Conservation of neural progenitor identity and the emergence of neocortical neuronal diversity.

One paramount challenge for neuroscientists over the past century has been to identify the embryonic origins of the enormous diversity of cortical neurons found in the adult human neocortex and to unravel the developmental processes governing their emergence. In all mammals, including humans, the radial glia lining the ventricles of the embryonic telencephalon, more recently reclassified as apical radial glia (aRGs), have been identified as the neural progenitors giving rise to all excitatory neurons and inhibitory interneurons of the six-layered cortex. In this review, we explore the fundamental molecular and cellular mechanisms that regulate aRG function and the generation of neuronal diversity in the dorsal telencephalon. We survey the key structural features essential for the retention of the highly polarized aRG morphology and therefore impose aRG identity after cytokinesis. We discuss how these structures and associated molecular signaling complexes influence aRG proliferative capacity and the decision to undergo proliferative self-renewing symmetric or neurogenic asymmetric divisions. We also explore the intriguing and complex question of how the extensive neuronal diversity within the adult neocortex arises from the small aRG population located within the cortical proliferative zone. We further highlight the recent clonal lineage tracing and single-cell transcriptomic profiling studies providing compelling evidence that individual neuronal identity emerges as a consequence of exposure to temporally regulated extrinsic cues which coordinate waves of transcriptional activity that evolve over time to drive neuronal commitment and maturation.

Pathology of inherited manganese transporter deficiency.

We followed a patient with manganese transporter deficiency due to homozygous SLC30A10 mutations from age 14 years until his death at age 38 years and present the first postmortem findings of this disorder. The basal ganglia showed neuronal loss, rhodanine-positive deposits, astrocytosis, myelin loss, and spongiosis. SLC30A10 protein was reduced in residual basal ganglia neurons. Depigmentation of the substantia nigra and other brainstem nuclei was present. Manganese content of basal ganglia and liver was increased 16-fold and 9-fold, respectively. Our study provides a pathological foundation for further investigation of central nervous system toxicity secondary to deregulation of manganese metabolism.

Methadone use in a male with the FMRI premutation and FXTAS.

The fragile X-associated tremor ataxia syndrome (FXTAS) is caused by the premutation in FMR1 gene. Recent reports of environmental toxins appear to worsen the progression of FXTAS. Here we present a case of male adult with FXTAS and a long history of methadone use. The patient shows a faster progression in both symptoms of disease and MRI changes compared to what is typically seen in FXTAS. There has been no research regarding the role of narcotics in onset, progression, and severity of FXTAS symptoms. However, research has shown that narcotics can have a negative impact on several neurodegenerative diseases, and we hypothesize that in this particular case, methadone may have contributed to a faster progression of FXTAS as well as exacerbating white matter disease through RNA toxicity seen in premutation carriers.

The neurobiology of the Prader-Willi phenotype of fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism, caused by a CGG expansion to greater than 200 repeats in the promoter region of FMR1 on the bottom of the X chromosome. A subgroup of individuals with FXS experience hyperphagia, lack of satiation after meals and severe obesity, this subgroup is referred to have the Prader-Willi phenotype of FXS. Prader-Willi syndrome is one of the most common genetic severe obesity disorders known and it is caused by the lack of the paternal 15q11-13 region. Affected individuals suffer from hyperphagia, lack of satiation, intellectual disability, and behavioral problems. Children with fragile X syndrome Prader-Willi phenotye and those with Prader Willi syndrome have clinical and molecular similarities reviewed here which will impact new treatment options for both disorders.

Current research, diagnosis, and treatment of fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a premutation CGG-repeat expansion in the 5'UTR of the fragile X mental retardation 1 (FMR1) gene. The classical clinical manifestations include tremor, cerebellar ataxia, cognitive decline and psychiatric disorders. Other less frequent features are peripheral neuropathy and autonomic dysfunction. Cognitive decline, a form of frontal subcortical dementia, memory loss and executive function deficits are also characteristics of this disorder. In this review, we present an expansion of recommendations for genetic testing for adults with suspected premutation disorders and provide an update of the clinical, radiological and molecular research of FXTAS, as well as the current research in the treatment for this intractable complex neurodegenerative genetic disorder.

Addictive substances may induce a rapid neurological deterioration in fragile X-associated tremor ataxia syndrome: A report of two cases.

A debilitating late-onset disorder of the premutation in the FMR1 gene is the neurodegenerative disorder fragile X-associated tremor ataxia syndrome (FXTAS). We report two patients with FXTAS who have a history of substance abuse (opiates, alcohol, and cocaine) which may have exacerbated their rapid neurological deterioration with FXTAS. There has been no case report regarding the role of substance abuse in onset, progression, and severity of FXTAS symptoms. However, research has shown that substance abuse can have a negative impact on several neurodegenerative diseases, and we propose that in these cases, substance abuse contributed to a faster progression of FXTAS as well as exacerbated white matter disease.