Table 4.

Genes Associated with Dystonia-Parkinsonism in the Differential Diagnosis of DNAJC6 Parkinson Disease

GeneDisorder (Designation 1)MOIDystonia-ParkinsonismOther Key Clinical Features
Neurotransmitter disorders
DDC Aromatic L-amino acid decarboxylase deficiency (DYT-DDC) 2ARInfantile-onset parkinsonism & dystoniaBulbar dysfunction, oculogyric crisis, autonomic dysfunction, ID, DD
GCH1 GTP cyclohydrolase 1-deficient dopa-responsive dystonia (DYT/PARK-GCH1)ADAdult-onset dystonia-parkinsonism; childhood-onset L-dopa-responsive dystoniaDiurnal fluctuation, female predominance
PTS 6-pyruvoyl-tetrahydropterin synthase deficiency 3 (DYT/PARK-PTS)ARInfantile-onset dystonia & parkinsonismDD, ID, seizures, autonomic dysfunction, hyperphenylalaninemia
QDPR Dehydropteridin reductase deficiency 4 (DYT/PARK-QDPR)ARInfantile-onset dystonia & parkinsonismDD, ID, hypotonia, seizures, autonomic dysfunction, hyperphenylalaninemia
SLC6A3 Dopamine transporter deficiency syndrome (DYT/PARK-SLC6A3)ARInfantile-onset dystonia & parkinsonism; atypical onset w/juvenile-onset dystonia/ parkinsonismMild DD, hypotonia, oculogyric crisis, bulbar dysfunction
SLC18A2 Brain dopamine-serotonin transport disease 5ARChildhood-onset parkinsonismMood disturbance, autonomic instability, DD
SPR Sepiapterin reductase deficiency (DYT/PARK-SPR)ARInfantile-onset L-dopa-responsive dystonia, infantile-onset parkinsonismDD, ID, spastic paraparesis, autonomic dysfunction, oculogyric crisis, psychiatric symptoms
TH Tyrosine hydroxylase deficiency (DYT/PARK-TH)ARMild infantile- to childhood-onset L-dopa-responsive dystonia, moderate-to-severe infantile-onset parkinsonismHypotonia, limb spasticity, oculogyric crisis, severe autonomic dysfunction
Disorders of heavy metal metabolism
SLC30A10 Dystonia/parkinsonism, hypermanganesemia, polycythemia, & chronic liver disease (DYT/PARK-SLC30A10)ARInfantile- to childhood-onset dystonia & parkinsonismPolycythemia, chronic liver disease, MRI brain abnormalities w/T1-weighted basal ganglia hyperintensity
SLC39A14 SLC39A14 deficiency (hypermanganesemia w/dystonia 2)ARInfantile- to childhood-onset dystonia & parkinsonismMRI brain abnormalities, w/T1-weighted basal ganglia hyperintensity
ATP7B Wilson disease (DYT-ATP7B)ARAdolescent-/adult-onset parkinsonism, dystoniaTremor, psychiatric symptoms, liver disease, ocular Kayser-Fleischer rings; on MRI: features of basal ganglia heavy metal deposition ("face of giant panda" sign)
Inherited metabolic disorders
GLB1 GM1 gangliosidosis type III - chronic/adult form (See GLB1-Related Disorders.) (DYT/PARK-GLB1)ARAdolescent-/adult-onset dystonia & parkinsonismMild ID/DD, pyramidal signs, dysarthria, skeletal abnormalities, cardiomyopathy, cataract, vacuolated lymphocytes
NPC1
NPC2 		Niemann-Pick disease type C ARChildhood-/adolescent-/adult-onset dystonia, adolescent-/adult-onset parkinsonismVertical supranuclear gaze palsy, oculomotor apraxia, cerebellar ataxia, gelastic cataplexy
SLC19A3 Biotin-thiamine-responsive basal ganglia disease (DYT-SLC19A3)ARChildhood-onset dystonia & parkinsonismSubacute encephalopathy/coma, cerebellar signs, pyramidal signs, ID/DD, epilepsy
HPRT1 Lesch-Nyhan disease (See HPRT1 Disorders.)XLInfantile-/adolescent-/adult-onset dystonia & parkinsonismVariety of neurologic & behavioral problems (incl self-mutilation), ID/DD
Mitochondrial disorders 6
DLAT
DLD
PDHA1
PDHB
PDHX
PDK3
PDP1 		Primary pyruvate dehydrogenase complex deficiency AR
XL		Adult-onset parkinsonism & dystoniaChorea, ataxia, dysarthria, dementia
POLG POLG-related disorders AR
(AD)		Juvenile-/adult-onset parkinsonismContinuum of overlapping phenotypes 7
mtDNA Leber hereditary optic neuropathy MatAdult-onset parkinsonismOptic atrophy
Early-onset neurodegeneration with brain iron accumulation (NBIA) disorders 8
C19orf12 Mitochondrial membrane protein-associated neurodegeneration
(HSP/NBIA-C19orf12)		AR (AD)Early childhood-onset parkinsonism & dystoniaSpasticity, dystonia, dementia, psychiatric features, motor axonopathy, optic atrophy; on MRI: features of BIA in basal ganglia (globus pallidus, substantia nigra)
CP Aceruloplasminemia (NBIA/DYT/PARK-CP)ARAdult-onset dystonia & parkinsonismAtaxia, chorea, diabetes mellitus, retinal degeneration, psychiatric symptoms, anemia, ↑ serum ferritin, ↓ serum copper, absent ceruloplasmin, liver iron storage; on MRI: features of BIA (basal ganglia & dentate nuclei on MRI)
PANK2 Pantothenate kinase-associated neurodegeneration (NBIA/DYT-PANK2)ARChildhood-onset dystonia & parkinsonismNeuropsychiatric features, pyramidal signs, pigmentary retinopathy; on MRI: features of BIA (globus pallidus) w/"eye of the tiger" sign)
PLA2G6 PLA2G6-associated neurodegeneration (NBIA/DYT/PARK-PLA2G6)ARAdolescent/adult-onset dystonia & parkinsonismID/DD (in early-onset disease)/dementia, pyramidal signs, ataxia, psychiatric features; on MRI: features of progressive cerebellar atrophy, cerebellar gliosis & BIA (globus pallidus & substantia nigra)
WDR45 Beta-propeller protein-associated neurodegeneration (NBIA/PARK-WDR45)XLAdolescent-onset parkinsonism & dystoniaDD/ID, spasticity, seizures, abnormal behavior; on MRI: features of BIA (substantia nigra & globus pallidus), T1-weighted hyperintense "halo" midbrain, cerebral & cerebellar atrophy
Other monogenic disorders with prominent parkinsonism
ATP1A3 Rapid-onset dystonia-parkinsonism (See ATP1A3-Related Neurologic Disorders.) (DYT/PARK-ATP1A3)ADAdolescent-/adult-onset dystonia & parkinsonismPyramidal degeneration w/spasticity, supranuclear palsy; symptoms can be triggered by fever, infection, physical/ emotional stress, alcohol consumption
HTT Childhood or juvenile-onset Huntington diseaseADChildhood-/juvenile-onset parkinsonism (rigid-hypokinetic)Severe mental deterioration, prominent motor & cerebellar symptoms, rapid progression, seizures
PRKRA Young-onset dystonia-parkinsonism (See Hereditary Dystonia Overview.) (DYT-PRKRA)ARInfantile-/childhood-onset dystonia (lower limb) & parkinsonismSevere laryngeal dystonia in most persons
TAF1 X-Linked dystonia-parkinsonism
(DYT/PARK-TAF1)		XLAdult-onset dystonia (craniofacial, lower limb, cervical) & parkinsonismMost frequent in Filipino males of Panay Islander ancestry

AD = autosomal dominant; AR = autosomal recessive; BIA = brain iron accumulation; DD = developmental delay; DYT = dystonia; HSP = hereditary spastic paraplegia; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; PARK = parkinsonism; XL = X-linked

1.

Movement disorder nomenclature is based on Marras et al [2016].

2.

OMIM 608643

3.

OMIM 261640

4.

OMIM 261630

5.

OMIM 618049

6.

Mitochondrial dysfunction can be associated with infantile-onset parkinsonism, pyramidal signs, and axonal neuropathy and should be considered in the differential diagnosis of any progressive multisystem disorder. Many nuclear and mitochondrial genes are known to be associated with respiratory chain defects; see Mitochondrial Disorders Overview).

7.

Most affected individuals have some, but not all, of the features of a given phenotype. Associated phenotypes are: Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy spectrum, myoclonic epilepsy myopathy sensory ataxia, ataxia neuropathy spectrum, autosomal recessive progressive external ophthalmoplegia, and autosomal dominant progressive external ophthalmoplegia.

8.

From: DNAJC6 Parkinson Disease

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