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Xanthomatosis is a genetic disease inherited in an autosomal recessive manner. The specific phenotypic features are associated with patient's genetic profile. The result of the mutation is disorder of cholesterol synthesis and the accumulation of its precursors in tissues. The characteristic symptoms are progressive cerebellar ataxia, cataract, diarrhea, and the deposition of cholesterol in the tendons. Our objective is to follow-up information to treatment efficacy of 22-yearold patient diagnosed with cerebrotendinous xanthomatosis through 1.5 year observation. In 2012, an 11-year-old patient with a long history of deformed feet and frequent yellowing of the skin, was admitted to the Department of Neurology due to seizures. In 2013, the patient began to suffer from diarrhea, and its frequency was correlated with the concentration of bilirubin in the blood. In the same year cataract was diagnosed. Gradually, the patient starts to complain about progressive difficulties in moving. In 2019, genetic tests confirmed the diagnosis of cerebrotendinous xanthomatosis. Since July 2021, the patient has been treated with chenodeoxycholic acid. The deterioration of patient's mobility has been significantly inhibited, consequently his quality of life has improved. The presented case report underscores the efficacy of CDCA supplementation in halting the progression of CTX, resulting in marked improvements in the patient's quality of life. [ABSTRACT FROM AUTHOR]

Cerebrotendinous xanthomatosis (CTX) is an inborn error of metabolism caused by recessive variants in the cytochrome P450 CYP27A1 gene. CTX is said to manifest with childhood‐onset chronic diarrhea and the classic triad of juvenile‐onset cataracts, Achilles tendons xanthomas, and progressive ataxia. It is currently one of the few inherited neurometabolic disorders amenable to a specific treatment. The diagnosis may be significantly delayed resulting in permanent neurological impairment. A retrospective review of the clinical characteristics and diagnostic findings in case series of six Polish patients with CTX. Additional retrospective review of symptoms and pathogenic variants of 568 CTX available cases and case series from the past 20 years. To the best of our knowledge, this is the widest review of CTX cases reported in years 2000–2021. We report the largest cohort of Polish patients ever published, with the identification of two hot‐spot mutations. During the review of available 568 cases, we found significant differences in the clinical phenotypes and the localization of variants within the gene between Asian and non‐Asian populations. These findings may facilitate molecular testing in the Polish and Asian populations. Invariably better screening for CTX and wider awareness is needed. [ABSTRACT FROM AUTHOR]

Retinoid acid receptors (RAR) are transcription factors that bind retinoic acid (RA), a metabolite of vitamin A. RARs are composed of three subunits encoded by RARA, RARB and RARG. In humans, RARB defects cause syndromic microphthalmia. So far, no germline pathogenic variants have been identified in RARA or RARG. We describe a girl with a de novo mutation NM_000964 c.826C > T (p.Arg276Trp) in RARA with symptoms overlapping those described in RARB patients (coloboma, muscular hypotonia, dilated pulmonary artery, ectopic kidney). RARA Arg276 residue is functionally important, as it was previously shown that its substitution for Ala or Gln causes a 50‐ or 21‐fold impairment of RA binding, respectively. Moreover, in leukemic cells, the p.Arg611Trp mutation in a chimeric PML/RARA gene (corresponding to the RARA p.Arg276Trp detected in our patient) conferred resistance to therapy by decreasing binding of all‐trans RA. The functional effect of RARA p.Arg276Trp was further confirmed by in silico modeling which showed that binding of RA by the Trp276 variant was similarly defective as in the deleterious model Ala276 mutant. We propose that RARA p.Arg276Trp causes the disease by affecting RA interaction with the RARA receptor. [ABSTRACT FROM AUTHOR]

Unlabelled: The Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive hypomyelination disorder caused by mutations of the proteolipid protein1 gene (PLP1). There is a spectrum of PLP1-related disorders from very severe connatal PMD, through classical PMD to mild spastic paraplegia type 2 (SPG2), with some correlation between the type of mutation and the phenotype. In general, missense mutations give rise to more severe forms of the disease, deletions and null mutations to mild PMD and SPG2. The most common variations, duplications, result in the classical-intermediate form of PMD., The Aim: To report the analysis of mutations in the PLP1 gene and phenotype di!erences in ten male patients diagnosed with PMD. Although they had different types of PLP1 mutations (duplications, missense and nonsense mutations), all of them were clinically classi"ed with the classical form of PMD (clPMD)., Material and Methods: The subjects of analysis were ten male patients aged 1.5 to 21 years who were diagnosed with PMD. All patients developed the "rst clinical symptoms between 1 an 8 months of age and showed developmental delay, mainly in motor skills. All were classified with the classical form of the disease, according to international clinical criteria and the electrophysiological and brain MRI criteria of hypomyelination. The molecular analysis of the PLP1 gene involved dosage analysis and direct sequencing of all exons and promotor region of the gene., Results: The clinical diagnosis of PMD was con"rmed for all subjects by molecular analysis of the PLP1gene. Although all had the classical form of PMD, it was caused by mutations of di!erent types: duplications of the entire gene, missense and nonsense mutations., Conclusions: Our clinical and molecular "ndings showed that the phenotypic spectrum resulting from PLP1 mutations seems to be broader in patients with the PLP1 gene duplication compared to patients with both nonsense and missense mutation. Nevertheless, apart from the type of mutation, all our patients’ clinical manifestation falls into the category of the classical form of PMD according to international criteria. Obviously the type of mutations, but also other unidentified factors may a!ect the clinical course of PMD.The Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive hypomyelination disorder caused by mutations of the proteolipid protein 1 gene (PLP1). There is a spectrum of PLP1-related disorders from very severe connatal PMD, through classical PMD to mild spastic paraplegia type 2 (SPG2), with some correlation between the type of mutation and the phenotype. In general, missense mutations give rise to more severe forms of the disease, deletions and null mutations to mild PMD and SPG2. The most common variations, duplications, result in the classical-intermediate form of PMD., The Aim: To report the analysis of mutations in the PLP1 gene and phenotype differences in ten male patients diagnosed with PMD. Although they had di!erent types of PLP1 mutations (duplications, missense and nonsense mutations), all of them were clinically classi"ed with the classical form of PMD (clPMD)., Material and Methods: The subjects of analysis were ten male patients aged 1.5 to 21 years who were diagnosed with PMD. All patients developed the "rst clinical symptoms between 1 an 8 months of age and showed developmental delay, mainly in motor skills. All were classified with the classical form of the disease, according to international clinical criteria and the electrophysiological and brain MRI criteria of hypomyelination. The molecular analysis of the PLP1 gene involved dosage analysis and direct sequencing of all exons and promotor region of the gene., Results: The clinical diagnosis of PMD was con"rmed for all subjects by molecular analysis of the PLP1 gene. Although all had the classical form of PMD, it was caused by mutations of di!erent types: duplications of the entire gene, missense and nonsense mutations., Conclusions: Our clinical and molecular findings showed that the phenotypic spectrum resulting from PLP1 mutations seems to be broader in patients with the PLP1 gene duplication compared to patients with both nonsense and missense mutation. Nevertheless, apart from the type of mutation, all our patients' clinical manifestation falls into the category of the classical form of PMD according to international criteria. Obviously the type of mutations, but also other unidentified factors may a!ect the clinical course of PMD.