Fragile X Syndrome in children

Abstract

Fragile X syndrome is caused by the expansion of CGG triplets in the FMR1 gene, which generates epigenetic changes that silence its expression. The absence of the protein coded by this gene, FMRP, causes cellular dysfunction, leading to impaired brain development and functional abnormalities. The physical and neurologic manifestations of the disease appear early in life and may suggest the diagnosis. However, it must be confirmed by molecular tests. It affects multiple areas of daily living and greatly burdens the affected individuals and their families. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism spectrum disorder; the diagnosis should be suspected in every patient with neurodevelopmental delay. Early interventions could improve the functional prognosis of patients with Fragile X syndrome, significantly impacting their quality of life and daily functioning. Therefore, healthcare for children with Fragile X syndrome should include a multidisciplinary approach.

Keywords: Fragile X Syndrome; child; developmental disabilities; fragile x mental retardation protein; pediatrics.

Figure 1. Genetic aspects of Fragile X syndrome. A. Different alleles can give rise to Fragile X syndrome. Even though the most common is the triplet-expansion allele, point mutations in FMR1 or deletion of the gene can produce a phenotype of Fragile X syndrome. B. The severity of the phenotype can be reduced if there are mosaicisms. Mosaicism can be in the number of CGG triplets or in the methylation status of the gene.

Figure 2. The phenotype of children with Fragile X syndrome is variable between individuals and during the stages of development. Some children may have a typical phenotype since early age (A), while others can have subtler or even absent physical manifestations (6 y.o.) (B). However, the physical characteristics of Fragile X syndrome may accentuate during the adolescence, as illustrated by the same patient from panel B, nowadays at with 13 y.o. (C). The diagnosis is not based solely on physical characteristics, as they are not sufficiently sensitive and specific. *The patients and their guardians authorized the use of their image by informed consent.

Figure 3. The phenotype of Fragile X syndrome varies with age. Some manifestations are present early in life, while others appear when the patient reaches adulthood. Some manifestations, such as seizures and otitis media, tend to disappear with age.

Figura 1. Aspectos moleculares del síndrome de X frágil. A. Diferentes alelos pueden causar el síndrome de X frágil. Aunque el más común es el alelo de expansión de tripletas, mutaciones puntuales en FMR1 o deleciones del gen pueden producir un fenotipo de síndrome de X frágil. B. La severidad del fenotipo puede reducirse si hay mosaicismos. El mosaicismo puede ser en el número de tripletas CGG o en el estado de metilación del gen.

Figura 2. El fenotipo de niños con síndrome de X frágil varía entre individuos y a lo largo de las etapas del desarrollo. Algunos niños pueden tener el fenotipo típico desde edades tempranas (A), mientras que otros pueden tener manifestaciones físicas más sutiles o incluso ausentes (B, con 6 años). Sin embargo, las características físicas del síndrome de X frágil se acentúan durante la adolescencia, como ilustra el mismo paciente del panel B, en la actualidad con 13 años de edad (C). El diagnóstico no se base solamente en características físicas, ya que no son suficientemente sensibles y específicas. *Los pacientes y sus acudientes autorizaron el uso de las imágenes por consentimiento informado.

Figura 3. El fenotipo del síndrome de X frágil varía con la edad. Algunas manifestaciones están presentes desde edades tempranas, mientras que otras aparecen cuando el paciente se va acercando a la adultez. Otras manifestaciones, como las crisis epilépticas y otitis media, tienden a desaparecer con la edad.