The eldest case of MICPCH with CASK mutation exhibiting gross motor regression

Nishio, Yosuke; Kidokoro, Hiroyuki; Takeo, Toshiki; Narita, Hajime; Sawamura, Fumi; Narita, Kentaro; Kawano, Yoshihiko; Nakata, T.; Muramatsu, Hideki; Hara, Shinya; Kaname, Tadashi; Natsume, Jun

doi:10.1016/j.braindev.2020.11.007

Cited by 9 publications

(7 citation statements)

References 17 publications

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“…These boys exhibit epileptic encephalopathy with pronounced cerebellar hypoplasia and progressive supratentorial atrophy 4 15 16. Regression of motor skills has also been noted in a girl with MICPCH in adolescence 17. The cellular pathology of CASK-linked disorders remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Complete loss of the X-linked geneCASKcauses severe cerebellar degeneration

et al. 2022

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BackgroundHeterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes developmental delay in girls, while in boys, loss of the only allele of these genes leads to epileptic encephalopathy. The mechanism for these disorders remains unknown. CASK-linked cerebellar hypoplasia is presumed to result from defects in Tbr1-reelin-mediated neuronal migration.MethodHere we report clinical and histopathological analyses of a deceased 2-month-old boy with a CASK-null mutation. We next generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum.ResultThe CASK-null human brain was smaller in size but exhibited normal lamination without defective neuronal differentiation, migration or axonal guidance. The hypoplastic cerebellum instead displayed astrogliosis and microgliosis, which are markers for neuronal loss. We therefore hypothesise that CASK loss-induced cerebellar hypoplasia is the result of early neurodegeneration. Data from the murine model confirmed that in CASK loss, a small cerebellum results from postdevelopmental degeneration of cerebellar granule neurons. Furthermore, at least in the cerebellum, functional loss from CASK deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum do not display neurodegeneration.ConclusionWe suggest that X-linked neurodevelopmental disorders like CASK mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.

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Section: Introductionmentioning

confidence: 99%

Complete loss of the X-linked geneCASKcauses severe cerebellar degeneration

et al. 2022

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“…These boys exhibit epileptic encephalopathy with pronounced cerebellar hypoplasia and progressive supratentorial atrophy 4,15,16 . Regression of motor skills has also been noted in a girl with MICPCH in adolescence 17 . The cellular pathology of CASK-linked disorders remains uncertain.…”

Section: Introductionmentioning

confidence: 79%

Complete loss of CASK causes severe ataxia through cerebellar degeneration in human and mouse

Patel

Hegert

Cristian

et al. 2021

Preprint

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Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes neurodevelopmental disorders (NDD) in girls, while in boys such loss leads to profound encephalopathy. The cellular basis for these disorders remains unknown. CASK is presumed to work through the Tbr1-reelin pathway in neuronal migration during brain development. Here we report our clinical and histopathological analysis of a deceased 2-month-old boy with a CASK-null mutation. We demonstrate that although smaller in size, the CASK-null human brain exhibits normal lamination without defective neuronal differentiation, migration, or axonal guidance, excluding the role of reelin in CASK-linked pathology. The disproportionately hypoplastic cerebellum in humans without CASK expression is associated with cerebellar astrogliosis, a marker for neuronal loss. Cerebellum-specific deletion in mouse confirms a post-developmental degeneration of cerebellar granular neurons that results in a small cerebellum. Mechanistically, cerebellar hypoplasia in CASK mutation thus results from neurodegeneration rather that developmental defects. Zygosity-pathology correlation suggests that NDDs like CASK mutation and Rett syndrome are pathologically neurodegenerative; however, random X-chromosome inactivation in the typical heterozygous mutant girls results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.

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“…Because microcephaly in CASK -linked pathology progresses postnatally, there may be a temporal window when therapeutic intervention might prevent or slow further brain cell loss. Regression, even in adolescence, has also been observed in some cases of MICPCH [ 119 ], again offering the tantalizing possibility that a therapeutic approach might prevent such decline under conditions when degeneration is known to progress. The potential benefits of intervention might extend even further given that non-cell-autonomous toxicity could also affect functioning of the remaining neurons; reduction of such toxicity, especially when coupled with high-intensity rehabilitative measures [ 120 ], might offer real hope for a positive impact on functional outcomes.…”

Section: Remaining Questionsmentioning

confidence: 99%

The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model

Mukherjee

LaConte

Srivastava

2022

Cells

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Most human disease manifests as a result of tissue pathology, due to an underlying disease process (pathogenesis), rather than the acute loss of specific molecular function(s). Successful therapeutic strategies thus may either target the correction of a specific molecular function or halt the disease process. For the vast majority of brain diseases, clear etiologic and pathogenic mechanisms are still elusive, impeding the discovery or design of effective disease-modifying drugs. The development of valid animal models and their proper characterization is thus critical for uncovering the molecular basis of the underlying pathobiological processes of brain disorders. MICPCH (microcephaly and pontocerebellar hypoplasia) is a monogenic condition that results from variants of an X-linked gene, CASK (calcium/calmodulin-dependent serine protein kinase). CASK variants are associated with a wide range of clinical presentations, from lethality and epileptic encephalopathies to intellectual disabilities, microcephaly, and autistic traits. We have examined CASK loss-of-function mutations in model organisms to simultaneously understand the pathogenesis of MICPCH and the molecular function/s of CASK. Our studies point to a highly complex relationship between the potential molecular function/s of CASK and the phenotypes observed in model organisms and humans. Here we discuss the implications of our observations from the pathogenesis of MICPCH as a cautionary narrative against oversimplifying molecular interpretations of data obtained from genetically modified animal models of human diseases.

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The eldest case of MICPCH with CASK mutation exhibiting gross motor regression

Cited by 9 publications

References 17 publications

Complete loss of the X-linked geneCASKcauses severe cerebellar degeneration

Complete loss of the X-linked geneCASKcauses severe cerebellar degeneration

Complete loss of CASK causes severe ataxia through cerebellar degeneration in human and mouse

The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model

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