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Genotype–phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease

INSERM U384, Faculté de Médecine, Clermont-Ferrand, France.
European Journal of HumanGenetics (Impact Factor: 4.23). 12/2000; 8(11):837-45. DOI: 10.1038/sj.ejhg.5200537
Source: PubMed

ABSTRACT Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) are X-linked developmental defects of myelin formation affecting the central nervous system (CNS). They differ clinically in the onset and severity of the motor disability but both are allelic to the proteolipid protein gene (PLP), which encodes the principal protein components of CNS myelin, PLP and its spliced isoform, DM20. We investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by genomic PCR amplification and sequencing of the PLP gene. We identified 29 and 4 abnormalities respectively. Patients with PLP mutations presented a large range of disease severity, with a continuum between severe forms of PMD, without motor development, to pure forms of SPG. Clinical severity was found to be correlated with the nature of the mutation, suggesting a distinct strategy for detection of PLP point mutations between severe PMD, mild PMD and SPG. Single amino-acid changes in highly conserved regions of the DM20 protein caused the most severe forms of PMD. Substitutions of less conserved amino acids, truncations, absence of the protein and PLP-specific mutations caused the milder forms of PMD and SPG. Therefore, the interactions and stability of the mutated proteins has a major effect on the severity of PLP-related diseases.

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    • "Missense mutations resulting in nonconservative amino acid substitutions are mostly associated with severe connatal form of PMD. Mutations in the latter half of exon 3 (exon 3B) of PLP1 are an exception because this region is spliced-out in DM20 mRNA and does not affect its expression and function, resulting in a milder form of PMD [1] [2] [3] [4]. Deletions or early truncating mutations are also associated with a milder form of PMD or SPG2 [1–3,5,7,9,10]. "
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    • "Missense mutations resulting in nonconservative amino acid substitutions are mostly associated with severe connatal form of PMD. Mutations in the latter half of exon 3 (exon 3B) of PLP1 are an exception because this region is spliced-out in DM20 mRNA and does not affect its expression and function, resulting in a milder form of PMD [1] [2] [3] [4]. Deletions or early truncating mutations are also associated with a milder form of PMD or SPG2 [1–3,5,7,9,10]. "
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    ABSTRACT: Background Pelizaeus–Merzbacher disease (PMD), a hypomyelinating leukodystrophy, and the related but less severe allelic spastic paraplegia 2 (SPG2) are caused by mutations in the proteolipid protein 1 (PLP1) gene. Magnetic resonance imaging (MRI) is pivotal for diagnosing these disorders. The severity of PMD/SPG2 varies, and for a milder form of PMD, there have been some reports of near-normal findings in T1-weighted images but abnormal findings in T2-weighted images. Patient We report the case of a 5-year-old boy diagnosed with a milder form of PMD caused by a novel PLP1 mutation in exon 3: c.300delC (p.I100IfsX13). He had delayed development from several months of age and was able to walk with support at 19 months in spite of the spasticity in his lower extremities. Hypomyelination was noted at 12 months by brain MRI. Motor nerve conduction studies showed decreased velocities with reduced amplitudes. Follow-up MRI at 1-year intervals from 18 months until 55 months of age showed gradual myelination progress. Discussion The single nucleotide deletion identified in this patient can cause a frameshift and premature termination of PLP1. Via the nonsense-mediated mRNA decay mechanism of this mutation will result in loss-of-function, leading to a milder form of PMD. The present case is compatible with previously reported cases of milder form of PMD. We incidentally identified progressive myelination in this patient by T1-weighted images obtained by serial MRI. This finding adds to our understanding of the pathological stages of a milder form of PMD.
    Brain and Development 07/2014; 37(4). DOI:10.1016/j.braindev.2014.06.011 · 1.54 Impact Factor
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    • "Abnormal spinal integration of sensory information could sustained the pain experiments observed in genetic and inflammatory myelin disorders Plp-null mice reproduce many of the features observed in SPG2 and MS patients. In both myelin diseases, (a) sensitivity to pain is frequently associated with motor symptoms (MS: Michalski et al., 2011; Solaro and Uccelli, 2011; SPG2: Cailloux et al., 2000; Inoue, 2005), (b) the neuropathological defects observed combine CNS demyelination, axonal Fig. 12. Expression of the sensory neuropeptide galanin in the spinal dorsal horn of 3-and 15-month-old Plp-null and wild-type (WT) mice. Photomicrographs showing examples of galanin expression in the dorsal horn of WT and Plp-null mice at 4× and 10× magnifications at 3 months (A) and 15 months (B). "
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    ABSTRACT: Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 (PLP1), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 - mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis.
    Neurobiology of Disease 01/2014; 65. DOI:10.1016/j.nbd.2014.01.005 · 5.20 Impact Factor
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