先天性無痛無汗症

INTRODUCTION: Congenital Insensitivity to Pain with Anhidrosis (CIPA) is a rare, autosomal recessive genetic condition characterized by an inability to sweat, intellectual disability, a lack of pain sensation and self-mutilating behaviours. This report describes the dental management and longitudinal oral findings of a child with CIPA, highlighting a restorative approach and novel findings in the permanent dentition. INTRODUCTION: Methods: A 3-year-10-month-old boy presented with severe early childhood caries, premature exfoliation of primary teeth, traumatic tongue biting and recurrent oral ulceration. Comprehensive dental treatment was performed under general anaesthesia, including restorations and extraction of unrestorable primary teeth. INTRODUCTION: Results: Subsequent follow-up revealed altered eruption sequence, premature eruption and hypomineralisation and hypoplasia of permanent teeth. At 7-year-1-month, he developed a large palatal ulcer and swelling associated with a recently exfoliated upper left second molar (#65). Wound debridement, excision of malformed upper left second premolar (#25) and restorative treatment of affected permanent teeth were performed under general anaesthesia. Tooth morphology was modified to reduce soft tissue trauma. Healing was observed 1 month post-operatively. INTRODUCTION: Conclusion: Conservative restorative management may preserve oral function in selected patients with CIPA, while long-term surveillance is essential because of developmental dental anomalies, altered eruption sequence and recurrent traumatic injury.

Mutations in the DNA methyltransferase 1 (DNMT1) enzyme can lead to neurodegenerative diseases, including autosomal dominant cerebellar ataxia-deafness and neuropathy (ADCA-DN) and hereditary sensory and autonomic neuropathy type 1E (HSAN1E). The impact of these mutations on the structural dynamics of DNMT1 remains largely unknown. Here, we present an extensive molecular dynamics investigation of wild-type (WT) DNMT1 and its mutants associated with ADCA-DN (A554V, G589A, and V590F) and HSAN1E (D490E-P491Y and Y495C). The first group of mutants increases structural flexibility and disrupts the allosteric communication relative to WT DNMT1. These findings provide a molecular explanation for the reduced in vitro thermostability observed in these mutants. The second group has a similar impact on structural flexibility and allosteric communication and increases solvent exposure at mutant sites, offering a plausible structural explanation for the experimentally observed aberrant protein degradation and cleavage. Furthermore, all the investigated variants alter the most significant large-scale motions of the enzyme. This disruption of motion, together with decreased structural stability, may affect DNMT1's molecular recognition processes with its cellular partners. Overall, this study sheds light on the molecular mechanisms underlying ADCA-DN and HSAN1E, which could inform the development of therapies.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene, characterized by impaired pain perception, autonomic dysfunction, and progressive musculoskeletal damage. A 6-year-old girl with ocular and cutaneous albinism, psychomotor retardation, and bilateral hip dislocation was diagnosed with CIPA due to the presence of atraumatic lower limb fractures. Genetic testing revealed a novel NTRK1 splice site mutation (c.851-2A>G). The patient experienced bilateral medial longitudinal arch injuries, multiple Salter-Harris fracture patterns, and imaging characteristics suggestive of neuropathic arthropathy and an unusual periosteal reaction during the course of an 8-year follow-up. Recurrent septic arthritis also resulted in severe deformity of the elbow joint. Unusual periosteal reaction, complex physeal injuries, and synchronous bilateral medial longitudinal arch fractures are among the novel radiologic findings highlighted in this case of CIPA. In this potentially fatal condition, early identification of such patterns is essential for diagnosis, interdisciplinary care, and prevention of irreversible joint damage.

BACKGROUND: Hereditary variant transthyretin amyloidosis (ATTRv) is caused by > 140 pathogenic TTR gene variants. The heterogeneous presentation of ATTRv clinical phenotypes complicates diagnosis and staging of patients. Tools that improve early detection of ATTRv symptoms and signs and identify risk of transition to clinically detectable disease are needed. METHODS: A retrospective, multicenter study at amyloid centers in France, Spain, Portugal, and the United Kingdom (December 2023-December 2024) assessed asymptomatic carriers (ACs) and ACs who transitioned to symptomatic disease within the previous 2 years (newly symptomatic carriers [NSCs]). A new 23-question asymptomatic carrier neurologic assessment (ACNA) was developed to screen for the potential transition to clinically detectable ATTRv-polyneuropathy (PN). Question topics spanned sensory, autonomic, and systemic signs and symptoms. Fisher's exact tests were conducted to evaluate the association between each individual question and disease status (i.e., NSC vs. AC). Logistic regression models with a Firth correction were used to estimate odds ratios and corresponding 95% confidence intervals. RESULTS: The study included 217 carriers (AC, n = 128; NSC, n = 89) with 18 unique transthyretin variants; 166 (76.5%) had p.Val50Met. Of 23 ACNA questions, 17 were significantly associated with transition to symptomatic disease for all patients. The pattern of neurologic signs and symptoms found to be associated with p.Val50Met and other common variants reflected what is known about variant-specific symptomatology. Confounding factors included age, medical center of treatment, and variant type. CONCLUSION: The ACNA questionnaire may be a clinically valuable tool to screen ACs for risk of transition to symptomatic ATTRv-PN but requires validation.

The extracellular matrix (ECM) provides biophysical and biochemical cues necessary for cellular migration, differentiation and survival during development. Laminins are major ECM proteins consisting of α, β and γ chains. However, the function of laminin β4, encoded by LAMB4, remains unknown. Using human pluripotent stem cells (hPSCs), we characterize the role of LAMB4 in human peripheral sensory neuron (SN) biology. We found that LAMB4 is expressed during early SN specification, and it is required for SN development and survival. To assess clinical relevance, we examined familial dysautonomia (FD), a genetic disorder specifically affecting peripheral neurons. LAMB4 variants previously identified in individuals with severe FD sharply downregulated LAMB4 expression in SNs. Moreover, restoring a healthy ECM rescued the FD-related developmental phenotypes, suggesting that ECM defects contribute significantly to the etiology of FD. Finally, we showed that LAMB4/laminin β4 interacts with laminin α4 and laminin γ3 to form the previously unreported laminin-443 and is required for actin filament formation in SNs. Together, these results identify LAMB4 as a crucial regulator of SN development and survival with clinical implications.