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Lowe syndrome (LS) is an X-linked disorder caused by OCRL mutations, encoding a phosphatidylinositol 5-phosphatase. OCRL regulates phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2]-dependent cytoskeletal dynamics and membrane trafficking in multiple cell types, including platelets. Clinically, LS manifests with cataracts, hypotonia, developmental delay, and progressive kidney disease. A subset of LS individuals shows bleeding tendency and occasional mild thrombocytopenia despite normal coagulation tests. Studies reveal impaired thrombus growth under flow, delayed platelet spreading on fibrinogen, abnormal clot retraction, and altered platelet formation with circulating barbell-shaped immature platelets, supporting a platelet dysfunction phenotype in LS, though exact molecular mechanisms remain undefined. Experimental studies suggest OCRL controls PI(4,5)P2 pools required for coordinated actin and microtubule remodeling during platelet adhesion and thrombopoiesis. Pharmacological OCRL inhibition recapitulates defective spreading, persistent filopodia, actin nodules, and impaired marginal microtubule band depolymerization without major loss of GPIb-IX-V or αIIbβ3 receptors, supporting a signaling and cytoskeletal mechanism. Elevated plasma fibrinogen, VWF, and FVIII in LS may partially offset bleeding, though their contribution to the LS phenotype and relationship to vascular/hepatic involvement remains unclear. Similarly, while the OCRL homolog INPP5B is abundant in platelets, its capacity to compensate for OCRL deficiency appears limited and requires further investigation. Recognition of this OCRL-dependent platelet phenotype has important clinical implications, including caution before surgical procedures and usage of medications that may worsen bleeding, highlighting the need for targeted diagnostic approaches and further mechanistic studies to improve the management of individuals with LS.

BACKGROUND: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy characterized by clinicopathological heterogeneity. The complex interplay between tau deposition, structural changes, and disease spread are unclear. OBJECTIVES: To investigate the temporospatial patterns of tau propagation and neurodegeneration using multimodal imaging with MRI and flortaucipir (FTP) PET, and determine relationship with clinical heterogeneity. METHODS: 150 PSP patients (n = 66 Richardson's syndrome [PSP-RS], n = 26 parkinsonism [PSP-P], n = 25 speech-language [PSP-SL], n = 13 progressive gait freezing (PSP-PGF), n = 10 corticobasal syndrome [PSP-CBS], n = 3 frontal, n = 1 oculomotor and n = 6 postural instability) underwent 3 T-MRI and FTP-PET. Forty-three patients died and underwent autopsy. Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that separates data-driven disease phenotypes distinguished by diverse temporal progression patterns, was applied to both MRI and FTP-PET W-scores (adjusted for age, sex and scanner, using 102 controls). Longitudinal MRI (n = 76) and FTP (n = 56) data, analysed with linear mixed models, were used to assess regional progression patterns and compared with the machine learning predictions. RESULTS: Two subtypes emerged across modalities. Subtype 1 exhibited initial subcortical involvement, mainly included PSP-RS and PSP-P patients and mostly featured PSP pathology, while subtype 2 exhibited early cortical involvement, PSP-SL patients and CBD pathology. FTP-PET stages preceded MRI stages, suggesting tau deposition anticipates atrophy. MRI stages were better in capturing clinical progression and predicting longitudinal disease evolution. CONCLUSIONS: These findings suggest the existence of subcortical and cortical subtypes of PSP, with distinct clinicopathological features. Tau PET and MRI provide complementary insights into disease progression, with MRI more closely reflecting clinical evolution.

Persistent somatic symptoms are common and contribute substantially to population health burden. However, the intersectional social patterning of somatic symptom burden remains insufficiently understood. This study examined inequalities in somatic symptom severity across intersections of gender, educational attainment, and migration history. Utilizing a trans-diagnostic patient sample (including the diagnoses primary biliary and primary sclerosing cholangitis, ulcerative colitis, irritable bowel syndrome, chronic kidney disease, pruritus, and somatic symptom disorder; N = 1254) pooled from five research projects of the SOMACROSS research unit, we applied Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA). Gender, history of migration (German-speaking sample), and education were included as indicators of social inequalities. Symptom severity was assessed using the Patient Health Questionnaire 15 (PHQ-15). The sample was predominantly female (62.4%), 81.8% reported no history of migration, and participants were on average 52.2 years old (SD = 16.6). MAIHDA results revealed that social inequalities in somatic symptom severity operate primarily through additive main effects rather than multiplicative interactions. Gender displayed the strongest associations with these inequalities, followed by education, with higher burdens among females and those with lower educational levels, while only weak associations were observed for history of migration. The predominantly additive pattern suggests that interventions targeting individual social determinants may be effective across multiple intersectional groups, supporting a strategy of proportionate universalism. The presence of differences across intersectional strata, irrespective of primary diagnosis, underscores the importance of monitoring health inequalities through an intersectional lens to ensure equitable outcomes.

Nail-patella syndrome (NPS) is an autosomal dominant disorder caused by LMX1B mutations and typically associated with glomerular proteinuria. We report three brothers carrying a maternally inherited heterozygous LMX1B mutation (NM_001174147.2: c.309C > G (p.Cys103Trp)), all presenting with classical skeletal features of NPS. Two siblings developed early-onset proteinuria predominantly composed of low-molecular-weight proteins, hypercalciuria, and ophthalmologic abnormalities including cataracts and glaucoma; one also exhibited nephrocalcinosis. Further genetic analysis identified a hemizygous OCRL pathogenic mutation (NM_000276.4: c.2209G > A (p.Glu737Lys)) in the two affected brothers but not in the third sibling, who had no renal involvement. This intrafamilial discordance supports a dual genetic diagnosis. Our findings emphasize the importance of reconsidering the initial diagnosis when clinical features are atypical and highlight the value of comprehensive genetic testing in patients with unusual renal presentations.

BACKGROUND: Functional somatic disorders (FSD), characterised by persistent physical symptoms and associated impairment, remain diagnostically fragmented across medical specialties, contributing to inconsistent patient care. The FSD classification addresses this by classifying symptom presentations into multi-system, single-system, and single-symptom subcategories, yet its utility in clinical populations is largely unexamined. This study evaluated the applicability and clinical utility of FSD classification in patients with Somatic Symptom Disorder (SSD). METHODS: Observational, cross-sectional analysis of baseline data from the SOMA.SSD cohort. Patients with SSD (N = 239), diagnosed using the Structured Clinical Interview for DSM-5-TR (SCID-5), were recruited from a German psychosomatic outpatient clinic. FSD subcategories were operationalised using the Bodily Distress Syndrome Checklist. Group differences were examined using chi-square and Mann-Whitney U tests, and binary logistic regression identified factors associated with multi-system FSD. RESULTS: Most patients met multi-system FSD criteria (n = 207, 86.6%). Multi-system FSD was associated with greater psychological and behavioural burden, including higher somatosensory amplification, perceived stress, health anxiety, and negative affect, compared with other subgroups. Single-system FSD showed limited correspondence with established syndrome-based diagnoses (e.g., fibromyalgia or irritable bowel syndrome). Comorbid musculoskeletal, vascular, and neurological conditions were common but often not aligned with the presenting symptom system. CONCLUSIONS: The FSD classification captured variation within SSD, supporting its value as a complementary tool for characterisation and differentiation. Transdiagnostic factors such as health anxiety, somatosensory amplification, and negative affectivity may play a key role in multi-system presentations. Future research should examine the FSD classification's utility in longitudinal and treatment settings.