Biallelic SIGMAR1 variants in early-onset distal hereditary motor neuropathy: A Japanese case series

Clinical features of four unrelated Japanese patients with autosomal recessive spinocerebellar ataxia type 32.

Exploring the clinical and mutational spectrum of MORC2-associated disorders.

BACKGROUND Pathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals. METHODS Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level. RESULTS A total of 11 different missense variants in the MORC2 gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases. CONCLUSION A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the MORC2 gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.

SEPTIN9 R106W in a Chinese family with hereditary neuralgic amyotrophy: phenotypic heterogeneity and rehabilitation in a pediatric case

The broad clinical spectrum associated with the SEPTIN9 R106W mutation in a Chinese pedigree spanning from childhood to adulthood is delineated, highlighting the critical role of active inter vention in childhood-onset HNA.

Neuropathy With Demyelinating Features in a Patient With Biallelic HARS1 Variants

There is moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype, suggesting that the allelic and clinical heterogeneity of HARS1‐related disease is expanded.

Novel Homozygous Pathogenic Variant in DNAJC6 Causes Rapid Progressive Parkinsonism.

The novel DNAJC6 p.Cys325* variant is associated with severe, early-onset parkinsonism and developmental regression and should be considered in children and adolescents presenting with parkinsonism plus neurodevelopmental decline, particularly when levodopa benefit is modest, and dose-related adverse motor crises occur.

VRK1 ‐Related Motor Neuropathy With Upper Motor Neuron Signs and Selective Muscle Involvement

ABSTRACT Introduction Hereditary motor neuropathies (HMN) represent a heterogeneous group of disorders with wide clinical and genetic variability. Despite advances in molecular diagnostics, approximately 50% of cases remain genetically unresolved, particularly those where distinguishing length‐dependent motor neuropathy from motor neuron disorder with disproportionate segmental involvement is a challenge. Variants in the VRK1 gene, originally described in association with pontocerebellar hypoplasia, are now known to produce a broad clinical spectrum, including amyotrophic lateral sclerosis, dHMN, and less frequently, spastic paraplegia. Objectives This study's aim was to characterize the clinical presentation, electrophysiological findings, and muscle MRI patterns associated with VRK1‐related motor neuron disease in a cohort of nine patients from five unrelated families. Methods Five unrelated families with inherited motor neuropathy were investigated using next‐generation sequencing techniques, including targeted gene panels or whole‐exome sequencing, with subsequent confirmation by Sanger sequencing. A total of nine affected individuals underwent detailed clinical evaluation, nerve conduction studies (NCS), electromyography (EMG), and whole‐body muscle MRI (wbMRI). Results Nine affected individuals carrying biallelic VRK1 variants were evaluated. In most cases (66%), symptom onset occurred during the first decade of life. All patients presented with gradually progressive distal muscle weakness. Mean Medical Research Council (MRC) scores were 2.8 for ankle dorsiflexion and 1.9 for plantar flexion. Sensory nerve conduction studies were normal in all individuals evaluated (8/9), although mild sensory complaints were reported in four patients. Muscle cramps were observed in two‐thirds of the cohort, while fasciculations were uncommon (11%). EMG findings consistently demonstrated a neurogenic pattern with predominant distal involvement, and evidence of both acute and chronic denervation was present in four patients. Whole‐body muscle MRI, available for all patients, revealed a consistent pattern of fatty infiltration predominantly affecting posterior muscle compartments, with minimal STIR signal changes. Brain and spinal imaging, performed in all individuals, showed no abnormalities. Interpretations Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement, along with a distinctive posterior‐predominant pattern on muscle MRI. Identifying this phenotype, a known presentation of VRK1‐related disorders, highlights the importance of targeted genetic testing in unresolved cases of hereditary motor neuropathy.