Search Results (11)

Pontocerebellar hypoplasia (PCH) encompasses a group of autosomal recessive neurodegenerative disorders marked by cerebellar and pontine atrophy. Multiple subtypes of PCH have been identified, among which the rare subtype PCH type 16 is caused by MINPP1 genetic variants. MINPPI encodes an enzyme essential for inositol polyphosphate dephosphorylation, regulating calcium and iron homeostasis. We conducted genome sequencing on a proband from the consanguineous family, who presented with a severe neurodegenerative disorder, to identify the underlying cause of disease. A comprehensive clinical assessment in addition to neuroradiological findings are described. We performed the functional validation of the identified variant and conducted untargeted metabolomic analyses. The clinical and radiological assessment of the patient showed a congenital brain anomaly and neurodegenerative symptoms. Further genetic analysis identified a homozygous loss-of-function variant (c.1401del, p.Ser468Valfs10*) in MINPP1, providing molecular confirmation of a clinical PCH diagnosis. While real-time quantitative PCR (RT-qPCR) showed that MINPP1 gene expression was unaffected in the proband, Western blot analysis demonstrated reduced protein abundance, supporting a pathogenic role of the variant. Metabolomic profiling revealed elevated lipid levels and disrupted inositol metabolism, providing further insights into the disease mechanism. These findings establish the pathogenicity of the p.Ser468Valfs10* variant in MINPP1 and highlight inositol metabolism as a potential pathway involved in PCH16, advancing the understanding of the pathophysiology of the disease. Full article

Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders. Full article

We describe the case of a 63-year-old man with pontocerebellar hypoplasia without the claustrum (CL). The patient had a history of cerebral palsy, intelligent disability, cerebellar atrophy, and seizures since birth. At age 61, brain computed tomography (CT) revealed significant cerebellar and brainstem atrophy. At age 63, he was admitted to our hospital for aspiration pneumonia. Although he was treated with medications, including antibiotics, he died one month after admission. The autopsy revealed a total brain weight of 815 g, with the small-sized frontal lobe, cerebellum, and pons. The cross-section of the fourth ventricle had a slit-like appearance, rather than the typical diamond shape. In addition, bilateral CLs were not observed. Apart from CL, no other missing brain tissue or cells could be identified. Microscopic examinations disclosed neurofibrillary tangles in the hippocampus but not in the cortex; however, neither senile plaques nor Lewy bodies were detected. No acquired lesions, including cerebral infarction, hemorrhage, or necrosis, were noted. We pathologically diagnosed the patient with pontocerebellar hypoplasia without CL. As there have been no prior reports of pontocerebellar hypoplasia lacking CL in adults, this case may represent a new subtype. Congenital CL deficiency is likely associated with abnormalities in brain development. CL may play a role in seizure activity, and the loss of bilateral CLs does not necessarily result in immediate death. Further studies are needed to clarify the functions of CL. Full article

Thrombotic microangiopathy (TMA) in association with RNA exosome encoding mutations has only recently been recognized. Here, we present an infant (female) with an EXOSC5 mutation (c.230_232del p.Glu77del) associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA. At the age of four months, she presented with signs of septic illness, after which she developed TMA. A stool culture showed rotavirus as a potential trigger. The patient received eculizumab once, alongside supportive treatment, while awaiting diagnostic analysis of TMA, including genetic complement analysis, all of which were negative. Eculizumab was withdrawn and the patient’s TMA recovered quickly. A review of the literature identified an additional four patients (age < 1 year) who developed TMA after a viral trigger in the presence of mutations in EXOSC3. The recurrence of TMA in one of these patients with an EXOSC3 mutation while on eculizumab treatment underscores the apparent lack of responsiveness to C5 inhibition. In conclusion, mutations in genes influencing the RNA exosome, like EXOSC3 and EXOSC5, characterized by neurodevelopment and neurodegenerative disorders could potentially lead to TMA in the absence of complement dysregulation. Hence, these patients were likely non-responsive to eculizumab. Full article

The number of genes implicated in neurodevelopmental conditions is rapidly growing. Recently, variants in PPP2R1A have been associated with syndromic intellectual disability and a consistent, but still expanding, phenotype. The PPP2R1A gene encodes a protein subunit of the serine/threonine protein phosphatase 2A enzyme, which plays a critical role in cellular function. We report an individual showing pontocerebellar hypoplasia (PCH), microcephaly, optic and peripheral nerve abnormalities, and an absence of typical features like epilepsy and an abnormal corpus callosum. He bears an unreported variant in an atypical region of PPP2R1A. In silico studies, functional analysis using immunofluorescence, and super-resolution microscopy techniques were performed to investigate the pathogenicity of the variant. This analysis involved a comparative analysis of the patient’s fibroblasts with both healthy control cells and cells from an individual with the previously described phenotype. The results showed reduced expression of PPP2R1A and the presence of aberrant protein aggregates in the patient’s fibroblasts, supporting the pathogenicity of the variant. These findings suggest a potential association between PPP2R1A variants and PCH, expanding the clinical spectrum of PPP2R1A-related neurodevelopmental disorder. Further studies and descriptions of additional patients are needed to fully understand the genotype–phenotype correlation and the underlying mechanisms of this novel phenotype. Full article

Pontocerebellar hypoplasia (PCH) is an autosomal recessive, neurodegenerative disorder with multiple subtypes leading to severe neurodevelopmental disabilities. PCH type 1 D is linked to alterations in the EXOSC9 gene. EXOSC9 is a component of the RNA exosome, an evolutionarily conserved ribonuclease complex essential for RNA degradation and processing. The clinical phenotype is characterized by cerebellar and pontine hypoplasia associated with motor neuronopathy. To date, nine patients have been reported in the literature with PCH1D. We report the case of an infant with PCH type 1D due to two variants in the EXOCS9 gene (NM_001034194.1: c.41T>C-p.Leu14Pro) and a novel variant (c.643C>T-p.Arg212*). This report thoroughly reviews the literature PCH1D and highlights the crucial role of the exosome in cellular homeostasis. Full article

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. Full article

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. Full article

SLC25A46 (solute carrier family 25 member 46) mutations have been linked to various neurological diseases with recessive inheritance, including Leigh syndrome, optic atrophy, and lethal congenital pontocerebellar hypoplasia. SLC25A46 is expressed in the outer membrane of mitochondria, where it plays a critical role in mitochondrial dynamics. A deceased 7-month-old female infant was suspected to have Leigh syndrome. Clinical exome sequencing was non-diagnostic, but research reanalysis of the sequencing data identified two novel variants in SLC25A46: a missense (c.1039C>T, p.Arg347Cys; NM_138773, hg19) and a donor splice region variant (c.283+5G>A) in intron 1. Both variants were predicted to be damaging. Sanger sequencing of cDNA detected a single missense allele in the patient compared to control, and the SLC25A46 transcript levels were also reduced due to the splice region variant. Additionally, Western blot analysis of whole-cell lysate showed a decrease of SLC25A46 expression in proband fibroblasts, relative to control cells. Further, analysis of mitochondrial morphology revealed evidence of increased fragmentation of the mitochondrial network in proband fibroblasts, compared to control cells. Collectively, our findings suggest that these novel variants in SLC24A46, the donor splice one and the missense variant, are the cause of the neurological phenotype in this proband. Full article

In the study of cerebellar degenerative diseases, morphologic imaging (computed tomography, CT and magnetic resonance imaging, MRI) is the most common examination. From the clinical and genetic point of view, cerebellar degenerative diseases include heterogeneous conditions in which MRI may show isolated cerebellar atrophy or cerebellar atrophy associated with other cerebellar or supratentorial abnormalities. Neuroradiological progression is often observed. In congenital disorders of glycosylation (CDG), for example, MRI may be normal, may demonstrate mild cerebellar atrophy or, in the advanced stages of the disease, marked atrophy of the cerebellar hemispheres and vermis associated with the abnormal signal intensity of the cerebellar cortex and white matter and brainstem hypotrophy. In spinal cerebellar ataxias (SCAs), very rare in the pediatric population, MRI may demonstrate isolated cerebellar atrophy or cerebellar and brainstem atrophy. MRI shows characteristic findings in other diseases, strongly suggesting a distinct disorder, such as neuroaxonal dystrophy, ARSACS, ataxia-telangiectasia, or precise mitochondrial diseases. An example of neurodegenerative disorder with prenatal onset is pontocerebellar hypoplasia (PCH). PCH represents a group of neurodegenerative disorders characterized by microcephaly, early cerebellar hypoplasia, and variable atrophy of the cerebellum and ventral pons, genetically divided into several subtypes. Cerebellar hypoplasia visible on MRI is often the first sign that suggests the clinical diagnosis. In most cases, the PCH subtype may demonstrate a characteristic pattern distinguishable at MRI. Selective involvement of the cerebellum, sometimes accompanied by brainstem or supratentorial abnormalities in different combinations, may help restrict the differential diagnosis and may address the specific molecular screening. Full article

Acquisition of detailed anatomical and molecular knowledge from intact biological samples while preserving their native three-dimensional structure is still a challenging issue for imaging studies aiming to unravel a system’s functions. Three-dimensional micro-CT X-ray imaging with a high spatial resolution in minimally perturbed naive non-transparent samples has recently gained increased popularity and broad application in biomedical research. Here, we describe a novel X-ray-based methodology for analysis of β-galactosidase (lacZ) reporter-driven gene expression in an intact murine brain ex vivo by micro-CT. The method relies on detection of bromine molecules in the product of the enzymatic β-galactosidase reaction. Enhancement of the X-ray signal is observed specifically in the regions of the murine brain where expression of the lacZ reporter gene is also detected histologically. We performed quantitative analysis of the expression levels of lacZ reporter activity by relative radiodensity estimation of the β-galactosidase/X-gal precipitate in situ. To demonstrate the feasibility of the method, we performed expression analysis of the Tsen54-lacZ reporter gene in the murine brain in a semi-quantitative manner. Human mutations in the Tsen54 gene cause pontocerebellar hypoplasia (PCH), a group of severe neurodegenerative disorders with both mental and motor deficits. Comparing relative levels of Tsen54 gene expression, we demonstrate that the highest Tsen54 expression is observed in anatomical brain substructures important for the normal motor and memory functions in mice. Full article