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Pelizaeus Merzbacher Disease PMD is an X-linked developmental defect of myelination that causes a childhood chronic spastic encephalopathy. Its genetic aetiology 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 jnicef of myelination is evident. We present a series of seven Colombian patients diagnosed with this leucodystrophy, describing their genotypic and phenotypic characteristics and heterogeneity.

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 unief frequently diagnosed, as compared to the connatal phenotype. Only three patients were able to achieve gait, though altered. All cases had abnormalities in neuroimages. Molecular studies were used in the majority of the cases dell confirm the diagnosis For two cases molecular confirmation was not considered necessary given their affected male brothers had already been tested.

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PLP1 gene dosage alterations duplications were found in Pelizaeus Merzbacher Disease PMD is a chronic pediatric leukoencephalopathy caused by disorders of the axonal myelination and the myelin metabolism in the oligodendrocytes, reported for the first time on by doctor Friedrich Pelizaeus 1 and revisited on by Ludwig Merzbacher 2.

Its genetic etiology affects the expression of the Proteolipidic Protein type 1 34varying from hemizygous mutations to gene dosage alterations of the PLP1 Xq Given the location of the causal gene, PMD is inherited in a X-linked recesive manner 3. Although clinical manifestations are heterogeneous 56the most relevant neurological signs are nistagmus, developmental delay, spasticity, along with neuroimaging supporting aberrant myelination of the Central Nervous System CNS compromising primarily the periventricular white matter, with a tigroid striation pattern that responds to the conservation of myelinated islets, and also an alteration of the N-acetyl aspartate and choline profiles on the brain magnetic resonance spectroscopy 57.

Unlike other leukodystrophies in which there is a period of normal cortical myelination an then comes a disruption resulting in the lost of myelin sheaths demyelinationPMD has, from the beginning, an abnormal or low production of this very important protein hypomyelinationdue to a damage on the PLP1 gene coding for the Protelipidic Protein type 1 that interferes with the oligodendrocyte synthesis of fully functional myelin sheaths and probably also affects the peripheral function of myelinated axons 38.

PMD corresponds to a larger group of neurological phenotypes known as PLP1 related disorders, all being allelic diseases: In general, PLP1 gene duplications result in a classical form of PMD, nonsense mutations in either form of SPG2 and connatal form of PMD, and other monoallelic mutations have been related to less circumscribed clinical phenotypes 6. Patients suffering from a connatal form of PMD, the most severe phenotype, have histopathological studies revealing complete absence of myelination in the brain, explaining the rapid clinical deterioration and suggesting tan death of this patients may respond to nervous conduction alterations in brain control centers.

Frequently, the connatal form of PMD is expressed during the first weeks of life, through key findings in the clinical neurological examination, that include pendular nystagmus, hypotonia and laryngeal stridor; later in life, seizures and sever motor deficits appear, and hypotonia turns to weakening limb spasticity; affected patients may never walk Verbal language is limited, but patients understand simple orders and can follow them.

Affected individuals with the connatal form of PMD die in infancy, usually secondary to respiratory or deglutition complications, such as bronchoaspiration 9. Classic PMD is characterized in the first stages of disease by nystagmus, hypotonia and tremor in male affected patients, joint progressively by ataxia and spastic quadriparesis in the school age. Motor impairment of the limbs is less severe tan that presented in the connatal form, and patients can frequently achieve walking even if requiring special aids, and have better control of voluntary movement of the upper limbs 9 Classic PMD affected males also have improved cognitive development, with acceptable speech.


Survival rates in this patients have been described to be up to the seventh decade of life. On the other hand, NS patients suffer from a less harmful condition also caused by large deletions or damaging mutations resulting in loss of PLP1 protein product.

Interestingly, it has been described NS affected individuals to have a multifocal demyelinating neuropathy 812 sometimes being the only clinical feature of the syndrome; NS patients do not present with nystagmus, their spastic paraplegia is mild, affecting primarily the lower limbs, and ataxic compromise may vary.

Another differential diagnosis to consider is SPG2, an allelic disorder to PMD and NS, consisting of an heterogeneous constellation of clinical phenotypes primarily characterized by weakening and progressive lower limb spasticity during the first decade of life, with previous normal motor development.

Patients can also have nystagmus, optic atrophy, dysarthria, ataxic features and variable range of intellectual disability; however, symptoms appear to be less compromising tan those presenting in classic PMD. Most of mutations detected on individuals diagnosed with SPG2 are missense 8.

Also, it is worth mentioning that SPG2 affected males can reproduce, while there are no reports of PMD affected males who have descendants 9. This article describes seven Colombian individuals with clinical, paraclinical and molecular diagnosis of PMD, through phenotype and gene variant characterization. Copies of the written consents are. Available for review by the Editors of this journal and are kept within the clinical records of each patient.

This study was approved by the ethics committee of the Faculty of Medicine of Universidad Nacional. Seven individuals ages 6 months to 16 years 4 probands, 3 male relatives of the probandsdiagnosed clinically, paraclinically and molecularly as Pelizaeus Merzbacher patients, attended in different medical care centers in Colombia Fig.

They underwent clinical evaluations, neuroimaging i. Also, we applied the PMD functional disability scoring system and the WHO Abbreviated Scale of Development to assess the degree of developmental retardation esccala disability on our patients Note that patients are cited on the tables with their assigned pedigree numbers.

In order to evaluate umicef impact of the molecular alterations detected, we used softwares as PolyPhen – 2 v. All patients were male, 6 months to 16 years of age, one of them died by the age of 5 due to complications of a respiratory infection. Mean age at diagnosis was 5 years 5 months, being classic PMD most frequently unlcef, in five cases, whereas the connatal phenotype was only present in two of the patients, In our sample, two patients had history of cerebral palsy, being an actual comorbidity in only one of them.

It is worth saying that all patients exhibited some level of speech delay or learning difficulties, and that only two were going to school. In the physical examination, As for the two patients who had diagnosis of connatal PMD, it dwsarrollo documented both had experienced swallowing or deglutory disorders, history of seizures, microcephaly in just one of them and maturational ages in danger zones according to the WHO Abbreviated Scale of Psychosocial Development WHO Abbreviated Scale of Psychosocial Development, https: When testing them for the PMD functional disability scoring systemall seven individuals had any level of disability, being moderate in Neuroimaging of patients with classic PMD showed evidence of T2 hyperintensities both diffuse or periventricular in the supratentorial withe matter.

Other encephalic structures such as the brainstem, basal nuclei and cerebellum showed no abnormalities. In the connatal form affected individuals, we also observed hypo intensities of the basal nuclei and grey matter atrophy. Molecular studies were used in the majority of the cases to confirm the diagnosis. I47Ta missense variant classified as pathogenic, and two previously unreported alterations, the c. Q99X nonsense variant in two patientsand in one patient the c. Laboratory endpoints are knicef in Table 2.

We present one of the first Latin-American series of patients with clinical diagnosis and molecular confirmation of Pelizaeus Merzbacher disease, being the classical form more frequent than the connatal form in the evaluated patients. Along with the high clinical suspicion, supporting neuroimaging and molecular analysis permit an appropriate genetic counselling. Connatal form escaoa PMD is less frequent and far more severe than the classic phenotype. In our study, it is to note patients with the connatal form showed worse scores of disability High severity scores in the PMD Disability Scoring System and more pronounced developmental delay, and those continue to worsen until their deaths.


Diagnosis can be mistaken primarily with SPG2, also caused by mutations on the PLP1 gene, differing on signs such as autonomic dysfunction and characteristic paraplegia.

NS, a variant of the PMD spectrum, presents as a periferic demyelinating neuropathy. Among other differential diagnosis we can count Krabbe disease, Canavan escalaa, other leukodystrophies and cerebral palsy. Connatal form of PMD is more severe than the classical form, a verifiable fact in our series, and with a reported expectancy of life lower than the first decade of life. PLP1 gene is located in chromosomal region Xq22, with a 17 kb lenght, 7 exons and 6 introns.

Exon 1 only transcribes the start codon, while exons 2, 3, 4, desarrlllo 5 encode the hydrophobic domains and the hydrophilic chains of the protein. C-terminal transmembrane domain is encoded by exons 6 and 7. PLP1 is further translted into the proteolipid protein 1 PLP1a aminoacid peptide, or the isoform called DM20, which loses 35 residues inside its intracellular loop.

A wide range of mutations in PLP1 has been described, recurrently detecting a whole gene duplication as the most frequent alteration 1718 Ile47IlefsX4 and resulted in a truncated protein product, 4 aminoacids downstream We believe it is important to establish the biochemical functionality of I47 position on the myelin proteolipidic protein to evaluate abreviasa impact on the connatal phenotype of PMD disease, given that there are not functional studies to this date that prove in vitro or in vivo effects.

Q99X and missense mutation c. Vesarrollo variants express as a compromise of two functional domains of the PLP1 protein: Q99X affects the cytoplasmic domain while c. F51Y affects an extracellular topological domain 14 To our knowledge, this is not only one of first Latin-American case series but the larger one, presenting the main characteristics of the clinical diagnosis and molecular signatures of PMD male affected patients, being the classical form overall more frequent than the connatal form.

Both patients desartollo the connatal form of the disease abrebiada severe disability scores and poor vital prognosis, despite having the chance of an earlier diagnosis.

In spite of the incapacitating character of this disease, patients with less severe or moderate forms of PMD have rather normal life expectancy, but there are records of patients with severe classical forms who died past the second decade of life.

Because of this, it is a priority for the clinical specialists and treating physicians to improve the diagnosis algorithms in order to shorten time before establishment of the specific therapeutic plan and the appropriate genetic counseling for the families. Z Ges Neurol Psychiatr. Am J Hum Genet. The espectrum of PLP1 gene mutations in patients with classical form of the Pelizaeus Merzbacher disease. Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating disorders.

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

PLP1-related inherited dysmyelinating disorders Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Hobson GM, Kamholz J.

Saray Esther Polo Polo

University of Washington, Seattle; https: Boulloche J, Aicardi J. Pelizaeus-Merzbacher disease clinical and nosological study. The burden of inherited leukodystrophies in children.

Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation.

Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease

Neuroradiologic correlates of clinical disability and progression in the Desarrolllo leukodystrophy Pelizaeus-Merzbacher disease. Individual exons encode the integral membrane domains of human myelin proteolipid protein.

Proc Nat Acad Sci. The proteolipid protein gene and myelin disorders in man and animal models. Structure and molecular arrangement of proteolipid protein of central nervous system myelin. Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease.

Gow A, Lazzarin RA. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease.