Paediatric motor neuronopathies
Gene: SLC52A2
Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in paediatric motor neuropathies, as identified from biallelic loss-of-function variants from >20 unrelated individuals/ families from multiple ethnicities and supported by results from functional studies. Several of these patients treated with oral riboflavin responded well to the treatment.
Unrelated individuals carrying homozygous variants (e.g. c.916G>A/ p.Gly306Arg) and compound heterozygous variants (e.g. c.368T>C/ p.Leu123Pro & c.1016T>C/ p.Leu339Pro) were reported with Brown-Vialetto-Van Laere syndrome-2. According to report from Foley et al (2014), patients were presented with ataxia (9 out of 18 patients), hearing loss (all 18 patients), limb/ muscle weakness (17 patients), optic atrophy/ impaired vision (14 of 15 patients), tongue fasciculations (11 of 18 patients) and axonal sensorimotor neuropathy (all 18 patients). The onset of ataxia ranged from 1.5 to 8 years of age and some of these patients were confined to a wheelchair in their childhood (ranging from 1.5 to 8 years old). Respiratory insufficiency developed in 13 patients (PMID:24253200). One patient from this study and patient from Ciccolella et al (2012) bearing compound heterozygous variants were hospitalized for respiratory failure and died at 3-4 years of age (PMID:24253200; PMID:23243084).
An eight year old patient with already identified homozygous variant (c.916G>A/ p.Gly306Arg) was presented with progressive ataxia since the age of 2.5 years and cerebellar atrophy and peripheral polyneuropathy despite the absence of other common symptoms of Brown-Vialetto-Van Laere syndrome including motor neuropathy, bulbar palsy, optic atrophy, and sensorineural hearing loss (PMID:30377535).
A recent review and statistical analysis by Zhou et al reports data of 62 BVVL type 2 patients from 43 different families, of which 40 patients had homozygous and 22 patients had compound heterozygous variants. A total of 32 variants have been reported to date, with the most common being missense variants. The symptoms of BVVL type 2 appear at the earliest shortly after birth and at the latest at 10 years of age. In all, 61.3% of the patients had ataxia, often secondary to sensory neuropathy. The other common symptoms are hearing loss (83.9%), muscle weakness (80.6%), visual impairment (64.5%) and bulbar dysfunction (40.3%). In addition, this study also suggests that homozygous pattern was more likely to present with ataxia as the first symptom in patients with missense mutations (p < 0.05), while compound heterozygous pattern was more likely to develop respiratory insufficiency during the course of disease (p < 0.001) (PMID:36186484).
Transfection and overexpression of SLC52A2 gene containing mutant alleles in HEK293 showed that the riboflavin uptake activity was abolished in certain mutants and moderately reduced in others. In addition, the expression levels of mutants were decreased (in correlation with the reduction in activity) with the exception of only one mutant tested (PMID:22864630; PMID:24253200).Created: 11 Dec 2022, 11 a.m. | Last Modified: 11 Dec 2022, 11 a.m.
Panel Version: 2.1
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Hereditary sensory and autonomic neuropathy, MONDO:0015364; Progressive bulbar palsy, MONDO:0008890
Publications
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Infantile onset motor neuronopathy; bulbar palsy; respiratory insufficiency; sensorineural hearing loss; cranial neuropathy;
Publications
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Optic atrophy; auditory neuropathy
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Variants in this GENE are reported as part of current diagnostic practice
Added the 'treatable' tag, as riboflavin treatment may be beneficial to patients.Created: 13 Aug 2018, 4:37 p.m.
Originally submitted as "RFVT2" by the expert.Created: 23 Jul 2015, 1:21 p.m.
Publications for gene: SLC52A2 were set to 23243084; 22864630
Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, OMIM:614707 to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Hereditary sensory and autonomic neuropathy, MONDO:0015364
Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, 614707 to Brown-Vialetto-Van Laere syndrome 2, OMIM:614707
Gene panel promoted to v1 on 7 March 2017 following external review and internal curation
Publications for SLC52A2 were set to 23243084; 22864630
Mode of pathogenicity for SLC52A2 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
Model of inheritance for gene SLC52A2 was changed to BIALLELIC, autosomal or pseudoautosomal
SLC52A2 was added to Paediatric motor neuronopathiespanel. Sources: Expert list
SLC52A2 was added to Paediatric motor neuronopathiespanel. Sources: UKGTN
SLC52A2 was added to Paediatric motor neuronopathiespanel. Sources: Radboud University Medical Center, Nijmegen