Pelizaeus-Merzbacher Disease: Molecular and Cellular Pathologies and Associated Phenotypes.

Pelizaeus-Merzbacher disease (PMD) represents a group of disorders known as hypomyelinating leukodystrophies, which are characterized by abnormal development and maintenance of myelin in the central nervous system. PMD is caused by different types of mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major myelin membrane lipoprotein. These mutations in the PLP1 gene result in distinct cellular and molecular pathologies and a spectrum of clinical phenotypes. In this chapter, I discuss the historical aspects and current understanding of the mechanisms underlying how different PLP1 mutations disrupt the normal process of myelination and result in PMD and other disorders.

Hypomyelinating Leukodystrophy due to HSPD1 Mutations: A New Patient.

The hypomyelinating leukodystrophies (HMLs) encompass the X-linked Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations and known as the classical form of HML as well as Pelizaeus-Merzbacher-like disease (PMLD) (Online Mendelian Inheritance in Man [OMIM] 608804 and OMIM 260600) due to GJC2 mutations. In addition, mutations in at least 10 other genes are known to cause HMLs. In 2008, an Israeli family with clinical and neuroimaging findings similar to those found in PMD was reported. The patients were found to have a homozygous missense mutation in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60), and the disorder was defined as the autosomal recessive mitochondrial Hsp60 chaperonopathy (MitCHAP-60) disease. We here report the first case of this severe neurodegenerative disease since it was first described. Given the fact that the families carried the same mutation our patient probably belongs to the same extended family as the Israeli family. In conclusion, the MitCHAP-60 disease should be considered as a rare differential diagnosis in HML.

Modeling the natural history of Pelizaeus-Merzbacher disease.

Major gaps in our understanding of the leukodystrophies result from their rarity and the lack of tissue for the interdisciplinary studies required to extend our knowledge of the pathophysiology of the diseases. This study details the natural evolution of changes in the CNS of the shaking pup (shp), a model of the classical form of the X-linked disorder Pelizaeus-Merzbacher disease, in particular in glia, myelin, and axons, which is likely representative of what occurs over time in the human disease. The mutation in the proteolipid protein gene, PLP1, leads to a delay in differentiation, increased cell death, and a marked distension of the rough endoplasmic reticulum in oligodendrocytes. However, over time, more oligodendrocytes differentiate and survive in the spinal cord leading to an almost total recovery of myelination, In contrast, the brain remains persistently hypomyelinated. These data suggest that shp oligodendrocytes may be more functional than previously realized and that their early recruitment could have therapeutic value.

Plp1 gene duplication inhibits airway responsiveness and induces lung inflammation.

Mice with Plp1 gene duplication model the most common form of Pelizaeus-Merzbacher disease (PMD), a CNS disease in which patients may suffer respiratory complications. We hypothesized that affected mice would lack airway responsiveness compared to wild-type and carrier mice during methacholine challenge. Wild-type (n = 10), carrier female (n = 6) and affected male (n = 8) mice were anesthetized-paralyzed, tracheostomized and ventilated. Respiratory mechanics were recorded at baseline and during escalating doses of nebulized methacholine followed by albuterol. Lung resistance (RL) was the primary endpoint. Lung tissues were assayed for inflammatory and histological differences. At baseline, phase angles were higher in carrier and affected mice than wild-type. Dose-response RL curves in affected and carrier mice indicated a lack of methacholine response. Albuterol reduced RL in wild-type and carrier, but not affected mice. Affected mice exhibited lower interleukin (IL)-6 tissue levels and alveolar inflammatory infiltrates. Affected and carrier mice, compared to wild-type, lacked airway reactivity during methacholine challenge, but only affected mice exhibited decreased lung tissue levels of IL-6 and inflammation.

Gait abnormalities and progressive myelin degeneration in a new murine model of Pelizaeus-Merzbacher disease with tandem genomic duplication.

Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating leukodystrophy caused by mutations of the proteolipid protein 1 gene (PLP1), which is located on the X chromosome and encodes the most abundant protein of myelin in the central nervous sytem. Approximately 60% of PMD cases result from genomic duplications of a region of the X chromosome that includes the entire PLP1 gene. The duplications are typically in a head-to-tail arrangement, and they vary in size and gene content. Although rodent models with extra copies of Plp1 have been developed, none contains an actual genomic rearrangement that resembles those found in PMD patients. We used mutagenic insertion chromosome engineering resources to generate the Plp1dup mouse model by introducing an X chromosome duplication in the mouse genome that contains Plp1 and five neighboring genes that are also commonly duplicated in PMD patients. The Plp1dup mice display progressive gait abnormalities compared with wild-type littermates. The single duplication leads to increased transcript levels of Plp1 and four of the five other duplicated genes over wild-type levels in the brain beginning the second postnatal week. The Plp1dup mice also display altered transcript levels of other important myelin proteins leading to a progressive degeneration of myelin. Our results show that a single duplication of the Plp1 gene leads to a phenotype similar to the pattern seen in human PMD patients with duplications.

High frequency of GJA12/GJC2 mutations in Turkish patients with Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease is an early onset dysmyelinating leukodystrophy. About 80% of PMD cases have been associated with duplications and mutations of the proteolipid protein 1 (PLP1) gene. Pelizaeus-Merzbacher-like disease is a genetically heterogeneous autosomal recessive disease and rarely caused by mutations in gap junction protein α12 (GJA12/GJC2) gene. The molecular basis of the disease was investigated in a cohort of 19 Turkish families. This study identified novel chromosomal rearrangements proximal and distal to, and exclusive of the PLP1 gene, showed equal frequencies of PLP1 and GJA12/GJC2 mutations at least in our cohort, and suggested further genetic heterogeneity.

Axon-glial interaction in the CNS: what we have learned from mouse models of Pelizaeus-Merzbacher disease.

In the central nervous system (CNS) the majority of axons are surrounded by a myelin sheath, which is produced by oligodendrocytes. Myelin is a lipid-rich insulating material that facilitates the rapid conduction of electrical impulses along the myelinated nerve fibre. Proteolipid protein and its isoform DM20 constitute the most abundant protein component of CNS myelin. Mutations in the PLP1 gene encoding these myelin proteins cause Pelizaeus-Merzbacher disease and the related allelic disorder, spastic paraplegia type 2. Animal models of these diseases, particularly models lacking or overexpressing Plp1, have shed light on the interplay between axons and oligodendrocytes, and how one component influences the other.

Lamin B1 Accumulation's Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes.

Autosomal dominant leukodystrophy (ADLD) is an extremely rare and fatal neurodegenerative disease due to the overexpression of the nuclear lamina component Lamin B1. Many aspects of the pathology still remain unrevealed. This work highlights the effect of Lamin B1 accumulation on different cellular functions in an ADLD astrocytic in vitro model. Lamin B1 overexpression induces alterations in cell survival signaling pathways with GSK3ß inactivation, but not the upregulation of ß-catenin targets, therefore resulting in a reduction in astrocyte survival. Moreover, Lamin B1 build up affects proliferation and cell cycle progression with an increase of PPARγ and p27 and a decrease of Cyclin D1. These events are also associated to a reduction in cell viability and an induction of apoptosis. Interestingly, ADLD astrocytes trigger a tentative activation of survival pathways that are ineffective. Finally, astrocytes overexpressing Lamin B1 show increased immunoreactivity for both GFAP and vimentin together with NF-kB phosphorylation and c-Fos increase, suggesting astrocytes reactivity and substantial cellular activation. These data demonstrate that Lamin B1 accumulation is correlated to biochemical, metabolic, and morphologic remodeling, probably related to the induction of a reactive astrocytes phenotype that could be strictly associated to ADLD pathological mechanisms.

Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects.

Pelizaeus-Merzbacher Disease is an X-linked hypomyelinatiing leukodystrophy. We report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53 families affected by hypomyelinating leukodystrophies of unknown aetiology. The 12 MCT8 mutated patients express initially a Pelizaeus-Merzbacher-Like disease phenotype with a latter unusual improvement of magnetic resonance imaging white matter signal despite absence of clinical progression. This observation underlines the interest of determining both free T3 and free T4 serum concentrations to screen for MCT8 mutations in young patients (<3 y) with a severe Pelizaeus-Merzbacher-Like disease presentation or older severe mentally retarded male patients with "hypomyelinated" regions.

Cell-specific loss of kappa-opioid receptors in oligodendrocytes of the dysmyelinating jimpy mouse.

Jimpy is a murine mutation in myelin proteolipid protein, leading to premature death of oligodendrocytes and severe central nervous system hypomyelination. Jimpy is a bona fide model of human Pelizaeus-Merzbacher disease. This paper describes a severe reduction in expression of kappa-opioid receptors (KOP) in oligodendrocytes of jimpy mice. A cell-specific reduction of >90% is apparent by 5 days of age. Expression is not reduced in neurons, and mu-opioid receptor expression is normal. Mechanism(s) leading to deficient KOP expression in jimpy mice remain unclear. We speculate that loss of KOP may be related to increased [Ca(2+)](i) and premature death of jimpy oligodendrocytes.

The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease.

The unfolded protein response (UPR) is a eukaryotic signaling pathway linking protein flux through the endoplasmic reticulum to transcription and translational repression. Herein, we demonstrate UPR activation in the leukodystrophy Pelizaeus-Merzbacher disease (PMD) as well as in three mouse models of this disease and transfected fibroblasts expressing mutant protein. The CHOP protein, widely known as a proapoptotic transcription factor, modulates pathogenesis in the mouse models of PMD; however, this protein exhibits antiapoptotic activity. Together, these data show that the UPR has the potential to modulate disease severity in many cells expressing mutant secretory pathway proteins. Thus, PMD represents the first member of a novel class of disparate degenerative diseases for which UPR activation and signaling is the common pathogenic mechanism.

The molecular and cellular defects underlying Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a recessive X-linked dysmyelinating disorder of the central nervous system (CNS). The most frequent cause of PMD is a genomic duplication of chromosome Xq22 including the region encoding the dosage-sensitive proteolipid protein 1 (PLP1) gene. The PLP1 duplications are heterogeneous in size, unlike duplications causing many other genomic disorders, and arise by a distinct molecular mechanism. Other causes of PMD include PLP1 deletions, triplications and point mutations. Mutations in the PLP1 gene can also give rise to spastic paraplegia type 2 (SPG2), an allelic form of the disease. Thus, there is a spectrum of CNS disorder from mild SPG2 to severe connatal PMD. PLP1 encodes a major protein in CNS myelin and is abundantly expressed in oligodendrocytes, the myelinating cells of the CNS. Significant advances in our understanding of PMD have been achieved by investigating mutant PLP1 in PMD patients, animal models and in vitro studies. How the different PLP1 mutations and dosage effects give rise to PMD is being revealed. Interestingly, the underlying causes of pathogenesis are distinct for each of the different genetic abnormalities. This article reviews the genetics of PMD and summarises the current knowledge of causative molecular and cellular mechanisms.

Hearing profile and MRI myelination of auditory pathway in Pelizaeus-Merzbacher disease.

CONCLUSIONS: This study showed that delayed auditory pathway myelination is common in Pelizaeus-Merzbacher disease (PMD), but this delay does not necessarily indicate poor hearing function. OBJECTIVE: PMD is a rare recessively inherited X-linked leukodystrophy characterized by defective central nervous system myelination owing to a mutation in the proteolipid protein gene (PLP). The aims of this study were to evaluate the hearing function and auditory brain response (ABR) findings of patients with PMD and relate these findings to MRI-assessed myelination in the central auditory pathway. PATIENTS AND METHODS: We retrospectively studied eight male pediatric patients with PMD. Serial auditory examinations included audiometry, behavior audiometry, distortion product otoacoustic emission (DPOAE), and ABR. MRI-assessed myelination in the auditory pathway was evaluated in the PMD patients and in 23 normal young children as a control group. RESULTS: Audiometry showed normal to moderate hearing impairment and the hearing threshold improved with age and became almost normal over time. DPOAEs positivity and only ABR wave I or waves I and II were found in all the patients. MRI showed delayed myelination in all the patients and the auditory pathway was myelinated up to the inferior colliculus in four cases and up to the medial geniculate body in four cases. Serial MRIs showed no progression in myelination. No clear relation was found between hearing threshold and MRI-assessed myelination in the auditory pathway.

Discrepancy between auditory brainstem responses, auditory steady-state responses, and auditory behavior in two patients with Pelizaeus-Merzbacher disease.

We reported two cases of Pelizaeus-Merzbacher disease. Both cases visited our hospital manifesting horizontal nystagmoid movements present from birth, and delayed motor development. Magnetic resonance imaging of the brain showed diffuse dysmyelination of the cerebral white matter, and auditory brainstem response showed waves I and II but absence of all subsequent components. Conditioned orientation reflex (COR) audiometry showed poor reactions in an infantile case whose development was severely retarded, and who spoke no meaningful words. Auditory steady-state response (ASSR) was a helpful tool for identifying her auditory ability; thereafter, her communication skills improved naturally. The other case was mildly developmentally retarded, and the results of COR audiometry and ASSR were considered the same level. The discrepancy between results of these hearing tests may arise under the influence of developmental level of the case.

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.

The impact of Pelizaeus-Merzbacher disease on the family.

The impact of Pelizaeus-Merzbacher disease on families and caregivers of affected children has not been well-studied. Parents, relatives, and caregivers from 18 families with 20 affected children with Pelizaeus-Merzbacher disease were asked to complete the Children's Health Questionnaire-Parent Form 50, an instrument used to assess health-related quality of life in children and family impact of illness. Mean and standard deviation (S.D.) of subscale scores were calculated and compared with previously published norms. Agreement between mothers and fathers was calculated using Cronbach's test. Mean scale scores in this cohort were lower than previously published norms for the following categories: physical function (25.9 vs 96.1, >2 S.D.); family activity (55.6 vs 89.7, >1 S.D.); and parental time impact (66.2 vs 87.8, >1 S.D.). However, family cohesion (73.3 vs 72.3, <1 S.D.), self-esteem (71.1 vs 79.8, <1 S.D.), behavior (78.9 vs 75.6, <1 S.D.), and mental health scale scores (74.2 vs 78.5, <1 S.D.) were similar to previously published norms. Parental agreement was poor, with 5 of 8 parent pairs (63%) differing in their responses (<0.7) Although impact on caregiver time and limitation of physical function and family activities is high, parents and caregivers in the cohort appear to remain cohesive and view their children's psychosocial health as similar to normal children.

'Unfolding' pathways in neurodegenerative disease.

The endoplasmic reticulum responds to stress by initiating a cascade of events known as the 'unfolded-protein response' (UPR). The accumulation of misfolded proteins in the leukodystrophy Pelizaeus-Merzbacher disease activates this stress response, resulting in apoptosis of oligodendrocytes. Although it remains uncertain whether the UPR plays a mechanistic role in prototypical neurodegenerative disorders such as Alzheimer's disease, this is plausible because misfolded proteins are directly implicated in the pathogenesis of these disorders.

A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings.

BACKGROUND AND PURPOSE: Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare progressive neurological disorder caused by Lamin B1 duplication (LMNB1). Our aim was to investigate longitudinally the pattern of the autonomic dysfunction and the degree of neuropsychological involvement. METHODS: Three related ADLD patients and one asymptomatic carrier of LMNB1 duplication underwent a standardized evaluation of autonomic nervous system, including cardiovascular reflexes, pharmacological testing, microneurography, skin biopsy, Metaiodobenzylguanidine scintigraphy and a complete neuropsychological battery. RESULTS: An early neurogenic orthostatic hypotension was detected in all patients and confirmed by a low rise in noradrenaline levels on Tilt Test. However infusion of noradrenaline resulted in normal blood pressure rise as well as the infusion of clonidine. At the insulin tolerance test the increase in adrenaline resulted pathological in two out three patients. Microneurography failed to detect muscle sympathetic nerve activity bursts. Skin biopsy revealed a poor adrenergic innervation, while cardiac sympathetic nerves were normal. None of ADLD patients showed a global cognitive deficit but a selective impairment in the executive functions. CONCLUSION: Autonomic disorder in ADLD involves selectively the postganglionic sympathetic system including the sympatho-adrenal response. Cognitive involvement consisting in an early impairment of executive tasks that might precede brain MR abnormalities.