Plasma neurofilament light chain as a potential biomarker in Charcot‐Marie‐Tooth disease

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders. METHODS: Ninety-six CMT patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single molecule array (Simoa) NfL assay. RESULTS: The NfL concentration was significantly higher in the CMT patient group than in the controls (p<0.001). Of the CMT patients, ones with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT types) (p=0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 (rs =0.25, p=0.012). In one CMT patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. ROC analysis showed that an NfL concentration of 8.9 pg/mL could be used to discriminate CMT patients from controls, with an area under the curve of 0.881. CONCLUSIONS: Our study confirmed that the plasma NfL concentration is significantly higher in CMT patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT; however, several issues need to be addressed first

Clinical and genetic characterization of Netherton syndrome due to SPINK5 founder variant in Latvian population.

OBJECTIVE: Netherton syndrome (NS) (OMIM:256500) is a very rare autosomal recessive multisystem disorder mostly affecting ectodermal derivatives (skin and hair) and immune system. It is caused by biallelic loss-of-function variants in the SPINK5 gene, encoding the protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI). MATERIAL, METHODS AND RESULTS: Here, we describe NS clinical and genetic features of homogenous patient group: 9 individuals from 7 families with similar ethnic background and who have the same SPINK5 variant (NM_006846.4: c.1048C > T, p.(Arg350*)) in homozygous or compound heterozygous states, suggesting that it is a common founder variant in Latvian population. Indeed, we were able to show that the variant is common in general Latvian population, and it shares the same haplotype among the NS individual. It is estimated that the variant arose >1000 years ago. Clinically, all nine patients exhibited typical NS skin changes (scaly erythroderma, ichthyosis linearis circumflexa, itchy skin), except for one patient who has a different skin manifestation-epidermodysplasia. Additionally, we show that developmental delay, previously underrecognized in NS, is a common feature among these patients. CONCLUSIONS: This study shows that the phenotype of NS individuals with the same genotype is highly homogeneous

Plasma neurofilament light chain as a potential biomarker in Charcot‐Marie‐Tooth disease

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders. METHODS: Ninety-six CMT patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single molecule array (Simoa) NfL assay. RESULTS: The NfL concentration was significantly higher in the CMT patient group than in the controls (p<0.001). Of the CMT patients, ones with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT types) (p=0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 (rs =0.25, p=0.012). In one CMT patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. ROC analysis showed that an NfL concentration of 8.9 pg/mL could be used to discriminate CMT patients from controls, with an area under the curve of 0.881. CONCLUSIONS: Our study confirmed that the plasma NfL concentration is significantly higher in CMT patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT; however, several issues need to be addressed first

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for approximately 5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS