Digenic FLNA and UCHL1 variants resulting in a complex phenotype.

Aim: X-linked variants in Filamin A (FLNA) are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (UCHL1) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype.

Methods: A 67-year-old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss.

Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot-Marie-Tooth disease with congenital cataracts.

Background And Purpose: Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB.

Methods: Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features.

Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1.

Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a genomic duplication encompassing the dosage-sensitive PMP22 gene. MicroRNAs act as repressors on post-transcriptional regulation of gene expression and in rodent models of CMT1A, overexpression of one such microRNA (miR-29a) has been shown to reduce the PMP22 transcript and protein level. Here we present genomic and functional evidence, for the first time in a human CNV-associated phenotype, of the 3' untranslated region (3'-UTR)-mediated role of microRNA repression on gene expression.

Charcot-Marie-Tooth disease type 2CC due to variants causes a progressive, non-length-dependent, motor-predominant phenotype.

Objective: Neurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC).

Methods: In this large observational study, we present phenotype-genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families.

Results: The majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.

Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature.

Purpose: The purpose of this study was to report retinal dystrophy as a novel clinical feature and expand the ocular phenotype in patients harboring biallelic candidate FDXR variants.

Methods: Patients carrying biallelic candidate FDXR variants were identified by whole genome sequencing (WGS) as part of the National Institute for Health Research BioResource rare-disease and the UK's 100,000 Genomes Project (100KGP) with an additional case identified by exome sequencing. Retrospective clinical data were collected from the medical records.

Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease.

Objective: To investigate the effectiveness of targeted next-generation sequencing (NGS) panels in achieving a molecular diagnosis in Charcot-Marie-Tooth disease (CMT) and related disorders in a clinical setting.

Methods: We prospectively enrolled 220 patients from 2 tertiary referral centers, one in London, United Kingdom (n = 120), and one in Iowa (n = 100), in whom a targeted CMT NGS panel had been requested as a diagnostic test. duplication/deletion was previously excluded in demyelinating cases.

Clinical, ophthalmological, imaging and genetic features in Brazilian patients with ARSACS.

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis.

Objective And Methods: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles.

Structure and denaturation of 4-chlorobenzoyl coenzyme A dehalogenase from Arthrobacter sp. strain TM-1.

The secondary structure of the trimeric protein 4-chlorobenzoyl coenzyme A dehalogenase from Arthrobacter sp. strain TM-1, the second of three enzymes involved in the dechlorination of 4-chlorobenzoate to form 4-hydroxybenzoate, has been examined. E(mM) for the enzyme was 12.

The purification and characterisation of 4-chlorobenzoate:CoA ligase and 4-chlorobenzoyl CoA dehalogenase from Arthrobacter sp. strain TM-1.

4-Chlorobenzoate:CoA ligase, the first enzyme in the pathway for 4-chlorobenzoate dissimilation, has been partially purified from Arthrobacter sp. strain TM-1, by sequential ammonium sulphate precipitation and chromatography on DEAE-Sepharose and Sephacryl S-200. The enzyme, a homodimer of subunit molecular mass approximately 56 kD, is dependent on Mg2+-ATP and coenzyme A, and produces 4-chlorobenzoyl CoA and AMP.