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Cerebellum (London, England) Oct 2023Pontocerebellar-hypoplasia (PCH) related to TSEN54-gene mutation, a rare autosomal recessive disorder, can be associated with three different phenotypes: PCH2A, PCH4...
Pontocerebellar-hypoplasia (PCH) related to TSEN54-gene mutation, a rare autosomal recessive disorder, can be associated with three different phenotypes: PCH2A, PCH4 and PCH5. Prenatal imaging features are very scant, in particular for PCH4 and PCH5. The aim of this letter is to illustrate key role of prenatal MR imaging in better evaluation of the cerebellar vermis-hemispheres and pons, which may lead to the differential diagnosis between three PCH TSEN54-related phenotypes already at mid-gestation based on the pattern of the degree of involvement of the vermis and the cerebellar cortex respectively.
Topics: Pregnancy; Female; Humans; Cerebellum; Cerebellar Diseases; Olivopontocerebellar Atrophies; Nervous System Malformations; Magnetic Resonance Imaging; Endoribonucleases
PubMed: 35962274
DOI: 10.1007/s12311-022-01457-6 -
American Journal of Medical Genetics.... Jul 2023Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and...
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and cognitive impairments, microcephaly, distinctive facial features, and other features according to the type. Several classes of PCH1 have been linked to mutations in the evolutionarily conserved RNA exosome complex that consists of nine subunits (EXOSC1 to EXOSC9) and facilitates the degradation and processing of cytoplasmic and nuclear RNA from the 3' end. Only a single individual with an EXOSC1 mutation was reported with clinical features of PCH type 1 (PCH1F). Here, we report a 3-month-old female with PCH and additional clinical features not previously reported to be associated with PCH1, including dilated cardiomyopathy. On assessment, failure to thrive, microcephaly, distinctive facial features, and bluish sclera, were noted. Whole-exome sequencing was performed and revealed a novel homozygous missense variant c.547C > T (p.Arg183Trp) in the EXOSC1 gene. Functional studies in a budding yeast model that expresses the human EXOSC1 variant Arg183Trp show a slow-growth phenotype, whereas the previously identified PCH1F allele EXOSC1-Ser35Leu is lethal, indicating impaired exosome function for both of these variants. The protein levels of both EXOSC1 variants are reduced compared with wild-type when expressed in budding yeast. Herein, we ascertain the second case of PCH associated with a EXOSC1 variant that causes defects in RNA exosome function and provide a model organism system to distinguish between benign and pathogenic variants in EXOSC1.
Topics: Humans; Female; Infant; Microcephaly; Cerebellar Diseases; Olivopontocerebellar Atrophies; Mutation; Nervous System Malformations; Exosome Multienzyme Ribonuclease Complex; RNA-Binding Proteins
PubMed: 37024942
DOI: 10.1002/ajmg.a.63198 -
American Journal of Medical Genetics.... Nov 2020The CAMK2B gene encodes the β-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2), an enzyme that has crucial roles in synaptic plasticity, especially in...
Severe intellectual disability, absence of language, epilepsy, microcephaly and progressive cerebellar atrophy related to the recurrent de novo variant p.(P139L) of the CAMK2B gene: A case report and brief review.
The CAMK2B gene encodes the β-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2), an enzyme that has crucial roles in synaptic plasticity, especially in hippocampal and cerebellar neurons. Heterozygous variants in CAMK2B cause a rare neurodevelopmental disorder, with 40% of the reported cases sharing the same variant: c.416C>T, p.(P139L). This case report describes a 22-year-old patient with this recurrent variant, who presents with severe intellectual disability, absence of language, hypotonia, microcephaly, dysmorphic features, epilepsy, behavioral abnormalities, motor stereotypies, optic atrophy, and progressive cerebellar atrophy. Notably, this patient is the oldest reported so far and allows us to better delineate the clinical phenotype associated with this variant, adding clinical aspects never described before, such as epilepsy, optic atrophy, scoliosis, and neuroradiological changes characterized by progressive cerebellar atrophy.
Topics: Adult; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Epilepsy; Female; Humans; Intellectual Disability; Language Disorders; Mutation; Olivopontocerebellar Atrophies; Phenotype; Prognosis; Young Adult
PubMed: 32875707
DOI: 10.1002/ajmg.a.61803 -
Journal of Neuroimmunology Dec 2020To identify biomarkers for multiple system atrophy-cerebellar type (MSA-C), we used flow cytometry to measure surface marker expression of peripheral blood monocytes...
To identify biomarkers for multiple system atrophy-cerebellar type (MSA-C), we used flow cytometry to measure surface marker expression of peripheral blood monocytes from patients with MSA-C or hereditary spinocerebellar degeneration (hSCD) and from healthy controls (HCs). The percentage of intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs and showed significant positive correlations with disease duration and unified MSA rating scale scores. The percentage of CD62L intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs. Early decrease of peripheral blood intermediate monocytes is characteristic of MSA-C and is a biomarker.
Topics: Aged; Cerebellum; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Monocytes; Multiple System Atrophy; Olivopontocerebellar Atrophies
PubMed: 32977251
DOI: 10.1016/j.jneuroim.2020.577395 -
Epilepsia Open Feb 2024Defects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial...
OBJECTIVE
Defects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial disease. Here, we report two male patients and their respective family histories.
METHODS
We describe the clinical presentation and magnetic resonance imaging (MRI) findings of these patients. Whole-exome sequencing was used to identify the genetic mutations.
RESULTS
One patient showed hypoglycemia, high lactic acid levels (fluctuating from 6.7 to 14.1 mmol/L), and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and pons. The other patient presented with early infantile developmental and epileptic encephalopathies (EIDEEs) with an initial developmental delay followed by infantile epileptic spasm syndrome (IESS) at 5 months old, with no imaging changes. Whole-exome sequencing identified compound heterozygous RARS2 variants c.25A>G (p.I9V) with c.1261C>T (p.Q421*) and c.1A>G (p.M1V) with c.122A>G (p.D41G) in these two patients. Of these loci, c.1261C>T and c.122A>G have not been previously reported.
SIGNIFICANCE
Our findings have expanded the RARS2 gene variant spectrum and present EIDEEs and IESS as phenotypes which deepened the association between PCH6 and RARS2.
PLAIN LANGUAGE SUMMARY
Defects in RARS2 cause cerebellopontine hypoplasia type 6, a rare autosomal recessive inherited mitochondrial disease. Two patients with RARS2 variants were reported in this article. One patient showed hypoglycemia, high lactic acid levels, and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and Page 3 of 21 Epilepsia OpenFor Review Only pons. The other patient presented with an initial developmental delay followed by refractory epilepsy at 5 months old, with no imaging changes. Our findings deepened the association between PCH6 and RARS2.
Topics: Infant; Humans; Male; Seizures; Epilepsy, Generalized; Atrophy; Mitochondrial Diseases; Lactic Acid; Hypoglycemia; Arginine-tRNA Ligase; Olivopontocerebellar Atrophies
PubMed: 38009286
DOI: 10.1002/epi4.12862 -
Clinical Nuclear Medicine Sep 2020Olivopontocerebellar atrophy is a rare neurodegenerative syndrome associated with 2 distinct disorders: multiple system atrophy and spinocerebellar ataxia. We present a...
Olivopontocerebellar atrophy is a rare neurodegenerative syndrome associated with 2 distinct disorders: multiple system atrophy and spinocerebellar ataxia. We present a case involving a 66-year-old man with adult-onset progressing cerebellar signs reflective of a cerebellar syndrome with no significant family history and unremarkable genetic testing for spinocerebellar ataxia. This case was found to be most consistent with sporadic olivopontocerebellar atrophy, which falls under the multiple system atrophy category. This diagnosis can be made using F-FDG PET/CT scanning and with MRI in some cases. However, in this case, relatively new PET/CT quantification and parametric imaging software was used for analysis, CortexID Suite.
Topics: Aged; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Olivopontocerebellar Atrophies; Positron Emission Tomography Computed Tomography
PubMed: 32657870
DOI: 10.1097/RLU.0000000000003180 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Nov 2020To summarize the clinical features of two early onset epileptic encephalopathy (EOEE) patients with arginyl-tRNA synthetase (RARS2) gene variations and to review... (Review)
Review
To summarize the clinical features of two early onset epileptic encephalopathy (EOEE) patients with arginyl-tRNA synthetase (RARS2) gene variations and to review related literature. The clinical data and genetic features of two pontocerebellar hypoplasia type 6 (PCH6) patients with RARS2 variation diagnosed by the Department of Neurology, Beijing Children's Hospital from January 2017 to December 2018 were analyzed retrospectively. A literature search with "RARS2" "pontocerebellar hypoplasia type 6" and "early onset epileptic encephalopathy" as key words was conducted at China national knowledge infrastructure (CNKI), Wanfang Data Knowledge Service Platform and PubMed (up to May 2020), literature about RARS2 gene variation patients and their complete clinical data were chosen and reviewed. The onset age of the two cases (1 male, 1 female) were 2 months and 29 days respectively and the early onset symptom of them was epileptic encephalopathy. The main symptoms included seizures, development delay, microcephaly and lactic acidosis. In addition to these symptoms, the female also had dyspnea, hypoglycemia and metabolic acidosis after birth. Brain magnetic resonance imaging (MRI) of the two patients were normal at first. Follow up at four-month (case 1) and eight-month (case 2) MRI showed atrophy of cerebral and cerebellar, but the pons was not affected. All four heterozygous variations in RARS2 gene revealed by whole-exome sequencing (p.Arg560His and p.Arg6His from case 1, p.Arg254Trp and p.Phe5Ser from case 2) were novel. No eligible reports were found in Chinese journals, while 17 reports were found in English literature. Excluded cases with incomplete data together with these two cases, a total of 34 patients from 20 families were found. All patients had developmental delay while 94% (32/34) patients showed the initial symptoms within 3 months, 93% (28/30) patients were diagnosed as epilepsy, 89% (25/28) patients had progressively microcephaly and 52% (16/31) cases did not show the pons atrophy on brain MRI. Twenty of 28 cases (71%) were refractory epilepsy. There were 31 types of gene variations and most of them were missense variations (21/31, 68%). The majority of PCH6 cases caused by RARS2 gene variation show the initial symptoms within 3 months, characterized by EOEE, most of them are refractory epilepsy, accompanied by developmental delay, microcephaly and increased lactic acid. Brain MRI indicates progressive cerebral or pontocerebellar atrophy.
Topics: Arginine-tRNA Ligase; Child; China; Epilepsy; Female; Humans; Magnetic Resonance Imaging; Male; Mutation; Olivopontocerebellar Atrophies; Retrospective Studies
PubMed: 33120460
DOI: 10.3760/cma.j.cn112140-20200716-00729 -
European Journal of Medical Genetics Mar 2020Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy caused by biallelic mutations in RARS2 that encodes the mitochondrial...
Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with edema, Hypsarrhythmia and Optic atrophy). The proband presented with severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly conserved amino acid and a frameshift variant with consequent degradation of the transcript resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO syndrome patients. The study highlights the challenges in clinical diagnosis of patients with neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI findings.
Topics: Alleles; Arginine-tRNA Ligase; Brain Edema; Cerebellum; Epilepsy; Frameshift Mutation; Humans; Infant; Intellectual Disability; Magnetic Resonance Imaging; Male; Microcephaly; Muscle Hypotonia; Mutation, Missense; Neurodegenerative Diseases; Nuclear Proteins; Olivopontocerebellar Atrophies; Optic Atrophy; Phenotype; Seizures; Spasms, Infantile; Transcription Factors
PubMed: 31536827
DOI: 10.1016/j.ejmg.2019.103766 -
Journal of Neural Transmission (Vienna,... Feb 2020Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized by striatonigral degeneration and olivopontocerebellar atrophy. The main hallmark of...
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized by striatonigral degeneration and olivopontocerebellar atrophy. The main hallmark of MSA is the aggregation of alpha-synuclein in oligodendrocytes, which contributes to the dysfunction and death of the oligodendrocytes, followed by neurodegeneration. Studies suggested that oxidative-excitatory pathway is associated with the progression of the disease. The aim of the current study was to test this concept by overexpression of excitatory amino acid transporter 2, glutamate dehydrogenase and nuclear factor (erythroid-derived 2)-related factor 2 genes in the striatum of two established mouse models of MSA. To induce the first model, we injected the mitochondrial neurotoxin, 3-nitropropionic acid (3-NP), unilaterally into the right striatum in 2-month-old C57BL/6 male mice. We demonstrate a significant improvement in two drug-induced rotational behavior tests, following unilateral injection the three genes. For the second model, we used transgenic mice expressing the alpha-synuclein gene under the proteolipid protein, in the age of 7 months, boosted with 3-NP to enhance the motor deficits and neurodegeneration. We show that the overexpression of the three genes attenuated the motor-related deficit in the elevated bridge and pole tests. Thus, our study indicates that glutamate excito-oxidative toxicity plays a major role in this MSA model and our gene therapy approach might suggest a novel strategy for MSA treatment.
Topics: Animals; Behavior, Animal; Convulsants; Corpus Striatum; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Genetic Therapy; Glutamate Dehydrogenase; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple System Atrophy; NF-E2-Related Factor 2; Nitro Compounds; Propionates
PubMed: 32065333
DOI: 10.1007/s00702-020-02158-2 -
Journal of Human Genetics Apr 2021Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing....
Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.
Topics: Atrophy; Cerebellar Diseases; Exosome Multienzyme Ribonuclease Complex; Female; Genetic Association Studies; Humans; Infant; Male; Motor Neuron Disease; Muscular Atrophy, Spinal; Mutation; Olivopontocerebellar Atrophies; Pedigree; RNA-Binding Proteins
PubMed: 33040083
DOI: 10.1038/s10038-020-00853-2