Long-term course of a case with a novel homozygous kyphoscoliosis peptidase variant.

We herein report a case with a novel homozygous variant in the kyphoscoliosis peptidase (KY) gene. A 58-year-old Japanese female was referred to our hospital with a gait disturbance that gradually worsened after the age of 50. She had bilateral equinus foot deformity since early childhood. Neurological examination revealed moderate weakness of the neck, trunk, femoral, and brachial muscles, mild respiratory failure, and areflexia. Whole-exome sequencing revealed a novel homozygous frameshift variant of the KY gene, NM_178554.6:c.824del p.(Glu275Glyfs*53). Our case demonstrated that KY-associated neuromuscular disease can present with extremely slow progressive muscle weakness and respiratory failure over a long natural course.

Impact of Baseline Neuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study.

INTRODUCTION: Hereditary transthyretin (ATTRv, v for variant) amyloidosis is a rare, progressive, fatal disease with multisystem manifestations, caused by pathogenic variants in the transthyretin (TTR) gene. Vutrisiran, an RNA interference therapeutic that results in rapid TTR knockdown, improved neuropathy and quality of life (QOL) versus external placebo in patients with ATTRv amyloidosis with polyneuropathy in the phase 3 HELIOS-A study (NCT03759379). This post hoc analysis evaluates the impact of baseline neuropathy severity on response to vutrisiran treatment. METHODS: Patients were randomized (3:1) to vutrisiran (n = 122; 25 mg subcutaneous injection once every 3 months) or patisiran (n = 42; 0.3 mg/kg intravenous infusion once every 3 weeks), which served as a reference group. In this post hoc analysis, patients were grouped into quartiles of increasing baseline Neuropathy Impairment Score (NIS): Quartile (Q)1 ≥ 5.0 to ≤ 20.5; Q2 > 20.5 to ≤ 44.1; Q3 > 44.1 to ≤ 73.1; Q4 > 73.1 to ≤ 127.0. Mean change from baseline to Month 18 was summarized by quartile for a range of efficacy endpoints. RESULTS: Across all baseline NIS quartiles, vutrisiran demonstrated benefit versus external placebo in measures of neuropathy severity (modified NIS + 7), QOL (Norfolk Quality of Life-Diabetic Neuropathy), disability (Rasch-built Overall Disability Scale), gait speed (10-m walk test), and nutritional status (modified body mass index). Overall, patients in lower versus higher NIS quartiles (less severe neuropathy) at baseline maintained better scores at Month 18. The external placebo group progressively worsened in all measures at Month 18. CONCLUSIONS: Vutrisiran demonstrated benefit in neurologic function and other key efficacy measures versus external placebo across all four baseline neuropathy severity quartiles. Patients initiating vutrisiran earlier in their disease course retained the highest neurologic function level after 18 months, highlighting the importance of early diagnosis and treatment. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03759379.

A Novel Mutation of VPS13D-related Disorders with Parkinsonism.

We herein report a case of VPS13D-related disorder with a novel homogeneous variant. A 58-year-old Japanese woman was referred to our hospital with slowly progressive gait disturbance and cognitive impairment. A neurological examination revealed decreased spontaneity, recent memory impairment, Parkinsonism, cerebellar ataxia, pyramidal signs, and autonomic dysfunction. Dopamine transporter single-photon-emission computed tomography showed a markedly reduced uptake in the striatum bilaterally. Whole-exome sequencing revealed a novel homozygous missense variant of the VPS13D gene (Arg3267Pro). Our case suggests that mutations in VPS13D may cause parkinsonism, in addition to the previously reported cerebellar ataxia and spastic paraplegia.

Origin of Transthyretin in Cerebral Amyloid Angiopathy.

This case series evaluates the correlation between transthyretin and cerebral amyloid angiopathy progression in individuals with hereditary transthyretin amyloidosis.