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EPM1 is the most common form of Progressive Myoclonus Epilepsy characterized by late-childhood onset, ever-worsening and disabling myoclonus, seizures, ataxia, psychiatric disease, and shortened lifespan. EPM1 is caused by expansions of a dodecamer repeat sequence in the promoter of CSTB (cystatin B), which dramatically reduces, but does not eliminate, gene expression. The relatively late onset and consistent presence of a minimal amount of protein product makes EPM1 a favorable target for gene replacement therapy. If treated early, these children's normally developed brains could be rescued from the neurodegeneration that otherwise follows, and their cross-reactive immunological material (CRIM) positive status greatly reduces transgene related toxicity. We performed a proof-of-concept CSTB gene replacement study in Cstb knockout mice by introducing full-length human CSTB driven by the CBh promoter packaged in AAV9 and administered at postnatal days 21 and 60. Mice were sacrificed at 2 or 9 months of age, respectively. We observed significant improvements in expression levels of neuroinflammatory pathway genes and cerebellar granule cell layer apoptosis, as well as amelioration of motor impairment. The data suggest that gene replacement is a promising therapeutic modality for EPM1 and could spare affected children and families the ravages of this otherwise severe neurodegenerative disease., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Purpose: A common isolated reported finding in brain imaging studies on developmentally delayed children is delayed myelination. We hypothesized that brain MR imaging scans of these children would show delayed subcortical myelination of white matter with specific involvement of the subcortical U-fibers as these represent terminal zones of myelination and are the last areas to myelinate., Materials and Methods: A total of 93 children (31 controls, 62 with idiopathic developmental delay [IDD]) aged 17 to 46 months were identified on the basis of having brain MR imaging for evaluation of IDD (cases) or for another condition (controls). Children with diseases that primarily affect white matter or overt intracranial lesions or malformations were excluded. IDD was defined as psychomotor retardation without a clear cause on the basis of history, physical, genetic, metabolic, and neuroimaging examinations. Developmental quotients (DQs) were calculated for all children with IDD on the basis of clinical history, examination, and psychometric testing. Three board-certified pediatric neuroradiologists examined axial T2-weighted brain images and used a published scoring system to rate the extent of myelination in the frontal, temporal, parietal, and peritrigonal brain regions. In addition, subcortical U-fibers in the frontal, temporal, and parietal lobes were scored separately. Data were analyzed at both the intraobserver and interobserver levels, and scores were compared between groups and tested for interactions with age and DQ., Results: There were no differences in the timing or extent of myelination in the control and IDD groups at any age in any brain region. In the IDD group, there was no relationship between myelination scores and DQ or developmental domain., Conclusions: Our findings did not support the hypothesis that there is a correlation between IDD and the maturity of myelination, including the terminal zones, as seen on conventional brain MR imaging. Neuroimaging evaluation of maturity of subcortical myelination is not a marker of IDD in young children, and the isolated "finding" of delayed myelination should be interpreted with caution.

In the developing nervous system, neurons are generated at sites distant from their ultimate location. In the vertebrate CNS, neurons utilize distinct migration strategies to reach their ultimate residence. This review discusses the contribution of tangential migration to the architectural development of the cerebral cortex and cerebellum.

Pax-2 is a paired box transcription factor expressed in several regions of the developing mammalian central nervous system. First found in the midbrain/hindbrain region, Pax-2 expression is later found in the cerebellum, hindbrain, and spinal cord. We have examined the expression pattern of Pax-2 from embryonic day 12 (E12) through postnatal day 35 (P35) using immunohistochemistry and in situ hybridization. Expression of Pax-2 is found in scattered cells of the cerebellar ventricular zone at E13. Pax-2-expressing cells migrate away from this germinative center to positions in the deep cerebellar nuclei (DCN), internal granule cell layer, molecular layer, and folial white-matter tracts of the cerebellum. Immunocytochemistry of both tissue sections and primary dissociated cultures demonstrates that Pax-2 is expressed by cells of a neuronal lineage, but not by cells of either an astrocytic or oligodendrocytic lineage. Specifically, the presence of Pax-2 identifies the entire population of gamma-aminobutyric acid (GABA)ergic interneurons in the cerebellar cortex (Golgi II, basket and stellate cells) and in the DCN. Bromodeoxyuridase labeling and 4',6-diamino-2-phenylindole (DAPI) staining of cells in M-phase reveals that Pax-2-expressing cells in the folial white-matter tracts of the cerebellum constitute an actively dividing population. We propose that these cells are migratory precursors of the molecular layer interneurons (basket and stellate cells). Our data suggest that the role of Pax-2 in cerebellar development changes after E12, shifting from the specification of an anatomical field to the marking of a specific class of cells. Our findings also suggest a previously uncharacterized relationship among GABAergic interneurons found posterior to the midbrain. Finally, our data support the hypothesis that the basket and stellate cells arise from neuronally restricted, migratory precursors located in the early postnatal cerebellar white matter., (Copyright 1999 John Wiley & Sons, Inc.)

Aldolase C is regarded as the brain-specific form of fructose-1, 6-bisphosphate aldolase whereas aldolase A is regarded as muscle-specific. In situ hybridization of mouse central nervous system using isozyme-specific probes revealed that aldolase A and C are expressed in complementary cell types. With the exception of cerebellar Purkinje cells, aldolase A mRNA is found in neurons; aldolase C message is detected in astrocytes, some cells of the pia mater, and Purkinje cells. We isolated aldolase C genomic clones that span the entire protein coding region from 1.5 kb 5' to the transcription start site to 0.5 kb 3' to the end of the last exon. The bacterial gene, lacZ, was inserted in two different locations and the constructs tested in transgenic mice. When the protein coding sequences were replaced with lacZ, three of five transgenic lines expressed beta-galactosidase only in cells of the pia mater; one line also expressed in astrocyte-like cells. When lacZ was inserted into the final exon (and all structural gene sequences were retained) transgene expression was observed in astrocytes in all regions of the central nervous system as well as in pial cells. Thus, with the exception of Purkinje cell expression, the behavior of the full-length transgene mimics the endogenous aldolase C gene. The results with the shorter transgene suggest that additional enhancer elements exist within the intragenic sequences. The absence of Purkinje cell staining suggests that the cis elements required for this expression must be located outside of the sequences used in this study.

The mouse neurological mutant weaver has an atrophic cerebellar cortex with deficits in both Purkinje and granule cell number. Although granule cells are known to die postnatally shortly after their final cell division, the cause of the Purkinje cell deficit (cell death vs lack of production) is unknown. We report here a quantitative analysis of large cerebellar neurons of the weaver mutant during postnatal development. We explored the hypothesis that the cells of the entire cerebellar anlage were affected by the mutation by including in our study the neurons of the deep cerebellar nuclei (DCN). Our analysis reveals that in homozygous weaver mutants (1) the DCN are displaced laterally, display an abnormal anatomy, and suffer a 20-25% decrease in neuron number; (2) this numerical deficit is located in medial regions, similar to the localization of cortical deficits in both Purkinje and granule cells; (3) pyknotic figures are present in the juvenile DCN and in the Purkinje cell layer; and (4) the majority of cell death in these populations occurs not in medial regions where the numerical deficits are observed, but rather laterally where adult cell number is nearly normal. These results lead us to propose that the complete weaver phenotype includes a failure of the cell movements that lead to the fusion of the bilateral cerebellar anlage, and that this failure to migrate properly leaves some of the Purkinje cells and DCN neurons in a position where they are unable to make appropriate connections, leading to their death. In addition to implications for normal development, these observations suggest that weaver effects on the cerebellum can be unified into one consolidated model in which failure of cell movement affects all major cerebellar neurons.