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Dystonia, chorea or related movement disorder, childhood onset v8.19 SLC2A1 Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT
Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected.
Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis.

BIALLELIC CASES:
PMID: 20687207 Rotstein et al., 2011
F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529.
F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955.
Only SLC2A1 was analysed, method not described.

PMID: 20221955 Klepper et al., 2009
Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1.

PMID: 10980529 Wang et al., 2000
Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V
(K256V inherited from an asymptomatic mother).
Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2.

SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026
Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected.
Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis.

PMID: 20687207 Rotstein et al., 2011
F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529.
F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955.
Only SLC2A1 was analysed, method not described.

PMID: 20221955 Klepper et al., 2009
Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1.

PMID: 10980529 Wang et al., 2000
Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V
(K256V inherited from an asymptomatic mother).
Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2.

SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).
Dystonia, chorea or related movement disorder, childhood onset v7.7 ADCY5 Achchuthan Shanmugasundram changed review comment from: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).; to: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).
Dystonia, chorea or related movement disorder, childhood onset v7.7 ADCY5 Achchuthan Shanmugasundram commented on gene: ADCY5: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).
Dystonia, chorea or related movement disorder, childhood onset v3.65 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. 7/10 patients are reported to show spasticity although it is not reporterd whether they all shared the same founder variant in ASL.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53  years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 4 were reported to show tremor/dystonia, with this phenotype present at ages 9, 11, 24 and 25 years of age. Homozygous or compound het ASL variants were recorded in 25/60 patients including 3 out of the 4 patients with tremor/dystonia (patients 4,9 and 25 with c.719-2A>G; c.857A>G, c.1153C>T; c.1153C>T and c.437G>A; c.446+1G>A respectively). Genotype data was not available for other patients. Although patient 4 from this study and patient 9 from the Baruteau et al 2017 study share the same genotype and are both male, their phenotypic descriptions differ so assuming here that they are not the same patient.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Tremors or dystonia were reported in 4 individuals (1,4,9 and 25). All were diagnosed before the age of 3 although it is not stated at what age the tremors/dystonia were first noted. The first 3 of these patients had homozygous or compound het variants in ASL identified (c.35G>A;c.35G>A, c.377G>A;c.377G>A and c.719-2A>G, c.857A>G respectively).

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.
PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries, PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient.

More recent retrospectives show that tremors and/or dystonia is reported in some individuals with Argininosuccinic aciduria. 6 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53  years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 4 were reported to show tremor/dystonia, with this phenotype present at ages 9, 11, 24 and 25 years of age. Homozygous or compound het ASL variants were recorded in 25/60 patients including 3 out of the 4 patients with tremor/dystonia (patients 4,9 and 25 with c.719-2A>G; c.857A>G, c.1153C>T; c.1153C>T and c.437G>A; c.446+1G>A respectively). Genotype data was not available for other patients. Although patient 4 from this study and patient 9 from the Baruteau et al 2017 study share the same genotype and are both male, their phenotypic descriptions differ so assuming here that they are not the same patient.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Tremors or dystonia were reported in 4 individuals (1,4,9 and 25). All were diagnosed before the age of 3 although it is not stated at what age the tremors/dystonia were first noted. The first 3 of these patients had homozygous or compound het variants in ASL identified (c.35G>A;c.35G>A, c.377G>A;c.377G>A and c.719-2A>G, c.857A>G respectively).

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Dystonia, chorea or related movement disorder, childhood onset v0.0 ARG1 Ellen McDonagh gene: ARG1 was added
gene: ARG1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: London North GLH,Expert Review Red
Mode of inheritance for gene: ARG1 was set to