Early onset or syndromic epilepsy
Gene: RRM2B
Mitochondrial disorders can associated with seizures, but the evidence is not specifically implicated. There are reports of disease-causing variants being associated with mitochondrial DNA depletion syndrome.Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; Mitochondrial DNA depletion syndrome 8B (MNGIE type), 612075; Progressive external ophthalmoplegia with mitochondrial DNA deletions 5, 613077
Publications
As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Kept rating as Amber.Created: 25 Nov 2019, 8:43 p.m. | Last Modified: 25 Nov 2019, 8:43 p.m.
Panel Version: 1.436
As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: RRM2B is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).Created: 15 Aug 2019, 8:09 a.m. | Last Modified: 15 Aug 2019, 8:09 a.m.
Panel Version: 1.223
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: Green.Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
Comment on list classification: Kept rating as Amber after reviewing the literature evidence. The main phenotype manifests as hypotonia with lactic acidosis. Although seizures have been reported, they are variable and not common (PMID:29241262 summary records seizures in 6/78 patients, PMID:18504129 don't report seizures in any of their three patients).Created: 24 Jun 2019, 1:07 p.m. | Last Modified: 24 Jun 2019, 1:07 p.m.
Panel Version: 1.71
Bourdon et al., 2007 (PMID:17486094) studied 7 cases of mitochondrial depletion in 4 unrelated families with RRM2B variants. Seizures were reported in Family 2: Subject 4 showed trunk hypotonia and tubulopathy shortly after birth. At 20 days of life he developed seizures, and died at 2 months after status epilepticus. His sister (Subject 5) had a similar clinical course (the authors don't explicitly state whether she had seizures).Created: 24 Jun 2019, 12:57 p.m. | Last Modified: 24 Jun 2019, 12:57 p.m.
Panel Version: 1.68
Bornstein et al., 2008 (PMID:18504129) sequenced the RRM2B gene in 3 unrelated cases- The common clinical feature was myopathy with lactic acidosis, and none had overt seizures.Created: 24 Jun 2019, 12:41 p.m. | Last Modified: 24 Jun 2019, 12:41 p.m.
Panel Version: 1.66
PMID:19138848 (Kollberg et al., 2009) report two Sudanese brothers with a severe form of fatal autosomal recessive encephalomyopathic mtDNA depletion syndrome-8B caused by a homozygous mutation in the RRM2B gene. Both brothers had seizures amongst their phenotypes.Created: 24 Jun 2019, 12:41 p.m. | Last Modified: 24 Jun 2019, 12:43 p.m.
Panel Version: 1.68
PMID:28482374 (Kropach et al) report 2 siblings with a variant in RRM2B and early fatal encephalomyopathy. At least the older brother had focal seizures. As pointed out in http://www.currentneurobiology.org/neurobiology/phenotypic-heterogeneity-of-rrm2b-mutations.pdf, limited information is provided about the patients and the variant.Created: 24 Jun 2019, 11:05 a.m. | Last Modified: 24 Jun 2019, 11:05 a.m.
Panel Version: 1.64
Seizures are part of the phenotype of this mitochondrial disorder.Created: 20 Aug 2018, 12:44 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), MIM#612075
Publications
Variants in this GENE are reported as part of current diagnostic practice
Gene: rrm2b has been classified as Amber List (Moderate Evidence).
Source Wessex and West Midlands GLH was added to RRM2B.
Source NHS GMS was added to RRM2B.
Gene: rrm2b has been classified as Amber List (Moderate Evidence).
Publications for gene: RRM2B were set to
Phenotypes for gene: RRM2B were changed from Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures; status epilepticus
Phenotypes for gene: RRM2B were changed from to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures
Mode of inheritance for gene: RRM2B was changed from to BIALLELIC, autosomal or pseudoautosomal
Zornitza Stark: Seizures are part of the pheno
Expert Review Amber was added to RRM2B. Panel: Genetic Epilepsy Syndromes
RRM2B was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services
RRM2B was created by Sarah Leigh