Hereditary ataxia - adult onsetGene: PRDX3
Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update.
Rebelo et al., 2021 (PMID: 33889951) reported five simplex families with biallelic variants in PRDX3 leading to complete loss of its encoded protein. Clinical presentation in all individuals predominantly consisted of gait and upper limb ataxia and cerebellar atrophy. Age of onset was at 13, 15, 21, 22 and 23 years of age. Pathogenicity supported by molecular studies using patient fibroblasts, cerebellar medulloblastoma cells and Drosophila.
Created: 4 Jan 2022, 3:27 p.m. | Last Modified: 4 Jan 2022, 3:27 p.m.
Panel Version: 2.138
Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote with a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense, suggestive of founder effect.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRDX3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Created: 7 Aug 2021, 6:23 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Cerebellar ataxia (early onset, mild to moderate, progressive)
Variants in this GENE are reported as part of current diagnostic practice
Tag Q1_22_rating tag was added to gene: PRDX3.
Gene: prdx3 has been classified as Amber List (Moderate Evidence).
gene: PRDX3 was added gene: PRDX3 was added to Hereditary ataxia - adult onset. Sources: Literature Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRDX3 were set to 33889951 Phenotypes for gene: PRDX3 were set to Cerebellar ataxia (early onset, mild to moderate, progressive) Review for gene: PRDX3 was set to GREEN gene: PRDX3 was marked as current diagnostic