Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth.

Biallelic loss-of-function variants in TBC1D2B have been reported in five subjects with cognitive impairment and seizures with or without gingival overgrowth. TBC1D2B belongs to the family of Tre2-Bub2-Cdc16 (TBC)-domain containing RAB-specific GTPase activating proteins (TBC/RABGAPs). Here, we report five new subjects with biallelic TBC1D2B variants, including two siblings, and delineate the molecular and clinical features in the ten subjects known to date. One of the newly reported subjects was compound heterozygous for the TBC1D2B variants c.2584C>T; p.(Arg862Cys) and c.2758C>T; p.(Arg920*). In subject-derived fibroblasts, TBC1D2B mRNA level was similar to control cells, while the TBC1D2B protein amount was reduced by about half. In one of two siblings with a novel c.360+1G>T splice site variant, TBC1D2B transcript analysis revealed aberrantly spliced mRNAs and a drastically reduced TBC1D2B mRNA level in leukocytes. The molecular spectrum included 12 different TBC1D2B variants: seven nonsense, three frameshifts, one splice site, and one missense variant. Out of ten subjects, three had fibrous dysplasia of the mandible, two of which were diagnosed as cherubism. Most subjects developed gingival overgrowth. Half of the subjects had developmental delay. Seizures occurred in 80% of the subjects. Six subjects showed a progressive disease with mental deterioration. Brain imaging revealed cerebral and/or cerebellar atrophy with or without lateral ventricle dilatation. The TBC1D2B disorder is a progressive neurological disease with gingival overgrowth and abnormal mandible morphology. As TBC1D2B has been shown to positively regulate autophagy, defects in autophagy and the endolysosomal system could be associated with neuronal dysfunction and the neurodegenerative disease in the affected individuals.

Single-center experience with Beta-propeller protein-associated neurodegeneration (BPAN); expanding the phenotypic spectrum.

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) that presents with childhood developmental delay (especially speech delay), occasionally associated with epileptic encephalopathy, autism, or Rett-like syndrome. The majority of children described to date have been severely affected, with little to no expressive speech function, severe developmental delay, and cognitive impairment. Herein, five additional patients with BPAN identified in the same center in Canada are described, four with the typical severe phenotype and one with a milder phenotype. Our findings provide further evidence that a spectrum of severity exists for this rare and newly described condition. Challenges in identifying iron accumulation on brain MRI are also addressed. Additionally, the importance of including the WDR45 gene on epilepsy and Rett-like syndrome genetic panels is highlighted.

The role of pulmonary veins in atrial fibrillation: a complex yet simple story.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increased incidence among the elderly population. The concept that ectopic activity in pulmonary veins (PVs) could be responsible for triggering AF has been put forward, and the inter-relationship between PVs and left atrium has been the subject of many anatomical and physiological investigations. Variable configuration of action potentials among various PV cardiomyocytes has been reported. PV myocytes were shown to have a higher resting membrane potential and a lower action potential amplitude and duration than the left atrium. Much evidence has accumulated to indicate that spontaneous depolarization and/or re-entry from PVs could be the mode by which AF is initiated and/or sustained. Attempts have been made to link AF in certain pathophysiological states, notably, congestive heart failure, valvular disease and hyperthyroidism to PVs. There has been evidence to suggest that an increase in PV diameter may be the trigger for initiating AF. However, there is limited clinical knowledge available on the nature of the antiarrhythmic drugs that act upon PVs to alleviate AF. Most drugs currently employed are the standard agents generally utilized for the treatment of AF. Radiofrequency ablation (RFA) of the PVs and its isolation from the left atrium has become a major curative measure of AF. It is also possible that pharmacotherapy may be more effective or provide extra benefit to patients after a RFA procedure. The trend of the clinical evidence seems to suggest that a hybrid treatment may be beneficial in some population of patients.