Fragile X syndrome (FXS) was first identified by James Purdon Martin and Julia Bell in Britain in 1943 it was initially known as Martin-Bell syndrome. During the interviewing process, they determined the disease was linked to sex and was heritable. It is now recognized as one of the most common and serious chromosomal disorders. It leads to intellectual disabilities and developmental challenges from an early age. FXS is caused by a deficiency of the Fragile X mental retardation 1 protein (FMRP). Epidemiologically, FXS affects about 1 in 4,000 males and 1 in 6,000 to 8,000 females in the USA, with males more frequently and severely affected than females. Women are often carriers of the altered gene. FXS affects all ethnic groups. While early symptoms can be subtle, they become more pronounced as the patient ages.

Pathophysiology

FXS is caused by a mutation in the FMR1 gene, characterized by an expansion of CGG (cytosine-guanine-guanine) triplet repeats. Normally, CGG repeats occur 10-58 times, but in FXS carriers, the repeats range from 60 to 200 (permutations). When the repeats exceed 200, it constitutes a full mutation, leading to the diagnosis of FXS. This is known as a trinucleotide repeat disorder. The repeats are classified into four allelic classes:

• Normal: 30 to 40 repeats

• Intermediate: 41 to 54 repeats

• Permutations: 55 to 200 repeats

• Mutation: >200 repeats

During the premutation stage, the FMR1 gene can still produce FMRP, albeit in reduced quantities. Once the CGG repeats surpass 200, the gene becomes methylated, ceasing FMRP production. FMRP is crucial for the translation control of various mRNAs in neurons, influencing the postsynaptic activity of group 1 metabotropic glutamate receptors (mGluRI). Other roles include:

• Activation of potassium channels KCNT1 and BK

• Chromatin-dependent roles in DNA damage response and RNA editing

• Neuronal functions such as hippocampal-dependent learning and regulation of the endocannabinoid system

Clinical Manifestations

FXS presents early with intellectual disabilities and autism-like symptoms. As patients age, physical characteristics like large ears, a long face, macroorchidism, and hyperflexible joints become apparent. Behavioral issues such as ADHD, aggression, self-harm tendencies, social anxiety, and autism spectrum disorder (ASD) are common.

Life Stage-Specific Manifestations

• Infancy: Poor suck or latch, reflux, emesis

• Childhood: Seizures, hyperactivity, language delays, anxiety, recurrent otitis media

• Adolescence: Aggression, anxiety, impulsivity, hyperactivity, poor attention

• Adulthood: Episodic dyscontrol, poor attention

• Aging: Parkinsonism symptoms, cognitive decline

Diagnosis

FXS is diagnosed through PCR and Southern blot analysis of blood samples. These methods identify and quantify the size of CGG repeat expansions and full mutations. Diagnosis can typically be made by age three if speech is delayed or absent and other issues like hypotonia, delayed motor milestones, hand flapping, and poor eye contact are present. Gender-specific symptoms for diagnosis include ADHD with impulsivity and anxiety. Behavioral changes such as hand biting, head banging, and rocking often lead to an initial diagnosis of ASD before FXS is confirmed.

Family members are also tested to determine if they carry permutations or full mutations, indicating a potential risk of passing the gene to offspring. Genetic counseling is crucial for families to understand FXS and manage its implications. PCR with primers flanking the repeat region is used to determine the number of CGG repeats, while the Southern blot of genomic DNA assesses methylation status and mutation size. These combined procedures have 99% sensitivity for accurate FXS diagnosis.

MedBound Times connected with Dr. Vishal Nanavaty, PhD scientist and expert in genomics diagnostics and research, and he is currently working as a Consultant Senior Scientist at Neuberg Diagnostics, Neuberg Supratech Reference Laboratory, Ahmedabad, Gujarat, the primary limitation in diagnosing Fragile X Syndrome is the high cost associated with DNA-based methods. These methods are expensive, which can be a significant barrier. Furthermore, Fragile X Syndrome can potentially be prevented if couples undergo DNA testing before planning a family.

According to the paper, "Fragile X syndrome: Diagnostic and Carrier Testing" by Stephanie Sherman PhD, Beth A. Pletcher MD, and Deborah A. Driscoll, MD The purpose of these recommendations is to provide general guidelines to aid clinicians in making referrals for testing the repeat region of the FMR1 gene. DNA studies are used to test for Fragile X syndrome. Genotypes of individuals with symptoms of FXS and individuals at risk for carrying the mutation can be determined by examining the size of the trinucleotide repeat segment and the methylation status of the FMR1 gene.

DNA studies are used to test for fragile X syndrome, determining the size of the trinucleotide repeat segment and the methylation status of the FMR1 gene

Challenges and Future Directions

One significant limitation of FXS management is early detection. Subtle initial symptoms make early diagnosis challenging, often delaying treatment until symptoms become more severe. Early detection through comprehensive genome testing in newborns could identify chromosomal disorders and carrier status, potentially preventing the transmission and onset of hereditary diseases like FXS. Advanced genetic editing techniques, such as CRISPR, hold promise for future treatments that could mitigate or eliminate the effects of FXS if detected early.

Conclusion

Early detection and intervention are crucial for managing FXS effectively. By implementing widespread genome testing in newborns, we can identify chromosomal abnormalities and carrier status, providing opportunities for early intervention and potentially preventing the transmission of FXS to future generations. This proactive approach could significantly improve the quality of life for individuals with FXS and their families.

References:

Cited on 4/7/2024

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By Yash Kamble