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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).