Familial pontocerebellar hypoplasia type I with anterior horn cell disease

Görgen-Pauly, Ute; Sperner, J.; Reiss, Irwin K M; Gehl, Hans-Björn; Reusche, E.

doi:10.1053/ejpn.1999.0177

Cited by 30 publications

(13 citation statements)

References 16 publications

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“…In few patients without mutations motor nerve conduction velocities were delayed or action potentials could not be elicited in motor or sensory nerves. While the absence of an electric response by nerve conduction studies might be of technical nature in small children, markedly reduced conduction velocities, as also reported in some patients from the literature, 4,18,21,23,24 or reduction of demyelinated nerve fibers in sural nerve biopsies 19,24 might point toward distinct genetic entities.…”

Section: How Mutations Inmentioning

confidence: 72%

“…6 The clinical features associated with "classical" PCH1 with prenatal onset, congenital respiratory and feeding difficulties, arthrogryposis multiplex congenita, and neonatal death are infrequent in patients with EXOSC3 mutations but were most prevalent among the mutation-negative patients and also in the literature. 1,[19][20][21][22][23][24] Electromyographic examinations give evidence of neurogenic changes in the muscle in all patients based on the diagnostic entry criteria. Nerve conduction studies were normal in all patients with EXOSC3 mutations and in the majority of patients without.…”

Section: How Mutations Inmentioning

confidence: 99%

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Pontocerebellar hypoplasia type 1

et al. 2013

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Objectives: Pontocerebellar 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.Methods: We 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.Results: Biallelic 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.Conclusion: EXOSC3 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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Section: How Mutations Inmentioning

confidence: 72%

Section: How Mutations Inmentioning

confidence: 99%

Pontocerebellar hypoplasia type 1

et al. 2013

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“…). Prenatal onset of extended brain malformations have rarely been recorded in PCH1 [Görgen‐Pauly et al, ; Ryan et al, ]. Few patients were described with gonadal dysgenesis [Kamoshita et al, ; Rudnik‐Schöneborn et al, ], and it remains to be identified whether there is a common pathogenetic background for these patients and PCH7.…”

Section: Pch Classification and Defined Subtypesmentioning

confidence: 99%

Pontocerebellar hypoplasia

Rudnik‐Schöneborn¹,

Barth²,

Zerres³

2014

American J of Med Genetics Pt C

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Pontocerebellar hypoplasia (PCH) is a clinically and genetically heterogeneous group of autosomal recessively inherited neurodevelopmental disorders. Following the rapidly increasing number of genes identified in different subtypes, the clinical spectrum has been broadened to completely different neurological phenotypes. In this review we will address the clinical picture, neuroradiological, pathoanatomic, and genetic findings in the currently known PCH subtypes.

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“…3–6 The diagnosis of PCH1 is often delayed or never made because the combination of cerebellar and spinal motor neuron degeneration is not commonly recognized, and the presentation of diffuse weakness and devastating brain involvement is atypical of classical proximal spinal muscular atrophy (SMA) 8 . The literature contains only a handful of case series 9–12 and reports on PCH1 13–19 . The responsible gene has not been identified in the majority of PCH1 patients.…”

mentioning

confidence: 99%

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

et al. 2012

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RNA exosomes are multi-subunit complexes conserved throughout evolution1 and emerging as the major cellular machinery for processing, surveillance, and turnover of a diverse spectrum of coding and non-coding RNA substrates essential for viability2. By exome sequencing, we discovered recessive mutations in exosome component 3 (EXOSC3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly, and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 [PCH1; OMIM 607596]3–6. We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment with small brain and poor motility, reminiscent of human clinical features and largely rescued by coinjected wildtype but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome gene responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

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Familial pontocerebellar hypoplasia type I with anterior horn cell disease

Cited by 30 publications

References 16 publications

Pontocerebellar hypoplasia type 1

Pontocerebellar hypoplasia type 1

Pontocerebellar hypoplasia

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

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