Hereditary spastic paraplegia - childhood onset

Gene: HPDL

Amber List (moderate evidence)

HPDL (4-hydroxyphenylpyruvate dioxygenase like)
EnsemblGeneIds (GRCh38): ENSG00000186603
EnsemblGeneIds (GRCh37): ENSG00000186603
HPDL is in 6 panels

3 reviews

Cristina Dias (The Francis Crick Institute)

Green List (high evidence)

Clinical and experimental evidence (in vitro and mouse in vivo) for pathogenicity.
Created: 4 May 2021, 9:07 a.m. | Last Modified: 4 May 2021, 9:07 a.m.
Panel Version: 2.28

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
microcephaly; spastic paraplegia; seizures; demyelinating neuropathy; regression; developmental delay; chronic progression; movement disorder

Publications

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: New gene added by Evan Reid (University of Cambridge). There is enough evidence for this gene to be rated Green at the next major review.
Created: 9 Feb 2021, 3:18 p.m. | Last Modified: 9 Feb 2021, 3:18 p.m.
Panel Version: 2.26
Associated with relevant phenotype in OMIM and has a 'probable' disease confidence for 'HPDL Neurodegenerative Disease' in Gene2Phenotype.

At least 34 cases from 21 unrelated families with a paediatric-onset spastic movement disorder and biallelic variants in this gene (PMIDs: 32707086 and 33188300). There is broad clinical variability ranging from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated HSP. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease (with exceptions in PMID:33188300 of 2 individuals from families 4 and 7 who did not present spasticity, and family 3 for whom this information was not available).

Supportive functional studies were reported, including localization of HPDL protein to the mitochondria and muscle fibre abnormalities and a KO mouse model displaying features of seizures, early lethality, smaller brain sizes, and cellular apoptosis.
Created: 9 Feb 2021, 3:18 p.m. | Last Modified: 9 Feb 2021, 3:18 p.m.
Panel Version: 2.25

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613; Spastic paraplegia 83, autosomal recessive, OMIM:619027; Spastic paraplegia 83, autosomal recessive, MONDO:0033614

Publications

Evan Reid (University of Cambridge)

Green List (high evidence)

Newly identified gene that can give a phenotype ranging from infantile epileptic encephalopathy to juvenile onset progressive spastic paraplegia.
Sources: Literature
Created: 4 Feb 2021, 3:11 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual and motor disability

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026
  • Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613
  • Spastic paraplegia 83, autosomal recessive, OMIM:619027
  • Spastic paraplegia 83, autosomal recessive, MONDO:0033614
Tags
Q2_21_rating
Clinvar variants
Variants in HPDL
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

18 May 2021, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: HPDL were set to 32707086; 33188300

9 Feb 2021, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: HPDL were changed from spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual and motor disability to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613; Spastic paraplegia 83, autosomal recessive, OMIM:619027; Spastic paraplegia 83, autosomal recessive, MONDO:0033614

9 Feb 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: HPDL were set to PMID: 32707086; 33188300

9 Feb 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: hpdl has been classified as Amber List (Moderate Evidence).

9 Feb 2021, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_21_rating tag was added to gene: HPDL.

4 Feb 2021, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Evan Reid (University of Cambridge)

gene: HPDL was added gene: HPDL was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HPDL were set to PMID: 32707086; 33188300 Phenotypes for gene: HPDL were set to spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual and motor disability Penetrance for gene: HPDL were set to Complete Review for gene: HPDL was set to GREEN