General anesthesia for an adolescent with Pelizaeus-Merzbacher disease: A case report

Pelizaeus-Merzbacher disease (PMD) is a progressive and degenerative chromosomal disorder of the central nervous system caused by defective myelin production. Few case reports have been issued on the anesthetic management of PMD, because of its extremely low incidence. We anesthetized a 13-year-old female patient diagnosed with PMD for ophthalmic surgery because of intermittent exotropia. General anesthesia was induced and maintained with propofol and sevoflurane in air and oxygen. Rocuronium was administered to facilitate orotracheal intubation, and residual neuromuscular blockage was reversed with pyridostigmine. Between emergence to 24 hours postoperatively, her muscle power completely recovered and no unpredictable events occurred. Summarizing, anesthesiologists should be concerned about the high possibility of aspiration, spasticity, and seizure during the perioperative period in patients with even mild PMD. Appropriate preoperative evaluation, intraoperative monitoring, and choice of proper anesthetic drugs enable safe anesthesia in patients with PMD.

Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease / Heterogeneidad clínica y mutacional en pacientes colombianos con Pelizaeus Merzbacher

Abstract Case Presentation: Pelizaeus Merzbacher Disease (PMD) is an X-linked developmental defect of myelination that causes childhood chronic spastic encephalopathy. Its genetic etiology can be either a duplication (or other gene dosage alterations) or a punctual mutation at the PLP1 locus. Clinically, it presents with developmental delay, nystagmus and, spasticity, supported by neuroimaging in which the defect of myelination is evident. We present a series of seven Colombian patients diagnosed with this leucodystrophy, describing their genotypic and phenotypic characteristics and heterogeneity. Clinical Findings: All patients included were male, 6 months to 16 years of age. Mean age at onset of symptoms was 8 months. Mean age at diagnosis was 5 years 5 months, being classic PMD most frequently diagnosed, as compared to the connatal phenotype. All cases had a primary diagnosis of developmental delay on 100%, and in 28.7% of cases, early onset nystagmus was described. 85.7% of patients had spasticity, 71.4% cerebellar signs, 57.0% hypotonia, and 28.5% had an abnormal movement disorder. Only three patients were able to achieve gait, though altered. In the two patients who had a diagnosis of connatal PMD maturational ages in danger zones according to the WHO Abbreviated Scale of Psychosocial Development were documented. All cases had abnormalities in neuroimages. Molecular Analysis and Results: Molecular studies were used in the majority of the cases to confirm the diagnosis (85.7 %). For two cases molecular confirmation was not considered necessary given their affected male brothers had already been tested. PLP1 gene dosage alterations (duplications) were found in 28.5 % of the patients (two siblings), whereas three different single nucleotide variants were detected. Clinical Relevance: According to these findings, as authors we propose the diagnostic algorithm in Colombian population to begin on a high clinical suspicion, followed by paraclinical extension, moving on to the molecular confirmation by using approaches to simultaneously sequence the PLP1 gene in order to detect point mutations and in/dels and performing a copy number variation analysis for the detection of gene dosage alterations.

Resumen Descripción del caso: La enfermedad de Pelizaeus Merzbacher es una leucodistrofia ligada al X que causa encefalopatía espástica crónica en la infancia. Su etiología es genética, por duplicaciones u otros trastornos de la dosis génica o mutaciones puntuales del gen PLP1, lo que condiciona la formación anormal de las vainas de mielina principalmente en el sistema nervioso central. Clínicamente se caracteriza por un cuadro de retardo del neurodesarrollo, nistagmus y espasticidad, con neuroimágenes que evidencian la dismielinización. Presentamos una serie de siete casos colombianos con esta leucodistrofica en la que describimos fenotípica y genotípicamente la heterogeneidad de esta enfermedad en nuestra población. Hallazgos clínicos: Todos los pacientes analizados fueron de sexo masculino, con edad promedio de inicio de síntomas hacia los ocho meses de vida. La edad media al diagnóstico fue de 5 años 5 meses, siendo más frecuente el diagnóstico de PMD clásica que el tipo connatal. Se describe retardo del desarrollo motor en el 100% de los casos, acompañado de nistagmus en el 28.7%. 85.7% de los casos tenía algún grado de espasticidad, 71.4 % signos cerebelosos, 57.0% hipotonía, y hasta en 28.5% se evidenciaron movimientos anormales. Solo tres pacientes lograron marcha, aunque patológica. En los dos pacientes con la forma connatal se documentó una edad maduracional motora en el rango de Alerta, de acuerdo a la escala abreviada del desarrollo de la OMS. En todos los casos se detectó algún tipo de anormalidad en el estudio imagenológico cerebral. Estudios Moleculares y Resultados: El diagnóstico molecular se empleó en la mayoría de los casos (85.7%), encontrando alteraciones en la dosis génica en el 28.5% y tres diferentes mutaciones puntuales. Relevancia clínica: Dados los hallazgos en los resultados del estudio molecular, sugerimos que en el abordaje diagnóstico confirmatorio para la población colombiana se debería contemplar en un mismo tiempo tanto la secuenciación como el estudio de variantes del número de copias del gen afectado, contrario a lo sugerido en literatura mundial en la que se inicia con estudio para duplicación / deleción.

Magnetic resonance imaging and spectroscopic analysis in 5 cases of Pelizaeus-Merzbacher disease: metabolic abnormalities as diagnostic tools / 소아과

Pelizaeus-Merzbacher disease (PMD) is a rare, X-linked recessive disorder characterized by dysmyelination in the central nervous system. PMD results from deletion, mutation, or duplication of the proteolipid protein gene (PLP1) located at Xq22, leading to the failure of axon myelination by oligodendrocytes in the central nervous system. PMD may be suspected when there are clinical manifestations such as nystagmus, developmental delays, and spasticity, and genetic analysis can confirm the diagnosis. Further diagnostic manifestations of the disease include a lack of myelination on brain magnetic resonance (MR) imaging and aberrant N-acetyl aspartate (NAA) and choline concentrations that reflect axonal and myelination abnormalities on phroton MR spectroscopy. We report 5 cases of PMD (in 1 girl and 4 boys). PLP1 duplication was detected in 2 patients. Brain MR analyses and MR spectroscopy were performed for all the patients. The brain MR images showed white matter abnormalities typical of PMD, and the MR spectroscopic images showed diverse patterns of NAA, creatinine, and choline concentrations. We propose that MR spectroscopic analysis of metabolic alterations can aid the PMD diagnosis and can contribute to a better understanding of the pathogenesis of the disease.

Clinical Manifestations of Leukodystrophies: A Single Center Study

PURPOSE: Leukodystrophies have been defined as inherited metabolic disorders of myelin resulting in abnormal development or progressive destruction of the white matter. This study was performed to investigate the clinical manifestations and treatments of leukodystrophies in a single Korean tertiary center. METHODS: We retrospectively analysed the medical records of patients who had been diagnosed with leukodystrophy from May 1995 to May 2010 at the Asan Medical Center. RESULTS: During the 15-year study period, 36 cases of leukodystrophies were diagnosed with an verage age at symptom presentation of 49 months. Prominent symptoms at presentation were developmental delay (41%) and seizure (25%); however, nystagmus, developmental regression, hearing loss, gait disturbance, visual disturbance, attention deficit, hypotonia, hyperpigmentation, and hemiparesis were also observed. On MRI, periventricular involvement was noted frequently. The most common diagnoses were adrenoleukodystophy (25%), metachromatic leukodystrophy (11%), Krabbe disease (11%), and Pelizaeus-Merzbacher disease (8.3%). No final diagnosis was made in 14 cases (41%). Bone marrow transplantation was performed in 4 patients and showed favorable prognoses. CONCLUSION: Clinical features of leukodystrophies are not specific to diagnosis and most leukodystrophies remain undiagnosed; however, a logical algorithm based on prevalence could aid the laboratory testing. Because early detection and diagnosis is crucial for treatment and prognosis, it is important to have a high index of suspicion and watchful screening of familial history.

Identification of Proteolipid Protein 1 Gene Duplication by Multiplex Ligation-Dependent Probe Amplification: First Report of Genetically Confirmed Family of Pelizaeus-Merzbacher Disease in Korea

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder with a prototype of a dysmyelinating leukodystrophy that is caused by a mutation in the proteolipid protein 1 (PLP1) gene on the long arm of the X chromosome in band Xq22. This mutation results in abnormal expression or production of PLP. We here present a Korean boy with spastic quadriplegia, horizontal nystagmus, saccadic gaze, intentional tremor, head titubation, ataxia, and developmental delay. The brain magnetic resonance imaging (MRI) showed abnormally high signal intensities in the white matter tract, including a subcortical U fiber on the T2-weighted and fluid attenuated inversion recovery (FLAIR) image. The chromosomal analysis was normal; however, duplication of the PLP1 gene in chromosome Xq22 was detected when the multiplex ligation-dependent probe amplification (MLPA) method was used. We also investigated the pedigree for a genetic study related to PMD. This case suggests that the duplication mutation of the PLP1 gene in patients with PMD results in a mild clinical form of the disorder that mimics the spastic quadriplegia of cerebral palsy.

Proteolipid protein 1 gene mutation in nine patients with Pelizaeus-Merzbacher disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder with symptoms including nystagmus, impaired motor development, ataxia, and progressive spasticity. The proteolipid protein 1 (PLP1) gene is the only pathogenic gene of PMD. Duplication of the PLP1 gene is the most frequent gene defect, accounting for 50%-70% of PMD cases, whereas point mutations in the coding sequence or the splice sites account for 10%-25% of PMD cases. This study aimed to identify PLP1 mutations in nine unrelated Chinese patients (P1-9) with PMD, and 14 subjects from the family of patient 2 were also described.</p><p><b>METHODS</b>Genomic DNA was extracted from peripheral blood samples. Gene dosage was determined using the multiplex ligation-dependent probe amplification (MLPA). All 7 exons and exon-intron boundaries of the PLP1 gene were amplified and analyzed using direct DNA sequencing.</p><p><b>RESULTS</b>Of these nine patients, there were four transitional, four classical, and one connatal PMD according to their clinical and radiological presentations. PLP1 duplications were identified in patients 1-7 with PMD. Their mothers were PLP1 duplications carriers as well. Both duplication carriers and normal genotypes of PLP1 were identified in the family members of patient 2. A c.517C > T (p. P173S) hemizygous missense mutation in exon 4 was found in patient 8 with PMD, and his mother was shown to be a heterozygote of this mutation.</p><p><b>CONCLUSIONS</b>We identified seven genomic duplications and one missense mutation (p. P173S) of the PLP1 gene in eight Chinese patients with PMD. This is the report about PLP1 mutations in PMD patients from the mainland of China.</p>

Clinical and genetic analysis of a family with Pelizaeus-Merzbacher disease / 中华儿科杂志

<p><b>OBJECTIVE</b>Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive leukoencephalopathy. Few reports of PMD patients without genetic confirmation have been published in the mainland of China. The clinical and genetic features of a family with PMD were analyzed, which may contribute to definite diagnosis, genetic counseling and prenatal diagnosis of this rare hereditary disease in China.</p><p><b>METHODS</b>Clinical data of the proband and other family members as well as 14 DNA samples were collected. Clinical features including symptoms, signs and cranial MRI were analyzed. Multiplex ligation-dependent probe amplification (MLPA) assays were performed to detect PLP1 duplication, which helps identify the type of PLP1 mutation in this family and the genotype-phenotype correlations.</p><p><b>RESULTS</b>(1) The proband and the other 3 male patients in the family presented with nystagmus, motor retardation followed by regression. The cranial MRI of proband showed evidence of poor myelination with diffused high signal in white matter region on T2-weighed image and reduced amount of white matter in volume, which is consistent with the typical features of cranial MRI in PMD. (2) PLP1duplication was identified in the proband. Combined with the clinical features of the proband and other patients in this family, the diagnosis of classic form of PMD was confirmed. Another 3 females with normal phenotype in the family were proved to be carriers of PLP1duplication.</p><p><b>CONCLUSIONS</b>(1) The Classic form of PMD in this pedigree is resulted from the PLP1 duplication, which is consistent with the previously reported genotype-phenotype correlations; (2) The results serve as an evidence for reliable genetic counseling and prenatal diagnosis for this family. (3) MLPA, which is a newly developed method, is a rapid and reliable technique to detect the whole gene duplication of PLP1.</p>

Pelizaeus-Merzbacher Disease: A case report

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder characterized by dysmyelination of the central nervous system (CNS) caused by mutations in the proteolipid protein (PLP) gene. PLP is located at Xq22 and its mutation result in abnormal expression or production of PLP, the most abundant protein in CNS myelin. We present a case of PMD in the 7-year-old boy with nystagmus, ataxia, spastic quadriplegia and severe psychomotor delay. His brain MRI revealed totally dysmyelinated white matter involving entire supratentorial region, atrophic change, and overaccumulation of the iron in both basal ganglia. He also showed soft-tissue contractures of the hip adductors, associated hip dislocations and equinovarus foot deformities due to severe spasticity of lower extremities. Orthopaedic surgery was performed on both hips. Antispastic medication and physical therapy were maintained for reduction of spasticity. We report this case with the review of literatures.

Two Cases of Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher disease (PMD) is a rare sudanophilic leukodystrophy with a reduced number of mature oligodendrocytes as well as diffuse central nervous system hypomyelination (dysmyelination) due to abnormal synthesis of proteolipid protein. PMD is characterized with pendular nystagmus, stridor, delay in psychomotor development, hypotonia, ataxia, athetosis and extrapyramidal signs. Abnormal high signal intensity is shown in the entire white matter of cerebrum and cerebellum at early stage by T2-weighted magnetic resonance imaging (MRI). We report two cases of PMD diagnosed with characteristic clinical manifestations and brain MRI findings.

Pelizaeus-Merzbacher Disease: Two Cases in a Family Diagnosed by the Clinical Features and Magnetic Resonance Imaging

Pelizaeus-Merzbacher disease(PMD) is very rare x-liked recessive leukodystrophy, rather dysmyelinating d due to defect of biosynthesis of proteolipid protein, a component of myelin. Its usual clinical features are stridor, pendular nystagmus, extrapyramidal sign, pyramydal sign, developmental delay and cognition deterioration. Until now PMD has not been published in our country. A 4-year 3 month-old boy developed abnormal eye movement at 3 months of age. His psychomotor development was delayed. On our examination, definite horizontal pendular nystagmus was noted. He showed severe dysarthria, quadriparesis with generalized hyperreflexia, bilateral extensor plantar signs. All laboratory findings including cerebrospinal fluid study were normal. Brain magnetic resonance image (MRI) -revealed diffuse and symmetrical white matter changes in cerebrum and cerebellum. His 23-year-old younger maternal uncle also showed similar clinical history and brain MRI findings. Although the diagnosis of PMD depended on histopathologic investigation, recently MRI can make an important contribution to the diagnosis of PMD with characteristic clinical features. So we could diagnose him and his uncle as PMD.