306. Oertel W, Berardelli A, Bloem B . Late (complicated) Parkinson \200\231s dis- ease. In : Gilhus M, Barnes MP, Brainin M (eds) European Handbook of Neurological Management (2nd ed n), pp. 237 \200\22367 . Chichester : Wiley \200\223 Blackwell , 2011. 291. Braak H, Rub U, Jansen Steur EN, Del Tredici K, de Vos RA . Cognitive status correlate s with neuropathologic stage in Parkinson disease. Neurology 2005; 64 : 1404 \200\2231 0 . This page intentionally left blank CHAPTER 12 Th e Many Faces of Parkinsonism: A Review of the Parkinson Look-alike Syndromes Susanne A. Schneider and Christine Klein Introduction Parkinson \200\231s disease (PD) has many faces. Indeed, the phenotypic variab ility is even greater for syndromes of parkinsonism present- ing with atypical or other neu rological features. Because of the long list of diff erential diagnoses, physicians may fac e a challenge when confronted with a parkinsonian patient. In addition to idiopathic PD and secondary forms, numerous genetic causes of parkinson- ism, sometimes mimicking idiopathic PD, have been identifi ed in recent years. Th ese include mutations in genes which have be en grouped together under the umbrella of \200\230PARK disorders \200\231 such as alpha-Sy nuclei n (PARK1/PARK4), Parkin (PARK2), PINK1 (PARK6), DJ- 1 (PARK7), LRRK2 (PARK8), ATP13A 2 (PARK9), and PLA2G6 (PARK14) as well as numerous other non-PARK genes. While the well-est ablished monogenic forms with PARK acronyms have been reviewed extensively (1 \200\2234), t hese other inherited condi- tions of parkinsonism have received less attention. We wish to draw attention to these latter conditions in this chapter. A. Disorders which have been assigned a PARK locus that present with either classic parkins onism or parkinsonism with addi- tional atypical features. B. Classic parkinsonism due to mutations in a non-PARK or \200\230other-than-PARK \200\231 gene (e.g. a DYT or SCA gene) where par- kinsonism is a well-recognized concomitant or eve n an isolated feature. C. Atypical parkinsonism in genetic disorders which are usually characterized by features other than parkinsonism. We will summarize the clinical characteristics and main genetic fi ndings. Pathological dat a or results of investigations (such as imaging or electrophysiology) will be mentioned if they are useful for diff erentiation from other diseases (see also Table 12.2). PARK-associated disorders with signs of parkinsonism with or without atypical features Muta tions in PARK genes have unequivocally been linked with parkinsonism. LRRK2 -associated par kinsonism (PARK8) clini- cally resembles idiopathic PD most closely (6). LRRK2 mutations ar e inherited in an autosomal dominant fashion. Th e major- ity of patients carry the same sp ecifi c genetic alteration (the G2019S mutation). Notably, patients with homozygous muta- t ions do not show overt clinical diff erences compared to those with homozygous mutations. T h us, there do not seem to be major gene dosage eff ects (7). In addition to familial cases , LRRK2 has recently been confi rmed as a risk locus for PD in a genome-wide association st udy in a mixed patient cohort from the USA and Europe (8). Th us, LRRK2 mutations should be considered in patients with a positive family history suggestive of dominant We chose to group the various causes of heritable parkin sonian syndromes according to pres ence of classic or atypical parkinson- ism. We use the term \200\230classic parkinsonism \200\231 for cases with the typical clinical characteristics of rest tremor, bradykinesia, and rigidity (not all features are mandatory), an excellent and sustained therapeutic levod opa response, and the frequent development of motor compli- cations aft er several years of levodopa therapy (5). \200\230Parkinsonism \200\231 refers to patients who display some p arkinsonian signs but also exhibit atypical or other neurological features. Based on these fi nd- ings, conditions have been classifi ed into three subgroups in order to account for the high degree of clinical and genetic heterogeneity (Table 12.1). Financial disclosure: CK is supported by a Lichtenberg grant from the Volkswagen Foundation and a Career Development Award from the Hermann and Lilly Schilling Foundation. Oxford Textbook of Movement Disorders 118 Table 12.1 Overview of inherited forms of parkinsonism, grouped into three categories to ac count for the high degree of clinical and genetic heterogeneity Subgroup \200\230PARK synd romes \200\231 with atypical features Gene/protein/locus Parkin/ PARK2 PINK1/ PARK6 DJ- 1/ PARK7 SNCA/ PARK1+4 ATP13A2/ PARK9 Comment, clinical correlate Early-onset parkinsonism with slower disease course Early-onset parkinsonism with rapid progression and dementia Juvenile parkinsonism with rapid progression, pyramidal signs, supranuclear gaze palsy, and dementia; iron accumulation in some PLA2G6/PARK14/NBIA type 2 Early-onset pyramidal extrapyramidal syndrome Early-onset form: infantile neuroaxonal dystr ophy (INAD) MRI with or without iron deposition (Classic) parkinsonism due to mutations in non-PARK or \200\230other than-PARK \200\231 ge nes (e.g. DYT or SCA gene) where parkinsonism is a well-recognized concomitant or even an i solated feature TAF1/ DYT3 GTP cyclohydrolase I and tyrosine-hydroxylas e /DYT5 ATP1A3/DYT12 X-linked dystonia parkinsonism; Lubag Dopa-responsive dystonia, Segawa \200\231s disease Rapid-onset dystonia-parkinsonism PRKRA/ DYT16 SCA types 2, 3, 6, 8, 17 Dystonia (parkinsonism) Ataxia, parkinsonism may be present Glucocerebrosidase Gaucher disease Mitochondrial gene mutations Often complex syndromes Atypical parkinsonism in genetic disorders which are usually characterized by features othe r than parkinsonism Fragile X-associated tremor \200\223ataxia syndrome FMR1 Frontotemporal dementia parkinsonism linked to chromosome 17 MAPT Progranulin Prion protein Creutzfeldt \200\223Jakob disease Wilson disease ATP7B PANK2/ NBIA type 1 FBXO7 Panthothenate-kinase-2-associated neurodegeneration Extrapyramidal \200\223pyramidal syndrome Chorea \200\223acanthocytosis CHAC Neuroferritinopathy FTL1 Huntington \200\231s disease, Westphal variant Huntington \200\231s disease-like 2, Westpha l variant Huntingtin JPH3 Haemochromatosis HFE CHAC , chorea \200\223acanthocytosis; FBXO7, F-box protein 7; FTL1, ferritin light chain; F MR1 , fragile-X mental retardation 1; JPH3 , junctophilin-3; MAPT , microtubule-associated protein tau; PANK2 , pantothenate kinase 2; PINK1 , PTEN induced putative kinase 1; PRKRA , protein kinase interferon-inducible double-stranded RNA-dependent activator; SCA, spinocer ebellar ataxia; SNCA, -synuclein; TAF1 , TATA-box binding protein \200\223associated fac tor 1 or recessive inheritance as well as in sporadic cases (for further review of PARK8, see ref . 9) and in particular in North Africans and Ashkenazi Jews. to space limitations, these disorders and their role will not be dis- cussed further in thi s chapter. Th e recessive forms of PARK9- and PARK14-associated parkin- sonism are examples of more co mplex phenotypes. Homozygous mutations in the ATP13A2/ PARK9 gene were found to cause Kufor \200\223Rakeb disease (16), a syndrome of juvenile atypical par- kinsonism with rapid prog ression which is responsive to levodopa treatment in initial stages, but with early develop ment of dyskine- sias and additional neurological features including pyramidal signs and de mentia (17). Th e most striking clinical features on exami- nation are a bradykinetic \200 \223rigid syndrome, axial rigidity, spasticity, pyramidal weakness and Babinski signs, a su pranuclear vertical gaze palsy, slow vertical and horizontal saccades, and facial, faucial, and fi nger mini-myoclonus (17 \200\22319). in the genes encoding Parkin/ PARK2, PINK1/ PARK6 and DJ- 1/ PARK7 should be consid- ered a s they can also resemble classic PD. Th ey are characterized by a good response to levodopa and have a rather benign disease course (10, 11). Dystonia, mild hyperrefl exia, and psych iatric fea- tures may be present in some patients and can be a diagnostic clue (12 \200\223 14). Most data are available for the Parkin variant which is by far the most common cause o f early-onset parkinsonism, account- ing for nearly 80% of patients with onset before age 3 0 (10). Less is known about the PINK1 or DJ-1 type. Th ese recessive parkinso- nian disorde rs are being studied with great interest as a number of patients carrying only one mutated allele (rather than the expected two) have been identifi ed who may provide important insig hts into the pathophysiology of idiopathic PD (15). However, owing In young-onset cases mutations Numerous cytoplasmic inclusion bodies within the Schwann, perineurial, and epineurials, but not in axons, were present in a sural nerve biopsy (20). On electron microscopy assessment , the CHAPTER 12 The many faces of parkinsonism: A Review of the Parkinson Look-Alike Syndromes 119 Table 12.2 Additional investigations which may be useful in the process of the diagnostic w ork-up Test Result Disorder Laboratory tests Peripheral blood smear Acanthocytes ChAc, MLS, also reported rarely in HDL2 and PKAN Serum biochemistry Elevated CK MLS, ChAc Elevated LFTs ChAc, MLS, Wilson disease Erythrocyte antigen markers Absent Kx, reduced Kell antigen expression MLS N14 \200\2233-3, tau, NSE, S100b, PrP Sc CJD (PRNP) CSF Urinary tests Elevated urinary copper Wilson disease Neurophysiology Neuromuscular testing Sensory and motor neuropathy ChAc, MLS NCS Peripheral neuropathy ChAc, MLS; PLA2G6-associated neurodegeneration, Niemann \200\223Pick EEG and polysomnography Temporal abnormalities and seizure onset ChAc Sleep fragmentation and poor sleep e \203 ciency ChAc, MLS Periodic bi- and triphasic sharp wave complexes CJD (PRNP) Ophthalmological assessment Pigmentary retinal degeneration PKAN Optic nerve atrophy INAD (PLA2G6) Neuroimaging MRI Marked atrophy of the caudate nucleus and putamen, to a lesser extent of the cortex HD, HDL2, ChAc, MLS Calci \201 cation Fahr \200\231s disease Iron deposition in the globus pallidus PKAN ( \200\230eye of the tiger \200\231 sign), PLA2G6 (PARK14), Kufor \200\223Rakeb diseas e (PAR9), aceruloplasminaemia, neuroferritinopathy Generalized atrophy PLA2G6-associated neurodegeneration, Kufor \200\223Rakeb disease Symmetric hyperintensities in putamen and caudate T 2 -signal intensity of the middle cereb ellar peduncles Markedly reduced metabolic activity in the striatum on \202 uorodeoxygluc ose PET CJD (PRNP) FXTAS PET HD, ChAc, MLS Pathology, histology Neuropathology Atrophy of the caudate, putamen, to a lesser extent globus pallidus, neuronal cell loss and astrocytic gliosis in the striatum HD, HDL2, ChAc, MLS Ubiquitin-immunoreactive neuronal intranuclear inclusions HDL2 Mosaic astrocytosis in the striatum DYT3 (Lubag) Eosinophilic intranuclear, neuronal, and astrocytic inclusions; Purkinje cell loss FXTAS Tau-positive inclusions MAPT TDP43-positive inclusions PGRN, DCTN1 Muscle/nerve biopsy Spheroid bodies PLA2G6- associated neurodegeneration Kufor \200\223Rakeb disease Irregular primary lysosomes Granular inclusion bodies Neuroferritinopathy ChAc, chorea \200\223acanthocytosis; CK, creatine kinase; CJD, Creutzfeldt \200\223Jakob di sease; CSF, cerebrospinal \202 uid; DCTN1, dynactin1; EEG, electroencephalography; FXTAS, fragile X-associated tremor \200\223ataxia syndrome; HD, Huntington \200\231s disease; HDL 2, Huntington \200\231s disease looks like disease type 2; INAD, infantile neuroaxonal dyst rophy; MAPT, microtubule-associated protein tau, MLS, McLeod neuroacanthocytosis syndrome; MRI, magnetic resonance imaging; NSE, neuron-speci \201 c enolase; PET, positron emission tomography; PKAN, pantothenate-kinase-associated neurodegeneration; PRNP, prion protein; Pr PSc, scrapie prion protein; TDP43, TAR DNA-binding protein 43. Based on data from Klein et al. (169). inclusions were found to be membrane-bound, irregular, and occa- sionally folded. Overall, there was resemblance to irregular pri- mary lysosomes, in line with the function of the en coded protein. ATP13A2 encodes a predominantly neuronal lysosomal type 5 P-type ATPase. Som e patients may have cerebral iron accumulation as demonstrated by T 2 *-weighted MRI (21, 22). Th us the condi- tion falls into the group of syndromes with neurodegeneration with brain iron accumulation (see below). Heterozygous mutations in the ATP13A2 gene have been associated with a more benign phenotype, resembling young-onset PD, akin to the Parkin type Oxford Textbook of Movement Disorders 120 X-linked recessive dystonia \200\223parkinsonism (DYT3, XDP, Lubag) in the Philippines DYT3 dystonia is an X-linked recessive form of dystonia found in the Philippines. Th ere is com plete penetrance by the end of the fi ft h decade. While XDP typically aff ects males, rare ly women may also be aff ected, possibly due to severe X-inactivation or based on homozygos ity for the mutation. While DYT3 has been associated with specifi c sequence changes in the TAF1 gene (33), analysis of peripheral blood lymphocytes may fail to reveal mutations or a lterations in gene expression, and therefore these may not be suit- able surrogate disease markers for DYT3. It has been proposed that ancestral DYT3 haplotype and disease-specifi c SVA (short inter- spersed nuclear elements, variable number of tandem repeats, and Alu comp osite) retrotransposon insertion may be useful for genetic counseling (34). (23, 24). Interestingly, mutations in the ATP13A2 gene were recently also identifi ed in an imal models of neuronal ceroid lipofuscinosis (NCL), but screening humans with the compatib le phenotype of Kuf \200\231s disease did not reveal mutations (25). Similarly, homozygous mutations in PLA2G6 /PARK14 are a cause of complex parkinsonism, dyst onia with additional pyrami- dal involvement, and other complicating features, with both ad o- lescent and adult onset (26). In children, PLA2G6 mutations cause infantile neuroaxonal dystrophy (INAD) and are another impor- tant cause of brain iron accumulation (27). In the adult-onset cases described recently, parkinsonism was characterized by the presence of tre mor, including a pill-rolling rest component, rigidity, and severe bradykinesia, with a goo d response to levodopa. However, there was early development of dyskinesias. Cerebellar sig ns and sensory abnormalities, which are oft en prominent in the early childhood variant of INAD, were absent. DAT SPECT imaging was abnormal and both Lewy body and tau pathology were observed in molecularly confi rmed cases (20). Th e average age of onset in women (52 years) is higher than in men and may be as late as 7 5 years (35). Dystonic symptoms in DYT3 usually start focally in adulthood (36), and subseq uently progress and generalize. Parkinsonism is a frequent concurrent fea- ture (37). In a study of 42 DYT3 patients, 36% of the cases showed at least one of the cardinal signs of PD (36). Parkinsonism may even precede the onset of dystonia, be the predominant phenotype (3 8), and remain an isolated feature (39). It has been suggested that pre- dominant or isolat ed parkinsonism may constitute a more benign phenotype of XDP (38, 39). Parkinsonism may im prove with levo- dopa in the early stages, but becomes less responsive or unrespon- sive ov er time. Compared with males, parkinsonism is relatively common among women with XDP. Other forms of PARK-associated parkinsonism include the autosomal dominantly inherited alph a-synuclein -associated vari- ant ( SNCA/PARK1 ). In addition to mutations, duplications an d triplications have been identifi ed. It has been suggested that dupli- cations lead to la te-onset autonomic dysfunction and parkinson- ism, whereas triplications and point mutation s are associated with early-onset PD and dementia (28). Th e latter form tends to pro- duce more severe parkinsonism with a rapid course and a reduced life span (29). Th e alpha-synu clei n gene codes for a protein that is abundantly expressed in neurons, where it is believ ed to participate in the maturation of presynaptic vesicles and to function as a nega- tive co-regulator of neurotransmitter release (30). Investigations in XPD patients show hyperechogenicity of the substantia nigra on transcrani al ultrasound, moderately decreased putaminal dopamine transporter activity on FP-CIT SPECT , and decreased dopamine D2 receptor expression, as demonstrated by IBZM SPECT (40). Positr on emission tomography reveals selec- tively reduced striatal glucose metabolism. Fluorodop a uptake is normal, suggesting that the origin of the extrapyramidal symptoms is localized postsynaptically to the nigrostriatal pathway (41). Th e imaging fi ndings are in line with the post-mortem fi ndings of a stri- atal degeneration in a mosaic pattern with evidence f or selective loss of striosomal neurons with multifocal mosaic astrocytosis in the caudate nucleus and lateral putamen (42). Classic parkinsonism due to mutations in \200\230other-than-PARK \200\231 genes or other g enes Numerous \200\230other-than-PARK \200\231 disorders may also present with classic par kinsonism as a concomitant or even isolated feature, clinically mimicking idiopathic PD. Of these, some associated genes are not assigned to any list while others may have been added to \200\230other-than-PARK \200\231 lists, for example the DYT or SCA compilations (refl ecting that their usual presentation is not with parkinsonism). Dopa-responsive dystonia (DYT5, Segawa \200\231s disease) Th e syndrome of dopa-responsive dystonia (DRD) encompasses both autosomal dominant and autosomal recessive forms. Of these, the dominantly inherited DRD variants are more frequent and are oft en caused by mutations in the GTP cyclohydrolase I ( GCHI ) gene ( DYT5a ). Recessive variants are rarer ( DYT5b ) and associated with mutations in the tyrosine hydroxylase ( TH ) gene and other genes. Dystonia syndromes: dystonia \200\223parkinsonism, and parkinsonism in dystonia-plus syndro mes Dystonias are hyperkinetic movement disorders characterized by involuntary twisting and repetitive movements and abnor- mal postures (31). Monogenic dystonias have been grouped t ogether in the DYT classifi cation which currently holds 21 forms assigned to 21 DYT loci. Th ree of these present with com- bined features of dystonia and parkinsonism ( \200\230dys tonia \200\223parkin- sonism \200\231), i.e. DYT3 (X-linked dystonia \200\223parkinsonism, Lubag), DYT5 (dopa-responsive dystonia, Segawa \200\231s disease), and DYT12 (rapid-onset d ystonia \200\223parkinsonism). Although in DYT16 par- kinsonism has been reported in carrie rs of PRKRA mutations (32), this appeared to be isolated bradykinesia which was not levodop a-responsive and occurred in the context of severe dys- tonia. Th erefore it remains to be seen whether true parkinsonism is indeed a clinical feature of DYT16. GCHI encodes the enzyme GTPCH that catalyzes the fi rst step in the biosynthesis of tetrahy drobiopterin (43). In patients, there is a decrease in GTPCH activity, leading to dopamine depletion and explaining the remarkable therapeutic eff ect of levodopa sub- stitution. TH and other DRD-associated enzymes are functionally involved in the same metabolic pathways, in line with the overlap- ping clinical phenotypes. DRD is usually characterized by childhood onset of dystonia, diur- nal fl uctuation of symp toms, and a dramatic response to levodopa CHAPTER 12 The many faces of parkinsonism: A Review of the Parkinson Look-Alike Syndromes 121 therapy. Later in the course of the disease, parkinsonian features fre- quently occur (44). Rarely, both TH (45, 46) and GCHI mutations (47) may present as a levodopa-responsive, inf antile hypokinetic rigid syndrome. However, TH mutations tend to present with a more severe phenotype with mild mental retardation and pronounced signs of dopamine defi ciency includ ing tremor, hypersensitivity to levodopa, oculogyric crises, akinesia, rigidity, and dyston ia (48). In contrast, carriers of GCHI mutations may also show more typi- cal late-onset is olated classic parkinsonism (49), but patients usu- ally report a positive family history f or DRD (50, 51). Similar to the dystonic symptoms, classical parkinsonism in DRD responds w ell to levodopa therapy but, unlike in idiopathic PD, patients do not usu- ally develop sev ere long-term motor fl uctuations and dyskinesias (52, 53). While the response to levodopa treatment seems to set in more slowly and persists longer in subjects with DRD than in pati ents with PD, re-emergence of parkinsonian signs upon withdrawal of levo- dopa occurs at si milar rates in the two conditions (54). (70). In a recent study, using a mouse model of RDP, the cerebellum was observed to be the primary instigator of dystonia; aberrant cer- ebellar activity altered basal ganglia functi on, which in turn caused dystonia (71). Most recently, mutations in ATP1A3 were also identi - fi ed as a major cause of alternating hemiplegia of childhood. Spinocerebellar ataxias Inherited autosomal dominantly inherited ataxias represent a clin- ically and genetically heterogeneous group of neurodegenerative disorders in which progress ive degeneration of the cerebellum and spinocerebellar tracts of the spinal cord are associ ated with a vari- able combination of signs of central and peripheral nervous sys- tem invo lvement (72). To date, SCAs have been associated with at least 37 gene loci (73) (see also http://www.ncbi.nlm.nih.gov/ omim). Extrapyramidal features, including parkinsonism, have b een described in several of them. For example, it may occur as a prominent sign in SCA2, SC A3, SCA8, and SCA17, or as a mild additional feature in SCA6, which is usually considered a \200\230pure ataxia \200\231 (74), and other SCAs. If parkinsonism is prominent, an important diff erential diagnosis of DRD is early-onset pa rkinsonism due to mutations in one of the recessive \200\230PARK \200\231 genes, and in bo th conditions leg dystonia respon- sive to levodopa may be a presenting sign. For example, Parkin mutations may account for some cases of \200\230 GCHI mutation-negative DRD \200 \231 (55). As molecular testing for both GCHI and Parkin muta- tions is time-consuming and expensive, transcranial sonography is being explored regarding its potential to distinguish Parkin and GCHI mutation carriers based on the presence ( Parkin ) or absence ( GCHI ) of hyperechogenicity of the substantia nigra (56). Biochemical studies with CSF analysis (57) and functional imag- ing may also help to diff erentiate the two syndromes. Early-onset DRD patients show normal fl uorodopa uptake on PET studies (58) and normal dopamine transporte r imaging on SPECT, but these are expected be abnormal in the PARK-associated disorders (59 ). Pathological data in DRD are limited. It appears that there is a reduction of melanin pi gment in the substantia nigra, which is more pronounced in the lateral than the medial aspe ct, in a pattern similar to neuronal loss in PD. However, there are no Lewy bod- ies, and d opaminergic neurons and noradrenergic neurons in the substantia nigra and the locus coerule us, respectively, are normal in number but severely hypomelanized (60, 61). SCA2 may present with levodopa-responsive parkinsonism in patients from diff erent genetic backgrounds (75), and seems to be particularly frequent among patients of Asian origin in w hom it accounts for about 10% of familial parkinsonism (76). Th e parkin- sonian phenotype consists of rest tremor, rigidity, and bradykinesia in conjunction with mild dysarthria, at axic gait, and instability, particularly in later stages of the condition (76). Although mo st SCA2 patients have a positive family history of ataxia or ataxia plus parkinsonism (77), rarely SCA2 families with phenotypic famil- ial homogeneity of classic parkinsonism (77, 7 8) have also been described. SCA2 is a polyglutamine disease associated with an increased n umber of CAG/CAA repeats. Th e confi guration of the repeat expansion has recently been sho wn to play an important role in phenotypic variability. While uninterrupted SCA2 repeat exp an- sions cause an ataxic presentation, parkinsonism is associated with CAA interruptions a nd shorter repeats (79, 80). Overall, repeat expansions in SCA genes are a rare cause of par- kinsonism (81). One family with SCA3 showed at least two of the cardinal features of parkinsonism without any atypica l signs and a good response to levodopa (82). However, although ataxia may be negligible in SCA3 (83), parkinsonism is usually accompanied by peripheral neuropathy (84, 85), dystonia , and spasticity (83). Neuropathology studies of SCA3 showed nigral involvement, which prob ably accounts for the parkinsonism and the good levo- dopa response (86). A small number of patients with isolated levodopa-responsive parkinsonism have been described as carry- ing trinucleotide repeat expansions in the Ataxin8 and TBP genes, adding SCA8 and SCA17 to the (rare) diff erential diagnosis of par- kinsonism (87, 88). To our knowledge there are no da ta on patho- logical fi ndings of patients with SCA mutations who have presented with a par kinsonian phenotype. Rapid-onset dystonia \200\223parkinsonism (DYT12) Mutations in the Na + /K + -ATPase alpha 3 gene ( ATP1A3 ) cause rap- id-onset dystonia \200\223parkinsonism (RDP) (62, 63). Mean ag e of onset is in adolescence or young adulthood, and the mode of inheritance is autosomal d ominant with reduced penetrance (64, 65). Symptoms usually manifest over hours to weeks, an d may be followed by mod- erate or no progression. Some patients report mild (focal) dysto- nia preceding the onset (66, 67). RDP is clinically characterized by orofacial dystonia, d ysarthria, dysphagia, and involuntary dystonic spasms, predominantly of the upper limbs wit h superimposed par- kinsonian features, primarily bradykinesia and postural instability (66 ) with or without rigidity (68). Other features of classic parkin- sonism, such as rest tre mor and response to dopaminergic medica- tion, are not a typical feature (66, 69). A presen tation which could be more easily confused with PD has recently been described in a genetic ally proven patient with gradual onset of unilateral bradyki- nesia and rigidity at age 38 years, which did not improve on levodopa therapy. Th is was followed by overnight onset of oromandibular dys- tonia, 3.5 years aft er his fi rst clinical presentation with parkinsoni sm Mitochondrial gene mutations Mitochondrial syndromes may be phenotypically complex, includ- ing disorders from a variety of medical subspecialties such as diabetes mellitus, deafness , and visual disturbance, in addition to neurological features. Genetically, mitochondrial diseases may be due to mutations in either mtDNA (associated with strictly maternal inherit ance) or nDNA (nuclear encoded, Mendelian inheritance). Oxford Textbook of Movement Disorders 122 With respect to parkinsonism, the aforementioned proteins PINK1, DJ-1, and Omi/HtrA2 are nu clear encoded and form a link to mitochondria (89, 90). Furthermore, movement disorders are associated with mutations in the nuclear genes DNA polymerase gamma ( POLG ) and the PEO1 ( encoding Twinkle) genes. POLG disorders have a broad phenotypic range, including mitochon drial recessive ataxia syndrome without ophthalmoplegia (MIRAS), and sensory ataxic neuropa thy, dysarthria, and ophthalmoparesis (SANDO) (91). Myoclonus is the main movement disorder presen- tation in POLG disorders, but parkinsonism with features similar to PD, including asymmetrical onset, resting tremor, and response to levodopa, may occur (91 \200\22393). Pa rkinsonism is typically preceded several years earlier by the development of ophthalmoplegi a, but may also be the presenting feature (94). Fluorodopa PET imaging shows reduced tracer uptake in the caudate and putamen. Marked neuronal loss in the substantia nigra has been d emonstrated on pathological examination, although Lewy bodies are absent. early-onset treatment-refractory parkinsonism, through classic parkinsonism, to features co nsistent with Lewy body dementia (103, 104). Th e role of GBA mutations appears to be highly ethnically dependent (105). Th ey have been found, mostly in the het- erozygous state, in 29 \200\22331% of patients with classic park inson- ism from Israel (106), in 12% of a Venezuelan cohort with very early onset (107), in 6% of a sample of Canadian patients with a Caucasian background (108), in 4.3% of ethnic C hinese (109), and in only 2.3% of a Norwegian PD population (110). Th e last of these studi es found similar rates of functional mutations in the GBA protein in controls (1.7%) (111). Th e age of onset was found to be either similar (105) between patients with parkinsonism with or without heterozygous GBA mutations (112) or slightly reduced (106). It was conclude d that both severe and mild GBA mutations markedly increased the risk of developing PD (106 ). With respect to response to treatment, even carriers of two muta- tions, who otherwise b enefi t from enzyme replacement therapy, may require dopaminergic therapy to treat their pa rkinsonism adequately (113). Similarly, there is phenotypic heterogeneity for PEO1 muta- tions (91), and infantile-onset SCA, SANDO syndrome, and a form of hepatocerebral mtDNA depletion syndrome have all been d escribed. Parkinsonism with a history of reduced smell function was observed in an autosoma l dominant pedigree with progressive external ophthalmoplegia. Th ere was reduced uptake in the stria- tum bilaterally on 123 I-FP-CIT SPECT imaging. Atypical parkinsonism in genetic disorders that are usually mainly characterized by feature s other than parkinsonism Parkinsonian features in patients with classical Gaucher disease Typical features of Gaucher disease are painless hepatomegaly and splenomegaly. Other neuro logical symptoms and signs may include myoclonus, oculomotor apraxia, dementia, and convuls ions. Parkinsonism may also develop in patients with otherwise typical Gaucher disease and two mutated GBA alleles (97, 98). Furthermore, maternally inherited \200\230mitochondrial parkinsonism \200\231, associated with mutations in the Cytochrome b gene, the 12sRNA gene, and tRNA genes, has been identifi ed in single families (95, 96). However, patients from such families usually present with additional signs, such as deafness and neuropathy. Overall, mito- chondrial disease appears to be an exceedingly rare cause of classic parkinsonism. Th e role of Glucocerebrosidase Finally, mutations in the Glucocerebrosidase ( GBA ) gene a re an increasingly recognized cause of parkinsonism. Historically, it was the presence of p arkinsonian features in some cases with Gaucher disease and the identifi cation of GBA muta tions in individuals with PD that revealed the link between Gaucher disease and parkinson- ism. Th erefore this gene shares features with two of our categories and will be discussed here as causing parkinsonism alone (category B) in otherwise healthy individuals, and will also initiate a discus- sion of category C with mutations causing atypical parkinsonism in patients with classic Gaucher disease (97, 98). Fragile X-associated tremor \200\223ataxia syndrome (FXTAS) FXTAS is a neurodegenerative di sorder occurring largely, but not exclusively, in men. It is caused by moderate expansions (55 \200\223200 repeats, so-called pre-mutation range) of a CGG trinucleotide in the FMRI g ene (114, 115). Longer repeat lengths cause fragile X syndrome. Th e core clinical features of FXTAS are action tremor and cerebel- lar gait ataxia, with a n average age of onset of 60 years. Parkinsonism, primarily rigidity, is one of the frequen t associated fi ndings and is a minor clinical component of the proposed diagnostic criteri a for FXTAS. In fact, parkinsonism has been among the most frequent false diagnoses given t o patients with FXTAS (116). However, the phenotype usually diff ers from that of classic p arkinsonism (117, 118) in that other features, including dementia, neuropathy, and dysauton omia, may also be present. Mutations in the Glucocerebrosidase gene: association with classic parkinsonism Gaucher dis ease is the most common of the lipidoses and is one of the most frequently inherited disord ers among Ashkenazi Jews. It is due to recessively inherited defi ciency of the lysosomal e nzyme glucocerebrosidase (GBA). Family studies revealed that obligate or confi rmed carriers of GBA mutations from 10 famil ies developed parkinsonism (99). In addition, GBA mutations increase the risk of developing idio- pathic PD, and mutations were found in 8 \200\22314% of autopsy-proven PD cases (100 , 101). In fact, GBA variants are currently the most common genetic risk factor associated with parkinsonism, and both homozygous and heterozygous GBA mutations appear to predispose to parkinsonism (102). Th e phenotypic spectrum of parkinsonism associated with GBA mutatio ns ranges from Increased T 2 signal intensity in the middle cerebellar peduncles on MRI imaging (MCP sign) is present in a majority of patients. Similar signal alterations are found in deep and sub ependymal cerebral white matter, along with general cortical and subcorti- cal atrophy. Aut opsy studies have revealed eosinophilic intra- nuclear, neuronal, and astrocytic inclusions in the brain and brainstem as the major neuropathological feature, together with loss of P urkinje cells and regional vacuolation of the cerebral white matter (119). CHAPTER 12 The many faces of parkinsonism: A Review of the Parkinson Look-Alike Syndromes 123 Familial dementias Cognitive decline is common in idiopathic PD (120), and is par- ticularl y marked in some of the genetic parkinsonian disorders (e.g. Kufor \200\223Rakeb disease). However, not only is there consider- able clinical and pathological overlap between \200 \230PD with dementia \200\231 and \200\230dementia with Lewy bodies \200\231 (DLB), and be tween DLB and Alzheimer \200\231s disease (AD), but parkinsonism may also be a feature in p rimary dementia syndromes including AD and the frontotem- poral dementias (FTDs) (121). Diagnostic work-up should include serum and 24-hour urine copper, serum ceruloplasmin, free copper estimation, slit-lamp examination, and, if necessary, a liver biopsy. Genetic testi ng is not used for screening purposes because it is labor intensive, but it can confi rm th e exact mutation. Importantly, parkinson- ism as well as the other features of WD respond w ell to specifi c treatment for WD. Wilson disease is described in further detail in Chapter 23. Brain iron accumulation conditions Iron overload increases oxidative stress and may lead to neuro- degeneration presenting with parkinsonism. Dominantly inherited Presenilin 1 mutations are a cause of dementia, and early-onset levodo pa-responsive parkinsonism, in combination with progressive cognitive decline, has been an early sign in single cases (122, 123). In FTDs, particularly \200\230fronto- temporal deme ntia and parkinsonism linked to chromosome 17 \200\231 (FTDP-17) associated with mutations in the Tau ( MAPT ) gene or the Progranulin ( PGRN ) gene, the three major clinical feature s of FTDP-17 include behavioral disturbances, cognitive impair- ment, and parkinsonism (124 , 125). Prominent young-onset parkinsonism may be the earliest feature in some patients (12 6, 127). Age of onset is usually in the third to fi ft h decade. Overall, there is marked i nterfamilial, and even intrafamilial, phenotypic variability. Panthothenate kinase-associated neurodegeneration Panthothenate kinase-associated neurodege neration (PKAN) is a core disorder of syndromes with neurodegeneration with brain iron accu mulation (NBIA) type 1. This rare autosomal recessively inherited disease is due to PANK2 g ene mutations (136) encoding pantothenate kinase, the key regulatory enzyme in co-enzyme A synthesis. Classic PKAN manifests in the first decade with severe extrapyramidal signs and progresses rapidly to loss of ambulation within 15 years. The most common clinical features are dysarthria, dystonia, corticospinal signs causing gait disturbance, behavioral and cog nitive problems. Parkinsonian features include rigidity in the majority of patients, and so me- times tremor and freezing of gait (137). In contrast, atypical PKAN usually begins in t he second or third decade, and is asso- ciated with fewer extrapyramidal signs and slower p rogression, and patients usually retain ambulatory function. Very rarely, atypical PKAN may present as early-onset parkinsonism (136). However, screening of 67 PD patients with affec ted siblings or an early age of onset has not revealed any PANK2 mutation car- riers (138). Mutations in autosomal dominantly inherited Dynactin cause motor neuron disease and frontot emporal dementia. Recently, mutations in this gene have been associated with Perry syndrome (128) which is clinically characterized by rapidly progressive par- kinsonism, hypoventila tion, depression, and severe weight loss. Parkinsonism is poorly or only transiently levodo pa-responsive. Th e mean age of onset is 47 years and mean age at death is 52 years (129). Brain pathology reveals severe neuronal loss in the substan- tia nigra without Lewy bodies, in addition to TDP-43-positive neuronal inclusions, dystrophic neurites, and axonal sphero ids in a predominantly pallidonigral distribution (129). Brain MRI may be an important clue to the diagnosis, as it shows pallidal hypointensity wit h a central area of hyperintensity ( \200\230eye of the tiger \200\231 sign) on T 2 -weight ed images. PLA2G6-assocatiated neurodegeneration Th is cause of neurodegeneration of brain iron accumulation (NBIA type 2) has been dealed with under PARK14 . Prion disease Human prion diseases are mostly sporadic. Inherited forms due to point mutati ons and insertions within the prion protein ( PRNP ) gene represent about 10% of cases (130 ). Early symptoms of genetic Creutzfeldt \200\223Jakob disease (CJD) are somewhat non-speci fi c (per- sonality changes, disturbance of sleep and appetite). Eventually the triad of de mentia, myoclonus, and ataxia emerges. Additional pyramidal and extrapyramidal signs may be part of the phenotype. Rarely, parkinsonism, sometimes levodopa-responsive, may pre- domin ate (131), but it has not been described as an isolated or ini- tial symptom in CJD. Neuroferritinopathy Th e phenotype of neuroferritinopathy due to mutations in the fer- riti n light chain ( FTL1 ) gene is usually dominated by dystonia or chorea. Parkinsonism may al so develop (139, 140). Aceruloplasminaemia Th is autosomal recessive disorder aff ecting iron metabolism due to mu tations of the ceruloplasmin gene shows marked accumulation of iron in the liver, pancreas, retina, and basal ganglia. Clinically, it is characterized by the combination of movement disorders, dementia, and diabetes mellitus (141). Wilson disease Wilson disease (WD), which is due to mutations in the ATP7B gene (132), is a n autosomal recessive disorder of impaired forma- tion of ceruloplasmin, leading to copper accumulation in the liver, brain, kidney, and cornea. WD usually manifests in the fi rst de cade of life, although late onset may occur. A large series investigating 136 patients with neurological signs identifi ed that parkinsonism was the most common manifestation in both juveniles and adults. However, most cases had additional signs that were not compatible wi th classical parkinsonism (133).