オクシピタル・ホーン症候群

ATP7A is a P-type ATPase copper transporter and a central component of the intracellular network to maintain copper (Cu) homeostasis, trafficking between the trans-Golgi network (TGN) and the cell periphery in response to intracellular Cu levels. Pathogenic ATP7A variants cause Menkes disease (MNK), occipital horn syndrome (OHS) and X-linked distal hereditary motor neuropathy (HMNX), with the clinical severity inversely related to residual ATP7A function. In MNK and OHS, variants result in loss of ATP7A function due to absent (MNK) or markedly reduced (OHS) protein levels, leading to abolished ATP7A trafficking and/or impaired Cu transport capacity. HMNX-associated variants are thought to retain partial Cu transport activity, although functional data remain limited. To date, three missense variants (p.T994I, p.P1386S, p.A991D) are established causes of HMNX, but the number of ATP7A variants reported in patients with a distal motor neuropathy phenotype is increasing, creating a need for functional assessment of variants of uncertain significance (VUS). We have developed a functional framework for evaluating HMNX-associated ATP7A variants. Using three patient fibroblast lines carrying the confirmed variants, we demonstrate reduced ATP7A TGN localization under low-Cu conditions and impaired capacity of these cell lines to maintain intracellular Cu levels. By applying these assays to five VUS (p.R703H, p.Y760C, p.A768G, p.Q990P, p.M1311V) identified in individuals from unsolved peripheral neuropathy families, we identify p.Q990P as a novel ATP7A variant in a patient with progressive peripheral motor neuropathy. This approach enables comparison of Cu trafficking and handling across ATP7A alleles, providing a functional framework to support diagnostic variant classification.

Mutations in the copper (Cu) transporter ATP7A cause a spectrum of X-linked diseases, including Menkes Disease, Occipital horn syndrome, and distal hereditary motor neuropathy (dHMNX). We previously generated a conditional knock-in mouse model of dHMNX expressing Atp7aT985I, the murine orthologue of the human T994I variant identified in dHMNX patients. Although Atp7aT985I mice did not develop overt motor degeneration, affected males showed a trend toward reduced Cu levels in the peripheral nervous system (PNS). The high-affinity copper transporter Ctr1, encoded by Slc31a1, regulates Cu uptake, and ubiquitous heterozygosity for Slc31a1 (Ctr1+/-) has been reported to limit Cu availability in the nervous system without impairing motor performance. In this study, we genetically restricted Cu availability in Atp7aT985I mice by crossing them with Ctr1+/- animals. Atp7aT985I/Ctr1+/- males exhibited significantly reduced Cu levels in both the central nervous system and PNS compared to wild-type littermates. At 6 months of age, behavioural testing and histopathological assessment revealed mild motor deficits and axonal loss, preferentially affecting small-caliber fibres exclusively in the Cu-restricted Atp7aT985Imales. Tandem mass tag-based proteomics of sciatic nerve identified significant changes linked to energy metabolism, cytoskeletal integrity, and cellular stress responses. Together, these data show that limiting Cu availability unmasks a dHMNX-like phenotype in Atp7aT985I/Ctr1+/- mice, demonstrate the critical role of Cu availability in maintaining peripheral axons and suggest that reduced Cu in motor neurons contributes to axonal degeneration in dHMNX.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations, characterized by hepatic copper accumulation and multisystem involvement. Several rare inherited and acquired conditions can closely mimic WD, posing diagnostic challenges and the risk of inappropriate therapy. By examining neuroimaging patterns and distinguishing between diagnostic criteria, this narrative review provides a comprehensive synthesis of WD-mimicking disorders, emphasizing their molecular mechanisms, clinical phenotypes, and biochemical features. WD-mimicking disorders encompass ATP7A-related neurodegenerations (Menkes disease, occipital horn syndrome, X-linked distal hereditary motor neuropathy), MEDNIK syndrome, Huppke-Brendel syndrome, aceruloplasminemia, congenital disorders of glycosylation, primary familial intrahepatic cholestasis type 3, and acquired copper deficiency syndromes. Mechanisms include systemic copper deficiency, impaired intracellular trafficking, defective ceruloplasmin biosynthesis, secondary hepatic copper accumulation, and abnormal glycosylation. Clinical features range from neurodevelopmental delay, movement disorders, and hepatic dysfunction to dermatologic, hematologic, and connective-tissue abnormalities. Biochemical profiles may overlap with WD, particularly low serum ceruloplasmin and total copper, altered urinary copper excretion, and elevated hepatic copper in some disorders. Neuroimaging and genetic testing provide critical discriminative value. Management is largely supportive, with disease-specific therapies available in selected conditions, such as subcutaneous copper in Menkes disease or monosaccharide supplementation in certain congenital disorders of glycosylation subtypes. Accurate differentiation between WD and WD-mimicking disorders requires careful integration of clinical, biochemical, imaging, and molecular data. Recognition of distinctive features and understanding underlying pathophysiology are essential to avoid misdiagnosis and inappropriate anti-copper therapy, optimize management, and improve patient outcomes.

BACKGROUND: Bony projections arising from the ligament, tendon, or joint capsule site rarely seen in radiographs are generally termed enthesophytes. One such incidental finding noted prevalently in cephalometric radiographs of young individuals is occipital spurs or external occipital protuberance. The present study aims to assess the prevalence of occipital spurs in lateral cephalograms and correlate their type and shape with age and sex. MATERIAL AND METHODS: This retrospective observational study assessed the prevalence of occipital spurs in a sample of 986 lateral cephalograms. Two trained maxillofacial radiologists under the supervision of experienced maxillofacial radiologists classified the type and shape of occipital spurs according to age group and sex. Data were entered into an Excel sheet and then statistically analysed with a statistical significance set at a 95% confidence interval. RESULTS: Cohen’s kappa statistics revealed a strong inter- and intra-observer agreement (0.83 and 0.81, respectively). The prevalence of occipital spurs was 23.32%. Females exhibited longer occipital spurs and the smooth or flat spurs were most prevalent between both sexes. Analysis according to age group revealed that smooth type was commonly observed among all the assessed age groups. Additionally, the present study identified the presence of ossification of ligamentum nuchae (ONL) in 13 individuals. CONCLUSION: Occipital spurs are notable incidental findings on lateral cephalograms, particularly prevalent in younger age groups. The aetiology of these bony protrusions remains unclear. While often asymptomatic, understanding their potential for enlargement and associated clinical implications is crucial for appropriate patient management.

BACKGROUND: Menkes disease is an X-linked recessive disorder of human copper metabolism. Droxidopa is a synthetic amino acid effective in reversing neurogenic orthostatic hypotension and correcting neurochemical abnormalities in congenital absence of dopamine-beta-hydroxylase (DBH), a copper-dependent enzyme that influences autonomic function. Individuals with disorders associated with variants in the copper transport gene ATP7A may manifest symptoms of dysautonomia, due to deficient DBH activity. We aimed to evaluate the safety and efficacy of droxidopa for dysautonomia in adults with Menkes disease or with occipital horn syndrome (an ATP7A allelic variant). METHODS: We conducted a phase 1/2a, randomised, double-blind, placebo-controlled, crossover trial at one academic medical centre in Columbus, OH, USA. We compared placebo versus droxidopa treatment in adults with Menkes disease or occipital horn syndrome who manifested symptoms of dysautonomia (including orthostatic hypotension). Participants were recruited by invitation, screened, and randomly assigned to receive droxidopa or placebo for 6 weeks (Arm 1). Following a 7-10 day washout period, participants received the opposite treatment for 6 weeks (Arm 2/Crossover treatment). An open-label dose titration was utilised in advance to determine each participant's maximally tolerated dose (100, 200, or 300 mg) of droxidopa. The primary outcome of this trial was safety and tolerability assessed at 6 weeks, as reflected in the type and incidence of adverse events in the droxidopa treatment versus placebo groups. This trial is registered with ClinicalTrials.gov, NCT04977388. FINDINGS: Between July 12, 2021 and Oct 30, 2023, three male participants were enrolled: two individuals with Menkes disease (19 and 26 years old) and one individual with occipital horn syndrome (age 35). We found significant improvements in norepinephrine levels (P < 0.01) and in a critical parameter of orthostatic hypotension, diastolic blood pressure drop during tilt table testing, while receiving droxidopa (-8.6, 95% CI -15.5 to -1.7; P = 0.018). There was no substantial difference in adverse events between the droxidopa and placebo groups. INTERPRETATION: In this early phase trial, droxidopa was well tolerated in adults with Menkes disease and occipital horn syndrome and was associated with correction of orthostatic hypotension. These preliminary findings suggest that droxidopa at doses adjusted for patient tolerance is likely to be efficacious for treatment of dysautonomia in adults with ATP7A-related disorders. Further research is required, including in younger individuals with these conditions. FUNDING: The Menkes Disease Foundation UK, Associazione Angeli Per La Vita, and the Abigail Wexner Research Institute at Nationwide Children's Hospital.