Expanding the Clinical and Mutational Spectrum of the PLP1-Related Hypomyelination of Early Myelinated Structures (HEMS)

The PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1 and its isoform DM20. Mutations in PLP1 cause a spectrum of white matter disorders of variable severity. Here we report on four additional HEMS patients from three families harboring three novel PLP1 mutations in exon 3B detected by targeted next-generation sequencing. Patients experienced psychomotor delay or nystagmus in the first year of age and then developed ataxic–spastic or ataxic syndrome, compatible with a phenotype of intermediate severity in the spectrum of PLP1-related disorders. Regression occurred at the beginning of the third decade of the eldest patient. Extrapyramidal involvement was rarely observed. Brain MRI confirmed the involvement of structures that physiologically myelinate early, although the pattern of abnormalities may differ depending on the age at which the study is performed. These new cases contribute to expanding the phenotypic and genotypic spectrum of HEMS. Additional studies, especially enriched by systematic functional evaluations and long-term follow-up, are welcome to better delineate the natural history of this rare hypomyelinating leukodystrophy.

Pelizaeus-Merzbacher Disease with Novel Variant: Case Report

Context: Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, associated with myelin sheath development and stability. The result is a broad spectrum of clinical phenotypes. Diagnosis is confirmed by genetic testing. Clinical features include hypotonia followed by progressive spasticity, nystagmus, ataxia and cognitive impairment. Males are more affected. Females are asymptomatic or present milder symptoms. Most cases arise from duplications, point and null mutations. Null mutations are associated with milder phenotypes. Brain Magnetic Resonance Imaging (MRI) may reveal hypomyelination. There is no disease modifying treatment for PMD. We aim to present the case of a woman with a novel variant of the PLP1 gene. Case report: A 38-year-old female presented with 23 years of progression of upper limb tremor, speech impairment, lower limb rigidity and urinary incontinence. She reported abnormal development of reading and writing skills. She had a brother with cognitive impairment, delayed motor development, gait disorder and generalized tonic-clonic seizures; and a sister with upper limb tremor, dysarthria and behavioral disorder. Hypomyelination was detected on brain MRI. Complete exome sequencing detected a novel likely pathogenic variant of PLP1 gene: ChrX(GRCh37):NC_000023.10:g.103041651del:NM _000533.3:c449del, p.Asp150AlafsTer10, heterozygous. Conclusions: The patient’s case resembles a milder form of PMD. This is supported by literature linking deletions and female sex to milder phenotypes. In 20 to 40% of cases with suggestive clinical findings, no PLP1 mutation is found. New studies are needed to identify other variants associated with PMD.

Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease is a fatal X-linked leukodystrophy caused by mutations in the PLP1 gene, which is expressed in the CNS by oligodendrocytes. Disease onset, symptoms and mortality span a broad spectrum depending on the nature of the mutation and thus the degree of CNS hypomyelination. In the absence of an effective treatment, direct cell transplantation into the CNS to restore myelin has been tested in animal models of severe forms of the disease with failure of developmental myelination, and more recently, in severely affected patients with early disease onset due to point mutations in the PLP1 gene, and absence of myelin by MRI. In patients with a PLP1 duplication mutation, the most common cause of Pelizaeus-Merzbacher disease, the pathology is poorly defined because of a paucity of autopsy material. To address this, we examined two elderly patients with duplication of PLP1 in whom the overall syndrome, including end-stage pathology, indicated a complex disease involving dysmyelination, demyelination and axonal degeneration. Using the corresponding Plp1 transgenic mouse model, we then tested the capacity of transplanted neural stem cells to restore myelin in the context of PLP overexpression. Although developmental myelination and axonal coverage by endogenous oligodendrocytes was extensive, as assessed using electron microscopy (n = 3 at each of four end points) and immunostaining (n = 3 at each of four end points), wild-type neural precursors, transplanted into the brains of the newborn mutants, were able to effectively compete and replace the defective myelin (n = 2 at each of four end points). These data demonstrate the potential of neural stem cell therapies to restore normal myelination and protect axons in patients with PLP1 gene duplication mutation and further, provide proof of principle for the benefits of stem cell transplantation for other fatal leukodystrophies with ‘normal’ developmental myelination.

Rare Case of Female with Pelizaeus Mertzbacher Disease Due to Deletion of Proteolipid Protein 1

Pelizaeus Merzbacher Disease (PMD) is a rare X-linked central nervous system (CNS) disease involving the proteolipid protein 1 (PLP1) gene. Patients exhibit signs for instance nystagmus, hypotonia, ataxia. We report a three year old female patient with chief compliant of developmental delay. On physical examination, patient was alert but had poor eye contact while sitting in a stroller. Since no chromosomal evaluation was performed, a chromosomal microarray testing was performed. Review of geneticist report indicated that patient carries a deletion of at least 2.26 Mb within cytogenetic band Xq22.1 to Xq22.2 which is known to contain 39 genes. Out of the 39 genes, PLP1 is associated with known clinical disorder; PMD. Our case highlights the second only known female with PMD due to deletions of PLP1 gene. For a patient with developmental delay, the importance of performing genetic testing and/or radiological imaging early on is strongly recommended.

Effects of Intron 1 Sequences on Human PLP1 Expression: Implications for PLP1-Related Disorders

Alterations in the myelin proteolipid protein gene ( PLP1) may result in rare X-linked disorders in humans such as Pelizaeus–Merzbacher disease and spastic paraplegia type 2. PLP1 expression must be tightly regulated since null mutations, as well as elevated PLP1 copy number, both lead to disease. Previous studies with Plp1-lacZ transgenic mice have demonstrated that mouse Plp1 ( mPlp1) intron 1 DNA (which accounts for slightly more than half of the gene) is required for the mPlp1 promoter to drive significant levels of reporter gene expression in brain. However not much is known about the mechanisms that control expression of the human PLP1 gene ( hPLP1). Therefore this review will focus on sequences in hPLP1 intron 1 DNA deemed important for hPLP1 gene activity as well as a couple of “human-specific” supplementary exons within the first intron which are utilized to generate novel splice variants, and the potential role that these sequences may play in PLP1-linked disorders.

Familial Case of Pelizaeus-Merzbacher Disorder Detected by Oligoarray Comparative Genomic Hybridization: Genotype-to-Phenotype Diagnosis

Introduction. Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy characterized by nystagmus, spastic quadriplegia, ataxia, and developmental delay. It is caused by mutation in the PLP1 gene. Case Description. We report a 9-year-old boy referred for oligoarray comparative genomic hybridization (OA-CGH) because of intellectual delay, seizures, microcephaly, nystagmus, and spastic paraplegia. Similar clinical findings were reported in his older brother and maternal uncle. Both parents had normal phenotypes. OA-CGH was performed and a 436 Kb duplication was detected and the diagnosis of PMD was made. The mother was carrier of this 436 Kb duplication. Conclusion. Clinical presentation has been accepted as being the mainstay of diagnosis for most conditions. However, recent developments in genetic diagnosis have shown that, in many congenital and sporadic disorders lacking specific phenotypic manifestations, a genotype-to-phenotype approach can be conclusive. In this case, a diagnosis was reached by universal genomic testing, namely, whole genomic array.