先天性魚鱗癬

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by muscle weakness, thrombocytopenia, spleen anomalies and short stature. They are due to mutations affecting the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1 and leading to aberrant Ca2+ homeostasis. Therapeutic approaches aiming to rebalance intracellular Ca2+ levels largely rescued the multi-systemic phenotype in Stim1R304W/+ mice harboring the most common TAM/STRMK mutation. However, the currently used biomarkers to follow disease progression are costly and inadequate for longitudinal studies. Here, we investigated the suitability of MYOM3 to serve as a robust blood-based biomarker for TAM/STRMK. Using only minimal blood volumes, we detected highly elevated circulating MYOM3 levels in plasma samples from Stim1R304W/+ mice and TAM/STRMK patients with different mutations, and we found that the MYOM3 levels were normalized in Stim1R304W/+ mice undergoing efficient therapies. We also identified skeletal muscle as the primary source of circulating MYOM3, a structural protein of the contractile unit in myofibers, and uncovered that MYOM3 is primarily expressed in regenerating muscle fibers and in fast-twitch type IIa fibers. Overall, this work emphasizes the utility of MYOM3 as a minimally-invasive biomarker for disorders involving myofiber degeneration, and highlights the ability of MYOM3 to detect early muscle dysfunction in TAM/STRMK and evaluate therapeutic efficiency.

Autosomal recessive nonsyndromic epidermal differentiation disorders (AR-nEDDs), also known as autosomal recessive congenital ichthyosis (ARCI), are rare genetic skin diseases that lack curative treatments and can only be managed symptomatically. Their study is hampered by the limited availability of biological samples and donor tissues. Artificial skin models offer a valuable alternative for experimental research. Here, we generated epidermal skin equivalents (ESE) using primary keratinocytes from patients with AR-nEDDs carrying pathogenic variants in ALOX12B, CYP4F22, and CERS3, as well as immortalized N/TERT-2G cells. Whereas primary cells undergo senescence, N/TERT-2G cells offer a promising alternative to overcome this limitation. Histological staining and qPCR were applied to assess key epidermal proteins and AR-nEDD-related gene expression in patient- and control-derived models. Patient-derived ESE reproduced the major histopathological features and protein expression patterns characteristic of AR-nEDDs. In contrast, N/TERT-2G-based models showed earlier expression of 12R-LOX, CYP4F22, and CERS3 proteins in epidermal layers compared to healthy donor equivalents. These findings suggest that N/TERT-2G cells represent a reproducible platform for future gene-editing approaches of modelling epidermal differentiation disorders. However, as they do not inherently carry pathogenic variants, they are particularly suitable for gene-editing approaches such as CRISPR/Cas9-mediated disease modelling. Conversely, patient-derived keratinocyte models remain indispensable for validating disease mechanisms and evaluating therapeutic strategies.

BACKGROUND: Lamellar ichthyosis (LI) is a rare hereditary disorder of keratinization, most commonly inherited in an autosomal recessive manner and frequently associated with pathogenic variants in the TGM1 gene. Patients usually present with generalized scaling, xerosis, and pruritus from birth. Current therapeutic options remain limited, and systemic retinoids are often associated with considerable adverse effects. CASE DESCRIPTION: A 14-year-old female individual presented with generalized pruritic, lamellar scale-like skin changes present since birth. The diagnosis of LI was established based on clinical findings, histopathological evaluation, and genetic testing [two pathogenic variants in the TGM1 gene, consistent with autosomal recessive congenital ichthyosis type 1, Online Mendelian Inheritance in Man (OMIM): 242300]. Oral administration of acitretin (10 mg twice daily) was initiated; however, treatment was discontinued due to elevated hepatic transaminase levels and severe xerosis with pruritus. Subcutaneous administration of secukinumab (150 mg weekly) was subsequently initiated. After five weekly doses, the dosing frequency was reduced to once monthly. Over 8 weeks, substantial clinical improvement was observed, with a satisfactory therapeutic response. The patient remained on active treatment at the time of reporting. CONCLUSIONS: Secukinumab appeared to be effective in this patient with LI and may warrant further investigation as a potential therapeutic option for inherited ichthyosis.

INTRODUCTION: Sjögren-Larsson syndrome (SLS) (OMIM #270200) is an autosomal recessively inherited lipid disorder caused by pathogenic variants in ALDH3A2 gene encoding the fatty aldehyde dehydrogenase (FALDH) enzyme, that catalyzes the oxidation of fatty aldehyde to fatty acid. It is a rare neurocutaneous disorder characterized by the triad of congenital ichthyosis, spasticity, and intellectual disability. The aim of study was to investigate phenotypic and molecular characteristics of Turkish patients with SLS. METHODS: Literature search was performed by entering the keywords ALDH3A2, FALDH, SLS in TR index journal list in Turkish and PubMed in English. Turkish patients with SLS reported up to date were retrospectively analyzed. RESULTS: A total of 58 patients from 36 unrelated Turkish families were included in this study. Consanguinity was present in 73% of families. All but three patients younger than 18 months exhibited the triad of ichthyosis, developmental delay, and spastic di-/tetraplegia. Ophthalmological abnormalities were observed in 45% of patients, prematurity in 30%, epilepsy in 28%, and scoliosis in 17%. Additionally, only 2% of patients had peripheral neuropathy. Abnormal findings on brain imaging studies were detected in 84% of patients, all of whom demonstrated white matter involvement, while cerebral atrophy was present in 10%. All families had homozygous mutations, with missense in 45%, nonsense/frameshift/deletion in 35%, and splicing in 20%. Among the 15 distinct variants identified, only three, c.683G>A p.(Arg228His), c.24_25delinsTT p.(Arg9*), and c.1108-1G>C, were found to be recurrent. A review of the literature suggests that the c.24_25delinsTT p.(Arg9*) variant may be specific to the Turkish population, whereas the c.683G>A p.(Arg228His) variant appears to have a broader regional distribution across the Middle East. CONCLUSION: Although mild and severe phenotypes have been reported, the classical triad plays an important role in the preliminary diagnosis. Phenotypic findings were similar, but genotypic diversity was remarkable, and no clear genotype-phenotype correlation was observed. To make population-specific inferences, it is necessary to generate data from a larger patient cohort with haplotype analysis.