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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. Results: Neurophysiology including Somatosensory‐evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene. Conclusions: To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants. [ABSTRACT FROM AUTHOR]

Background and Aims: X‐linked Charcot–Marie–Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea, and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families. Methods: We conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole‐exome sequencing in the probands to investigate the genetic basis of the disease. Results: Males in the family carrying the Arg162His mutation displayed early‐onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain. Interpretation: We report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co‐segregates with the disease as expected in a X‐linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders. [ABSTRACT FROM AUTHOR]

X‐linked Charcot‐Marie‐Tooth type 1 (CMTX1) disease is one of the most common subtypes of inherited neuropathies and is caused by mutations in the GJB1 gene. To date, more than 400 mutations have been reported in GJB1 worldwide but none in sub‐Saharan Africa (SSA). We aimed to clinically characterize patients with CMTX1 and identify the genetic defects. All patients were examined thoroughly, and Nerve Conduction Studies (NCS) were done. EEG and pure tone audiometry (PTA) were also done in select individuals having additional symptoms. DNA was extracted for CMT gene panel testing (50 genes + mtDNA and PMP22 duplication), and putative variants were screened in available relatives. The predominant starting symptom was tingling, and the chief complaint was gait difficulty. Neurological examination found a distal muscle weakness and atrophy, and sensory loss, skeletal deformities, decreased or absent reflexes and steppage gait. The inheritance pattern was consistent with dominant X‐linked. NCS showed no response in most of the tested nerves in lower limbs, and normal or reduced amplitudes in upper limbs. A severe sensorineural hearing impairment and a focal epileptic seizure were observed in one patient each. A high intra and inter‐familial clinical variability was observed. Genetic testing found three pathogenic missense variants in GJB1, one in each of the families (Val91Met, Arg15Trp, and Phe235Cys). This is the first report of genetically confirmed cases of CMTX1 in SSA, and confirms its clinical and genetic heterogeneity. [ABSTRACT FROM AUTHOR]

The article informs that Glucose-6-phosphate dehydrogenase (G6PD) function is deficient, there is insufficient NADPH production for detoxification when the production of reactive oxygen species (ROS) increases, which contributes to oxidative damage and early hemolysis. It mentions G6PD activity during red cell storage under standard blood bank conditions.