Magdalena Krygier

When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants

Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.

Characterization of the genotypic and phenotypic spectrum of TCF7L2-related neurodevelopmental disorder (TRND).

PURPOSE TCF7L2 (OMIM:602228; HGNC:11641) is a transcription factor and critical effector of the Wnt/β-Catenin pathway. In 2021, 11 pediatric patients with mono-allelic predicted loss-of-function (pLOF) TCF7L2 variants and syndromic features were observed. Characterization of patients with pLOF TCF7L2 variants and neurodevelopmental features - herein referred to as TCF7L2-related neurodevelopmental disorder (TRND) - is urgently needed. METHODS We leveraged multiple methods (GeneMatcher, DECIPHER, literature review, public/private repositories) to identify an international cohort of 76 patients with pLOF TCF7L2 variants and neurodevelopmental features and phenotypically characterized them. We also retrospectively searched for an independent cohort of adults with pLOF TCF7L2 variants (n = 11) from 60,000+ PennMedicine BioBank (PMBB) patients. RESULTS Among 76 patients with pLOF TCF7L2 variants, speech delay (95.3%), craniofacial dysmorphisms (73.3%), ophthalmologic conditions (65.5%), autism (62.1%), and orthopedic abnormalities (52.6%) were most commonly observed. Phenotypic differences did not cluster by variant type or genomic locus. Among PMBB patients, an association of nominal significance with type 2 diabetes with renal manifestations (OR = 5.8; p-value = 0.03) was detected, warranting further investigation. CONCLUSIONS This represents the most comprehensive characterization to date of TRND, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectrum. We opened a Simons Searchlight natural history study (https://www.simonssearchlight.org/research/what-we-study/tcf7l2/) to enhance understanding of this condition.

Resolving Complex Structural Variants in Undiagnosed Rare Movement Disorders via Multimodal Genomics and Multi-omics.

BACKGROUND Long-read sequencing and multi-omic analytical frameworks are increasingly being adopted in rare disease diagnostics. However, clinical workflows comprehensively integrating these methodologies remain uncommon. OBJECTIVE This study aimed to assess the potential and limitations of integrating long-read genomic, transcriptomic, and proteomic analyses to characterize complex structural variants. METHODS Two unrelated patients presenting with dystonia and comorbid neurological features underwent nanopore-based long-read DNA sequencing. In patient 1, complementary transcriptomic and proteomic analyses were performed. RESULTS The workflow enabled the identification and characterization of two pathogenic complex structural variants: a homozygous AluY-mediated inversion disrupting PANK2, underlying neurodegeneration with brain iron accumulation (patient 1), and a heterozygous de novo 16p13.3 duplication-triplication event associated with an atypical dystonia-parkinsonism phenotype (patient 2). CONCLUSIONS Our findings underscore the diagnostic potential of integrated long-read and multi-omic approaches for complex structural variant characterization, while illustrating persistent limitations of automated pipelines and highlighting unpredictable relationships between genomic, transcriptomic, and proteomic findings. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Early sodium channel blocker initiation is associated with better outcomes in KCNQ2 disorders.

Pathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. We leveraged a large, multicentre international cohort comprising 282 individuals with pathogenic KCNQ2 variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed, including time-to-event and adjusted outcome analyses. SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, time-to-event analyses showed that early SCB initiation (≤1 month) was associated with earlier seizure offset. Early SCB initiation was also associated with significantly more favourable neurodevelopmental outcomes, including higher rates of attaining major motor milestones. This association remained significant after adjustment for seizure control by 1 month and total ASM burden. Considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation, suggesting that variant severity and additional genetic or biological modifiers contribute to outcome heterogeneity.Our results support the use of SCBs, particularly CBZ and OXC, as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE. Earlier SCB initiation was associated with earlier seizure offset and more favourable developmental outcomes, underscoring the importance of early genetic diagnosis and timely SCB therapy. We however emphasise that early treatment is not universally transformative and further prospective work, including exploration of targeted therapies and standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.

CMIP as a novel candidate gene for neurodevelopmental and neuropsychiatric disorders