X-linked myotubular myopathy: a clinical report and a review of the mild phenotype. / Miopatía miotubular ligada al cromosoma X: informe clínico y revisión del fenotipo leve.

INTRODUCTION: X-linked myotubular myopathy is a rare centronuclear myopathy that affects approximately 1 in 50,000 male newborns caused by pathogenic variants in the myotubularin 1 gene (MTM1). The clinical severity varies, however the need for ventilatory support occurs almost invariably. CASE REPORT: We report the case of a 4-year-old boy presenting mild muscle hypotonia at 12 months-old, expressive language disorder, global developmental delay, and a sensory processing disorder. Clinical exome sequencing identified the hemizygous variant c.722G>A p.(Arg241His) in exon 9 of the myotubularin 1 gene (NM_000252.2). The mother is a heterozygous carrier of the same variant. A diagnosis of a mild form of maternal inherited X-linked myotubular myopathy was established. The child presented significant improvement with speech, occupational, and physical therapies, with no respiratory intercurrences or ventilator dependency. CONCLUSION: The presentation of a mild form of this myotubular myopathy, being less commonly reported, added challenge to the diagnosis. The combination of mild hypotonia, feeding difficulties and expressive language disorder should raise suspicion of a neuromuscular disease. There is a lack of verified motor or developmental scores specific to this myopathy to further determine prognosis and need of other therapies. While currently the severity myotubular myopathy is classified according to ventilator dependency, this may be insufficient and unapplicable to milder cases. There is an evident need for a grading system for mild and moderate cases assessing muscle weakness and fatigue, daily life limitations, motor developmental delay, early phenotypical scores, or recurrent respiratory infections.

TITLE: Miopatía miotubular ligada al cromosoma X: informe clínico y revisión del fenotipo leve.Introducción. La miopatía miotubular ligada al X es una miopatía centronuclear rara que afecta aproximadamente a 1 de cada 50.000 recién nacidos varones causada por variantes patógenas en el gen de la miotubularina 1 (MTM1). La gravedad clínica varía; sin embargo, la necesidad de soporte ventilatorio ocurre casi invariablemente. Caso clínico. Presentamos el caso de un niño de 4 años que presentaba hipotonía muscular leve a los 12 meses, trastorno del lenguaje expresivo, retraso global del desarrollo y trastorno del procesamiento sensorial. La secuenciación clínica del exoma identificó la variante hemicigótica c.722G>A p.(Arg241His) en el exón 9 del gen de la miotubularina 1 (NM_000252.2). La madre es portadora heterocigota de la misma variante. Se estableció el diagnóstico de una forma leve de miopatía miotubular ligada al cromosoma X de herencia materna. El niño presentó una mejoría significativa con terapias del habla, ocupacional y física, sin intercurrencias respiratorias ni dependencia de ventilador. Conclusión. La presentación de una forma leve de esta miopatía miotubular, al notificarse más raramente, añadió desafío al diagnóstico. La combinación de hipotonía leve, dificultades de alimentación y trastorno del lenguaje expresivo debe hacer sospechar una enfermedad neuromuscular. Se carece de puntuaciones motoras o de desarrollo verificadas específicas de esta miopatía para determinar el pronóstico y la necesidad de otras terapias. Aunque actualmente la gravedad de la miopatía miotubular se clasifica según la dependencia del ventilador, esto puede ser insuficiente e inaplicable a los casos más leves. Es evidente la necesidad de un sistema de clasificación para los casos leves y moderados que evalúe la debilidad muscular y la fatiga, las limitaciones de la vida diaria, el retraso del desarrollo motor, las puntuaciones fenotípicas tempranas o las infecciones respiratorias recurrentes.

Molecular mechanisms underlying large genomic deletions in ornithine transcarbamylase (OTC) gene.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle error causing hyperammonemia and orotic aciduria. Clinical diagnosis is generally confirmed by mutation detection. However, in approximately 20% of the patients, no mutation is found by conventional mutation-searching strategies, which fail to detect deletions spanning at least a whole exon, large rearrangements, or mutations at non-coding regions. To detect large deletions or duplications, we have applied the multiplex ligation-dependent probe amplification (MLPA) methodology to three OTCD patients (two females and one male). MLPA revealed copy number alterations of OTC exons in all of them. The two females were found to be heterozygous for deletions of either exon 2 or exons 6-9, and the male was confirmed to lack all OTC exons. Females' characterization of the deletion breakpoints by long polymerase chain reaction and sequencing revealed the mutations c.78-3544_217-129del5921 and c.541-600_1005 + 1880del10862 corresponding to exon 2 and exon 6-9 deletions, respectively. Examination of the deletion-flanking regions suggests that exon 2 deletion probably resulted from replication slippage facilitated by a secondary structure formed by two inverted Alu repeats, whereas an Alu-Alu homologous recombination was probably responsible for the exon 6-9 deletion. This work contributes to the identification of novel disease-causing mutations in OTCD and increases the knowledge on possible mutational mechanisms generating deletions in OTC.

Congenital disorder of glycosylation type Ia: searching for the origin of common mutations in PMM2.

Congenital Disorders of Glycosylation (CDG) are a group of recessive genetic disorders characterized by hypoglycosylation of glycoproteins. CDG-Ia, the most common type, is caused by mutations in the PMM2 gene, coding for a phosphomannomutase (PMM2; EC 5.4.2.8). The mutational spectrum of PMM2 comprises more than 80 different mutations but one of them, R141H, is particularly interesting due to its high frequency among CDG-Ia patients worldwide. In contrast, other mutations are ethnically or geographically restricted, such as D65Y which is only found in patients of Iberian ancestry. In the present study a population genetic approach was used in an attempt to clarify the origins of two important disease causing mutations: R141H and D65Y. Based on SNP and STR genotypic analysis, we ascertained an association between the R141H substitution and a particular haplotype, suggesting a common origin for all the mutated chromosomes. Similar results were found for D65Y, although the associated haplotype was different from that of R141H, suggesting independent origins for these two mutations. Our results enable us to infer an Iberian origin for the D65Y mutation.

Mutational spectrum and linkage disequilibrium patterns at the ornithine transcarbamylase gene (OTC).

Ornithine transcarbamylase (OTC; EC 2.1.3.3) is a hepatic enzyme involved in ammonia elimination via the urea cycle. Since the sequence of the OTC gene was reported many types of mutations continue to be found in OTC deficiency patients, continuing to increase the already wide mutational spectrum known for this gene. In this study we present the clinical, biochemical and molecular features of thirteen late-onset OTC deficiency patients. Mutations were identified in all these patients, among which six were novel point substitutions (L59R, A137P, L148S, Y176L, L186P, and K210N) and one was a 2-bp deletion at exon 4 (341-342delAA). In addition, a de novo genomic deletion of maternal origin encompassing exons 1 to 5 was also identified by the analysis of LD patterns using intragenic polymorphic markers. This work exemplifies the potential value of population genetic studies for the detection of large deletions.