Early onset or syndromic epilepsy
Gene: PMPCB
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 1 Feb 2023, 9:39 a.m. | Last Modified: 1 Feb 2023, 9:39 a.m.
Panel Version: 3.29
Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Neurodegeneration in Early Childhood. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).Created: 11 May 2021, 4:34 p.m. | Last Modified: 11 May 2021, 4:34 p.m.
Panel Version: 2.345
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 11 May 2021, 4:28 p.m. | Last Modified: 11 May 2021, 4:28 p.m.
Panel Version: 2.345
Five individuals from four families; seizures in 4/5 individuals reported, onset in infancy.Created: 5 Feb 2020, 5:25 a.m. | Last Modified: 5 Feb 2020, 5:25 a.m.
Panel Version: 2.0
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Multiple mitochondrial dysfunctions syndrome 6, MIM# 617954
Publications
Review from the ID panel:
Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).
5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).
Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.
Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]
The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).
Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.
Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).
PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).
As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: LiteratureCreated: 26 Sep 2019, 12:21 a.m. | Last Modified: 26 Sep 2019, 5:41 p.m.
Panel Version: 1.342
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Multiple mitochondrial dysfunctions syndrome 6, 617954
Publications
Tag Q2_21_rating was removed from gene: PMPCB.
Source Expert Review Green was added to PMPCB. Source NHS GMS was added to PMPCB. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q2_21_rating tag was added to gene: PMPCB.
Gene: pmpcb has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Tag for-review was removed from gene: PMPCB.
Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954
Tag for-review tag was added to gene: PMPCB.
gene: PMPCB was added gene: PMPCB was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PMPCB were set to 29576218 Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954 Penetrance for gene: PMPCB were set to Complete Review for gene: PMPCB was set to GREEN