Early onset or syndromic epilepsy

Gene: TIMM50

Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.

Created: 20 Oct 2020, 8:56 a.m. | Last Modified: 20 Oct 2020, 8:56 a.m.

Panel Version: 2.180

Green List (high evidence)

Biallelic pathogenic TIMM50 variants cause 3-methylglutaconic aciduria, type IX (MIM 617698).

At least 9 affected individuals from 5 unrelated (but often consanguineous) families of variable origin have been reported (based on a conference abstract and PMIDs : 27573165, 30190335, 31058414).

TIMM50 encodes encodes a subunit of the mitochondrial presequence import machinery called the TIM23 complex. TIMM50 serves as a major receptor in the intermembrane space that binds to proteins on their way to cross the mitochondrial inner membrane (summary by Shahrour et al., 2017 and OMIM).

The highly overlapping patient clinical features [seizures, DD and ID - the latter in all age-appropriate individuals (5 from 3 families - refs 2,4)], metabolic investigations (lactate elevations in many, elevated urinary 3MGA in almost all, variable mitochondrial complex deficiencies in some), additional extensive functional evidence of mitochondrial dysfunction or the similar phenotypes in other types of 3-methylglutaconic aciduria all support a role for the gene.

[AUH- / CLPB- / DNAJC19- / HTRA2- / OPA3- / SERAC1-related methylglutaconic acidurias are all included as relevant disorders in the ID panel, with the respective genes rated green.]

TIMM50 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx).

The gene is not associated with any phenotype in G2P

As a result this gene could be considered for inclusion/upgrade as green in both ID and epilepsy panels respectively.

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[1] - Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T) reported on a patient born to consanguineous parents of South Asian ancestry with intractable epilepsy, microcephaly, DD and spastic quadriplegia. Metabolic investigations revealed increased urinary 3MGA. Two similarly affected sisters with demonstrated increase of 3MGA, were deceased following an infection. WES in the affected child, 2 unaffected sibs and the parents suggested a homozygous missense variant as the likely cause of the disorder in the proband (c.1114G>A / p.G372S - Reference not specified though the variant probably corresponds to ENST00000314349.4 and ClinVar's entry VCV000208697.1 - www.ncbi.nlm.nih.gov/clinvar/variation/208697/).

[2] - Shahroor et al. (2017, PMID: 27573165) reported on 2 consanguineous families, each with 2 affected individuals. Two sibs from the 1st family (of Bedouin origin) presented with seizures (onset at 3m and 4m respectively), DD and ID with slightly elevated plasma lactate and increased urinary 3MGA upon metabolic investigations. Enzymatic activities of mitochondrial complex I-V were carried out for 1 sib and were normal also after normalization for citrate synthase. Following a SNP array, WES was carried out in affected children and their parents. Both sibs were homozygous for a missense SNV [NM_001001563.1:c.755C>T / p.Thr252Met]. Segregation studies - also in 3 unaffected sibs - supported a role for the variant.

Two sibs from the 2nd family (of Muslim origin) presented with seizures (myoclonic jerks at 3m, generalized tonic movements at 2m - respectively) with DD and ID. Urinary 3MGA was elevated for both, with CSF lactate also elevated in one. WES revealed homozygosity for p.Arg217Trp (NM_001001563.1:c.649C>T) and segregation studies in parents and an unaffected sib were again compatible.

The authors could not demonstrate pathogenicity of the variants in a yeast based system although - as also commented on in Ref 4 - the human TIMM50 could not rescue the yeast ΔΤim50 growth defect and global conservation between the two proteins is poor.

[3] - Reyes et al. (2018, PMID: 30190335) reported on one individual with onset of infantile spasms at the age of 2m with hypsarrythmia upon EEG and psychomotor regression. Leigh-like features were noted upon brain MRI. Lactate was elevated in both plasma and CSF. Urinary 3MGA was normal. WES, Sanger confirmation and segregation studies demonstrated compound htz for 2 variants (NM_001001563:c.335C>A or p.S112* and c.569G>C or p.G190A). Functional studies demonstrated among others decrease in all components of the TIM23 complex and decreased mitochondrial membrane potential. Patient fibroblasts grown in glucose had lower levels of all complex II and IV subunits and one complex I subunit (due to the impairment in import system) with decreased mitochondrial respiration and increase in ROS production. Growth in galactose - shifting energy production toward OxPhos - caused massive cell death. The phenotype was rescued/substantially improved following complementation of patient fibroblasts with wt TIMM50.

[4] - Tort et al. (2019, PMID: 31058414) reported on a boy with seizures and ID (diagnosis of West syndrome), Leigh-like MRI anomalies, cardiomyopathy with elevated plasma and CSF lactate and persistent urinary elevation of 3MGA. The proband was found to be compound heterozygous for 2 TIMM50 variants [NM_001001563.5:c.341 G>A (p.Arg114Gln) in trans with c.805 G>A (p.Gly269Ser)] following WES and Sanger confirmation/segregation studies. In patient fibroblasts TIMM50 protein levels were severely reduced upon WB although mRNA levels were similar to control. Muscle biopsy revealed decreased activity of the complexes I-IV, when normalized to the citrate synthase activity. Accumulation of lipidic material in muscle fibers was shown to be associated with mitochondria upon EM. Expression and sublocalization of mitochondria-targeted proteins were not found to be affected in patient fibroblasts. In extracts from muscle biopsy reduced protein levels of SDHA, COX4L and MTCO1 were demonstrated, in line with the disruptions in the activities of the MRC. Mitochondrial morphology and network were shown to be altered in patient fibroblasts. Patient fibroblasts showed marked reduction of max respiratory capacity. Similar reduction was noted in CRISPR/Cas9 generated TIMM50-ko HEK293T cells, but rescued upon transient transfection with a plasmid encoding for wt TIMM50.

(Functional studies better summarized in the respective articles).

Created: 22 Sep 2019, 12:34 p.m. | Last Modified: 22 Sep 2019, 12:34 p.m.

Panel Version: 1.336

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
3-methylglutaconic aciduria, type IX (MIM 617698)

Publications

• 27573165
• 30190335
• 31058414
• Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T)

I don't know

Limited evidence: 4 cases from 2 consanguinous families were reported in PMID 27573165. The patients presented with seizures after a normal neonatal period.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
3-methylglutaconic aciduria, type IX, 617698

Publications

• 27573165

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

Publications

• 27573165

I don't know

Removed 'watchlist' tag, since this gene is no longer Amber. Note that TIMM50 is Green on the Intellectual disability panel (V3.73) and on the IEM panel (V2.8). Therefore added 'for-review' tag for discussion of alignment of epilepsy and metabolism panels.

Created: 1 Jun 2020, 12:45 p.m. | Last Modified: 1 Jun 2020, 12:45 p.m.

Panel Version: 2.73

Comment on list classification: Previous Amber rating was based on insufficient evidence (PMID:27573165/Shahrour et al 2017 who report 4 cases from 2 consanguineous families, plus a conference abstract reporting 3 further siblings). Zornitza Stark and Konstantinos Varvagiannis point out 2 new papers each with an additional case of TIMM50 variants in epileptic patients. Therefore have updated the rating from Amber to Green.

Created: 1 Jun 2020, 12:43 p.m. | Last Modified: 1 Jun 2020, 12:43 p.m.

Panel Version: 2.73

PMID:31058414 (Tort et al., 2019) report compound het TIMM50 variants in a boy with 3-MGA-uria (p.Arg114Gln, p.Gly269Ser). At 3.5 months, a diagnosis of West syndrome was made, and he showed a good response to ACTH and antiepileptic treatment.

Created: 1 Jun 2020, 12:39 p.m. | Last Modified: 1 Jun 2020, 12:39 p.m.

Panel Version: 2.69

PMID:30190335. Reyes et al., 2018 report a third unrelated family. WES identified compound het pathogenic TIMM50 variants (p.S112* and p.G190A) in an infant with rapidly progressive, severe encephalopathy, including infantile seizures and severe epilepsy. Sanger sequencing confirmed the two variants in the proband and showed that the two parents were each heterozygous for one of them. In the ExAc database, the p.G190A variant was present in <200,000 alleles, with the nonsense change not reported.

Created: 1 Jun 2020, 12:34 p.m. | Last Modified: 1 Jun 2020, 12:34 p.m.

Panel Version: 2.69

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Added 'watchlist' tag.

Created: 13 Nov 2018, 1:51 p.m.

Comment on list classification: Kept rating as Amber: 2 families reported in PMID:27573165 plus 1 family reported in a conference abstract. Further published or clinical cases required for diagnostic rating.

Created: 8 Nov 2018, 10:02 a.m.

In a conference abstract, Serajee et al identified a homozygous mutation, Gly372Ser, in the TIMM50 gene, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria.

Created: 8 Nov 2018, 10:01 a.m.

In 4 patients from 2 unrelated consanguineous families who presented with severe ID and seizure disorder alongside 3-methylglutaconic aciduria type IX (MGCA9; 617698), Shahrour et al. (2017, PMID:27573165) identified homozygous missense mutations in the TIMM50 gene (Arg217Trp and Thr252Met).

Created: 8 Nov 2018, 9:55 a.m.

Green List (high evidence)

More families reported, supporting gene-disease association; note seizures reported in all.

Created: 25 Jan 2020, 9:02 a.m. | Last Modified: 25 Jan 2020, 9:02 a.m.

Panel Version: 2.0

Seizures are part of the phenotype of this metabolic disorder; however, only two families reported so far.

Created: 22 Aug 2018, 5:41 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
3-methylglutaconic aciduria, type IX, MIM#617698

Publications

• 27573165
• 30190335
• 31058414

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