WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia

Confirmation of a Causal Role for SHQ1 Variants in Early Infantile‐Onset Recessive Dystonia

“…3 We expect that SHQ1-associated dystonia is underdiagnosed and may have been ignored in some exome-sequenced cases analyzed using standard filter settings (often removing variants present in homozygous controls). 7 Our report provides replication for the involvement of SHQ1 in autosomal recessive early-onset dystonia, which appears to be a more complex and progressive movement disorder. SHQ1 should be added to the compendium of dystonia-associated genes involved in translational control, expanding our understanding of common molecular themes in dystonia pathogenesis.…”

The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant

“…Since the original reports of the first WARS2 patients in 2017 with predominant cognitive impairment [ 3 , 4 , 5 ], an increasing number of patients with a predominant movement disorder phenotype have been added to the literature [ 6 , 12 , 13 , 14 ], resulting in a broad phenotypical spectrum, typical for mitochondrial disorders. While cognitive impairment is still the most commonly reported feature (in 67% of all patients), dystonia (at least 50%), tremor (at least 38%), and parkinsonism (at least 21%) are often present in patients with WARS2 -related disorder.…”

“…The p.Trp13Gly variant is reported in six homozygous carriers in gnomAD [ 23 ], which might lead to discarding this variant as a disease-causing variant if one is oblivious to its role in WASR2 -releated disorder in the compound heterozygous state. The variant has been classified as a hypomorphic variant [ 13 , 14 ], a variant that is only disease causing in the case of compound heterogenicity when coupled with another disease-causing variant and not harmful in the case of homozygosity. Patients carrying this hypomorphic variant in combination with a missense variant seem to have a milder form [ 13 ] with a later onset (mean 4 years compared to <1 year) in most cases, with patient P4 being one, but not the only exception [ 12 , 14 ].…”

“…The first cases with biallelic pathogenic variants in WARS2 , described in 2017, had a predominant neurodevelopmental phenotype with developmental delay and intellectual disability, with only mild movement disorders such as tremor (OMIM: #617710) [ 3 , 4 , 5 ]. Later, additional cases [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ] with prominent movement disorders (OMIM: # 619738) such as tremor and parkinsonism with a good response to levodopa [ 6 , 12 , 13 , 14 ] were described with only mild or no intellectual disability. Functional studies in different biosamples of patients with biallelic variants showed impaired or normal enzyme activity and protein levels of the mitochondrial respiratory chain depending on the type of investigated biomaterial and the specific variants [ 4 , 5 , 6 , 7 , 8 , 12 ].…”

Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment

“…These mutations with severe symptoms are part of a spectrum of clinical manifestations that encompass cognitive, behavioral, and movement disorders. Gene defects in WARS2 and AARS2 can cause intellectual disability, psychosis, and early onset movement disorders such as Parkinsonism (Hu ¨bers et al, 2020;Skorvanek et al, 2022). In fact, defects in AARS2 cause movement disorders in 71% of cases, cognitive impairment in 67%, and behavioral or psychiatric features in close to half of all the cases so far described (Parra et al, 2021).…”