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To report on a new phenotype in a patient carrying a novel, undescribed de novo variant in POLR3B , affected by generalized myoclonic epilepsy and neurodevelopmental disorder, without neuropathy. It is known that biallelic pathogenic variants in POLR3B cause hypomyelinating leukodystrophy-8, and heterozygous de novo variants are described in association to a phenotype characterized by predominantly demyelinating sensory-motor peripheral neuropathy, ataxia, spasticity, intellectual disability and epilepsy, in which the peripheral neuropathy is often the main clinical presentation. We collected clinical, electrophysiological and neuroimaging data from the affected subject and performed a Trio-Clinical Exome Sequencing. We detected a de novo novel heterozygous missense variant c.1132A> G in POLR3B (NM_018082.6) that was considered as likely pathogenic following ACMG criteria. We also consulted our custom genomic database of a total of 1485 patients that were genetically analysed from 2018 for epilepsy, and found no other de novo variants in the POLR3B gene. We hypothesize a possible genotype-phenotype correlation, particularly regarding epilepsy. We also provide a review of the literature about the previously described POLR3B heterozygous patients, with particular attention to the epileptic phenotype, underlining the association between POLR3B and early onset myoclonic epilepsy, which can represent the main manifestation of the disease at its onset. [ABSTRACT FROM AUTHOR]

(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight ERCC6/CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the ERCC6/CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 16.5-year-old girl with a progressive disorder caused by biallelic variants in the HPDL gene. The girl initially presented with mild lower limb hypertonia and poor social interaction, but later developed an ataxic-spastic syndrome and regression of developmental milestones. She also experienced an episode of acute ophthalmoplegia with a Wernicke-like MRI pattern. Treatment with oral steroids and antioxidant vitamins resulted in the resolution of her symptoms. The article highlights the need for broad genetic testing, such as exome sequencing, in the diagnosis of HPDL-related disorders. [Extracted from the article]