Table 2.

Genes of Interest in the Differential Diagnosis of SLC6A3-Related Dopamine Transporter Deficiency Syndrome

GeneDisorderMOIComment
Neurotransmitter disorders including:
DDC Aromatic L-amino acid decarboxylase deficiency ARClinical features assoc w/SLC6A3-related DTDS (progressive parkinsonism-dystonia, eye movement disorder, axial hypotonia, & delayed motor development) may be similar to those seen in other neurotransmitter disorders. 1, 2
DNACJ12 Hyperphenylalaninemia, non-BH4 deficient (OMIM 617384)AR
GCH1 GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD)AD
Dystonia w/motor delay (See GTPCH1-Deficient DRD, Genetically Related Disorders.)AR
PTS Hyperphenylalaninemia, BH4 deficient, A (OMIM 261640)AR
QDPR Hyperphenylalaninemia, BH4 deficient, C (OMIM 261630)AR
SLC18A2 Infantile-onset parkinsonism-dystonia 2 (OMIM 618049)AR
SPR Sepiapterin reductase deficiency AR
TH Tyrosine hydroxylase deficiency AR
Mitochondrial diseases including:
DLAT
DLD
PDHA1
PDHB
PDHX
PDP1
PDK3 		Primary pyruvate dehydrogenase complex deficiency XL
AR 3		The phenotypic features of the mitochondriocytopathies overlap w/SLC6A3-related DTDS. 4 ↑ HVA levels are also observed in some mitochondrial disorders. 5 See also Primary Mitochondrial Disorders Overview.
PC Pyruvate carboxylase deficiency AR
POLG AR POLG-related disordersAR
Metabolic syndromes including:
CBS Homocystinuria caused by cystathionine beta-synthase deficiency (classic homocystinuria)ARMetabolic syndromes incl lysosomal storage diseases can mimic SLC6A3-related DTDS. 6
GLB1 GM1 gangliosidosis (See GLB1-Related Disorders.)AR
HPRT1 Lesch-Nyhan disease (See HPRT1 Disorders.)XL
NPC1
NPC2 		Niemann-Pick disease type C AR
PAH Untreated phenylketonuria (See Phenylalanine Hydroxylase Deficiency.)AR
Monogenic movement disorders associated with infantile-onset dyskinesia/hyperkinesia including:
ADCY5 ADCY5 dyskinesia AD
AR 7		Monogenic movement disorders assoc w/infantile-onset dyskinesia/hyperkinesia may be reminiscent of early disease manifestations of classic early-onset SLC6A3-related DTDS. 2
ATP1A3 ATP1A3-related neurologic disorders AD
ATP8A2 Cerebellar ataxia, impaired intellectual development, & disequilibrium syndrome 4 (OMIM 615268)AR
FOXG1 Rett syndrome, congenital variant (See FOXG1 Syndrome.)AD
GNAO1 GNAO1-related disorder AD
PRRT2 PRRT2-related paroxysmal kinesigenic dyskinesia w/infantile convulsions (See PRRT2-Associated Paroxysmal Movement Disorders.)AD
AR 8
SLC2A1 Glucose transporter type 1 deficiency syndrome AD

AR 9

SYT1 SYT1-related disorder (OMIM 618218)AD
Monogenic juvenile parkinsonism syndromes including:
ATP1A3 ATP1A3-related neurologic disorders ADMonogenic juvenile parkinsonism syndromes may mimic classic early-onset & atypical later-onset SLC6A3-related DTDS. 2, 6
ATXN2 SCA2 AD
ATXN3 SCA3 AD
DNAJC6 PARK-DNAJC6 AR
FBXO7 PARK-FBXO7 (See Parkinson Disease Overview.)AR
HTT Juvenile Huntington diseaseAD
MAPT MAPT-related frontotemporal dementia AD
PRKN (PARK2) PARK-Parkin AR
PARK7 (DJ1) PARK-DJ1 (See Parkinson Disease Overview.)AR
PINK1 PARK-PINK1 AR
PRKRA DYT-PRKRA (See Hereditary Dystonia Overview.)AR
RAB39B Waisman syndrome (OMIM 311510)XL
SNCA PARK-SNCA (See Parkinson Disease Overview.)AD
SPG11 Spastic paraplegia 11 AR
SYNJ1 PARK-SYNJ1 (See Parkinson Disease Overview.)AR
TAF1 X-linked dystonia-parkinsonism XL
VPS13C PARK-VPS13C (See Parkinson Disease Overview.)AR
WARS2 WARS2-related movement disorder (See WARS2 Deficiency.)AR
Disorders of brain metal accumulation including:
ATP13A2
C19orf12
COASY
CP
DCAF17
FA2H
FTL
PANK2
PLA2G6
WDR45 		Neurodegeneration w/brain iron accumulation disorders AR
AD
XL		Disorders of brain metal accumulation may mimic SLC6A3-related DTDS.
ATP7B Wilson disease AR
SLC30A10 Hypermanganesemia w/dystonia 1 AR
SLC39A14 SLC39A14 deficiency (hypermanganesemia w/dystonia 2)AR
Other childhood disorders that can feature parkinsonism:
NUP62
VAC14 		Monogenic causes of striatal necrosis (OMIM PS271930)ARMonogenic striatonigral degeneration may cause similar dystonia-parkinsonism. 2
CLN2
CLN3
CLN6 		Neuronal ceroid lipofuscinoses 2 (NCL) (OMIM 204200, 204500, 601780)ARInfantile & late-infantile NCL may mimic SLC6A3-related DTDS. 2
SCN1A SCN1A-related Dravet syndrome (See SCN1A Seizure Disorders.)ADPredominantly early-onset epilepsies, but w/later parkinsonism & non-epileptiform disorders 2
STXBP1 STXBP1 encephalopathy w/epilepsy (OMIM 612164)AD
(AR)
CLTC CLTC-related intellectual developmental disorder (OMIM 617854)ADOther monogenic disorders that present in childhood, typically w/symptoms other than dystonia-parkinsonism, though that can feature parkinsonism often later in the disease course 2
CSF1R Leukoencephalopathy w/neuroaxonal spheroids 2AD
DHDDS DHDDS-related developmental delay & seizures ± movement abnormalities (OMIM 617836)AD
HEXA Tay-Sachs disease (See HEXA Disorders.)AR
LYST Chediak-Higashi syndrome AR
MECP2 MECP2-related classic Rett syndrome (See MECP2 Disorders.)XL
PGK1 Phosphoglycerate kinase 1 deficiency (OMIM 300653)XL
SLC20A2 SLC20A2-related primary familial brain calcification 2AD
TBC1D24 TBC1D24-related disorders AR10
TMEM240 Spinocerebellar ataxia 21 (OMIM 607454)AD
ZFYVE26 HSP-ZFYVE26 AR

AD = autosomal dominant; AR = autosomal recessive; DRD = dopa-responsive dystonia; DTDS = dopamine transporter deficiency syndrome; DYT = dystonia; HSP = hereditary spastic paraplegia; HVA = homovanillic acid; MOI = mode of inheritance; PARK = Parkinson disease; SCA = spinocerebellar ataxia; XL = X-linked

1.
2.
3.

PDHA1- and PDK3-related primary pyruvate dehydrogenase complex deficiency (PDCD) are inherited in an X-linked manner. Primary PDCD caused by pathogenic variants in DLAT, DLD, PDHB, PDHX, or PDP1 is inherited in an autosomal recessive manner.

4.
5.
6.
7.

ADCY5 dyskinesia is typically inherited in an autosomal dominant manner. Autosomal recessive inheritance has been reported in two families.

8.

PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) is caused by a PRRT2 heterozygous pathogenic variant (~99% of affected individuals); the 16p11.2 recurrent deletion that includes PRRT2 (<1% of affected individuals); or biallelic PRRT2 pathogenic variants (<1% of affected individuals, typically those with a more severe phenotype). PRRT2-PxMD caused by a heterozygous PRRT2 pathogenic variant or, rarely, the 16p11.2 recurrent deletion is inherited in an autosomal dominant manner. Rarely PRRT2-PxMD is inherited in an autosomal recessive manner.

9.

Glucose transporter type 1 deficiency syndrome (Glut1 DS) is most commonly inherited in an autosomal dominant manner. Rarely, Glut1 DS is inherited in an autosomal recessive manner.

10.

Most TBC1D24-related disorders are inherited in an autosomal recessive manner.

From: SLC6A3-Related Dopamine Transporter Deficiency Syndrome

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