DYT3 dystonia, which clusters in Filipinos, is an X-linked recessive disorder. Although this disorder typically affects males, rarely, females may also be affected, possibly due to severe X-inactivation or based on homozygosity for the mutation [103]. DYT3 reaches complete penetrance by the end of the fifth decade in males and later in females (up to 75 years) and is associated with specific sequence changes in the TAF1 gene [126, 183]. Usually symptoms start in adulthood as focal dystonia, tend to progress, and generalize. Parkinsonism is often present (up to 36 %) and in some cases may precede the onset of dystonia or can be the predominant or sole feature throughout the disease course [54, 75, 103]. Parkinsonism may improve with levodopa in the early stages but becomes less responsive or unresponsive over the course of the disease. Investigations in XPD patients show an abnormal DaTSCAN and a clearly abnormal IBZM SPECT, implying decreased dopamine D2 receptor expression. On positron emission tomography (PET), striatal glucose metabolism is selectively reduced. Fluorodopa uptake is normal, suggesting that the origin of the extrapyramidal symptoms is localized rather postsynaptically to the nigrostriatal pathway (see also Chap. 7) [196].

DYT5 was initially described by Segawa et al. in 1976 [178] and later by Nygaard and colleagues as dopa-responsive dystonia (DRD) because of the dramatic and sustained response to low dose of levodopa [132]. The disease is inherited as an autosomal dominant trait with reduced penetrance that appears to be gender dependent with females more frequently expressing symptoms. It is caused by mutations in the GTPCH1 (GTP cyclohydrolase 1) gene [80]. GTPCH1 is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, an essential cofactor for tyrosine hydroxylase (TH) which in turn is needed to synthesize dopamine, explaining the remarkable therapeutic effect of levodopa substitution. The typical phenotype includes childhood (average 6 years) limb-onset dystonia with diurnal variation (e.g., worsening of the symptoms as the day progresses), improvement after sleep, and dramatic response to levodopa [60, 193]. Later in the course of the disease, parkinsonian features occur frequently, and patients may also show typical, late-onset isolated parkinsonism, which responds well to levodopa therapy, but, unlike in idiopathic PD, patients usually do not develop motor fluctuations and dyskinesias [133], although this is not exclusive [41, 102]. Early-onset parkinsonism due to mutations in one of the recessive PARK genes (mostly Parkin) has to be considered in the differential diagnosis of a young patient presenting with prominent leg dystonia that is responsive to levodopa therapy. Early-onset DRD patients show normal DaTSCAN in contrast to patients with young-onset Parkinson’s disease [28]. The latter concept has been recently challenged, by demonstrating that later-onset DRD cases presenting with PD may have abnormal DaTSCANs; thus, GTPCH1 mutations may be risk factors to develop classic PD (see also Chap. 7) [123].

In a minority of cases, DRDs can also be inherited as an autosomal recessive disorder with mutations in the genes coding for other enzymes involved in dopamine synthesis including tyrosine hydroxylase (TH) [60, 113], sepiapterin reductase (SR), and aromatic l-amino acid decarboxylase (AADC) deficiency [3]. The clinical manifestations are often more severe and can include mental retardation, oculogyria, hypotonia, severe bradykinesia, drooling, ptosis, and seizures [189]. Recently it has been shown that TH patients may develop dyskinesias [148].

Hereditary dopamine transporter deficiency syndrome (DTDS) is the first biogenic amine “transportopathy” to be described. It is an autosomal recessive condition leading to infantile parkinsonism– dystonia caused by pathogenic mutations in the SLC6A3 gene encoding the dopamine transporter (DAT) [98], which mediates the active reuptake of dopamine and regulates the amplitude and duration of dopamine neurotransmission [98]. All children present with irritability, axial hypotonia, and feeding difficulties in infancy, with a hyperkinetic movement disorder that evolves into hypokinetic parkinsonism–dystonia. Ocular abnormalities included eye flutter, saccade initiation failure, slow saccadic eye movements, eyelid myoclonus, and oculogyric crises [98, 130, 131]. However, the phenotypic spectrum of this condition is expanding, with the first adults diagnosed with DTDS now recognized, and the condition is now considered as a differential for juvenile and early-onset parkinsonism [131]. Diagnosis can be based on CSF studies that show a raised ratio of HVA:5-HIAA >5 (normal range 1.3–4.0), a key finding in DTDS diagnosis [98]. The majority of patients are unresponsive to nearly all available therapeutic agents, including levodopa, anticholinergics, benzodiazepines, and deep brain stimulation [98, 120, 130].

Rapid-onset dystonia–parkinsonism is inherited as an autosomal dominant trait with reduced penetrance. Six heterozygous missense mutations have been identified in the Na⁺, K⁺-ATPase ATP1A3 (alpha 3 subunit) gene, and all are shown to impair cell viability in cell culture experiments [30, 40, 101]. The disease phenotype designated rapid-onset dystonia–parkinsonism because of key clinical features including abrupt onset, within hours to weeks, of dystonia with signs of parkinsonism usually triggered by physical or emotional stress (fever, childbirth, running, alcohol binging). The age of onset varies from 4 to 58 years but typically presents in the teens or early twenties, and the distribution follows a rostrocaudal (face > arm > leg) gradient with prominent bulbar involvement. A presentation that could be more easily confused with PD has been recently described in a genetically proven patient with gradual onset at age 38 years of unilateral bradykinesia and rigidity, however, without improvement on levodopa therapy. This was followed by overnight onset of oromandibular dystonia 3.5 years after his first clinical presentation with parkinsonism (see also Chap. 7) [85].

Wilson’s disease (WD) is an autosomal recessive disorder with reduced biliary excretion of copper and impaired formation of ceruloplasmin, leading to copper accumulation in the liver, brain, kidney, and cornea. WD is caused by mutations in the ATP7B gene and usually manifests in the first decade of life, although late presentations have also been described [72, 74, 119]. Clinical manifestations include liver damage, psychiatric symptoms, and neurologic features. Juvenile and adult-onset parkinsonism are common features, which do not respond to levodopa, but respond well to specific WD treatment [33]. Evaluation should include serum and 24-h urine copper, serum ceruloplasmin, slit lamp examination looking for Kayser-Fleischer rings, free copper estimation, and if necessary, a liver biopsy [119]. Mutational analysis is labor intensive and is thus not used for screening purposes but confirms the exact mutation in patients with suspected Wilson’s disease (see also Chap. 14).

A recessive inborn error of manganese metabolism [205] due to mutations in the SLC30A10 (solute carrier family 30, member 10) gene, encoding a manganese transporter, results in manganese accumulation mainly in the basal ganglia and cerebellum, and the liver, and causes a syndrome of early-onset generalized dystonia, cirrhosis, polycythemia, and hypermanganesemia [152, 205, 206]. Patients with parkinsonism–dystonia have also been described [44, 45, 152]. The metabolic signature of this disorder is the extreme hypermanganesemia with polycythemia and depleted iron stores (e.g., low ferritin, increased total iron-binding capacity), while laboratory findings reflecting hepatic dysfunction vary even between members of the same family [152, 205]. Manganese induces erythropoietin gene expression, and this could be the mechanism leading to polycythemia [52]. T1-weighted MRI images show hyperintensities in the basal ganglia and cerebellum [152, 191, 205]. As in Wilson’s disease, manganese chelation treatment is helpful for both neurologic and systemic features (see also Chap. 14) [191].

NBIA disorders cause complex dystonia–parkinsonism phenotypes and are discussed further in Chap. 13.

Huntington’s disease (HD), an autosomal dominant disorder due to a trinucleotide CAG repeat expansion in the huntingtin gene (normal: 15–30 repeats; disease associated: >40 repeats), usually begins in adulthood and is characterized by cognitive decline and psychiatric, oculomotor, and motor abnormalities, usually with chorea as the most prominent feature [51, 88, 154]. The Westphal variant of HD is a distinct presentation characterized by a rigid-hypokinetic syndrome and is usually associated with young-onset age (<20 years) and accounts for 5–10 % of all HD cases. Juvenile HD is predominantly paternally inherited and associated with larger trinucleotide expansions in the range of 60–100 repeats, but may be as long as 250 trinucleotides [51, 170]. Clinically, juvenile HD often presents as an akinetic rigid disorder and may occur without concomitant choreic movements, and there may be supranuclear gaze palsy. Caudate volume loss on neuroimaging can be seen in both adult-onset and juvenile HD [154].

Neuroacanthocytosis may also present with parkinsonism (Table 3.1) (see also Chap. 8).

Mitochondrial disorders may present with atypical parkinsonism and can be associated with specific point mutations, microdeletions, and also multiple mtDNA deletions due to, for example, polymerase gamma (POLG) mutations, which can be inherited in dominant or recessive mode [137]. PSP-like patients who presented in their sixties with parkinsonism, vertical SGP, and early cognitive dysfunction have been reported [68, 71]; associated features in these patients were deafness, ataxia, and lower motor neuron signs, which are absent in PSP [68, 71]. Of note, POLG-related parkinsonism can show an excellent response to levodopa, in contrast to sporadic PSP (see also Chap. 20) [137, 217].

In particular the adult-onset Niemann–Pick C (NPC1 and NPC2 gene mutations), an autosomal recessive lysosomal lipid storage disorder [81, 179], presents with vertical SGP, cerebellar ataxia, dysarthria, dysphagia, cognitive dysfunction, and psychiatric symptoms and should be thought in the differential of patients with a PSP-like phenotype [179]. Biochemical diagnosis of Niemann–Pick C is made by filipin staining of cultured skin fibroblasts, with subsequent confirmation of the diagnosis made by mutation analysis of the NPC1 (the majority) and NPC2 genes [1, 219]. Miglustat is the only approved treatment for the neurologic manifestations of the disease, and patients who begin treatment early respond better, highlighting the need for early diagnosis [1, 143, 219, 220].

In the adult-onset form of Gaucher’s disease, patients usually have slow horizontal saccades and increased latency launching horizontal saccades [16], which is usual in CBD [162], but not in PSP [11], in which the saccadic latency is normal and vertical saccades are more and earlier affected than horizontal, particularly downwards. However, some Gaucher’s disease patients with prominent slowness of vertical saccades and cognitive dysfunction, mimicking PSP, have been reported [62, 63, 122, 200, 201, 210]. Other neurologic features such as head thrusting (55 %), ataxia (20 %), seizures (16 %), and spasticity (15 %), which are not seen in PSP, provide important clues [8, 43, 67, 200, 201, 210]. Systemic associated features such as splenomegaly, hepatomegaly, bone crisis, bone pain, anemia, and thrombocytopenia are helpful diagnostic clues [200, 201, 210].

Genetic Creutzfeldt–Jakob disease (gCJD) has been linked to a variety of mutations within the prion protein gene (PRNP). Patients with disease onset between their fifth and seventh decade, vertical SGP, “worried facial appearance,” postural instability, axial rigidity, and frontal dementia mimicking PSP have been described in gCJD, mostly with the E200K but rarely also with further mutations and in sporadic CJD [20, 21, 95, 121, 171, 182]. These patients often have cerebellar and pyramidal signs as well as myoclonus, and the rapidity of evolution is helpful to suspect the disorder.

The combination of parkinsonism with leukoencephalopathy should prompt to test for colony-stimulating factor 1 (CSF1R) mutations, causing leukoencephalopathy with axonal spheroids [90, 124, 150, 158, 195]. Also in CADASIL due to NOTCH3 mutations, atypical parkinsonism has been described [159]. Mitochondrial disorders may also present with white matter changes in MRI.