先天性無痛無汗症

BACKGROUND AND AIMS: Hereditary neuropathies are a group of genetically and phenotypically heterogeneous neuropathies. These are classified into: hereditary sensory motor neuropathy (HSMN) aka Charcot-Marie-Tooth disease (CMT), distal motor neuropathy (dMN), hereditary sensory autonomic neuropathy (HSAN), episodic neuropathies and polyneuropathy as part of a complex clinical presentation. The aim of this study was to determine final diagnoses in patients referred from the tertiary center in Serbia under suspicion of hereditary neuropathy. METHODS AND MATERIALS: This research included 340 patients directed for genetic testing from the Neurology Clinic, University Clinical Center of Serbia during the period from 2009 to 2023, who underwent complete genetic analyses available. RESULTS: The most prominent demyelinating neuropathy was group consisted of patients with CMT1A (93 (27.3%)), followed by CMT1B (10 (2.9%)). In the group of patients with axonal form of the disease, the most prevalent was the one with pathogenic variant in HINT1 (18 (5.3%)). Nineteen (5.6%) patients have had variants in GJB1 gene. DMN group was composed of seven (2%) patients. HSAN was final diagnosis in 2 (0.6%) patients. Group of 16 (4.7%) patients have had neuropathy as part of a complex clinical presentation. In 70 (20.6%) patients no significant genetic variant was found, even though clinical presentation was highly suggestive of hereditary neuropathy. INTERPRETATION: In line with other populations, CMT1A was the most common cause of hereditary neuropathy in Serbia. The axonal cohort predominantly included patients with variants in the HINT1 gene, which represents a population-specific characteristic. These findings highlight the importance of targeted genetic analysis in diagnosing hereditary neuropathies in certain populations.

OBJECTIVES: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder caused by mutations in NTRK1 that is characterized by pain insensitivity, anhidrosis, and recurrent fever. While genetic testing is the gold standard for CIPA diagnosis, the complexity of NTRK1 variants poses major challenges. Conventional sequencing that is limited to the coding regions of NTRK1 results in misdiagnoses or missed diagnoses in approximately 57% of patients. Accordingly, to improve the diagnostic efficiency of CIPA, we integrated whole-genome sequencing (WGS) with functional assays to identify deep intronic variants in NTRK1. METHODS: All 18 probands were initially screened using polymerase chain reaction (PCR) and Sanger sequencing covering all exons and canonical splice sites of NTRK1. For patients with only one identified pathogenic allele, WGS was performed to detect potential deep intronic variants. Candidate variants were functionally validated using reverse transcription PCR (RT-PCR) and T cloning sequencing to evaluate their effects on pre-mRNA splicing. RESULTS: Total 23 pathogenic variants including 11 novel variants in NTRK1 were identified in 18 unrelated families with CIPA. Functional assays confirmed that five of these variants disrupted the normal splicing of NTRK1, resulting in multiple aberrant splicing patterns, including two exon-skipping events (c.428 + 273A>T, c.850 + 5G>A), three intron retentions (c.2187 + 389C>T, c.2188-459G>T, c.287 + 4A>C), and one pseudoexon insertion (c.2188-459G>T). CONCLUSION: This study expands the spectrum of pathogenic variants in NTRK1 and improves the genetic diagnosis of CIPA. The functional characterization of five novel non-canonical splicing variants provides deeper insight into the molecular pathogenesis of this disorder and establishes a foundation for future precision medicine approaches in CIPA.

BACKGROUND AND AIMS: This study aimed to systematically phenotype autonomic nervous system (ANS) involvement in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of undetermined significance-associated neuropathy (MGUS-PNP), Charcot-Marie-Tooth disease Type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP). METHODS: Autonomic symptoms were assessed using the SCales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT). Muscle strength and functional disability were evaluated using the Medical Research Council (MRC) scale, the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale, and the Overall Neuropathy Limitation Scale (ONLS). RESULTS: A total of 343 participants were included: 98 with CIDP (mean age: 59.2 ± 13.2 years), 51 with MGUS-PNP (66.0 ± 11.3 years), 51 with CMT1A (51.2 ± 13.1 years), 18 with HNPP (40.6 ± 15.1 years), and 125 healthy controls (58.2 ± 13.3 years). Compared with healthy controls, patients with CIDP, MGUS-PNP, and CMT1A showed significantly higher total SCOPA-AUT scores (p < 0.01). Distinct, disease-specific ANS symptom patterns were observed across neuropathy subtypes. Overall disability was independently associated with overall autonomic symptom burden in MGUS-PNP (β = 0.42, p < 0.05) and CMT1A (β = 0.68, p < 0.05). In CIDP, patients with active disease showed higher autonomic symptom burden than those with inactive disease (12.7 ± 11.7 vs. 8.6 ± 7.9, p = 0.042). INTERPRETATION: Patients with CIDP, MGUS-PNP, and CMT1A exhibit a substantial autonomic symptom burden with distinct disease-specific ANS patterns. These findings highlight the relevance of autonomic dysfunction in immune-mediated and hereditary neuropathies and warrant further studies to clarify their clinical and prognostic significance.

Macular telangiectasia (MacTel) is characterised by perifoveal capillary abnormalities, which can progress to retinal layer loss and cavitation-like changes. Though it occurs predominantly in isolation, a genetic association of MacTel has been noted. Our report aims to demonstrate one such association causing an alteration in serine metabolism leading to neuropathy and maculopathy secondary to Muller cell degeneration.

Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder. Its core clinical manifestations include profound pain insensitivity, generalized anhidrosis, and subsequent recurrent hyperthermia. To date, only a few hundred cases have been reported in the literature. An 8-month-old female infant was admitted with a 14-day history of recurrent fever that was unresponsive to systemic antimicrobial therapy. Dynamic clinical monitoring revealed an environment-dependent body temperature. Physical examination showed dry and coarse palms, accompanied by painless oral ulcers and painless distal finger injuries. Retrospective history taking confirmed a lack of sweating during febrile episodes and an absence of pain perception. Whole-exome and Sanger sequencing identified compound heterozygous variants in the NTRK1 gene, comprising a maternal intronic variant (c.851-33T > A) and a paternal large deletion at 1q23.1 encompassing exons 5-7. A definitive clinical diagnosis of CIPA was established. In infants presenting with refractory fever, clinicians should maintain a high index of suspicion for non-infectious etiologies. Early evaluation for anhidrosis and pain insensitivity, along with the inclusion of CIPA in the differential diagnosis, can expedite definitive diagnosis, prevent secondary injuries, and facilitate timely genetic counseling.