FRAGILE X SYNDROME

Alternate Names: Martin-Bell syndrome or marker X syndrome

Patient afflicted with Fragile X Syndrome

Overview: The most common cause of inherited mental retardation, intellectual disability, and autism and is the second most common cause of genetically associated mental deficiencies after trisomy 21. It results from mutations in a gene on the X chromosome that makes the protein needed for brain development.

Characteristic/Phenotype: Symptoms of Fragile X syndrome often vary depending on the extent of the change in the FMR1 gene and other factors. Some common symptoms are:

• Developmental and intellectual disabilities or learning disabilities
• Anxiety, especially in new situations, problems in paying attention, and aggressive behavior
• Trouble speaking clearly
• Sensitivity to bright lights, loud noises, or other sensations

Physical manifestations include:

• Childhood growth is marked by an early growth spurt.
• a long, thin face with prominent ears, facial asymmetry, a head circumference higher than the 50th percentile, and a prominent forehead and jaw.
• The mouth has dental overcrowding and a high-arched palate.
• Ears are typically large and may protrude.
• Strabismus is frequently noted. Ocassionally, nystagmus, astigmatism, and ptosis are present.
• Hands and feet manifest nonspecific findings, including hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus. Clubfeet may be present at birth.
• Pectus excavatum and scoliosis are frequent findings.
• Macroorchidism is nearly universal in postpubertal males. During childhood, an increased incidence of inguinal hernias is reported.
• A heart murmur or click consistent with mitral valve prolapse is often auscultated.

Frequency: About 1 of every 4,000 males and 1 of every 8,000 females has Fragile X syndrome. The prevalence of female carrier status has been estimated to be as high as 1 in 130-250 population; the prevalence of male carrier status is estimated to be 1 in 250-800 population. As many as 10% of cases of previously undiagnosed mental retardation in males and 3% of cases of previously undiagnosed mental retardation in females are attributed to fragile X syndrome.

Diagnosis: DNA testing for fragile X syndrome is recommended, since cytogenetic testing is not as sensitive as molecular testing. Karyotyping may also be considered along with molecular diagnosis.

Southern blot analysis provides a more accurate estimation of the number of CGG triplet repeats if a full mutation is present (with a large CGG expansion) while PCR more accurately estimates the number of CGG triplet repeats if a premutation is present (with small-to-moderate increases in CGG repeats).

Causes: The distal end of the long arm of the X chromosome contains the fragile X mental retardation-1 (FMR1) gene which is used to synthesize fragile X mental retardation protein (FMRP), a regulatory protein that binds messenger RNA (mRNA) in neurons and dendrites.

In patients with a full mutation in the FMR1 gene, FMRP is not manufactured because of hypermethylation of FMR1, and brain development is impaired primarily because of abnormal synapse connections.

The mutated gene was also discovered to contain a repeating base pair triplet (CGG) expansion, which is responsible for fragile X syndrome

Unaffected individuals have 5-54 CGG repeats, whereas affected individuals have 200 or more repeats as a full mutation. Full mutation results in hypermethylation of the cysteine bases and restricts protein binding, leading to gene inactivation and absent FMRP.

Although most patients with fragile X syndrome have a CGG triplet expansion, few patients have a point mutation in the FMR1 gene or a deletion of the gene. No spontaneous FMR1 full mutations have been reported

Additional Data: Mosaic patterns are common. The number of repeats is unstable from generation to generation, making the pattern of inheritance difficult to predict. In addition, the degree of methylation is directly proportional to the signs and symptoms of fragile X syndrome.

Treatment/Recommendations/Therapies: A comprehensive developmental evaluation by a speech and language therapist, physical therapist, and occupational therapist is recommended to assess weaknesses and to identify areas in which improvement is needed most. Appropriate intervention strategies will be employed to facilitate learning. As the patient matures, repeat evaluation may be necessary.

A behavioral intervention/modification team can identify specific areas of focus to encourage normal activities such as social eye contact and stress reduction training.

A special education professional is appropriate to assess the level of cognitive functioning, attention deficit hyperactivity disorder (ADHD) symptoms, and aggressiveness and to initiate sensory integration therapy for behavior problems.

Also, a psychology or behavioral specialist is important to assist families with methods for decreasing negative behavior. Additionally, some patients with fragile X syndrome benefit from social skills–oriented therapy and individual counseling.

Routine auditory examinations are advised; otolaryngology referral for chronic otitis media and evaluation for pressure equalization (PE) tube placement are recommended and also to cardiologists and orthopaedic surgeons to periodically check systems which may have malformed.

Genetic counseling is important to inform patients and families and to assist with family planning and reproducive decisions.

Support Groups:

National Fragile X Foundation

http://www.fragilex.org/

Fraxa Research Foundation

http://www.fraxa.org/default.aspx?gclid=CIGu_vbC9bUCFcV56wodjBAA0Q

References:

National Institute of Child Health and Human Development. (2012). Fragile X Syndrome: Condition Information. Retrieved March 12, 2013 from the URL: http://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/Pages/default.aspx

Genetics Home Reference. (2011) Fragile X syndrome. Retrieved March 12, 2013 from the URL: http://ghr.nlm.nih.gov/condition/fragile-x-syndrome

Jewell, J. (2013). Fragile X Syndrome. Retrieved March 12, 2013 from the URL: http://emedicine.medscape.com/article/943776-overview

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