here have been grouped according to the main pathomechanism (Table 1), as follows: disorders of dopamine biosynthesis, deficit of neurotransmitter transporters, other inherited dystonia-parkinsonism syndromes associated with PRKRA, ATP1A3, TAF1 and TUBB4A

Table 1 Overview of the main genetic conditions presenting with dystonia-parkinsonism.

GCH1 mutations TH mutations SPR mutations

Disorders of metal metabolism

SLC6A3 mutations SLC18A2 mutations PRKRA mutations ATP1A3 mutations TAF1 mutations TUBB4A mutations ATP7B mutations

Childhood onset of generalized dystonia, spasticity, postural instability, lateonset parkinsonism, T1-hyperintensities in the basal ganglia 3

Neurodegeneration with Brain Iron accumulation (NBIA: PANK2, PLA2G6, ATP13A2, C19orf12, WDR45, COASY, CP, FTL mutations) Hypermanganesemia (SLC30A10 and SLC39A14 mutations)

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Deficit of neurotransmitter transporters Other inherited dystoniaparkinsonism syndromes

Dystonia with childhood onset and sustained response to levodopa, diurnal fluctuation and parkinsonism Dystonia-parkinsonism with infantile onset, oculogyric crises, cognitive nad motor developmental delay Dystonia with axial hypotonia, parkinsonism, spasticity, motor and speech delay, oculogyric crises Severe progressive dystonia-parkinsonism with onset in infancy Infantile-onset parkinsonism-dystonia, autonomic dysfunction, sleep disturbances Young-onset generalized dystonia, opisthotonic posturing, involvement of oromandibular and bulbar regions, later appearance of parkinsonism Rapid onset dystonia-parkinsonism (RDP), asymmetric dystonia Lubag syndrome or X-linked dystonia-parkinsonism (XDP), cranio-cervical dystonia, parkinsonism in the later stages Whispering dysphonia, extrusional tongue dystonia, hobby-horse gait Wilson disease: Dystonia-parkinsonism, tremor, neuropsychiatric and cognitive feature, hepatic disease, Kayser-Fleischer corneal ring Dystonia combined with parkinsonism, neuropsychiatric abnormalities, ataxia, chorea, hypotonia with childhood or adult onset and MRI evidence of iron deposition in basal ganglia and other subcortical structures

Parkinsonism in diseases predominantly presenting with dystonia

Disorders of dopamine biosynthesis

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mutations, and disorders of metal metabolism (i.e., copper, iron, and manganese).

2. Disorders of dopamine biosynthesis Dopa-responsive dystonias (DRDs) comprise a heterogeneous group of diseases caused by a defect in the biosynthesis of dopamine (Fig. 1) and presenting typically as childhood-onset dystonia, which can be either isolated or associated with other neurological features depending on the underlying genetic defect, and showing a beneficial but variable response to low-dose levodopa therapy. Whereas the term DRD should be used to define one of the disorders of the dopamine biosynthesis described below,

Fig. 1 Pterins and dopamine pathway. (GTP: Guanosine-5-triphosphate; GCH1: GTP cyclohydrolase 1; NH2P3: Dihydroneopterin triphosphate; NP: Neopterin; 6-PPH4: 6Pyrovoyl-tetrahydropterin; SR: Sepiapterin reductase; BH4: Tetrahydrobiopterin; qBH2: q-Dihydrobiopterin; DHPR: dihydropteridine reductase; NAD: Nicotinamide adenine dinucleotide; Tyr: Tyrosine; TH: Tyrosine hydroxylase; HVA: homovanillic acid; Trp: Tryptophan; TPH: Tryptophan hydroxylase; 5-OH-Trp: 5-hydroxytryptophan; 5-HIAA: 5hydroxyindoleacetic acid; Phe: Phenylalanine; PAH: Phenylalanine hydroxylase).

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there is suggestion that other conditions that do no affect this pathway, including hereditary spastic paraparesis type 11, SCA3 and ataxia telangiectasia, can seldom manifest with a phenotype reminiscent of DRD (Wijemanne et al., 2015).

2.1 DYT-GCH1 DYT-GCH1, formerly known as Segawa disease or DYT-5, is an autosomal dominant condition resulting from deficiency of the GTP cyclohydrolase 1 (GTPeCHeI), which is encoded by GCH1 gene. GTPeCHeI is the initial and rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for aromatic amino acid hydroxylases (tryptophan hydroxylase and phenylalanine hydroxylase) and its deficiency results in reduction of nigrostriatal dopamine synthesis (Nygaard, 1993). DYT-GCH1 is a rare disease with a sex-related penetrance (about 38% in males and 84% in females) (Furukawa et al., 1998), which typically presents with lower-limb dystonia, causing gait disturbance and a tendency to fall. This phenotype might resemble that of early-onset Parkinson’s disease (EOPD), especially due to Parkin mutations, also because additional parkinsonian features, including rigidity and rest tremor, can be present. In a small minority of GCH1-patients the phenotype might be that of isolated parkinsonism (i.e., in the absence of dystonia), especially if the onset is in adulthood (Momma et al., 2009). In these cases, tremor if often present in combination with other signs, such as rigidity and bradykinesia, and the overall phenotype might be indistinguishable from EOPD due to autosomal recessive genes like Parkin, PINK1 and/or DJ-1. Some clinical features like diurnal fluctuation and sleep-benefit, which are typical hallmarks of GHC1 mutations, can be helpful in the differential diagnosis but tend to attenuate as the disease progresses. The occurrence of associated neurological signs including brisk deep tendon reflexes, ankle clonus, striatal toes, and myoclonus, has been occasionally reported (Leuzzi et al., 2002), but can be present in the aforementioned genetic forms of EOPD and are not usually helpful in terms of differential diagnosis. An interesting observation stemming from genome-wide association studies (GWASs) has suggested that GCH1 mutations are a risk factor for the development of degenerative PD, as demonstrated by reduced uptake of Ioflupane, a radioactive tracer which binds the dopamine transporter (DaT) on the presynaptic nigrostriatal terminal (Mencacci et al., 2014). Over the last years in fact, a few families have been reported on with patients having a “classic” DRD phenotype along with members having “classic”

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PD, even with onset in late adulthood. Mirroring the results of DaT-SPECT studies, it has been further shown that a subset of parkinsonian patients with GCH1 mutations can also display abnormal cardiac sympathetic innervation, in keeping with a neurodegenerative condition and reinforcing the concept that GCH1 mutation can be in fact a risk factor for the development of neurodegenerative parkinsonism (Yoshino et al., 2018). From the clinical standpoint, there are no clinical features able to predict whether a GCH1 carrier with a parkinsonian variant has an underlying abnormal nigrostriatal pathway and imaging investigations (i.e. DaT-SPECT) are warranted in this regard. The response to L-dopa, as in cases with a dystonic phenotype, is brilliant with low-doses (i.e. < 300e400 mg/daily) (Segawa, Nomura, & Nishiyama, 2003) with no development of the classic levodopa-associated complications observed in Parkinson Disease, despite mild levodopainduced dyskinesia having been reported in a small percentage of DYTGCH1 patients (Bendi et al., 2018; Kim, Jeon, & Lee, 2016). However, there are no long-term studies on those patients having an underlying nigrostriatial deficit and therefore it is unknown whether the progression of clinical features and development of motor fluctuations in these cases is similar to those patients having idiopathic EOPD.

2.2 DYT-TH and DYT-SPR Tyrosine Hydroxylase (TH) deficiency is a rare autosomal recessive disorder that can be associated with a wide spectrum of clinical manifestations (Willemsen et al., 2010). Based upon symptoms severity and levodopa responsiveness, three main phenotypes have been recognized, although atypical cases with intermediate phenotypes have been also described (Erro, Stamelou, & Bhatia, 2017a). From mildest to most severe, the three classic phenotypes are: TH-deficient DRD (formerly known as DYT5b); TH-deficient infantile parkinsonism with motor delay; and TH-deficient progressive infantile encephalopathy. In this context, we will only focus on the infantile parkinsonism variant. The onset is in early infancy (before the age of 4e5 years) and, usually, the parkinsonism is very severe with marked brady-/hypokinesia, hypertonic limbs with cogwheel rigidity and additional signs including dystonia with fisting hands and dysfunction of specific sympathetic neurons in the peripheral nervous system (i.e., ptosis), oculogyric crizes and autonomic dysfunction. Limb tremor can be present with an additional intentional component. Furthermore, there is commonly a severe delay of motor development and affected patients might also be unable

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to hold their head and/or sit up. As such, the differential diagnosis does not usually encompass early onset diseases presenting with isolated parkinsonism, but rather severe genetic disorders including those of metal metabolism or of neurotransmitter transporters (see below) that present with a combination of parkinsonism and dystonia with additional signs. In TH-deficiency, a partial response to L-dopa might represent a clue and should prompt clinicians to pursue a CSF examination for dopamine metabolism and pterins pathway (Fig. 1). Similarly, the phenotypic spectrum of sepiapterin reductase (SPR) deficiency, a rare autosomal recessive condition due to SPR mutations, ranges from significant motor and cognitive deficits to only minimal findings, which might show some degree of diurnal fluctuations and sleep benefit. Clinical features in the majority of affected individuals (>65%) include motor and speech delay, axial hypotonia, generalized dystonia, spasticity, and oculogyric crizes. Parkinsonian features are common but never isolated and, this condition should be therefore considered in infants or children with a complex dystonia-parkinsonism syndrome with developmental delay. More in general, and given the clinical similarities across these disorders and other monoamine neurotransmitter disorders including the Aromatic L-amino acid decarboxylase (AADC) deficiency, the suspicion should be raised in patients with any of the following three broad sets of findings: developmental delays with axial hypotonia and subsequent development of dystonia-parkinsonism; unexplained “cerebral palsy,” especially if dystonia/parkinsonism is present; and an L-dopa-responsive motor disorder that usually includes dystonia and severe parkinsonian signs (Friedman et al., 2012).

3. Deficit of neurotransmitter transporters These two rare, autosomal recessive disorders are caused by a deficit in the neurotransmitter transporting system rather than in the dopamine biosynthesis pathway and should be kept in mind when facing with children with a severe parkinsonian syndrome with additional dystonia and signs of autonomic dysfunction. Mutations in SLC6A3 result in DaT deficiency, the phenotype of which is characterized by a severe progressive dystonia-parkinsonism without diurnal fluctuations and levodopa response (Ng et al., 2014). The age at onset would be related to the residual DaT function. Affected individuals

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who develop movement disorders starting in infancy most often have DaT activity that is less than 5% of normal and have an unfavorable prognosis with shortened lifespan, although the long-term effects of this condition are not fully understood. DaT imaging is very useful in raising the suspicion, showing complete loss or a severe reduction of DaT binding in the basal ganglia. Mutations in SLC18A2 result in Vescicular Monoamine Transporter type 2 (VMAT2) deficiency (Rilstone, Alkhater, & Minassian, 2013). The disorder is characterized by infantile onset of parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. Some individuals show in addition variable degrees of developmental delay. The clinical picture is therefore similar to that of diseases affecting dopamine biosynthesis or transporting (i.e., due to dopamine transporter, tetrahydrobiopterin, tyrosine hydroxylase, sepiapterin and AADC deficiency). At variance with the disorders of dopamine biosynthesis, VMAT2 deficiency does not show diurnal fluctuations and displays normal CSF neurotransmitter levels. On the other side, similarly to AADC deficiency, there is a dramatic improvement following dopamine-agonist treatment.

4. Other inherited dystonia- syndromes 4.1 DYT-PRKRA Mutations in protein kinase, interferon-inducible double-stranded RNA-dependent activator (PRKRA) have been originally recognized in 2008 as a cause of dystonia associated with parkinsonism in two unrelated Brazilian families (Camargos et al., 2008). The inheritance is autosomal recessive and the prevalence is unknown, despite seems to be very rare. The phenotype is that of young onset, progressive moderate to severe generalized dystonia and mild parkinsonism. There is a gradual involvement of the neck and trunk with opisthotonic posturing. An important feature is the involvement of oromandibular and bulbar regions with a sardonic smile, tongue protrusion, significant speech disturbances, spasmodic dysphonia, and dysphagia. Parkinsonism, when present, is usually not a prominent feature, appears later than dystonia and is characterized by hypo-/bradykinesia, rigidity, and postural instability, whereas rest tremor is not usually observed. Pyramidal signs and cognitive impairment have also been described in some cases (Camargos et al., 2012; Quadri et al., 2016; Zech

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et al., 2014). A single case has been described with MRI abnormalities and an atypical presentation with abrupt onset of hypotonia, parkinsonism, pyramidal signs, and developmental regression following a febrile illness (Lemmon et al., 2013). In this case, brain MRI revealed T2 increased signal and volume loss in basal ganglia, but in all other DYT-PRKRA cases brain imaging is usually unremarkable, which helps the clinicians to differentiate this condition from other disorders that might present with a similar phenotype (i.e., of dystonia-parkinsonism with prominent oromandibular/bulbar involvement) such as those belonging to the spectrum of neurodegeneration with brain iron accumulation (NBIA; see below) (Camargos et al., 2012). Response to levodopa in DYT-PKRKA is very mild or absent. Other medications, such as anticholinergic drugs and botulinum toxin, are also usually ineffective. Only one patient has been treated with pallidal deep brain stimulation, with long-lasting benefit on limb and cranial dystonia (Quadri et al., 2016).

4.2 DYT-ATP1A3 Mutations in the ATP1A3 gene are the cause of Rapid-onset DystoniaParkinsonism (RDP), the phenotype of which consists of an abrupt onset of dystonia and parkinsonism over minutes to several weeks, usually triggered by febrile illness, physic or emotional stressors, alcoholic binges, or childbirth (de Carvalho Aguiar et al., 2004; Dobyns et al., 1993). Age at onset varies from 4 to 55 years, but is typically in the second to third decade of life. Initial symptoms rapidly evolve and then often stabilize over time (within a month), with a possible second abrupt worsening of symptoms after few years (Sweney, Newcomb, & Swoboda, 2015). However, a gradual progression of dystonia and parkinsonism has also been described (Brashear et al., 1996). Often, there is a clear rostrocaudal gradient of involvement (face > arm > leg) with prominent bulbar symptoms (dysarthria and hypophonia). Dystonia is frequently asymmetric (Brashear et al., 2007) and can be accompanied by minor parkinsonian features, such as hypo-/bradykinesia and postural instability (Brashear et al., 1996). Tremor is generally absent and levodopa treatment is ineffective (Brashear et al., 2007). Non-motor symptoms might be present and include anxiety, depression, psychosis, cognitive impairment with deficits in visual memory, attention and executive functions (Brashear et al., 2007). Overall, the phenotype might be similar to that of DYT-PRKRA, while it is usually different from other conditions causing EOPD. The acute onset of symptoms and the autosomal dominant mode of inheritance are distinctive features of DYT-ATP1A3

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that can help its differentiation from other conditions. Nonetheless, familial cases show variable penetrance and de novo mutations in sporadic cases have also been described (Kabakci et al., 2005), so that the absence of family history should not exclude the suspicion of DYT-ATP1A3. It should be remembered that ATP1A3 mutations are responsible of other phenotypes beyond RDP, including alternating hemiplegia of childhood (ACH) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss (CAPOS) syndrome (Sweney et al., 2015). While it is not within the scope of this chapter to review the other phenotypes associated with ATP1A3 mutations, it is important to acknowledge that these clinical features should be looked for also in patients with “classic” RDP (Carecchio et al., 2018; Erro & Bhatia, 2019). While some medications such as flunarizine have been reported to be beneficial on the paroxysmal events (Carecchio et al., 2018), there are no effective treatments for the non-paroxysmal dystonic and parkinsonian features.

4.3 DYT-TAF1 Also known as Lubag syndrome or X-linked dystonia-parkinsonism (XDP), DYT-TAF1 is an adult-onset X-linked recessive neurodegenerative disorder with high penetrance, thus affecting predominantly male, with a male to female ratio of 93:1, first described in patients from the island of Panay, Philippines in 1975. The prevalence is 5.24 per 100,000 in the island of Panay, but drops to 0.34/100,000 in the general population (Lee et al., 2002). It has been recently reported that a SINE-VNTR-Alu (SVA) retrotransposon insertion in intron 32 of the TAF1 gene is likely a founder mutation, thus explaining the higher prevalence in people of Filipino descent (Bragg et al., 2017). The insertion disrupts the splicing of TAF1 mRNA and decreases the full-length transcript (Bragg, Sharma, & Ozelius, 2019). TAF1 encodes for a TATA box-binding protein associated factor 1 and thus has a fundamental role in the transcription process. Recently the length of a hexanucleotide (CCCTCT)n repeat expansion within the SVA insertion has been inversely correlated with age at onset and TAF1 expression and has been associated with disease severity and cognitive dysfunction (Bragg et al., 2017). The temporal pattern of symptom manifestation initially described usually recognizes a first dystonic stage with onset in the third to fourth decade (mean age: 39 years). Dystonia at onset is usually focal in terms of distribution, but there is a tendency to become generalized over 2e5 years (with a range of 1e23 years). Dystonia frequently involves at onset the

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cranio-cervical region, with retrocollis, oromandibular dystonia, blepharospasm, and tongue protrusion, or the lower limb with foot inversion and dystonic gait (Lee et al., 2011). It is usually severe, painful, and unresponsive to oral medication. Botulinum toxin injection may improve the pain associated with dystonia. 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 (Pfeiffer, 2016). Regardless of any treatment, after 10e15 years after onset there is usually a decrease in dystonia severity and parkinsonism becomes gradually more prominent (Lee et al., 2011; The phenotype of the X-li, 1991). This temporal pattern is quite unique and help differentiating this conditions from other disorders where there is a progression of both dystonic and parkinsonian features. Symptomatic female carriers show non-progressive focal dystonia, mild parkinsonism, or even chorea (Domingo et al., 2014). As in male patients, parkinsonian features tend to progress and become predominant in the later stages when dystonia instead becomes less evident. Hypo-/bradykinesia, postural instability, freezing or festinating gait are the main parkinsonian features described as the disease progresses, while rigidity is less frequently reported. Despite the fact that the disease arises from the same founder mutation in an isolated environment, the phenotype is quite heterogeneous, and parkinsonism may accompany dystonia in the early stage or rarely be the presenting feature at disease onset (Lee et al., 2011; The phenotype of the X-li, 1991). Levodopa treatment may show some improvement, especially with regards of parkinsonism, and is not associated with the development of dyskinesia over the long-term. A mild cognitive impairment has been described in XDP patients, mainly involving the frontal executive functions. Other non-motor symptoms include major depression with an increased risk of suicide, and anxiety disorder. Unlike most of the other dystonia syndromes, DYT-TAF1 is a neurodegenerative disease. This was supported by imaging MRI studies showing progressive striatal atrophy. Post-mortem studies have showed severe atrophy of the caudate nucleus and the putamen with loss of striatal medium spiny neurons predominantly in the striosomal compartment, with normal findings in extrastriatal areas including the subastantia nigra (Bragg et al., 2019).

4.4 DYT-TUBB4A DYT-TUBB4A Is an extremely rare autosomal dominant early onset isolated dystonia with prominent laryngeal and oromandibular involvement.

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The clinical phenotype is distinctive, as it is characterized by “whispering dysphonia”, extrusional tongue dystonia, and a typical dystonic gait termed the “hobby-horse gait.” To date, only one family has been described with the “whispering dystonia” phenotype, which might suggest that the reported TUBB4A mutation in this family might be a private mutation (Erro et al., 2015; Nahhas et al., 2016). Most commonly, TUBB4A mutations cause another complex disorder named after its radiological features “H-ABC syndrome” (i.e., hypomyelination with atrophy of the basal ganglia and the cerebellum) (Erro et al., 2015; Nahhas et al., 2016). The H-ABC syndrome manifests with a childhood-onset, severe, generalized dystonia with aphonia and additional cerebellar and pyramidal signs, whereas parkinsonism is usually observed in terms of muscle rigidity, although it is difficult to ascertain whether other parkinsonian signs are present because of the severity of the dystonic manifestations (Erro et al., 2015; Nahhas et al., 2016). As such, this condition should be considered in children with a complex dystonia-parkinsonism syndrome with additional cerebellar and pyramidal signs and suggestive neuroradiological findings.

5. Disorders of metal metabolism 5.1 Wilson disease Wilson disease (WD), first described in 1912 as hepatolenticular degeneration, is an inherited neurometabolic disorder due to biallelic mutations in ATP7B, a copper transporter predominantly expressed in the liver (Trocello et al., 2013). WD is a rare disorder, with a prevalence of 1.5/100.000 in Europe (Tuschl et al., 2016). However, the frequency of ATP7B heterozygous carriers in UK was estimated to be 1/40, with an expected disease prevalence of 1/7000 (Stamelou et al., 2012). This discrepancy may suggest that the disease might be underdiagnosed. Mean age at onset ranges between 10 and 15 years of age for patients with hepatic symptoms (acute transient hepatitis, fulminant hepatic failure or cirrhosis) as the initial clinical manifestation, whereas it is usually later for those with neuropsychiatric onset, although it can range from 6 to 72 years of age. Tremor is the most frequent neurological manifestation at onset. The typical tremor observed in WD involves the upper limbs proximally, it is often irregular and might be asymmetric, resembling a bird beating its wing (i.e. the so-called “wing-beating tremor”). Dystonia is the initial manifestation in up to 65% and can be focal, segmental or generalized, with

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frequent involvement of the face, sometimes with a dystonic spasm of the risorius muscle (i.e., risus sardonicus). Parkinsonism is present in about 40% of WD patients and manifests as hypo-/bradykinesia, micrographia, rigidity and gait disturbances. Ataxia and dysarthria are also common findings. Besides the clinical manifestations described above, it should be noted that all types of movement disorders can develop or even be the initial manifestation of WD, including tics, chorea, myoclonus, and stereotypes (Poujois et al., 2018). In general, the most frequent clinical presentation would be a combination of dystonia, parkinsonism and cerebellar signs, which might raise the suspicion of cerebellar disorders presenting with parkinsonism (cfr. Chapter 10) or even multiple system atrophy. However, the age at onset and the presence of additional neurological (i.e. wing beating tremor, for instance) or systemic (i.e., thrombocytopenia, hemolytic anemia, unexplained bone pain, amenorrhea, repeated spontaneous abortion, and renal lithiasis) signs will easily help the differential diagnosis. Obviously, imaging is mandatory and, in case of WD, will show hyperintensity in T2-weighted images in the basal ganglia and thalamus as well as in the dentate nuclei, midbrain and pons. A typical radiological sign is the so-called “face of giant panda” sign characterized by the high signal intensity in the midbrain tegmentum sparing the red nucleus. While L-dopa treatment is ineffective for the parkinsonian features, current therapeutic approaches with the use of copper chelators (D-penicillamine and trientine) and zinc salt are usually able to remove the excess of copper and to maintain a negative copper balance, with significant symptomatic benefit (Pfeiffer, 2016).

5.2 Neurodegeneration with brain iron accumulation The group of disorders termed “Neurodegeneration with Brain Iron Accumulation” (NBIA) encompasses a heterogeneous group of rare diseases characterized by iron deposition in specific brain structures, mainly the basal ganglia, thalamus, substantia nigra and/or cerebellum. With age at onset ranging from infancy to adulthood, the clinical expression of NBIA is extremely variable, but usually dominated by a combination of hypo- and hyperkinetic movement disorders, associated with pyramidal, neuropsychiatric, cerebellar, cognitive and ocular signs. So far, dozen of NBIA subtypes has been identified following to the discovery of genes that are differently involved in biochemical pathways regulating iron metabolism, mitochondrial function, lysosomal activity, autophagy, and lipid metabolism (Di Meo & Tiranti, 2018). With the exception of PLA2G6 mutations, which

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have been reported to cause an isolated parkinsonian syndrome, all the other conditions manifest with a combination of dystonia-parkinsonism with or without additional signs. 5.2.1 PANK2-associated neurodegeneration (PKAN) Pantothenate-kinase associated neurodegeneration (PKAN) is the most common form of NBIA and accounts for about half of all NBIA cases, with an estimated prevalence of 1 per 1.000.000 people worldwide, and is due to biallelic mutations in PANK2 gene (Schneider, 2016; Zhou et al., 2001) Two age-dependent phenotypes have been associated with PANK2 mutations. In the classical form, which is usually caused by mutations leading to a complete loss of function of the protein, dystonia is the predominant feature and, although parkinsonism can be present, it is usually a minor feature. On the other hand, in patients with a later age of onset parkinsonism often prevails on the dystonic manifestations, but is never truly isolated. It is often symmetric, with a significant axial involvement and gait dysfunction. Tremor can be also present, but it does not resemble the classic pill-rolling tremor of PD. A certain degree dystonia, often in the oramnadibular region and/or trunk, is present and might represent a clinical clue to suspect this disorder. L-dopa unresponsiveness is another clue, which helps excluding a number of genetic disorders presenting with EOPD and that are responsive to L-dopa, where dystonia can also be observed (i.e. parkin, PINK1 or DJ-1). A distinctive radiological sign of PKAN is the so-called “eye of the tiger”, that refers to a core of hyperintense signal within an area of a hypointense signal restricted to the globus pallidi in T2-weighted images. Later in disease progression, iron sensitive sequences (i.e. SWI) may reveal iron overload also in the substantia nigra. (Zhou et al., 2001). 5.2.2 PLA2G6-associated neurodegeneration (PLAN) Mutations in PLA2G6 are the second most common cause of NBIA. PLA2G6 encodes for a phospholipase playing a role in remodeling of membrane phospholipids, loss of function of which results in altered lipid composition of the plasma membrane and vesicles (Di Meo & Tiranti, 2018). The clinical spectrum of PLAN includes three age-dependent different phenotypes, including infantile neuroaxonal dystrophy (INAD) with onset in infancy, atypical neuroaxonal dystrophy (atypical NAD) including Karak syndrome (e.g., slowly progressive ataxia associated with cognitive decline) with onset in childhood, and dystonia-parkinsonism (formerly associated with the PARK14 locus) in the absence of prominent ataxia or sensory

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disturbances with onset in adulthood, all of which are inherited with an autosomal recessive fashion. In this context, we will only focus on the PARK14 phenotype. The onset in early adulthood and features a parkinsonian syndrome, with a certain degree of levodopa response and development of dyskinesia. In the initial phase of the disease, parkinsonism can be isolated and might be asymmetric, thus resembling other EOPD disorders (Video 1). However, at variance with the latter, limb dystonia, spasticity, severe postural instability, as well as a moderate degree of cognitive impairment and psychiatric disorders invariably develop as the disease progresses. Levodopa response is usually lost over-time and loss of ambulation is observed within 10 years from onset (Paisan-Ruiz et al., 2009). Despite being a NBIA syndrome, brain iron accumulation is not always observed, especially in the early stages of the disease, whereas it has been suggested that cerebellar atrophy might be an early and consistent feature observed across all PLAN phenotypes (Erro et al., 2017b). Neuropathological observations in patients with the “PARK14” phenotype have revealed synuclein aggregates. 5.2.3 Kufor-Rakeb disease Mutations in the ATP13A2 gene, that encodes a lysosomal ATPase, cause a rare form of juvenile parkinsonism, called Kufor-Rakeb and formerly associated with the PARK9 locus (Di Fonzo et al., 2007). The typical phenotype is that of a severe levodopa-responsive akinetic-rigid parkinsonism with motor fluctuations and dyskinesia, associated with axial or limb dystonia, faucial-finger minimyoclonus, supranuclear vertical gaze palsy, spasticity, visual hallucination and dementia, with onset in the third to fourth decade of life. The full-blown phenotype is quite unique and does not usually pose difficulties in terms of differential diagnosis. However, in the initial phase of the disease when certain clinical features (i.e., faucial-finger minimyoclonus and supranuclear vertical gaze palsy) might be absent, the phenotype might be similar to other conditions presenting with severe, early-onset, parkinsonism, including those associated with SYNJ1 mutations and/or other NBIA syndromes such as PKAN and PLAN. MRI shows diffuse generalized atrophy, only occasionally associated with iron deposits in the caudate and the putamen (Di Meo & Tiranti, 2018). Recently, ATP13A2 mutation have also been associated with a phenotype resembling a complicated hereditary spastic paraparesis (i.e. SPG78) and, as for other disorders described above, patients with intermediate phenotypes are expected to be reported on (Erro et al., 2019).

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5.2.4 Other NBIA syndromes (MPAN, BPAN, CoPAN, Neuroferritinopathy, aceruloplasminemia) All other NBIA syndromes, which will be briefly described below, do not usually present with isolated parkinsonism, but give rise to a combination of dystonia and parkinsonism with onset in infancy or childhood, so that the differential diagnosis should comprise the rare disorders of dopamine metabolism, neurotransmitter transporters and metal metabolism, rather than diseases presenting with EOPD. C19orf12 mutation are associated to Mitochondrial membrane Proteinassociated Neurodegeneration (MPAN), the third most frequent subtype of NBIA accounting for about 30% of all NBIA cases (Hogarth et al., 2013). MPAN has onset from childhood to early adulthood (4e20 years) and shoe distinctive clinical features, including cognitive decline, prominent neuropsychiatric abnormalities and a motor neuronopathy. Parkinsonism occurs in about half of individuals reported, with varying combinations of hypo-/bradykinesia, rigidity, tremor, postural instability, and REM sleep behavior disorder. Parkinsonism is more common in adult-onset MPAN, especially in those with rapid progression. A good response to levodopa has been reported, but treatment should be carefully initiated because of the risk of inducing or worsening psychiatric disturbances, which are common in MPAN (Hogarth et al., 2013). BPAN is the only X-linked NBIA, caused by mutations in the WD repeat domain 45 (WDR45) gene (Haack et al., 2012), which encodes a protein involved in the autophagic process (Haack et al., 2012). Most cases are female patients arising from de novo mutations, as WDR45 mutations are predicted to be lethal for male embryos (Di Meo & Tiranti, 2018). However, male patients with somatic mosaicism have been described (Haack et al., 2012). BPAN is characterized by a stepwise clinical course with developmental delay and seizures in early childhood followed by parkinsonism-dystonia and cognitive impairment in early adulthood (Haack et al., 2012). CoPAN is a rare autosomal recessive form of NBIA associated to mutations in the COASY gene (Dusi et al., 2014), which encodes for an enzyme catalyzing the last steps of CoA biosynthesis and thus sharing a common pathway with PANK2. The clinical phenotype is characterized by childhood-onset dystonia with prominent oromandibular involvement, dysarthria and spasticity with later appearance of parkinsonism and spasticdystonic tetraparesis.

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Neuroferritinopathy and Aceruloplasminemia usually present with hyperkinetic movement disorders (dystonia and chorea) so that do not usually enter into the differential diagnosis of dystonia-parkinsonism syndromes (Di Meo & Tiranti, 2018). While some parkinsonian features might be present (i.e. hypokinesia and freezing of gait), isolated parkinsonism is extremely rare and only anecdotal cases have been reported (Pelucchi et al., 2018).

5.3 Hypermanganesemia Manganese (Mn) is an essential metal that is required for the correct functioning of several enzyme proteins in all human tissues. Mn homeostasis is tightly regulated and its excess causes neurotoxic effects as it tends to accumulate in the basal ganglia, particularly in the globus pallidus. As a result of Mn overload, the clinical manifestations of manganism are non-levodopa responsive akinetic parkinsonism with postural instability, neuropsychiatric and cognitive abnormalities, and dystonia that when affecting the lower limbs might give rise to a characteristic gait disorder termed “cock-walk gait”. Manganese deposition in the brain might result either from acquired conditions or from inherited, autosomal recessive, disorders affecting manganese transporters. Sporadic cases can occur following Mn occupational exposures, parenteral nutrition, cryptogenetic liver chirrosis (“acquired hepatocerebral degeneration”) or, more frequently, in methcathinone users. The drug is synthesized from over-the-counter cold remedies containing ephedrine or pseudoephedrine, but the final mixture contains a high concentration of manganese if potassium permanganate is used as the oxidant agent. As to the genetic forms causing Mn brain accumulation, two different genes have been reported so far (Quadri et al., 2015; Tuschl et al., 2016). Loss-of-function mutations in the SLC30A10 gene, encoding a Mn transporter, lead to chronic liver disease, hematologic abnormalities and neurological disturbances. The clinical spectrum encompasses progressive childhood-onset dystonia with typical gait, limb spasms, dysarthria, ataxia and late-onset parkinsonism (Quadri et al., 2015). Loss-of-function SLC39A14 mutations are another inherited cause of Mn brain accumulation presenting with a progressive childhood onset dystonia-parkinsonism (Tuschl et al., 2016). Affected children presented with loss of developmental milestones, progressive dystonia and bulbar dysfunction. Within the first decade of life, patients developed severe generalized dystonia, spasticity, loss of independent ambulation and a portion of them additionally show parkinsonian features including hypomimia, tremor and hypo-/

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bradykinesia. Differently from SLC30A10 mutations, SLC39A14 mutations do not cause polycythemia or liver disease. In both cases, the differential diagnosis is that of a childhood onset dystonia-parkinsonism and should therefore comprise disorders of dopamine metabolism, of neurotransmitter transporters and NBIAs, rather than EOPD syndromes. Both acquired and inherited hypermanganesemia are associated with pathognomonic MRI appearance of T1-hyperintensities in the globus pallidus, dorsal midbrain, and deep cerebellar nuclei in all patients with Mn accumulation. The recognition of these diseases is of paramount importance, considering that chelating agents (i.e., disodium calcium edetate) and iron supplementation greatly improve symptoms and help preventing the progression (Stamelou et al., 2012).

Supplementary materials Supplementary data related to this article can be found online at https://doi.org/10.1016/bs.irn.2019.10.007.

Conflict of interest None.

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