Final Diagnosis -- A 2-year-old male with Fragile X syndrome


Fragile X syndrome analysis: Full mutation, fully-methylated FMR1 allele.


Discussion: Fragile X syndrome is the second most common genetic cause of mental retardation (after Down syndrome), with a frequency of 1 in 1550 males and 1 in 8000 females. This X-linked disorder almost always is associated with expansion of a CGG trinucleotide repeat in the 5' untranslated region of the familial mental retardation-1 (FMR1) gene located on Xq23.7 (See Table 1 for CGG repeat numbers and their significance) . The disease originally received its name because of an inducible cytogenetic abnormality on the X chromosome (discontinuity of staining or constriction in this region of the long arm when cells are cultured in folate-deficient media). Expansion of the CGG repeat sequence to >200 - 230 repeats leads to transcriptional silencing of the FMR1 gene due to methylation of CpG islands upstream of the repeat region. Expansion of the trinucleotide to 56-~200-230 CGG repeats is called a premutation and is usually not associated with methylation and transcriptional silencing of the FMR1 gene. Premutation alleles are unstable and may expand to full mutations in further generations. Premutation carrier males typically transmit the CGG repeat region to their progeny with small changes in repeat number. When the premutation is transmitted by a carrier female, there is an increased probability of expansion of the CGG repeat region to a full mutation allele, leading to mental retardation in most male offspring and 50% of female offspring (as a result of unfavorable Lyonization of the X chromosome). The probability of a full mutation arising depends on the size of the mother's premutation allele (see Table 1). Thus, it appears that during the process of oogenesis, but not spermatogenesis, premutations can be converted to full mutations. These findings explained the peculiar pattern of inheritance with features not associated with other X-linked recessive disorders that perplexed geneticists for many years, known as the Sherman Paradox (also referred to as anticipation or dynamic mutation). Sherman observed that the effects of Fragile X syndrome seemed to worsen with each passing generation and theorized that the gene responsible for Fragile X syndrome becomes mutated through a two-step process. The first mutatation, called the premutation, doesn't cause any clinical symptoms. A second mutation was required to convert the premutation into a full mutation capable of causing the clinical symptoms associated with Fragile X syndrome. Additionally, premutations must pass through females in order to transform into the full mutation (can happen during oogenesis or postzygotically). Approximately 20% of the males that have the Fragile X chromosome remain unaffected and have unaffected daughters, but the sons and grandsons of these daughters have a high probability of being affected, and being severely affected.

The hallmark of Fragile X syndrome is mental retardation. Mental retardation is defined as a non progressive disorder evident during childhood, with disabilities in adapting to the environment, and a score on an IQ test below 70. Prominent parental concerns that might bring a child with a Fragile X syndrome to a pediatrician's attention very shortly after birth include: developmental delay, speech delay, short attention span or hyperactivity, mouthing of objects persisting at an age beyond expected, difficulty in disciplining the child, frequent temper tantrums, autistic-like behaviors such as rocking, talking to oneself, spinning, unusual hand movements, difficulty with transitions, preference for being alone, echolalia, poor eye contact; poor motor coordination; history of vomiting, spitting up or colic during infancy; history of frequent otitis media; self-abusive behavior; hand flapping; drooling persisting beyond expected; hypotonia; increased fighting with others; pica; hand/thumb sucking. While older children (8-12 years) are more likely to display the classic physical features of Fragile X syndrome (long face with a prominent jaw, large prominent ears, and post-pubertal macroorchidism, patients as young as 2 or 3 years have been noted to exhibit the following physical findings: long and/or wide and/or protruding ears; prominent jaw or long face; high arched palate; flattened nasal bridge; microcephaly or relative macrocephaly; apparent hypertelorism; epicanthal folds; simian creases of palms, vertical creases of soles; long philtrum; hemangioma; hyperextensible joints; antimongoloid slant; clinical impression of macroorchidism and prominent forehead.

Individuals with a premutation (1 in 800 males and 1 in 260 females) do not exhibit the classical phenotype of Fragile X syndrome and were initially thought to be asymptomatic, although a number of studies have reported autism, mild learning disabilities and social phobias or anxiety disorders in a subgroup of premutation carriers. Approximately 20% of female premutation carriers manifest decreased fertility and premature ovarian failure. The decrease in fertility is related to increased levels of some hormones, particularly FSH and decreased length of the follicular phase. Fragile X associated tremor/ataxia syndrome (FXTAS) is a recently described entity that develops predominantly in male (but also to some extent female) premutation carriers over 50 years of age. FXTAS represents a new form of inclusion disorder with a high prevalence in the general population (initial family-based studies point to a prevalence of 1 in 3000 for men aged over 50 years). The neurological phenotype of FXTAS includes intention tremor and ataxia. Associated features are dementia, Parkinson-like syndrome, neuropathy, and autonomic dysfunction. In contrast to the affected males with full mutation and total lack of FMR1 product - FMR protein, male premutation carriers show increased transcription of the mutant FMR1 gene due to lack of normal protein resulting in positive feedback on the transcription. The accumulation of the abnormal transcript initiates the formation of neuronal intranuclear inclusions, leading to functional impairment, sequestration of important cellular proteins and eventually to cell death.

Our case documents a classical presentation of Fragile X syndrome and demonstrates the unique pattern of its inheritance. Although no other family members have been tested yet, it can be assumed with a high level of certainty that the mother is an obligate carrier of a premutation or even a full mutation allele that she has transmitted to her two sons. Both her father and uncle, "transmitting males" in the family pedigree, have unspecified learning disabilities, a possible effect of a premutation or possibly an unmethylated or partially methylated full mutation FMR1 allele. The learning disabilities reported in her brother are worth further investigation as he did not receive his X chromosome from the father. Due to the high prevalence of learning disabilities in the general population (1 in 59 according to NHIS-97) and its various etiologies, it is probable that his symptoms are unrelated. Molecular genetic testing is indicated in the mother, her father and uncle as well as her children, including the youngest daughter who has a 50% risk of being a full mutation or premutation carrier.. Although there is currently no cure for Fragile X syndrome, early diagnosis, individualized education plans, along with physical, occupational and speech therapy can help patients achieve their maximum potential and considerably improve their life experience as well as the experience of their families.


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Contributed by Marie Dvorakova, MD and Jeffrey A Kant, MD, PhD

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