Childhood onset hereditary spastic paraplegia

Gene: IBA57

Comment on list classification: No further evidence has emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.

Created: 24 Nov 2021, 12:07 p.m. | Last Modified: 24 Nov 2021, 12:08 p.m.

Panel Version: 2.112

Green List (high evidence)

Three families with spastic paraparesis as a feature of the condition.

Created: 19 Sep 2020, 7:33 a.m. | Last Modified: 19 Sep 2020, 7:33 a.m.

Panel Version: 2.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 74, autosomal recessive MIM#616451

Publications

• 25609768
• 30258207

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

I don't know

Three families reported with childhood onset. No additional patients identified using Sheffield panel.

Created: 9 May 2019, 5:38 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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). Amber 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 by Helen Brittain, who notes that it is possible that the varied phenotypes are part of the spectrum of presentations within IBA57 regarding its mitochondrial function (the more commonly reported recessive phenotype of mitochondrial dysfunction encompasses spasticity in several patients). IBA57 is green on the 'Mitochondrial disorders' panel which is the better route for detecting this broader phenotype. Ideally, further cases with an understanding of the spectrum of pathogenic variants and detailed phenotypic information will help in being confident about inclusion on this HSP panel.
Rebecca Foulger (Genomics England curator), 2 Mar 2019

Comment on list classification: Updated rating from Grey to Amber: Gene added and rated Red by Chris Buxton (Bristol NHS) based on 1 family in PMID:25609768. 2 additional families in PMID:30258207 (2018) but phenotype is variable and 2 Jewish brothers with same compound het variants have different symptoms. Therefore rated Amber awaiting clinical feedback.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:30258207 (Hamanaka et al, 2018) performed whole-exome sequencing in 2 unrelated families (Sepharadi Jewish and Japanese) with leukodystrophy. The 29-year-old Sepharadi Jewish male had clinically asymptomatic leukodystrophy. His 19-year-old younger brother, with the same compound heterozygous IBA57 variants, had a similar clinical course until 7 years of age when he developed a rapidly progressive spastic paraparesis following a febrile illness. A 7-year-old Japanese girl had developmental regression, spastic quadriplegia, and abnormal periventricular white matter. Therefore HSP symptoms amongst the individuals but phenotypes are very varied.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

In affected members of a large consanguineous Arab family with AR spastic paraplegia, Lossos et al. (2015, PMID:25609768) identified a homozygous splice site variant in IBA57.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

Lossos (2015, 25609768). Homozygous donor splice-site mutation in the IBA57. mRNA studies done, some protein studies support pathogenicity. 1 family, limited evidence. Sources: Literature Provided in Sheffield Lab diagnostic HSP panel
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Red rating submitted.

Created: 2 May 2019, 4:04 p.m.

Green List (high evidence)

Victoria-spasticity, optic atrophy, and peripheral neuropathy in the first decade, in sheffields HSP panel

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

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Spastic paraplegia 74, autosomal recessive, 616451