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.

Pelizaeus-Merzbacher Disease: A Caregiver Assessment of Disease Impact

“…Although we did not collect data for the date of diagnosis, these results highlight the challenges many patients and families face with receiving a timely diagnosis of Pelizaeus-Merzbacher disease, which is an important consideration for the development of disease modifying therapeutics where early intervention is key. Consistent with the literature, 3,17 we found that across all phenotypes the most frequently reported symptoms are difficulty with gross and fine motor skills, speech, and communication. For the most common phenotypes of classic and connatal Pelizaeus-Merzbacher disease, difficulty with communication; difficulty eating and/or swallowing; difficulty with crawling, standing, or walking; difficulty with manual dexterity; nystagmus; difficulty learning; and spasticity are all reported as common symptoms in both groups (>50%).…”

“…7-11 Studies that investigate the natural disease course and clinical phenotypes of Pelizaeus-Merzbacher disease have been small and often limited to individual case series. 12-17 Prior to any potential disease-modifying therapy entering the clinic, it is important to assess the impact of the disease from the participant and caregiver perspectives to enable appropriate evaluation of potential benefit in this population. 18…”

“…[7][8][9][10][11] Studies that investigate the natural disease course and clinical phenotypes of Pelizaeus-Merzbacher disease have been small and often limited to individual case series. [12][13][14][15][16][17] Prior to any potential disease-modifying therapy entering the clinic, it is important to assess the impact of the disease from the participant and caregiver perspectives to enable appropriate evaluation of potential benefit in this population. 18 Here we present development and results from a caregiver survey investigating the path to diagnosis, symptomatology, including the identity and impact of the most bothersome symptoms, and the needs that future treatment should address for patients with Pelizaeus-Merzbacher disease.…”

The Natural History of Pelizaeus-Merzbacher Disease

“…All our patients exhibited onset within the first year of life, with nystagmus predominating as the first symptom noticed, consistent with previous reports. 7,8,10,11 In addition, most had nystagmus at some point in their lives and all had hypotonia, key characteristics of the classic PMD phenotype. In our cohort, all of our subjects exhibited delays in both motor and language development; however, many individuals were able to meet several developmental milestones.…”

The natural history of Pelizaeus–Merzbacher disease caused by PLP1 duplication: A multiyear case series

“… 7 , 8 , 10 , 11 In addition, most had nystagmus at some point in their lives and all had hypotonia, key characteristics of the classic PMD phenotype. Velasco Parra et al 12 reported on seven Columbian patients with Pelizaeus–Merzbacher disease ranging in age from 6 to 16 and with various PLP1 pathogenic variants. Unlike in our cohort.…”