Central nervous system abnormalities in patients with PMP22 gene mutations: a prospective study

Chanson, Jean‐Baptiste; Echaniz‐Laguna, Andoni; Blanc, F.; Lacour, Arnaud; Ballonzoli, Laurent; Kremer, Stéphane; Namer, Izzie Jacques; Lannes, Béatrice; Tranchant, C.; Vermersch, Patrick; Seze, J. de

doi:10.1136/jnnp-2012-303725

Cited by 36 publications

(45 citation statements)

References 26 publications

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“…Additionally, although most often associated with myelinating Schwann cells in the peripheral nervous system, we detected expression of PMP22 in MOL cells, consistent with reports of PMP22 expression in the mature CNS (Ohsawa, Murakami, Miyazaki, Shirabe, & Sunada, ) and CNS pathology reported in some cases of Charcot Marie Tooth peripheral neuropathy due to PMP22 gene duplication (Chanson et al, ).…”

Section: Discussionsupporting

confidence: 91%

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Perlman

Couturier

Yaqubi

et al. 2020

Glia

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Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte‐lineage cells with stage‐specific functional properties. Cells were isolated from surgical tissue samples of second‐trimester fetal, 2‐year‐old pediatric, 13‐year‐old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet‐based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e‐OPC) group, a late OPC group (l‐OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e‐OPCs included cell cycle and development, for l‐OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e‐OPCs were mostly confined to the premyelinating fetal group, and the l‐OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l‐OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL‐lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.

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Section: Discussionsupporting

confidence: 91%

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Perlman

Couturier

Yaqubi

et al. 2020

Glia

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“…Alternatively, alterations in central white matter in Tr J mice may contribute to early lethality, as PMP22 is expressed, albeit at lower levels, in the CNS (45). Consistent with this idea, reductions in the volume of CNS white matter as well as cognitive impairment have been reported in human CMT1A (46). …”

Section: Discussionsupporting

confidence: 65%

Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy

Scurry

Heredia

Feng

et al. 2016

J Neuropathol Exp Neurol

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Mutations in peripheral myelin protein 22 (PMP22) result in the most common form of Charcot-Marie-Tooth (CMT) disease, CMT1A. This hereditary form of peripheral neuropathy is characterized by dysmyelination of peripheral nerves, reduced nerve conduction velocity and muscle weakness. A PMP22 point mutation in leucine 16 to proline (L16P) underlies a form of human CMT1A as well as the Trembler-J mouse model of CMT1A. Homozygote Trembler-J mice (TrJ) die early postnatally, fail to make peripheral myelin, and therefore are more similar to congenital hypomyelinating neuropathy (CHN) than CMT1A. Because recent studies of inherited neuropathies in humans and mice have demonstrated that dysfunction and degeneration of neuromuscular synapses or junctions (NMJs) often precede impairments in axonal conduction, the structure and function of NMJs in end-stage TrJ mice was examined. Although synapses appeared normally innervated even in end-stage TrJ mice, the growth and maturation of the NMJ was altered. In addition, the amplitude of nerve-evoked muscle endplate potentials (EPPs) was reduced and transmission failure during sustained nerve stimulation was observed. These results suggest that the severe congenital hypomyelinating neuropathy that characterizes TrJ mice results in structural and functional deficits of the developing NMJ.

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“…Although always considered a disease affecting the peripheral nervous system, a recent report on 15 CMT1A patients described central nervous system involvement [60]. Decreased white matter volume was found in 73%, with minimal, predominantly executive, cognitive disorders in 77%.…”

Section: Pmp22 Duplication – Charcot-marie-tooth Disease Type 1a (Cmt1a)mentioning

confidence: 99%

PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

Paassen

Kooi

Spaendonck‐Zwarts

et al. 2014

Orphanet J Rare Dis

142

121

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PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal.

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Central nervous system abnormalities in patients with PMP22 gene mutations: a prospective study

Abstract: This study demonstrates that altered PMP22 gene expression induces significant CNS alterations in patients with HNPP and CMT1A, including cerebral WM abnormalities and cognitive impairment.

Cited by 36 publications

References 26 publications

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy

PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

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