Pontocerebellar Hypoplasia: a Pattern Recognition Approach

Rüsch, Christina T.; Bölsterli, Bigna K.; Kottke, Raimund; Steinfeld, Robert; Boltshauser, Eugen

doi:10.1007/s12311-020-01135-5

Cited by 39 publications

(46 citation statements)

References 94 publications

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“…Depletion of Purkinje cells and granule cells [ 25 , 28 , 29 ] and a great loss of neurons and gliosis of dentate nuclei, olivary nuclei and pontine nuclei [ 25 , 26 , 28 , 30 ] are hallmark pathological features of PMM2-CDG. Global PCH with superimposed atrophy and cerebellar cortex brightness on FLAIR are characteristics of PMM2-CDG among disorders with PCH-like imaging [ 31 ]. We found that additional neurological features such as severe intellectual disability and the presence of peripheral neuropathy were associated with worse functional abilities in patients with PMM2-CDG.…”

Section: Discussionmentioning

confidence: 99%

Clinical and radiological correlates of activities of daily living in cerebellar atrophy caused by PMM2 mutations (PMM2-CDG)

et al. 2021

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We aimed to identify clinical, molecular and radiological correlates of activities of daily living (ADL) in patients with cerebellar atrophy caused by PMM2 mutations (PMM2-CDG), the most frequent congenital disorder of glycosylation. Twenty-six PMM2-CDG patients (12 males; mean age 13 ± 11.1 years) underwent a standardized assessment to measure ADL, ataxia (brief ataxia rating scale, BARS) and phenotype severity (Nijmegen CDG rating scale, NCRS). MRI biometry of the cerebellum and the brainstem were performed in 23 patients (11 males; aged 5 months–18 years) and 19 control subjects with equal gender and age distributions. The average total ADL score was 15.3 ± 8.5 (range 3–32 out of 36 indicating severe functional disability), representing variable functional outcome in PMM2-CDG patients. Total ADL scores were significantly correlated with NCRS (r2 = 0.55, p < 0.001) and BARS scores (r2 = 0.764; p < 0.001). Severe intellectual disability, peripheral neuropathy, and severe PMM2 variants were all significantly associated with worse functional outcome. Higher ADL scores were significantly associated with decreased diameters of cerebellar vermis (r2 = 0.347; p = 0.004), hemispheres (r2 = 0.436; p = 0.005), and brainstem, particularly the mid-pons (r2 = 0.64; p < 0.001) representing the major radiological predictor of functional disability score in multivariate regression analysis. We show that cerebellar syndrome severity, cognitive level, peripheral neuropathy, and genotype correlate with ADL used to quantify disease-related deficits in PMM2-CDG. Brainstem involvement should be regarded among functional outcome predictors in patients with cerebellar atrophy caused by PMM2-CDG.

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Section: Discussionmentioning

confidence: 99%

Clinical and radiological correlates of activities of daily living in cerebellar atrophy caused by PMM2 mutations (PMM2-CDG)

et al. 2021

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“…Pontocerebellar hypoplasia (PCH) is a group of early-onset neurodegenerative disorders that includes at least 13 subtypes, based on neuropathological, clinical, and MRI criteria 24,25 . PCH is usually associated with a combination of degeneration and lack of development of the pons and the cerebellum, suggesting a prenatal onset.…”

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confidence: 99%

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

et al. 2020

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Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.

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“…Finally, some less frequent findings include thin corpus callosum, hypoplasia of basal ganglia or PCH-like conditions, thus potentially increasing the number of differential diagnoses. For example, tubulinopathies may show abnormalities of the corpus callosum and basal ganglia [ 36 ], while PCHs, especially some non-progressive forms such as CASK -related, VLDRL -related and RELN -related PCH, may show a combination of small pons and cerebellum coupled with a simplified gyral pattern [ 37 ]. From a clinical point of view, all of these forms mostly present with microcephaly, global developmental delay and spastic tetraparesis; however, a persistent cyanosis remains a unique diagnostic clue that must be considered in cases of suspected RHM2.…”

Section: Discussionmentioning

confidence: 99%

Neurological and Neuroimaging Features of CYB5R3-Related Recessive Hereditary Methemoglobinemia Type II

et al. 2022

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Recessive hereditary methemoglobinemia (RHM) due to NADH-cytochrome b5 reductase deficiency is a rare disease caused by pathogenic variants in CYB5R3. Unlike type I, in RHM type II (RHM2), the enzymatic defect affects erythrocytes and all body tissues, thus resulting in cyanosis and neurological impairment. Although the first description of RHM2 dates back to the mid-1950s, detailed clinical and neuroimaging information are available for only a few patients. Here, we describe a new patient with RHM2 that harbors an unreported homozygous 31 Kb deletion involving part of CYB5R3, and showing a peculiar neuroimaging pattern resembling a ponto-cerebellar hypoplasia-like condition. A careful review of the available literature was performed with the aim of better delineating neurological and neuroimaging as well as the genotypic spectra of this extremely rare disease.

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Pontocerebellar Hypoplasia: a Pattern Recognition Approach

Cited by 39 publications

References 94 publications

Clinical and radiological correlates of activities of daily living in cerebellar atrophy caused by PMM2 mutations (PMM2-CDG)

Clinical and radiological correlates of activities of daily living in cerebellar atrophy caused by PMM2 mutations (PMM2-CDG)

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Neurological and Neuroimaging Features of CYB5R3-Related Recessive Hereditary Methemoglobinemia Type II

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