CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63.
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ABSTRACT:
SUBMITTER: Marsh APL
PROVIDER: S-EPMC6303251 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
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CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63.
Marsh Ashley P L APL Novarino Gaia G Lockhart Paul J PJ Leventer Richard J RJ
European journal of human genetics : EJHG 20180808 1
1. NAME OF DISEASE (SYNONYMS): Pontocerebellar hypoplasia type 9 (PCH9) and spastic paraplegia-63 (SPG63). 2. OMIM# OF THE DISEASE: 615809 and 615686. 3. NAME OF THE ANALYSED GENES OR DNA/CHROMOSOME SEGMENTS: AMPD2 at 1p13.3. 4. OMIM# OF THE GENE(S): 102771. ...[more]
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Project description:BACKGROUND:Pontocerebellar hypoplasia type 2 (PCH2) is caused by a defect in the TSEN54-gene and leads to severe and early disruption of brain development, especially of cerebellum and pons. The aim of this work was to quantify the infra- and supratentorial brain growth during postnatal brain development in children with PCH2. METHODS:MRI data of 24 children with PCH2 (age 0.02-17 years., 13 females) were analysed volumetrically and compared to images of 24 typically developing age- and gender-matched children. All children with PCH2 had the homozygous p.A307S mutation in the TSEN54-gene. In 5 patients follow-up MRI investigations were available. Images of the children with PCH2 were available either on film (n?=?12) or in digital format (n?=?21). Images on film were digitalized. Brain structures were manually masked and further adjusted semi-automatically using intensity thresholding to exclude CSF. Volumes of cerebellum, brain stem, and pons were measured, as well as supratentorial brain and frontal lobe volume. For validation of the method part of the digital images were processed as images on film. In addition, intra- and inter-rater variabilities were tested. RESULTS:Children with PCH2 showed reduced volumes of all measured brain structures compared to healthy controls. Severely hypoplastic cerebellum, pons and brain stem only slightly increased in size postnatally. Supratentorial brain volume also showed reduced growth compared to the healthy controls. Differences between patients and controls could already be seen at birth but became more significant during childhood. Validation of the method showed high precision and reproducibility. CONCLUSIONS:In a genetically very homogenous group of children with PCH2 severely hypoplastic infratentorial structures, the hallmark of the disease, showed only slight increase in volume postnatally. Supratentorial brain structures, which are considered normal at birth, also showed smaller volumes neonatally and a lower growth rate compared to controls, leading to severe microcephaly. Volume loss, however, could not be observed during the first years of life. This argues for a severe disruption of the cerebellar-cerebral networks during pre- and postnatal development caused by a primary cerebellar dysfunction, rather than postnatal neurodegeneration. The developmental progress in these children, although little, further supports this.
| S-EPMC4950429 | biostudies-literature
Project description:INTRODUCTION: Pontocerebellar hypoplasia Type 2 (PCH2) is a rare autosomal recessive condition, defined on MRI by a small cerebellum and ventral pons. Clinical features are severe developmental delay, microcephaly and dyskinesia.Ninety percent carry a p.A307S mutation in the TSEN54-gene. Our aim was to describe the natural course including neurological and developmental features and other aspects of care in a homogeneous group of PCH2 patients all carrying the p.A307S mutation. PATIENTS AND METHODS: Patients were recruited via the German patients' organizations. Inclusion criteria were imaging findings of PCH2 and a p.A307S mutation. Data were collected using medical reports and patient questionnaires discussed in a standardized telephone interview. RESULTS: Thirty-three patients were included. When considering survival until age 11 years, 53% of children had died Weight, length and head circumference, mostly in the normal range at birth, became abnormal, especially head circumference (-5.58 SD at age 5 yrs). Neurologic symptoms: Choreathetosis was present in 88% (62% with pyramidal signs), 12% had pure spasticity. Epileptic seizures were manifest in 82%, status epilepticus in 39%. Non-epileptic dystonic attacks occurred in 33%. General symptoms: feeding difficulties were recorded in 100%, sleep disorder in 96%, apneas in 67% and recurrent infections in 52%; gastroesophageal reflux disease was diagnosed in 73%, 67% got percutaneous endoscopic gastrostomy and 36% a Nissen-fundoplication. Neurodevelopmental data: All children made progress, but on a low level: such as fixing and following with the eyes was seen in 76%, attempting to grasp objects (76%), moderate head control (73%), social smile (70%), rolling from prone to supine (58%), and sitting without support (9%). Ten percent lost achieved abilities on follow-up. The presence of prenatal symptoms did not correlate with outcome. CONCLUSION: Phenotype of this genetically homogeneous group of PCH2 children was severe with reduced survival, but compatible with some developmental progress. Our data support the hypothesis of an early onset degeneration which thereafter stabilizes.
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Project description:Pontocerebellar hypoplasia (PCH) is a group of autosomal recessive neurodegenerative disorders characterized by prenatal onset of stunted brain growth and progressive atrophy predominantly affecting cerebellum, pons and olivary nuclei, and to a lesser extent also the cerebral cortex. Six subtypes (PCH1-6) were described and genes for four types (PCH1, 2, 4 and 6) were identified. Mutations in the tRNA splicing endonuclease subunit (TSEN) genes 54, 2 and 34 are found in PCH2 and PCH4. One family with severe prenatal onset of PCH has been the only representative of PCH5 published so far, and the molecular genetic status of PCH5 has not been ascertained until now. We screened the previously reported PCH5 family for mutations in the TSEN54 gene. The PCH5 patient was found to be the result of compound heterozygosity for the common TSEN54 mutation (p.A307S) plus a novel splice site mutation. The mutations associated with PCH5 are similar to what has been reported in PCH4. Thus, PCH5, PCH4 and PCH2 represent a spectrum of clinical manifestations caused by different mutations in the TSEN genes. We, therefore, propose to classify PCH2, PCH4 and PCH5 as TSEN mutation spectrum disorders.
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Project description:Pontocerebellar hypoplasia type 2 (PCH-2; MIM 277470), an autosomal recessive neurodegeneration with fetal onset, was studied in six autopsies with ages at death ranging between 1 and 22 years. Three patients were distantly related. A case of olivopontocerebellar hypoplasia (OPCH; MIM 225753) was studied for comparison. Typical findings are: short cerebellar folia with poor branching ("hypoplasia"), relative sparing of the vermis, sharply demarcated areas of full thickness loss of cerebellar cortex probably resulting from regression at an early stage of development, segmental loss of dentate nuclei with preserved islands and reactive changes, segmental loss in the inferior olivary nucleus with reactive changes, loss of ventral pontine nuclei with near absence of transverse pontine fibers and sparing of spinal anterior horn cells. Variable findings are: cystic cerebellar degeneration, found in two, with vascular changes limited to the cerebellum in one. Comparison to olivopontocerebellar hypoplasia (OPCH) strongly suggests a continuum of pathology between this disorder and PCH-2. Immunohistochemical evaluation of the endoplasmic reticulum stress response is negative. We conclude that the neuropathological findings in PCH-2 are sufficiently specific to enable an unequivocal diagnosis based on neuropathology.
| S-EPMC2039791 | biostudies-literature
Project description:Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra- and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.
| S-EPMC5413457 | biostudies-literature
Project description:Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroimaging and genetic findings. Individuals with PCH type 9 (PCH9) have a unique combination of postnatal microcephaly, hypoplastic cerebellum and pons, and hypoplastic or absent corpus callosum. PCH9 is caused by biallelic variants in AMPD2 encoding adenosine monophosphate deaminase 2; however, a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63). We identified homozygous or compound heterozygous AMPD2 variants in eight PCH-affected individuals from six families. The eight variants likely affect function and comprise one frameshift, one nonsense and six missense variants; seven of which were novel. The main clinical manifestations in the eight new patients and 17 previously reported individuals with biallelic AMPD2 variants were postnatal microcephaly, severe global developmental delay, spasticity, and central visual impairment. Brain imaging data identified hypomyelination, hypoplasia of the cerebellum and pons, atrophy of the cerebral cortex, complete or partial agenesis of the corpus callosum and the "figure 8" shape of the hypoplastic midbrain as consistent features. We broaden the AMPD2-related clinical spectrum by describing one individual without microcephaly and absence of the characteristic "figure 8" shape of the midbrain. The existence of various AMPD2 isoforms with different functions possibly explains the variability in phenotypes associated with AMPD2 variants: variants leaving some of the isoforms intact may cause SPG63, while those affecting all isoforms may result in the severe and early-onset PCH9.
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Project description:ObjectivesPontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1. We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotype-phenotype correlation.MethodsWe documented clinical, neuroimaging, and morphologic data of 37 subjects from 27 families with PCH1. EXOSC3 gene sequencing was performed in 27 unrelated index patients of mixed ethnicity.ResultsBiallelic mutations in EXOSC3 were detected in 10 of 27 families (37%). The most common mutation among all ethnic groups was c.395A>C, p.D132A, responsible for 11 (55%) of the 20 mutated alleles and ancestral in origin. The mutation-positive subjects typically presented with normal pregnancy, normal birth measurements, and relative preservation of brainstem and cortical structures. Psychomotor retardation was profound in all patients but lifespan was variable, with 3 subjects surviving beyond the late teens. Abnormal oculomotor function was commonly observed in patients surviving beyond the first year. Major clinical features previously reported in PCH1, including intrauterine abnormalities, postnatal hypoventilation and feeding difficulties, joint contractures, and neonatal death, were rarely observed in mutation-positive infants but were typical among the mutation-negative subjects.ConclusionEXOSC3 mutations account for 30%-40% of patients with PCH1 with variability in survival and clinical severity that is correlated with the genotype.
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Project description:Mutations of EXOSC3 have been linked to the rare neurological disorder known as Pontocerebellar Hypoplasia type 1B (PCH1B). EXOSC3 is one of three putative RNA-binding structural cap proteins that guide RNA into the RNA exosome, the cellular machinery that degrades RNA. Using RNAcompete, we identified a G-rich RNA motif binding to EXOSC3. Surface plasmon resonance (SPR) and microscale thermophoresis (MST) indicated an affinity in the low micromolar range of EXOSC3 for long and short G-rich RNA sequences. Although several PCH1B-causing mutations in EXOSC3 did not engage a specific RNA motif as shown by RNAcompete, they exhibited lower binding affinity to G-rich RNA as demonstrated by MST. To test the hypothesis that modification of the RNA-protein interface in EXOSC3 mutants may be phenocopied by small molecules, we performed an in-silico screen of 50 000 small molecules and used enzyme-linked immunosorbant assays (ELISAs) and MST to assess the ability of the molecules to inhibit RNA-binding by EXOSC3. We identified a small molecule, EXOSC3-RNA disrupting (ERD) compound 3 (ERD03), which ( i) bound specifically to EXOSC3 in saturation transfer difference nuclear magnetic resonance (STD-NMR), ( ii) disrupted the EXOSC3-RNA interaction in a concentration-dependent manner, and ( iii) produced a PCH1B-like phenotype with a 50% reduction in the cerebellum and an abnormally curved spine in zebrafish embryos. This compound also induced modification of zebrafish RNA expression levels similar to that observed with a morpholino against EXOSC3. To our knowledge, this is the first example of a small molecule obtained by rational design that models the abnormal developmental effects of a neurodegenerative disease in a whole organism.
| S-EPMC6504997 | biostudies-literature
Project description:BACKGROUND: Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. METHODS: We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. RESULTS: EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. CONCLUSIONS: EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.
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Project description:Variants in FA2H have been associated with a wide range of phenotypes including hereditary spastic paraplegia type 35 (SPG35); however, genetically confirmed cases have not been reported in Africa. We report here the first African family with a variant in the FA2H gene causing SPG35. Four affected siblings with consanguineous parents presented with walking difficulty at age 2-3 and progressive limb weakness. They became wheelchair-bound 2 years after disease onset. Neurological examination confirmed lower greater than upper limb weakness and atrophy, brisk reflexes throughout, and spasticity with scissor legs. The patients also had choking, urinary urgency, and mental retardation. A brain MRI showed thin corpus callosum and periventricular leucodystrophy. Testing of 58 SPG genes showed a homozygous variant in FA2H at the exon 5 donor site c.786+1G>A, which has previously been shown to cause skipping of exons 5 and 6 of the gene transcript. This variant segregated with the disease in the family. This variant has been reported previously with a similar phenotype and slow progression in a population with different background. Here, we confirm its pathogenicity and expand its genetic epidemiology. Studying diverse populations may help to increase understanding of the disease mechanism and ultimately lead to therapeutic targets.
| S-EPMC6557683 | biostudies-literature