Pelizaeus-Merzbacher disease: on the cusp of myelin medicine.

Pelizaeus-Merzbacher disease (PMD) is caused by mutations in the proteolipid protein 1 (PLP1) gene encoding proteolipid protein (PLP). As a major component of myelin, mutated PLP causes progressive neurodegeneration and eventually death due to severe white matter deficits. Medical care has long been limited to symptomatic treatments, but first-in-class PMD therapies with novel mechanisms now stand poised to enter clinical trials. Here, we review PMD disease mechanisms and outline rationale for therapeutic interventions, including PLP1 suppression, cell transplantation, iron chelation, and intracellular stress modulation. We discuss available preclinical data and their implications on clinical development. With several novel treatments on the horizon, PMD is on the precipice of a new era in the diagnosis and treatment of patients suffering from this debilitating disease.

Pelizaeus-Merzbacher Disease: A Caregiver Assessment of Disease Impact.

Pelizaeus-Merzbacher disease is a rare X-linked leukodystrophy accompanied by central nervous system hypomyelination with a spectrum of clinical phenotypes. This is the first survey of caregivers of individuals with Pelizaeus-Merzbacher disease to investigate the presenting symptoms, path to diagnosis, identity and impact of most bothersome symptoms, and needs that future treatment should address. One hundred participants completed the survey. Results from this survey demonstrate that the majority of Pelizaeus-Merzbacher disease symptoms manifest before 2 years of age and commonly include deficits in gross and fine motor skills, speech, and communication. Caregivers rated difficulty crawling, standing, or walking as the most bothersome symptoms due to Pelizaeus-Merzbacher disease, with constipation and difficulty with sleep, manual dexterity, and speech and communication rated nearly as high. The most important treatment goals for caregivers were improved mobility and communication. The survey findings present a caregiver perspective of the impact of symptoms in Pelizaeus-Merzbacher disease and provide helpful guidance to affected families, physicians, and drug developers on the often-long path to diagnosis and the unmet medical needs of this patient population.

Genotype-phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus-merzbacher disease.

BACKGROUND: The natural history and genotype-phenotype correlation of Pelizaeus-Merzbacher disease (PMD) of Chinese patients has been rarely reported. METHOD: Patients who met the criteria for PMD were enrolled in our study. Genomic analysis was conducted by multiplex ligation probe amplification (MLPA) and Sanger or whole-exome sequencing (WES). Natural history differences and genotype-phenotype correlations were analyzed. RESULT: A total of 111 patients were enrolled in our follow-up study. The median follow-up interval was 53 m (1185). Among PMD patients, developmental delay was the most common sign, and nystagmus and hypotonia were the most common initial symptoms observed. A total of 78.4% of the patients were able to control their head, and 72.1% could speak words. However, few of the patients could stand (9.0%) or walk (4.5%) by themselves. Nystagmus improved in more than half of the patients, and hypotonia sometimes deteriorated to movement disorders. More PLP1 point mutations patients were categorized into severe group, while more patients with PLP1 duplications were categorized into mild group (p < 0.001). Compared to patients in mild groups, those in the severe group had earlier disease onset and had acquired fewer skills at a later age. CONCLUSION: PMD patients have early disease onset with nystagmus and hypotonia followed by decreased nystagmus and movement disorders, such as spasticit. Patients with PLP1 duplication were more likely to be categorized into the mild group, whereas patients with point mutations were more likely to be categorized into the severe group.

Pelizaeus-Merzbacher-Like Disease 1 Caused by a Novel Mutation in GJC2 Gene: A Case Report.

Pelizaeus-Merzbacher-Like Disease 1 is a genetic disorder affecting the central nervous system with an autosomal recessive inheritance pattern. It is a rare genetic disorder that affects the central nervous system. In this report, we demonstrated the clinical and paraclinical features of an Iranian consanguine pedigree with suspected hypomyelinating leukodystrophy, without any defined diagnosis. The proband, a 15-month-old girl, visited the Razi pathobiology and medical genetic laboratory of Karaj, where the study was conducted in 2020. Following whole-exome sequencing analysis of the proband and segregation analysis, a novel pathogenic mutation was discovered. GJC2 (NM_020435.4):c.1096dupG was found to be homozygous in the proband and heterozygous in both parents. This mutation was in the coding region of the protein, which results in D366Gfs*126 (p.Asp366GlyfsTer126). The site of mutation was at the 3' region of the connexin superfamily domain. The frameshift results in a different peptide sequence of the C-terminal and extended protein. Our findings led to the diagnosis of the proband's disease as Pelizaeus-Merzbacher-Like Disease 1 and led to the end of the diagnostic odyssey. We provided effective genetic counseling through the identification of a novel pathogenic mutation in gap junction protein C2 in this family and suggested preimplantation genetic diagnosis for the next pregnancy. Furthermore, our findings confirmed the association of GJC2 mutations with PMLD1. This discovery added to the repertoire of genetic mutations of Pelizaeus-Merzbacher-Like Disease 1. This knowledge could be applied for expanded carrier screening of other families, especially for Iranian consanguine marriages.

Prenatal diagnosis of PLP1 duplication by single nucleotide polymorphism array in a family with Pelizaeus-Merzbacher disease.

A family with a history of Pelizaeus-Merzbacher disease (PMD) received prenatal diagnosis of PLP1 gene duplication in a fetus using a single nucleotide polymorphism (SNP) array. A 27-year-old pregnant woman was referred for genetic counseling due to her four-year-old son being diagnosed with a suspected classic type of PMD. Amniocentesis was performed at 18 and 3/7 weeks of gestation, and the SNP array was carried out on DNA from the mother, her affected son, and fetus, then further confirmed by multiplex ligation-dependent probe amplification (MLPA). Cytogenetic analysis of the fetus showed 46,XY. SNP array analysis revealed that the male fetus did not carry PLP1 gene duplication but the affected boy did, and the mother was a carrier for the duplication of the PLP1 gene. All SNP array results were further confirmed by MLPA. SNP array and MLPA analyses of peripheral blood verified the nonduplication of the PLP1 gene in the infant after birth. At present, the child (without PLP1 duplication) is developing normally. This study preliminarily suggests that SNP array is a sensitive and accurate technology for identifying PLP1 duplication and is feasible for reliable diagnosis, including for the prenatal diagnosis of PMD resulting from PLP1 duplication.

Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease.

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.

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.

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.

Exome sequencing reveals a novel PLP1 mutation in a Moroccan family with connatal Pelizaeus-Merzbacher disease: a case report.

BACKGROUND: Epilepsy regroups a common and diverse set of chronic neurological disorders that are characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Epilepsies have a highly heterogeneous background with a strong genetic contribution and various mode of inheritance. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy. The variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the causal genetic mutation, making diagnosis, genetic counseling and treatment decisions difficult. We report the description of a Moroccan family referred to our genetic department with X-linked epileptic seizures as the only initial diagnosis. CASE PRESENTATION: Knowing the new contribution of Next-Generation Sequencing (NGS) for clinical investigation, and given the heterogeneity of this group of disorders we performed a Whole-Exome Sequencing (WES) analysis and co-segregation study in several members of this large family. We detected a novel pathogenic PLP1 missense mutation c.251C > A (p.Ala84Asp) allowing us to make a diagnosis of Pelizaeus-Merzbacher Disease for this family. CONCLUSION: This report extends the spectrum of PLP1 mutations and highlights the diagnostic utility of NGS to investigate this group of heterogeneous disorders.

Rare Case of Female with Pelizaeus Mertzbacher Disease due to deletion of Proteolipid Protein 1: A Case Report.

Pelizaeus Merzbacher Disease is a rare X-linked central nervous system disease involving the proteolipid protein 1 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, proteolipid protein 1 is associated with known clinical disorder; Pelizaeus Merzbacher Disease. Our case highlights the second only known female with Pelizaeus Merzbacher Disease due to deletions of proteolipid protein 1 gene. For a patient with developmental delay, the importance of performing genetic testing and/or radiological imaging early on is strongly recommended. Keywords: deletion; female; Genetic testing; Pelizaeus Merzbacher Disease; Proteolipid Protein 1.

[Borderline phenotype of Pelizaeus-Merzbacher disease]. / Fenotipo frontera de la enfermedad de Pelizaeus-Merzbacher.

TITLE: Fenotipo frontera de la enfermedad de Pelizaeus-Merzbacher.

Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a rare Mendelian disorder characterised by central nervous system hypomyelination. PMD typically manifests in infancy or early childhood and is caused by mutations in proteolipid protein-1 (PLP1). However, variants in several other genes including gap junction protein gamma 2 (GJC2) can also cause a similar phenotype and are referred to PMD-like disease (PMLD). Whole-exome sequencing in two siblings presenting with clinical symptoms of PMD revealed a homozygous variant in the arginyl-tRNA synthetase (RARS) gene: NM_002887.3: c.[5A>G] p.(Asp2Gly). Subsequent screening of a PMD cohort without a genetic diagnosis identified an unrelated individual with novel compound heterozygous variants including a missense variant c.[1367C>T] p.(Ser456Leu) and a de novo deletion c.[1846_1847delTA] p.(Tyr616Leufs*6). Protein levels of RARS and the multi-tRNA synthetase complex into which it assembles were found to be significantly reduced by 80 and 90% by western blotting and Blue native-PAGE respectively using patient fibroblast extracts. As RARS is involved in protein synthesis whereby it attaches arginine to its cognate tRNA, patient cells were studied to determine their ability to proliferate with limiting amounts of this essential amino acid. Patient fibroblasts cultured in medium with limited arginine at 30 °C and 40 °C, showed a significant decrease in fibroblast proliferation (P<0.001) compared to control cells, suggestive of inefficiency of protein synthesis in the patient cells. Our functional studies provide further evidence that RARS is a PMD-causing gene.

22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease.

Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., (2004); AJMGA 127: 149-151], of an individual with 22q duplication and sex-reversal syndrome. The subject's phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain of function rather than dominant negative activity underlies PCWH.

A novel PLP1 mutation associated with optic nerve enlargement in two siblings with Pelizaeus-Merzbacher disease: A new MRI finding.

Pelizaeus-Merzbacher disease (PMD) is a rare, X-linked disorder characterized by hypomyelination of the Central Nervous System due to mutations in the PLP1 gene. Certain mutations of the PLP1 gene correlate with specific clinical phenotypes and neuroimaging findings. We herein report a novel mutation of the PLP1 gene in two siblings with PMD associated with a rare and protean neuroimaging finding of optic nerve enlargement. To the best of our knowledge this is the first time that this novel mutation H133P of PLP1 gene is identified and clinically associated with optic nerve enlargement in PMD patients.

Hypomyelinating leukodystrophies - a molecular insight into the white matter pathology.

Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

Pelizaeus-Merzbacher disease in patients with molecularly confirmed diagnosis.

Pelizaeus-Merzbacher disease (PMD) is X-linked hypomyelinating leukodystrophy caused by mutations of the PLP1 gene, which codes the proteolipid protein 1. The result of mutations is abnormal myelination - hypomyelination and dysmyelination of cerebral white matter, and in some form of the disease hypomyelinating peripheral neuropathy. DNA samples from 68 patients suspected of PMD due to the clinical course and hypomyelination at magnetic resonance imaging (MRI) were analyzed. Medical history and detailed clinical course of PMD patients were also analyzed. Different mutations of the PLP1 gene were detected in 14 boys from 11 families (~20%). Amongst the molecularly confirmed patients, 13 presented classical PMD forms but clinical phenotypes varied in the severity even amongst siblings. One patient presented a severe connatal form. One mother, obligate carrier, presented complicated SPG2 (spastic paraparesis). There was no phenotype-genotype correlation in our material. In many cases PMD was suspected with a delay of many years, sometimes only after birth of another affected child in the family. Pelizaeus-Merzbacher disease was most frequently misdiagnosed as cerebral palsy.

Clínica y diagnóstico de la enfermedad de Pelizaeus-Merzbacher: descripción de cinco casos / Clinical features and diagnosis of Pelizaeus-Merzbacher disease: five case reports

Introducción. La enfermedad de Pelizaeus-Merzbacher es un trastorno hipomielinizante raro debido a alteraciones en el gen PLP1, que lleva a un fallo de la mielinización axonal de los oligodendrocitos en el sistema nervioso central. Existen dos formas descritas según la gravedad de su presentación: connatal y clásica. Se caracteriza por hipotonía neonatal, retraso del desarrollo psicomotor, espasticidad progresiva de predominio en los miembros inferiores y nistagmo, con signos y síntomas piramidales y extrapiramidales, y la forma connatal es mucho más grave. La resonancia magnética muestra leucoencefalopatía hipomielinizante difusa, los potenciales evocados usualmente se alteran y la confirmación se realiza mediante estudio molecular del gen PLP1. Casos clínicos. Se presentan cinco pacientes pediátricos afectados, cuatro con la forma clásica y uno con la forma connatal; se describen las características clínicas, los estudios complementarios y se realiza una revisión concisa de la bibliografía. Conclusión. Esta enfermedad tiene una evolución progresiva y casi invariable, lo cual es la clave clínica para diferenciarla de otras entidades como la parálisis cerebral infantil, neuropatías periféricas, esclerosis múltiple, entre otras, además de los hallazgos característicos en las neuroimágenes. Es necesario sospechar este diagnóstico y confirmar alteraciones en el gen PLP1 con el fin de obtener una incidencia real de esta entidad, probablemente subestimada, como otras leucodistrofias (AU)

Introduction. Pelizaeus-Merzbacher disease is an infrequent hypomyelinating disorder caused by alterations in the PLP1 gene, which leads to a fault in the axonal myelination of the oligodendrocytes in the central nervous system. Two forms have been reported, according to the severity of the presentation: connatal and classic. It is characterised by neonatal hypotonia, delayed psychomotor development, progressive spasticity predominantly in the lower limbs and nystagmus, with pyramidal and extrapyramidal signs and symptoms; the connatal form is far more severe. Magnetic resonance imaging shows diffuse hypomyelinating leukoencephalopathy, evoked potentials are usually altered and confirmation is obtained through a molecular study of the PLP1 gene. Case reports. We present the cases of five paediatric patients, four of whom had the classic form and one with the connatal form. The clinical characteristics and complementary studies are described, and a concise review of the literature is carried out. Conclusion. This disease has a progressive and almost unvarying course, which is the clinical key to be able to differentiate it from other entities such as infantile cerebral palsy, peripheral neuropathies or multiple sclerosis, among others, in addition to the characteristic neuroimaging findings. It is necessary to suspect this diagnosis and confirm alterations in the PLP1 gene with the aim of obtaining a real incidence of this entity, which is probably underestimated, like other leukodystrophies (AU)

[Clinical features and diagnosis of Pelizaeus-Merzbacher disease: five case reports]. / Clinica y diagnostico de la enfermedad de Pelizaeus-Merzbacher: descripcion de cinco casos.

INTRODUCTION: Pelizaeus-Merzbacher disease is an infrequent hypomyelinating disorder caused by alterations in the PLP1 gene, which leads to a fault in the axonal myelination of the oligodendrocytes in the central nervous system. Two forms have been reported, according to the severity of the presentation: connatal and classic. It is characterised by neonatal hypotonia, delayed psychomotor development, progressive spasticity predominantly in the lower limbs and nystagmus, with pyramidal and extrapyramidal signs and symptoms; the connatal form is far more severe. Magnetic resonance imaging shows diffuse hypomyelinating leukoencephalopathy, evoked potentials are usually altered and confirmation is obtained through a molecular study of the PLP1 gene. CASE REPORTS: We present the cases of five paediatric patients, four of whom had the classic form and one with the connatal form. The clinical characteristics and complementary studies are described, and a concise review of the literature is carried out. CONCLUSION: This disease has a progressive and almost unvarying course, which is the clinical key to be able to differentiate it from other entities such as infantile cerebral palsy, peripheral neuropathies or multiple sclerosis, among others, in addition to the characteristic neuroimaging findings. It is necessary to suspect this diagnosis and confirm alterations in the PLP1 gene with the aim of obtaining a real incidence of this entity, which is probably underestimated, like other leukodystrophies.

TITLE: Clinica y diagnostico de la enfermedad de Pelizaeus-Merzbacher: descripcion de cinco casos.Introduccion. La enfermedad de Pelizaeus-Merzbacher es un trastorno hipomielinizante raro debido a alteraciones en el gen PLP1, que lleva a un fallo de la mielinizacion axonal de los oligodendrocitos en el sistema nervioso central. Existen dos formas descritas segun la gravedad de su presentacion: connatal y clasica. Se caracteriza por hipotonia neonatal, retraso del desarrollo psicomotor, espasticidad progresiva de predominio en los miembros inferiores y nistagmo, con signos y sintomas piramidales y extrapiramidales, y la forma connatal es mucho mas grave. La resonancia magnetica muestra leucoencefalopatia hipomielinizante difusa, los potenciales evocados usualmente se alteran y la confirmacion se realiza mediante estudio molecular del gen PLP1. Casos clinicos. Se presentan cinco pacientes pediatricos afectados, cuatro con la forma clasica y uno con la forma connatal; se describen las caracteristicas clinicas, los estudios complementarios y se realiza una revision concisa de la bibliografia. Conclusion. Esta enfermedad tiene una evolucion progresiva y casi invariable, lo cual es la clave clinica para diferenciarla de otras entidades como la paralisis cerebral infantil, neuropatias perifericas, esclerosis multiple, entre otras, ademas de los hallazgos caracteristicos en las neuroimagenes. Es necesario sospechar este diagnostico y confirmar alteraciones en el gen PLP1 con el fin de obtener una incidencia real de esta entidad, probablemente subestimada, como otras leucodistrofias.

Costs of the diagnostic odyssey in children with inherited leukodystrophies.

OBJECTIVES: Our objective was to determine the extent of testing and costs solely related to diagnosis (the diagnostic odyssey) in a cohort of children with inherited leukodystrophies. METHODS: We determined all inpatient and outpatient laboratory testing, including brain MRIs obtained for the purpose of diagnosis, over an 8-year time period in a retrospective population cohort of children with inherited leukodystrophies. Costs were determined from an activity-based cost accounting system and were standardized to 2013 constant US dollars. RESULTS: Each patient had on average 20 tests (range 2-42 tests), with costs of $4,200 (range $357-$15,611). Diagnostic yield plateaued after 25 tests, and costs increased significantly after 32 tests. Fifty-three percent of patients were diagnosed in 20 or fewer tests, compared with 17% if more than 20 tests were performed. CONCLUSIONS: Our findings provide details on the amount and costs of testing in children who often undergo a diagnostic odyssey. Our results suggest that diagnostic testing is a relatively modest contributor to the overall health care costs in patients with leukodystrophy, and offer insights into the diagnostic odyssey of children with neurologic impairment.