Childhood onset hereditary spastic paraplegia

Gene: GCH1

Green List (high evidence)

Further HSP patients identified using Sheffield panel with monoallelic pathogenic variants.

Created: 9 May 2019, 5:17 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Amber gene with Green GLH rating, Gene discussed in view of discrepant rating(s) from GLH(s). Green rating agreed at the GMS Neurology Specialist Test Group Webex on 17th May 2019.

Created: 21 May 2019, 4:50 p.m.

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 4:54 p.m.

Amber rating on Hereditary spastic paraplegia panel 1.198

Comment on list classification: Kept rating as Amber following clinical review from Helen Brittain- Amber rating is appropriate for now, based upon the two cases and some phenotypic queries.
Rebecca Foulger (Genomics England curator), 2 Mar 2019

Comment on mode of inheritance: Both literature cases (PMID:24509643; 21935284) are heterozygous, so have kept MOI as Monoallelic for now while gene is rated Amber. Note that OMIM displays AR and AD inheritance for Dystonia, DOPA-responsive, with or without hyperphenylalaninemia (MIM:128230).
Rebecca Foulger (Genomics England curator), 28 Jan 2019

Comment on list classification: Updated rating from Grey to Amber awaiting feedback from clinical team. 2 literature cases of HSP phenotype in PMIDs:24509643,21935284 both of which involved previous misdiagnosis of DRD/cerebral palsy.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:21935284 (Lee et al. 2011) report a novel initiation codon mutation (c.1A>T; p.Met1Leu) in GCH1 in a patient with dopa-responsive dystonia (DRD) that had previously been mis-diagnosed as cerbral palsy.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:24509643 (Fan et al 2014) identified a heterozygous GCH1 variant (R216X) by WES in a patient presenting with progressive spastic paraplegia. The R216X variant had been previously reported as causal for dopa-responsive dystonia (MIM:128230), a phenotype that can resemble HSP.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

Fan (2014, 24509643) het for nonsense variant previously associated with dopa-responsive dystonia. Authors observe that Dopa-responsive Dystonia can resemble HSP Lee (2011, 21935284), another example of DRD misdiagnosed as Cerebral palsy with GCH1 c.1A>T; p.Met1Leu missense Diagnostic on Sheffield HSP panel Sources: Literature
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Green rating submitted.

Created: 2 May 2019, 3:59 p.m.

Green Review and rating submitted by Michael Bonello (The Walton Centre NHS Foundation Trust), submitted by Diane Cairns on behalf of North West GLH for GMS Neurology specialist test group.

Created: 28 Apr 2019, 5:18 p.m.

Green List (high evidence)

Upgrade from Amber to Green on the HSP panel. General neurologists may have difficulty distinguishing between patients with HSP and DOPA-responsive dystonia. Therefore if the clinician puts them forward for the HSP panel and this gene isn't included a differential diagnosis could be missed. Importantly - this is a life changing condition that could be treated if a pathogenic variant was identified.

Created: 28 Apr 2019, 4:34 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230

Green List (high evidence)

2 cases of HSP phenotype ipublications- :24509643,21935284. In sheffields HSP panel

Created: 28 Apr 2019, 4:16 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dystonia; Spastic paraplegia; progressive spastic paraplegia; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230