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Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease
Velasco Parra, Harvy Mauricio; Maradei Anaya, Silvia Juliana; Acosta Guio, Johanna Carolina; Arteaga Diaz, Clara Eugenia & Prieto Rivera, Juan Carlos
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.
Keywords
Pelizaeus Merzbacher disease; child development; developmental disorders; myelin sheath; Myelin proteolipidic protein; PLP1
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