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Leukodystrophy v0.378 SPG7 Bryony Thompson gene: SPG7 was added
gene: SPG7 was added to Leukodystrophy - paediatric. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: SPG7 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SPG7 were set to 20108356; 17646629
Phenotypes for gene: SPG7 were set to Spastic paraplegia 7, autosomal recessive 607259
Leukodystrophy v0.376 Bryony Thompson Copied gene SPAST from panel Leukodystrophy - adult onset
Leukodystrophy v0.376 SPAST Bryony Thompson gene: SPAST was added
gene: SPAST was added to Leukodystrophy - paediatric. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: SPAST was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPAST were set to 23968121
Phenotypes for gene: SPAST were set to Spastic paraplegia 4, autosomal dominant 182601
Leukodystrophy v0.350 GJA1 Bryony Thompson gene: GJA1 was added
gene: GJA1 was added to Leukodystrophy - paediatric. Sources: Expert Review Green,Royal Melbourne Hospital
Mode of inheritance for gene: GJA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GJA1 were set to 31023660
Phenotypes for gene: GJA1 were set to Hereditary spastic paraplegia; Oculodentodigital dysplasia, 164200, Oculodentodigital dysplasia, autosomal recessive, 257850
Leukodystrophy v0.333 TBCB Zornitza Stark Phenotypes for gene: TBCB were changed from Neurodevelopmental disorder, MONDO:0700092, TBCB-related to Neurodevelopmental disorder with behavioural abnormalities and childhood onset spastic paraplegia, MIM# 621382
Leukodystrophy v0.332 TBCB Zornitza Stark reviewed gene: TBCB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with behavioural abnormalities and childhood onset spastic paraplegia, MIM# 621382; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy v0.326 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Leukodystrophy v0.298 BORCS8 Lauren Rogers changed review comment from: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. 5/5 hypotonia, failure to thrive, global developmental delay, profound intellectual disability, muscle weakness and atrophy, dysmorphic features. 3/5 with microcephaly, 3/5 with seizures, 4/5 with spasticity, 3/5 with scoliosis, 4/4 with optic atrophy.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature; to: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. 5/5 hypotonia, failure to thrive, global developmental delay, profound intellectual disability, muscle weakness and atrophy, dysmorphic features. 3/5 with microcephaly, 3/5 with seizures, 4/5 with spasticity, 3/5 with scoliosis, 4/4 with optic atrophy.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature
Leukodystrophy v0.298 BORCS8 Lauren Rogers changed review comment from: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature; to: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. 5/5 hypotonia, failure to thrive, global developmental delay, profound intellectual disability, muscle weakness and atrophy, dysmorphic features. 3/5 with microcephaly, 3/5 with seizures, 4/5 with spasticity, 3/5 with scoliosis, 4/4 with optic atrophy.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature
Leukodystrophy v0.293 GPRC5B Lucy Spencer gene: GPRC5B was added
gene: GPRC5B was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: GPRC5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPRC5B were set to 37143309
Phenotypes for gene: GPRC5B were set to Megalencephalic leukoencephalopathy with subcortical cysts 3 MIM#620447
Review for gene: GPRC5B was set to GREEN
Added comment: PMID: 37143309
Cohort of 5 patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). 3 unrelated patients had variants in GPRC5B, 2 have the same inframe dup Ile175dup and the third has an in frame dup of Ala177. All 3 were de novo and unaffected siblings did not have the variants. All patients have macrocephaly, delayed motor development, seizures, all had varying degrees of cognitive deficits. 2 also had spasticity, ataxia and dystonia. MRI showed MLC, abnormal and swollen cerebral white matter.

Patient cell lines showed reduced regulatory volume decrease, and western blot showed a strong increase in GRPC5B levels in patient lymphoblasts. Together, these findings indicate disturbed volume regulation in lymphoblasts from patients with GPRC5B variants, potentially due to increased GPRC5B levels. Transfected cells caused increased volume-regulated anion channel activity.
Sources: Literature
Leukodystrophy v0.275 NOTCH1 Chern Lim gene: NOTCH1 was added
gene: NOTCH1 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: NOTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH1 were set to 35947102
Phenotypes for gene: NOTCH1 were set to Genetic cerebral small vessel disease (MONDO:0018787), NOTCH1-related
Mode of pathogenicity for gene: NOTCH1 was set to Other
Review for gene: NOTCH1 was set to GREEN
gene: NOTCH1 was marked as current diagnostic
Added comment: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Other clinical features include intellectual disability, spasticity and etc. Childhood onset in most individuals however 15y and 40y reported in two individuals.
- Missense and small inframe insertion variants in the negative regulatory region.
Sources: Literature
Leukodystrophy v0.262 ENTPD1 Zornitza Stark gene: ENTPD1 was added
gene: ENTPD1 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: ENTPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENTPD1 were set to 35471564
Phenotypes for gene: ENTPD1 were set to Spastic paraplegia 64, autosomal recessive, MIM# 615683
Review for gene: ENTPD1 was set to GREEN
Added comment: 27 individuals from 17 families published, expanding the phenotype to a complex neurodevelopmental disorder characterised by ID, white matter abnormalities and spastic paraplegia.
Sources: Literature
Leukodystrophy v0.252 LIG3 Zornitza Stark Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy to Mitochondrial DNA depletion syndrome 20 (MNGIE type), MIM# 619780
Leukodystrophy v0.244 ABHD16A Zornitza Stark Phenotypes for gene: ABHD16A were changed from Spastic paraplegia; intellectual disability; callosome to Spastic paraplegia 86, autosomal recessive, MIM# 619735; Intellectual Disability; Corpus callosum abnormalities
Leukodystrophy v0.243 ABHD16A Zornitza Stark reviewed gene: ABHD16A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 86, autosomal recessive, MIM# 619735, Intellectual Disability, Corpus callosum abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy v0.241 RNF220 Zornitza Stark Phenotypes for gene: RNF220 were changed from Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum to Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, MIM# 619688; Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Leukodystrophy v0.240 RNF220 Zornitza Stark edited their review of gene: RNF220: Changed phenotypes: Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, MIM# 619688, Leukodystrophy, CNS hypomyelination, Ataxia, Intellectual disability, Sensorineural hearing impairment, Elevated hepatic transaminases, Hepatic fibrosis, Dilated cardiomyopathy, Spastic paraplegia, Dysarthria, Abnormality of the corpus callosum
Leukodystrophy v0.239 ELOVL1 Zornitza Stark gene: ELOVL1 was added
gene: ELOVL1 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: ELOVL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELOVL1 were set to 29496980; 32123819; 30487246
Phenotypes for gene: ELOVL1 were set to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, MIM# 618527
Review for gene: ELOVL1 was set to GREEN
Added comment: Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity. Affected individuals have mild facial dysmorphism.

Same two individuals reported in two publications. Both had the same variant, p.S165F, which arose de novo, suggesting the residue is important in pathogenesis. Mouse model.
Sources: Literature
Leukodystrophy v0.235 ABHD16A Seb Lunke Phenotypes for gene: ABHD16A were changed from Spastic paraplegia to Spastic paraplegia; intellectual disability; callosome
Leukodystrophy v0.233 ABHD16A Lucy Spencer edited their review of gene: ABHD16A: Changed phenotypes: Spastic paraplegia, intellectual disability, callosome
Leukodystrophy v0.233 ABHD16A Lucy Spencer changed review comment from: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
From PMID: 34587489
Sources: Literature; to: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
From PMID: 34587489
Sources: Literature
Leukodystrophy v0.233 ABHD16A Lucy Spencer gene: ABHD16A was added
gene: ABHD16A was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to PMID: 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia
Review for gene: ABHD16A was set to GREEN
Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
From PMID: 34587489
Sources: Literature
Leukodystrophy v0.231 PI4KA Chirag Patel gene: PI4KA was added
gene: PI4KA was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to PMID: 34415322
Phenotypes for gene: PI4KA were set to Neurodevelopmental syndrome with hypomyelinating leukodystrophy
Review for gene: PI4KA was set to GREEN
Added comment: Used WES/WGS to identify 10 unrelated patients harbouring biallelic variants in PI4KA, and a spectrum of severe global neurodevelopmental delay, hypomyelination, and developmental brain abnormalities, and pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells.
Sources: Literature
Leukodystrophy v0.229 RNF220 Zornitza Stark gene: RNF220 was added
gene: RNF220 was added to Leukodystrophy - paediatric. Sources: Literature
founder tags were added to gene: RNF220.
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9).

The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263).

Extensive segregation analyses were carried out including several affected and unaffected members.

RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.
Sources: Literature
Leukodystrophy v0.217 LIG3 Zornitza Stark gene: LIG3 was added
gene: LIG3 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy
Review for gene: LIG3 was set to GREEN
Added comment: Seven individuals from three unrelated families and functional data, variable ages of onset from early childhood to late adolescence.
Sources: Literature
Leukodystrophy v0.215 CLDN11 Melanie Marty gene: CLDN11 was added
gene: CLDN11 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Hypomyelinating leukodystrophy
Review for gene: CLDN11 was set to GREEN
Added comment: In three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia, 2 different heterozygous de novo stop-loss variants were identified. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.
Sources: Literature
Leukodystrophy v0.204 HPDL Zornitza Stark gene: HPDL was added
gene: HPDL was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086
Phenotypes for gene: HPDL were set to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Review for gene: HPDL was set to GREEN
Added comment: Biallelic variants reported in 13 families with a neurodegenerative disease ranging from neonatal encephalopathy to adolescent-onset spastic paraplegia. Extensive MRI abnormalities described, primarily affecting white matter (white matter atrophy and deficient myelination), basal ganglia, thalamus and brainstem.
Sources: Literature
Leukodystrophy v0.181 FA2H Zornitza Stark reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: None; Publications: 31837835, 30446360, 22965561, 21592092; Phenotypes: Spastic paraplegia 35, autosomal recessive, MIM# 612319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy v0.165 GLRX5 Elena Savva gene: GLRX5 was added
gene: GLRX5 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: GLRX5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLRX5 were set to PMID: 24334290; 30770271
Phenotypes for gene: GLRX5 were set to Spasticity, childhood-onset, with hyperglycinemia 616859
Review for gene: GLRX5 was set to GREEN
Added comment: PMID: 24334290 - 3 patients (3 families) with non-ketotic hyperglycinemia, supported by functional studies. Patients had normal development with childhood-onset spastic paraplegia (3/3), spinal lesion (1/3), optic atrophy (1/3) and brain signal abnormalities involving the frontal and parietal white matter (2/3)

PMID: 30770271 - 1 patient with childhood onset cavitating leukoencephalopathy.

p.Lys51del is a recurring mutation.
Sources: Literature
Leukodystrophy v0.150 SPG11 Zornitza Stark edited their review of gene: SPG11: Changed publications: 18067136; Changed phenotypes: Spastic paraplegia 11, autosomal recessive, MIM# 604360
Leukodystrophy v0.149 SPG11 Zornitza Stark gene: SPG11 was added
gene: SPG11 was added to Leukodystrophy - paediatric. Sources: Expert list
Mode of inheritance for gene: SPG11 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SPG11 were set to Spastic paraplegia 11, autosomal recessive, MIM# 604360
Review for gene: SPG11 was set to GREEN
Added comment: Complex SPG with central involvement, including white matter changes.
Sources: Expert list
Leukodystrophy v0.143 ZFYVE26 Zornitza Stark gene: ZFYVE26 was added
gene: ZFYVE26 was added to Leukodystrophy - paediatric. Sources: Expert list
Mode of inheritance for gene: ZFYVE26 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ZFYVE26 were set to Spastic paraplegia 15, autosomal recessive, MIM# 270700
Review for gene: ZFYVE26 was set to GREEN
Added comment: Complex spastic paraplegia, including white matter changes. Variable age of onset ranging from paediatric to adult.
Sources: Expert list
Leukodystrophy v0.137 POLR3A Zornitza Stark gene: POLR3A was added
gene: POLR3A was added to Leukodystrophy - paediatric. Sources: Expert list
Mode of inheritance for gene: POLR3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3A were set to 21855841
Phenotypes for gene: POLR3A were set to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694
Review for gene: POLR3A was set to GREEN
Added comment: More than 10 families reported. Neurodegenerative disorder characterised by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other features may include hypodontia or oligodontia and hypogonadotropic hypogonadism.
Sources: Expert list
Leukodystrophy v0.128 AP4B1 Bryony Thompson gene: AP4B1 was added
gene: AP4B1 was added to Leukodystrophy - paediatric. Sources: Expert list
Mode of inheritance for gene: AP4B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4B1 were set to 29193663
Phenotypes for gene: AP4B1 were set to Spastic paraplegia 47, autosomal recessive MIM#614066
Review for gene: AP4B1 was set to GREEN
Added comment: White matter changes have been reported as a feature of the condition in at least ten unrelated cases with biallelic variants. The onset of the condition is paediatric.
Sources: Expert list
Leukodystrophy v0.105 GFAP Zornitza Stark gene: GFAP was added
gene: GFAP was added to Leukodystrophy - paediatric. Sources: Expert list
Mode of inheritance for gene: GFAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GFAP were set to Alexander disease, MIM# 203450
Review for gene: GFAP was set to GREEN
Added comment: 3 forms of Alexander disease are recognised, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity.
Sources: Expert list
Leukodystrophy v0.101 EPRS Zornitza Stark gene: EPRS was added
gene: EPRS was added to Leukodystrophy - paediatric. Sources: Expert list
Mode of inheritance for gene: EPRS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPRS were set to 29576217
Phenotypes for gene: EPRS were set to Leukodystrophy, hypomyelinating, 15, MIM# 617951
Review for gene: EPRS was set to GREEN
Added comment: Four unrelated families reported with this neurodegenerative disorder. Onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, dysphagia, severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum.
Sources: Expert list
Leukodystrophy v0.85 DARS Zornitza Stark gene: DARS was added
gene: DARS was added to Leukodystrophy - paediatric. Sources: Expert list
Mode of inheritance for gene: DARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DARS were set to 23643384
Phenotypes for gene: DARS were set to Hypomyelination with brainstem and spinal cord involvement and leg spasticity, MIM# 615281
Review for gene: DARS was set to GREEN
Added comment: Onset typically in infancy with lower limb spasticity. Brain MRI shows extensive white matter abnormalities involving the supratentorial white matter, brainstem, cerebellar peduncles, and dorsal columns and lateral corticospinal tracts of the spinal cord. HGNC approved name DARS1.
Sources: Expert list
Leukodystrophy v0.73 CYP7B1 Zornitza Stark gene: CYP7B1 was added
gene: CYP7B1 was added to Leukodystrophy - paediatric. Sources: Expert list
Mode of inheritance for gene: CYP7B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP7B1 were set to 24117163; 19439420; 19187859
Phenotypes for gene: CYP7B1 were set to Spastic paraplegia 5A, autosomal recessive, MIM# 270800
Review for gene: CYP7B1 was set to GREEN
Added comment: White matter lesions have been reported as a feature of the condition in >3 cases. Age of onset highly variable, generally in adolescence but onset in early childhood reported.
Sources: Expert list
Leukodystrophy v0.11 CYP2U1 Bryony Thompson gene: CYP2U1 was added
gene: CYP2U1 was added to Leukodystrophy - paediatric_RMH. Sources: Expert list
Mode of inheritance for gene: CYP2U1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP2U1 were set to 27292318
Phenotypes for gene: CYP2U1 were set to Spastic paraplegia 56, autosomal recessive 615030
Review for gene: CYP2U1 was set to AMBER
Added comment: White matter lesions have been reported in the condition, but are rare and not a prominent feature.
Sources: Expert list
Leukodystrophy v0.0 NKX6-2 Bryony Thompson gene: NKX6-2 was added
gene: NKX6-2 was added to Leukodystrophy - paediatric_RMH. Sources: Expert Review Green,Royal Melbourne Hospital
Mode of inheritance for gene: NKX6-2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NKX6-2 were set to Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy 617560
Leukodystrophy v0.0 HSPD1 Bryony Thompson gene: HSPD1 was added
gene: HSPD1 was added to Leukodystrophy - paediatric_RMH. Sources: Expert Review Green,Royal Melbourne Hospital
Mode of inheritance for gene: HSPD1 was set to
Phenotypes for gene: HSPD1 were set to Spastic paraplegia 13, autosomal dominant, 605280; Leukodystrophy, hypomyelinating, 4, 612233
Leukodystrophy v0.0 FA2H Bryony Thompson gene: FA2H was added
gene: FA2H was added to Leukodystrophy - paediatric_RMH. Sources: Expert Review Green,Royal Melbourne Hospital
Mode of inheritance for gene: FA2H was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FA2H were set to Spastic paraplegia 35, autosomal recessive, MIM#612319