Beta-mannosidosis is a lysosomal storage disorder caused by pathogenic variants in the MANBA gene, resulting in deficiency of beta-mannosidase. This enzyme is essential for terminal glycoprotein degradation within lysosomes, and its deficiency leads to glycoprotein accumulation in the brain and other organs. Clinical manifestations are heterogenous and may include hearing loss, developmental delay, seizures, angiokeratomas, vision abnormalities, and intellectual disability. Currently, no disease-specific treatment exists. We previously reviewed clinical features in 46 individuals worldwide. This study highlights six new cases of beta-mannosidosis. Patient 1, an 8-year-old male, presented with a failed newborn hearing screening and compound heterozygote c.550-1G > A and c.562 T > G variants. Patient 2, a 40-year-old male, was diagnosed at age 3 with language delay, hearing loss and behavioral issues. He has c.375_378del, p.Tyr126Alafs*11 and c.1513 T > C variants. Patient 3, a 6-year-old female, developed gait disturbances and visual difficulties at 3 years and is homozygous for the c.188 A > G variant. She also has homocystinuria. Patient 4, a 15-year-old female with sensorineural hearing loss at age 2 years, carries variants c.1454_1455del and c.550-3C > A. Patient 5 presented at age 12 years with sensorineural hearing loss, intellectual disability, juvenile glaucoma and is homozygous for the c.1452_1453del variant. Patient 6, a 14-year-old male failed the newborn hearing screening. He is homozygous for variant c.378 + 1G > A. Analysis of these patients highlights marked phenotypic variability with no clear genotype-phenotype correlation. Early screening may enable prompt diagnosis, improve management, and support future therapeutic development.

The pedunculopontine nucleus (PPN) is a heterogeneous cluster within the dorsolateral pontomesencephalic tegmentum, functioning as a critical neuromodulatory hub. A key organizing principle is its rostrocaudal functional gradient rostral glutamatergic Chx10+ neurons mediate global motor arrest, while caudal Vglut2+ neurons drive locomotor initiation and maintenance. This model, emphasizing topographically organized microcircuits, provides a coherent framework for reconciling heterogeneous outcomes of PPN stimulation across experimental and clinical settings. This review comprehensively analyzes the PPN's anatomical organization, neuronal composition, and connectivity, which collectively support its roles in locomotion, arousal, and reward processing. Particular focus is placed on its pathophysiological alterations in Parkinson's disease (PD), wherein selective degeneration of caudal cholinergic and Vglut2+ neurons contributes to treatment-resistant axial symptoms. The nucleus exhibits considerable neurochemical heterogeneity, encompassing cholinergic, glutamatergic, and GABAergic populations; this diversity underpins its broad functional roles and selective vulnerability in PD, with distinct implications for disease subtypes. We further examine disease-associated shifts in oscillatory activity, highlighting abnormal dynamics characteristic of the parkinsonian state. The therapeutic promise of PPN deep brain stimulation for alleviating gait freezing and falls in advanced PD is critically assessed, acknowledging challenges related to target localization, stimulation parameters, and patient selection. By integrating neuroanatomical, electrophysiological, and clinical evidence, this review offers a unified perspective on the PPN's central importance in PD pathophysiology and its growing relevance as a neuromodulation target.

A 4-year-9-month-old male presented with progressive gait instability, frequent falls, and mild impaired coordination, initially raising concern for a primary neuromuscular disorder. Duchenne muscular dystrophy (DMD) was considered because of the patient's age, sex, and motor weakness. However, serum creatine kinase was not elevated, and initial DMD molecular testing was negative. Further evaluation identified truncal ataxia, oculomotor apraxia, recurrent respiratory infections, lymphocytopenia, and markedly elevated alpha-fetoprotein (AFP). These findings guided the differential toward a disorder related to DNA-damage. Targeted molecular testing identified compound heterozygous pathogenic variants in ATM, establishing a diagnosis of ataxia-telangiectasia (A-T). This case illustrates how phenotype-directed laboratory testing can elucidate diagnostic probability, prevent an inaccurate initial diagnosis, and guide precision molecular testing. Early recognition of A-T permits coordinated neurologic, immunologic, malignancy-surveillance, and genetic-counseling interventions.

Background: Falls in older adults are a major public health and rehabilitation concern and may reflect interacting chronic disease-related mechanisms rather than diagnostic labels alone. Type 2 diabetes mellitus (T2DM), hypertension (HTN), and osteoarthritis (OA) are common in later life and may influence fall vulnerability through sensory, vascular, musculoskeletal, cognitive, medication-related, and functional pathways. This scoping review aimed to map mechanism-oriented evidence linking T2DM, HTN, and OA to falls and fall-related outcomes in older adults. Methods: A scoping review was conducted in accordance with established scoping review methodology and PRISMA-ScR guidance. PubMed, Web of Science, and Embase were searched for English-language studies published from 2016 to 2026; the final search was conducted on 15 April 2026. Evidence was charted in a structured table and synthesised descriptively and thematically across disease-specific and shared mechanism domains. Results: A total of 151 studies were included. The evidence was organised into T2DM-related sensory-neural, gait and balance, vestibular/visual-cognitive, strength-related, and glycaemic or medication-related mechanisms; HTN-related haemodynamic, cerebral perfusion, dizziness/syncope, and medication-related mechanisms; and OA-related pain, proprioceptive, strength-related, gait and balance, psychological, and compensatory-control mechanisms. Shared pathways included frailty, multimorbidity, polypharmacy, pain burden, cognitive impairment, sleep disturbance, ADL decline, dizziness, and reduced physical function. Conclusions: Falls in older adults with T2DM, HTN, OA, or multimorbidity may be better understood through interacting disease-specific and shared mechanisms than through diagnostic labels alone. Future longitudinal and multimorbidity-specific studies using standardised fall ascertainment are needed to test these pathways more directly.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising non-invasive neuromodulation approach for addressing gait impairments in Parkinson's disease (PD). However, evidence regarding its effects on daily-life gait remains limited. We report a case of a 67-year-old woman with PD and freezing of gait (FOG), based on the hypothesis that taVNS may enhance gait automaticity under daily-life conditions. A single-case A-B-C design was used, consisting of baseline, sham stimulation, and taVNS phases. Gait performance was assessed using wearable accelerometry in both experimental and daily-life settings. While no significant changes were observed in gait parameters during experimental assessments, daily-life walking measures-step velocity, step length, variability, and asymmetry-showed improvements during the taVNS phase. Importantly, no falls or FOG episodes were observed during the taVNS phase. These findings support the feasibility of taVNS and provide preliminary support for its potential therapeutic role in enhancing gait automaticity in daily life. Further controlled studies are warranted.

Lithium remains a cornerstone in the treatment of bipolar I disorder because of its well-established efficacy in reducing mood episode recurrence and suicide risk. However, its narrow therapeutic index makes patients particularly susceptible to clinically significant toxicity, especially following medication changes or drug-drug interactions. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recognized to increase serum lithium concentrations by reducing renal lithium clearance, although reports involving nabumetone remain limited. We report the case of a 50-year-old woman with bipolar I disorder who had remained psychiatrically stable on chronic lithium therapy for approximately seven years before developing severe lithium toxicity following recent escalation of both lithium and nabumetone dosages. The patient presented with progressive confusion, lethargy, recurrent falls, tremor, myoclonic jerks, gait instability, generalized weakness, and altered mental status. Initial serum lithium concentration exceeded 2.9 mmol/L despite preserved renal function. Lithium and nabumetone were discontinued, aggressive intravenous fluid administration was initiated, and serial lithium concentrations were monitored. Given preserved renal function, declining serum lithium concentrations, and rapid neurologic improvement with supportive management, hemodialysis was deferred. The patient experienced progressive clinical recovery with normalization of lithium concentrations and resolution of neurologic symptoms. Lithium was cautiously reintroduced at a reduced dosage without recurrence of toxicity. Application of the Naranjo Adverse Drug Reaction Probability Scale yielded a score of 9, supporting a definite adverse drug reaction. This case highlights that severe lithium toxicity may occur despite preserved renal function following concurrent escalation of lithium and nabumetone therapy. The report emphasizes the importance of comprehensive medication reconciliation, recognition of clinically significant drug-drug interactions, close serum lithium monitoring following medication changes, and early recognition of neurologic manifestations suggestive of lithium toxicity.