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). Further NBIA disorders Th ere have been additional single-case reports of NBIA with late-on set levodopa-responsive parkinsonism with an as yet undetermined genetic basis (142, 143). Rest tremor was asym- metric with a re-emergent component. Th ere was development of levodo pa-induced dyskinesias and good benefi t from deep brain stimulation (143). MRI showed an \200\230eye of the tiger \200\231 sign, but genetic testing was negative for known genes. It has been hypothesized that a single mutated ATP7B allele may act as a risk factor for (l ate-onset) parkinsonism (134, 135). Oxford Textbook of Movement Disorders 124 FBXO7-associated neurodegeneration Th is rare syndrome, which has recently been described, is char- acterized by childhood-onset dystonia with, in some cases, addi- tional parkinsoni sm with bradykinesia and rigidity but no tremor. Parkinsonism was responsive to dopaminergi c treatment with the development of dyskinesia (144, 145). In the third decade all fam- ily members developed lower limb spasticity. Dopamine trans- porter SPECT (FP-CIT) scan reveal ed severely reduced presynaptic nigrostriatal defi cits (145), and assessment using transcr anial magnetic stimulation showed abnormal cortical motor conduc- tion time. Other investig ations, including routine blood tests, ocu- lar examination, brain and spinal MRI, IBZM-SPE CT scanning (a measure of postsynaptic striatal dopamine binding), EEG, EMG, and a muscle b iopsy, were normal (144, 145). Overall, little is yet known about this syndrome. hyperkinesias, dysarthria, and dysphagia with frequent involun- tary vocalizations, chorea, and, less oft en, dystonia. Th e hyperki- netic state can gradually progress to parkinsoni sm (159, 160) and is observed in about a third of patients (161). Very rarely parkinson- is m is the presenting feature (162). Cognitive changes, seizures, and peripheral neuropathy m ay be present (161). McLeod syndrome, an X-linked form of neuroacanthocytosis associated wi th abnor- malities in the Kell antigens on red blood cells, may also have a parkinsonian ph enotype (163). Miscellaneous conditions In addition to the conditions described above, there are other dis eases which may present with parkinsonism and should be considered in the diff erential dia gnosis. Some of these cannot be discussed in detail because of space restrictions. Th ey in clude hereditary haemochromatosis due to mutations in the HFE gene (164), neurometabolic di sorders, such as Niemann \200\223Pick type C, due to mutations in the NPC1 gene (for a revi ew, see ref. 52), and individual cases of hereditary spastic paraplegia (165) which may som etimes present with parkinsonism. Atypical parkinsonism has been reported in Rett syndrome (166), and dystonia \200\223parkinsonism has been reported in the course of the immunodefi ciency disor- der X-linked agammaglobulinaemia (167). Th ere are also reports of individual families with parkinsonism due to as yet unknown gene defects (168). Fahr \200\231s disease Bilateral striopallidodentate calcifi cation, also referred to as Fa hr \200\231s disease, is characterized by basal ganglia and extra-basal ganglia brain calci fi cations, parkinsonism, and neuropsychiatric symp- toms. Causes are multiple and include inherited variants (146). An idiopathic case with progressive cognitive impairment, frontal lobe dysfunction, mild leg spasticity, levodopa-responsive parkinson- ism, and marked basa l ganglia hyperechogenicity on transcranial sonography has been reported (147). Acknowledgements CK is supported by a Lichtenberg grant from the Volkswagen Foundation and a Career Development Award from the Hermann and Lilly Schilling Foundation. SAS is supporte d by the German Research Foundation. Huntington \200\231s disease Th e autosomal dominant trinucleotide disorder Huntington \200 \231s dis- ease (HD), due to CAG repeat expansions in the huntingtin gene (148, 149) is the most important cause of inherited chorea charac- terized by cognitive decline and psychiat ric, oculomotor, and motor abnormalities, in addition to prominent chorea. Onset is typical ly in adulthood. However, the Westphal variant of HD is a distinct presentation characteriz ed by a rigid \200\223hypokinetic syndrome and is usually associated with young onset age. Juvenile HD (i.e. onset age 20 years or younger) accounts for 5 \200\22310% of all HD cases (150 \200\223152). While fi ne postural trunk and limb tremor may be seen (153), rest trem or has not been described. Some children show cerebellar signs or dystonia; eye movement di sturbances are prominent, and behav- ioural problems and cognitive decline are common, some times as presenting features. Seizures have been reported in about 30% of juvenile cases, w hereas they are rare in adult-onset patients. Very rarely, adult-onset patients may also pr esent with classical parkin- sonism without chorea in the initial stages of their illness ( 154). In rare instances, late-onset HD may mimic levodopa-responsive par- kinsonism (155) o r mild cardiovascular dysautonomia, which may mimic multiple system atrophy (156). In recen t years, phenocopies of HD have been recognized (157) and, similar to HD, progres- sion to a hypokinetic parkinsonian phenotype (157) and \200\230Westphal variants \200\231 have bee n described. Huntington \200\231s disease is discussed in more detail in Chapter 20. References 1. Klein C, Lohmann-Hedrich K . Impact of recent genetic fi ndings in Parkinson \200\231s disease. Curr Opin Neurol 2007; 20 : 453 \200\2236 4 . 2. Tan EK, Skipper LM . Pathogenic mutations in Parkinson disease. Hum Mutat 2007; 28 : 641 \200\2235 3 . 3. Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A . Genetics of Parkinson \200\231s disease and parkinsonism. Ann Neurol 2006; 60 : 389 \200\2239 8 . 4. Dodson MW, Guo M . Pink1, Parkin, DJ- 1 and mitochondrial dysfunc- tion in Parkinson \200\231s disease. Curr Opin Neurobiol 2007; 17 : 331 \200\2237 . 5. Galpern WR, Lang AE . Interface between tauopathies and synucleinopa- thies: a tale of two proteins. Ann Neurol 2006; 59 : 449 \200\2235 8 . 6. 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