fragile x syndrome clinical presentation pathology and treatment

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INTRODUCTION

The clinical features and diagnosis of FXS in children and adolescents are discussed in this topic review. Prenatal screening and the management of FXS in children and adolescents are discussed separately. (See "Fragile X syndrome: Prenatal screening and diagnosis" and "Fragile X syndrome: Management in children and adolescents" .)

PATHOGENESIS

There are two clinically significant levels of CGG expansion:

● Full mutation – Expansion of >200 repeats is known as full mutation and leads to methylation-coupled silencing of the FMR1 gene and absence of FMRP, causing the classical FXS phenotype. (See 'Full mutation in males' below and 'Full mutation in females' below.)

Fragile X Syndrome: From Molecular Aspect to Clinical Treatment

Affiliations.

• 1 Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia.
• 2 Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDH, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA.
• 3 Khoo Teck Puat-National University Children's Medical Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
• 4 Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA 95817, USA.
• 5 Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA.
• 6 Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia.
• 7 Department of Psychiatry, Fragile X Clinic, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
• 8 Department of Psychiatry & Behavioral Sciences-Child Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
• PMID: 35216055
• PMCID: PMC8875233
• DOI: 10.3390/ijms23041935

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 ( FMR1 ) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990-2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.

Keywords: FMR1 gene; FMRP; autism spectrum disorder; behavior problems; fragile X syndrome.

Publication types

• Brain / pathology
• Fragile X Mental Retardation Protein / genetics
• Fragile X Syndrome / genetics*
• Fragile X Syndrome / pathology
• Fragile X Mental Retardation Protein

Grants and funding

• 6431806/Science Fund of the Republic of Serbia, Program DIASPORA, Project: PREMED-FRAX

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• Intractable Rare Dis Res
• v.5(3); 2016 Aug

Fragile X syndrome: A review of clinical management

Reymundo lozano.

1 Medical Investigation of Neurodevelopmental Disorders MIND Institute, UC Davis, CA, USA

2 Department of Pediatrics, UC Davis, Sacramento, CA, USA

Atoosa Azarang

Tanaporn wilaisakditipakorn, randi j hagerman.

The fragile X mental retardation 1 gene, which codes for the fragile X mental retardation 1 protein, usually has 5 to 40 CGG repeats in the 5′ untranslated promoter. The full mutation is the almost always the cause of fragile X syndrome (FXS). The prevalence of FXS is about 1 in 4,000 to 1 in 7,000 in the general population although the prevalence varies in different regions of the world. FXS is the most common inherited cause of intellectual disability and autism. The understanding of the neurobiology of FXS has led to many targeted treatments, but none have cured this disorder. The treatment of the medical problems and associated behaviors remain the most useful intervention for children with FXS. In this review, we focus on the non-pharmacological and pharmacological management of medical and behavioral problems associated with FXS as well as current recommendations for follow-up and surveillance.

1. Introduction

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability (ID) and the most common monogenetic cause of autism (ASD) that is known. FXS was initially described in 1969 by Lubs and colleagues ( 1 ) and the first fragile X-linked pattern of inheritance was reported by Martin and Bell in 1949 ( 2 , 3 ). In FXS there is a mutation in the Fragile X Mental Retardation 1 ( FMR1 ) gene which involves an expansion of more than 200 CGG repeats. Individuals in the normal population have approximately 5 to 40 CGG repeats within FMR1 and individuals who are carriers for FXS (premutation) have 55 to 200 CGG repeats ( 4 – 6 ). The molecular basis of FXS is characterized by the CGG full mutation and methylation of the cytosine bases, which leads to silencing of transcription and deficiency or absence of the encoded protein, Fragile X mental retardation protein (FMRP). FMRP is a major protein regulator of the translation of many mRNAs involved in synaptic plasticity ( 7 ). Therefore, in FXS the lack of FMRP causes significant intellectual deficits. Usually, expansions occur between generations when passed on by a female with the premutation into a full mutation in the offspring ( 8 ). Women, who are known carriers of the FMR1 gene mutation, can obtain prenatal diagnosis including chorionic villus sampling (CVS) and/or amniocentesis studies as recommended by the American College of Obstetricians and Gynecologist ( 9 ). Preimplantation diagnostic services and in vitro fertilization are also available ( 10 – 12 ). Individuals with FXS present with a wide range of learning disabilities ranging from normal functioning to borderline cognition or mild to severe ID. The average Intelligence Quotient (IQ) of males with the full mutation is 40 ( 13 ). Intellectual and developmental disability occurs in 85% of males and 25% of females. Furthermore, FXS also accounts for approximately 2 to 5% of all individuals diagnosed with ASD. In FXS about 60% of males have ASD ( 14 ). Physical manifestations are subtle in infants and young boys. These include: midface hypoplasia with sunken eyes, arched palate, macroorchidism, and large cupped ears among others ( Figure 1 ).

Young boy with fragile X syndrome and his Go Talk device. Note prominent ears with cupping of the pinnae. The participant's family provided informed consent for the use of this picture.

Medical problems associated with FXS include mitral valve prolapse, otitis media, seizures, strabismus, joint laxity, sleep disturbances, and gastrointestinal problems. In this review, we provided a summary of the prevalence and clinical management of medical problems associated with FXS other than ID and ASD ( Table 1 ).

FXCRC: Fragile X Clinical and Research Consortium Study; FXS: Fragile X syndrome.

2. Fragile X syndrome associated medical problems

2.1. after birth problems.

Boys with FXS are slightly larger than average in weight at birth. The mean birth weight from earlier studies ranges from 3,490 gms. to 4,046 gms. in white male infants ( 15 ). The mean birth weight of boys with the FXS was in the 70 th percentile, they also had a higher birth weight than their siblings when this was corrected for gestational age and sex ( 16 ). The mean birth weight in FXS was increased and the average linear growth was also above the mean for typically developed boys with the greatest increase after the second year of life. In contrast, the weight measurements were on average below the mean until two years of age. It is suggested that in FXS there is a disturbance of early infantile growth ( 17 ); however, the overall proportion of infants with low birth weight was similar to that in the general population ( 18 ). After birth, the head circumference tends to rise above the 50 th percentile and continues to be larger than those without FXS. Jacobs c noted that in six of nine affected men, the head circumference was greater than the 90 th percentile ( 18 ), but other studies have shown that the mean head circumference ( 19 – 21 ) and the mean birth length are not different of those of control population ( 21 ). Hagerman and colleagues found no difference in the height, weight or head circumference of girls with FXS compared with those without the full mutation ( 22 ).

Some studies reported that the height of males with FXS is greater than the 50 th percentile and height curves for FXS were higher at nearly every point in the prepubertal section of the curves, but height was lower at postpubertal ages ( 23 , 24 ). A subset of children with FXS can be misdiagnosed as having Sotos syndrome or Prader-Willi syndrome ( 25 ). The Prader-Willi phenotype (PWP) can be observed in FXS and it consists of extreme obesity, hyperphagia, lack of satiation after meals, small genitalia, delayed puberty, sometimes short stature and stubby hands and feet ( 26 – 28 ). Sotos-like syndrome was reported in 1986 in two boys with FXS featuring large size at birth, unusual length, large head circumference and minor facial abnormality ( 29 ).

Structural longitudinal magnetic resonance imaging (MRI) study of preschoolers with FXS observed generalized brain overgrowth compared to controls, evident at age two and maintained across ages 4–5 ( 30 ). The molecular biology of FXS suggests a possible mechanism for brain growth patterns. Harlow and colleagues have demonstrated that FMRP inhibits the generation of progenitor neurons from glia cells but enhances the glial cell number in mouse cerebral cortex, suggesting that the lack of FMRP, as seen in FXS might result in an increased proliferation of progenitor glial cells and subsequent cerebral cortical overgrowth ( 31 ). The presence of early brain differences in young children with FXS points to aberrant early brain development in this condition ( 31 ).

FMRP also regulates the phosphatase and tensin homolog ( PTEN ) gene translation that in turn regulates growth. The results of genetic and regression analysis showed that in both boys and girls, total pubertal height gain is impaired, whereas the rate of growth during the preadolescent period is increased, compared with the growth rate of subjects without FXS. The study demonstrates the linear effect of progressively reduced levels of FMRP on a number of physical measurements ( 32 ). This effect is predictably less strong in females than in the males because of the presence of the second unaffected X chromosome. The inverse relationship of height and limb length with FMRP deficit supports a possible role of hypothalamic dysfunction in growth disturbances in FXS that may be more severe in those with the PWP ( 33 ). This dysfunction may cause a premature increase in the pulsating secretion of high doses of estrogen, thus leading to earlier epiphyseal maturation ( 34 ). The hypothesis of premature activation of the hypothalamic-pituitary-gonadal axis may explain the cause of growth impairment in FXS and occasional precocious puberty in females with FXS, a few cases have been reported ( 35 , 36 ).

2.2. Otitis media (OM)

OM is one of the most frequent medical problems associated with FXS. Even when children with FXS have a high pain threshold and may not specifically complain about ear pain, 85% of children with FXS have at least one diagnosed episode of OM ( 37 ). An ear examination is warranted for any change of behavior and sleep patterns as well other symptoms including fever, vomiting, and headache. Children with FXS commonly develop OM complications including decreased hearing acutely and at least one-fourth develop acute sinusitis. Furthermore, OM recurs in about 50% of children with FXS recurrent 5 years of age ( 37 ). There is not data reported about the rates of chronic otitis. Recurrent otitis media may cause conductive hearing deficits and exacerbate the cognitive, language, and behavior problems that exist in this syndrome ( 38 ); therefore, the treatment of OM should be aggressive. The American Academy of Pediatrics initial recommendation for uncomplicated OM is an observation period for children 6 months to 2 years with unilateral OM without otorrhea and for children older than 2 years with bilateral OM without otorrhea; however, we recommend to consider skipping the observation period and using antibiotic therapy in children with FXS ( 39 ). The craniofacial changes in FXS including a long face and collapsible Eustachian tubes predispose children to OM infections. Signs of slight redness, mobility impairments and abnormal positioning of tympanic membrane (TM) such as retraction or bulging, should be carefully assessed. Initial antibiotic therapy for 10 days includes a high dose of amoxicillin (80–90 mg/kg per day in 2–3 divided doses). If not improvement after 48–72 hour, Amoxicillin-clavulanate (same dose of amoxicillin + 6.4 mg/kg per day of clavulanate (amoxicillin to clavulanate ratio, 14:1) in 2 divided doses) or Ceftriaxone (50 mg IM or IV for 3 day) are recommended. A low threshold for early tympanostomy tube placement and antibiotic prophylaxis (amoxicillin low dose) is also advised. The potential adverse effects of antibiotics, principally allergic reaction and gastrointestinal tract consequences, such as diarrhea are important considerations for tympanostomy tubes over prophylaxis.

Clinicians should stress the recommendations of pneumococcal conjugate and influenza vaccine to all children, according to the schedule of the Advisory Committee on Immunization Practices, American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP). Multiple studies provide evidence that breastfeeding for at least 4 to 6 months reduces episodes of OM and recurrent OM ( 40 – 43 ). Eliminating passive exposure to tobacco smoke could also reduce the incidence of OM in infancy. In addition, bottles and pacifiers have been also associated with OM ( 44 – 49 ). Finally, Xylitol syrup, chemically a pentitol or 5-carbon polyol sugar alcohol, has shown a statistically significant reduction (25%) in the risk of occurrence of OM among healthy children ( 50 ).

2.3. Seizures

Seizure prevalence studies in FXS have shown discordant results; a study conducted in neurology clinics reported a broad prevalence range of 14% to 44%, while studies that focus on FXS patients in community hospitals or FXS clinics reported lower ranges of 12–18% ( 51 – 53 ). Typically, males have a higher prevalence when compare to females. In the national survey of caregivers of individuals with FXS, from 1,394 individuals, 14% of males and 6% of females were reported to have seizure ( 54 , 55 ). Studies in the Fmr1 knockout (KO) mouse shows immature dendritic connections, increased number of long and thin spines which point to the deficiency in the normal selection or pruning of the synaptic contacts that occurs in neuronal development ( 56 , 57 ). These results demonstrate that FMRP is important in the maturation of adult dendritic spine morphology ( 58 ). Immature dendritic connections can predispose the KO mouse to audiogenic seizures, although deficits in gamma amino butyric acid (GABA) inhibition are also related to the seizures in FXS ( 59 , 60 ). Similar abnormal dendritic formations are also observed in the brain of humans with FXS and may explain the higher frequency of seizures. In addition to structural changes, the absence or deficiency of FMRP leads to increased neuronal excitability and susceptibility to seizure ( 61 ). Other studies hypothesize that the pathophysiology of seizures in those with FXS can be related to the imbalance of the excitatory and inhibitory neurotransmitter systems ( 60 , 61 ).

It is important to consider that many children with FXS have abnormal electroencephalogram (EEG) without overt seizures ( 62 , 63 ). In those with overt seizures, all types of seizures can occur. Some studies have shown a predominance of generalized seizures ( 64 ), secondary generalized seizure and status epilepticus seizure ( 64 ). Seizures in FXS may also resemble benign focal epilepsy in childhood with centro-temporal spikes ( 65 , 66 ). In general, complex partial seizures are the major type of seizure in FXS. The observed seizures are – typically- not severe and mostly limited to childhood ( 66 ); however, the presence of seizures at an early age appears to be associated with developmental and behavioral morbidity that can impact brain function. Remarkably, those patients with FXS and seizures are more likely to have ASD ( 67 ). The current practice is to educate parents and follow-up patients closely for any possible episodes of seizure: starring spells, unexplained behavior, atypical facial gestures, vomiting at night, regression of development, language or behavior changes, as well as, significant sleep disturbance. If seizures are suspected, then it is recommended to obtain an EEG in both the waking and sleeping states ( 68 ). It is also important to tell families to avoid soy formulas in young children with FXS because of the recent report of soy formula intake increasing the prevalence of seizures in those with ASD and FXS ( 69 ).

Seizures are usually easily managed on monotherapy with anticonvulsants. Historically, most individuals with FXS have experienced good control with carbamazepine or valproic acid, with fairly limited adverse effects ( 69 ). Carbamazepine stabilizes the inactivated state of voltage-gate sodium channels. Its action leaves the affected neuronal cells less excitable. Carbamazepine has also α1, β2, and γ2 subunits containing GABA receptor agonist actions. Carbamazepine-gene testing, pharmacogenomics or pharmacogenetics, to look for the human leukocyte antigen B 1502 (HLA-B*1502), the variant may determine whether carbamazepine could be an effective treatment or whether side effects may develop. The United States Food and Drug Administration (FDA) recommends that patients with Asian ancestry should be tested for the HLA-B*1502 gene variant before treatment. Testing individuals of other ancestries is not typically performed ( 70 – 72 ). The carbamazepine label contains warning for blood dyscrasia and common side effects are drowsiness, dizziness, headaches and migraines, motor coordination impairment, nausea, vomiting, and/or constipation. Carbamazepine has also the advantage that can be used as a mood stabilizer at a typical dosage ( 73 ). The valproic acid mechanism of action is not fully understood, but the reduction of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), as well as, the blockade of voltage-dependent sodium channels may protect against seizures; the increased brain levels of GABA may contribute to its mood stabilizer properties as well as its antiepileptic mechanism of action. The most common adverse effects of valproic acid are digestive complaints (diarrhea, nausea, vomiting and indigestion), vision problems (double vision or lazy eye), hormonal disturbances (increased testosterone production in females and menstrual irregularities), hair loss, memory problems, weight gain, infections, low platelet count, dizziness, drowsiness, tremor and headache ( 74 , 75 ). The FDA recommends patient testing on the Valproate (VP) drug label to avoid prescribing the drug to individuals with urea cycle disorders, the information is lacking about what type of genetic testing and how it should be carried out. Newer studies correlating genotype-phenotype associations with the clinical response will be helpful to increase drug efficacy and to reduce drug-related toxicity ( 76 ).

For those who failed carbamazepine or valproic acid, lamotrigine can be used as a fairly effective second line. Phenytoin has the adverse effects of gum hypertrophy and can interfere with dental hygiene. Phenobarbital and gabapentin also should be avoided because they exacerbate behavioral problems including hyperactivity ( 76 ). Drug-specific blood level testing, liver function studies, electrolytes, complete blood count (CBC) and general health monitoring should be considered for any child taking anticonvulsant medications ( 76 ).

2.4. Mitral valve prolapse

Mitral Valve Prolapse (MVP, floppy mitral valve) is a valvular heart condition that is characterized by the displacement of an abnormally thickened mitral valve leaflet into the left atrium during systole ( 77 ). The prevalence of MVP in the general population is estimated at 2–3% ( 77 ); however, MVP is observed in 7% of autopsies in the United States ( 78 ). Studies of individuals with FXS have shown that MVP occurs in approximately 50% of males and 20% females with echocardiogram confirmation ( 79 , 80 ). However, a recent Fragile X Clinical Research Center (FXCRC) database study using only clinical reports showed a prevalence of only 0.8%. Perhaps this relates to the fact that MVP is more common in adults than children and often cannot be diagnosed by just auscultation. Careful cardiac auscultation is recommended during every annual physical examination and if a systolic murmur or the classical MVP murmur is detected (a mid-systolic click, followed by a late systolic murmur heard best at the apex), then it is recommended to request a cardiology evaluation which should include an echocardiogram ( 81 ). Individuals with MVP, particularly those without symptoms, often require no treatment ( 82 ). Those rare cases of MVP and symptoms of arrhythmias or dysautonomia may benefit from beta-blockers. Individuals with MVP are at higher risk of infective endocarditis, approximately three- to eightfold the risk of the general population ( 82 ). Before 2007, the American Heart Association recommended prophylaxis for dental surgery and other invasive procedures that could introduce bacteria into the blood stream. Thereafter, the association determined that individuals with MVP should not receive prophylaxis routinely; prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis ( 83 ).

Surveillance cardiac evaluations are necessary for those with moderate MVP, in order to evaluate the degree of regurgitation. In very rare instances when MVP is associated with severe mitral regurgitation, mitral valve repair or surgical replacement may be necessary. In the general population, MVP is observed in individuals who tend to have low body mass index (BMI), it is unknown if MVP in FXS is associated with lower BMI. Abnormal elastin fibers have been detected in the cardiac valves and in the skin of individuals with FXS so MVP is thought to be related to the connective tissue problems seen in FXS and are related to abnormalities of the elastin fibers ( 84 ). Dilation of the aortic root is also seen in many individuals with FXS in both childhood and adulthood and this is also associated with abnormal elastin fibers ( 35 , 58 ); Typically, this is not progressive nor have significant aneurisms been reported. In summary, MVP carries a very low risk of complications, but in rare severe cases complications may include mitral regurgitation, infective endocarditis and congestive heart failure. Further, larger longitudinal studies that described the prevalence and MVP and its complications are necessary.

2.5. Gastrointestinal problems

The frequency of gastro intestinal (GI) problems in FXS remains to be determined, but initial and current studies showed a similar proportion (prevalence ∼11%) of children suffering from diarrhea and gastro-esophageal reflux disease (GERD) ( 85 , 86 ). Interestingly GI problems have been described to be quite common in other connective tissue disorders, such as Ehlers-Danlos syndrome (EDS) and Marfan syndrome; such problems include GERD, irritable bowel syndrome, and diarrhea ( 87 – 90 ). Even more intriguing is the association of the premutation and irritable bowel syndrome and the fact that developmental disorders and autism are usually associated with constipation rather than diarrhea as observed in FXS ( 91 ). General recommendations should be provided and medication management, such as, thickening agents, antacids, histamine-2 (H-2) blockers and proton-pump inhibitors, should be prescribed if necessary. Individuals with FXS have higher pain threshold which along with the communication deficits can mask the frequency of abdominal pain and other gastrointestinal symptoms. Surveillance on height and weight are appropriate to determine a failure to thrive (FTT) and referral to gastroenterologist specialist and nutritionist are recommended in the presence of FTT or poor weight gain. It is likely that the frequent loose stools in FXS are related to autonomic dysregulation including sympathetic hyperarousal and chronic anxiety ( 92 ).

Sleep problems are very common in the general population and even more common in young children with FXS. There are many issues that disturb normal sleeping patterns such as problems falling asleep, frequent nighttime awakenings, waking up too early, and parasomnias. In children with FXS the prevalence of sleep problems was reported to be 26–47% ( 93 , 94 ) which is higher than the prevalence observed in typical children (10–25%) ( 95 , 96 ). A recent study showed that the prevalence did not have gender or demographic differences and that the severity of sleep disturbance in FXS children was more pronounced when compared to typically developing children. The most frequent problems reported were difficulty falling asleep and frequent nighttime awakening ( 97 ). In addition, altered sleep patterns and dysregulated melatonin profiles have been observed in adolescents with FXS as well as greater variability in total sleep time, difficulty in sleep maintenance, and significantly greater nocturnal melatonin production in the boys with FXS ( 98 ). Children with FXS are at a higher risk for sleep problems at very young age (∼3 years of age) and the sleep problems may not resolve with age. Therefore; it is recommended that a careful history of sleep habits must be included in every clinical visit ( 99 ), starting at a young age and continue throughout their life. The physician may simply ask the parents if they have any concerns about their child's sleep or if their child takes more than 30 minutes to fall asleep at bedtime. Standardized parent questionnaires, such as the Child's Sleep Habit's Questionnaire or a two-week sleep diary are good tools to assess sleep problems ( 99 ).

Treatment of sleep problems in FXS includes behavioral interventions and medications. Behavioral intervention should include bedtime routines, positive reinforcement, effective instructions and parental support. An example is "extinction" (removing reinforcement to reduce a behavior) which can effectively reduce the falling to sleep period and increase overall sleep time. The medications used to treat this medical problem include melatonin and if needed, clonidine ( 99 ). Melatonin can effectively improve total night sleep duration, sleep latency time, and sleep-onset time ( 100 ). A study in the Fmr1 KO mouse showed that the therapeutic effects of melatonin may be due to its antioxidant effects and ability to normalize synaptic connections ( 101 , 102 ). Other studies of antioxidants in the KO mouse include alpha-tocopherol (vitamin E) and N-acetyl-cysteine (NAC) ( 103 ) and omega-3 therapy ( 104 ) with improvement in the maturity of dendritic spines and enhanced Brain Derived Neurotropic Factor (BDNF) levels in the hippocampus respectively. However, these antioxidants have not been studied for improvement in sleep in FXS. Melatonin should be given 1 hour before bedtime. The dose recommended for children with FXS ranges 0.5–5 mg. It is recommended to start with the lowest dose of 0.5 mg then adjust the dose with the response ( 105 , 106 ). No significant adverse effects of melatonin have been reported in those with FXS although in some patients it can cause agitation ( 106 , 107 ). Another study reported increased seizures in children with neurologic disabilities treated with melatonin but this has not been seen in FXS ( 108 ). Clonidine is alpha-agonist with off-labeled use for insomnia in the pediatric population. It is also used to treat attention deficit hyperactive disorder (ADHD) symptoms because it can decrease motor activity ( 109 ). Clonidine has an overall calming effect for the treatment of ADHD in FXS, but clonidine can cause significant sedation at higher doses so it is helpful for facilitating sleep. Dangerous side effects can occur in overdose so its use must be carefully monitored. The clonidine patch or catapres transdermal therapeutic system (Catapres-TTS1, 2 and 3) should not be used in young children who might pull it off and eat it because this leads to a significant overdose. Clonidine should not be used in the patients with a history of cardiovascular disease or depression ( 109 ).

2.7. Obstructive sleep apnea

Obstructive sleep apnea (OSA) is characterized by repeat brief episodes of airflow obstruction in the oral-nasal airway that occurs during sleep ( 110 ). These episodes of complete airflow cessation (apnea) or partial airflow obstruction (hypopnea) result in both frequent and transient reduction of brain oxygen levels ( 111 ). It occurs more often during rapid eye movement (REM) sleep and is rarely proceed by body movements ( 112 ). The prevalence of OSA among normal children is about 0.8% to 2.8% ( 113 ); however, it can be higher among children with neurodevelopment problems including FXS ( 114 , 115 ). OSA-related symptoms included loud snoring, apnea, awakening with gasping breaths, enuresis and daytime sleepiness ( 116 , 117 ). OSA in children is associated with concentration deficits, reduce learning ability, lower cognitive function, and school difficulties. Vigilance impairments and neuropsychological deficits are among the main symptoms seen in OSA ( 118 ). Some studies suggest that vigilance impairment is attributed mostly to nocturnal hypoxemia ( 118 ). In addition to cognitive issues, a large number of studies found that OSA is associated with medical problems such as cardiac tissue changes as well as systolic and diastolic blood pressure changes. Previous reports suggest that children with OSA and hypertrophied tonsils tend to aspirate oropharyngeal secretion which can lead to pneumonia ( 119 ). The association of GERD with OSA has been documented previously, possible due to higher esophageal negative pressure which is generated by increased respiratory efforts ( 120 ). Studies suggest that in typically developing children, early diagnosis, and treatment of pediatric OSA may improve the child's long-term cognitive, social potential and school performance. The standard diagnostic procedure for establishing the presence of OSA is the overnight polysomnography (PSG) ( 120 ). Although overnight PSG can be very effective in diagnosing OSA, for some patients the test is labor-intensive. The management of OSA has three main aspects. The first step is drug therapy, which may alleviate adenoidal and tonsillar hypertrophy. The second is drainage of nasal secretions, and the third step is surgery. Adenoidectomy with or without tonsillectomy is the primary treatments for OSA and it is usually very effective for those with FXS ( 121 ). Continuous positive airway pressure (CPAP) is a feasible therapeutic intervention in children with neurodevelopment deficits including FXS, although it is reported that patients have a low compliance to this therapy ( 121 ).

2.8. Strabismus

Strabismus is one of the phenotypic characteristics in FXS and it is an abnormality of the ocular motility and deviation of the eyes away from binocular vision. Strabismus is better defined as exotropia, esotropia, hypotropia, and hypertropia which describe the orientation of the eyes. Exotropia is the most common type of strabismus found in FXS and it is thought to be caused by an asymmetrical tone of the extraocular muscles ( 122 ). Early studies reported the prevalence of strabismus in FXS ranging from 28 to 57% ( 123 – 125 ), however later studies found that the prevalence was only 4.4–8% ( 126 , 127 ) and a recent FXCRC study reported a prevalence of 17.5%. The initial higher rates are thought to be related to selection bias in the earlier studies. Nevertheless, the prevalence was significantly higher than the prevalence in typical children (2.6% vs . 4%) ( 128 , 129 ).

It is crucial to detect strabismus early in life because if left untreated strabismus may progress to amblyopia, a permanent decrease in visual acuity due to the disuse of the abnormal eye during visual development. Tests used to detect the strabismus are; corneal light reflex, cover/uncover test and simultaneous red reflex test. Once strabismus is detected, the child should be referred to a pediatric ophthalmologist for further evaluation and management. It is recommended that every child with FXS have a comprehensive ophthalmologic examination by age 4 or sooner if an abnormality is detected ( 130 ). The treatment of strabismus should improve vision impairment and alignment abnormalities. The vision impairment leading to amblyopia can be treated by occluding the preferred eye and correcting the refractive errors of the affected eye with eyeglasses. The ocular alignment can be corrected by visual training exercises, but surgery is needed in many cases ( 131 ).

2.9. Tic disorder

Tics disorders are generally classified according to the age of onset, duration, and severity of symptoms and the presence of vocal and/or motor tics ( 132 ). The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) lists three types of tic disorders: Tourette syndrome (TS), chronic motor or vocal tic disorder, and provisional (transient) tic disorder ( 133 ). The prevalence of transient tic disorders in children aged 13–14 years is from 3–15% and chronic motor tics ranges from 2–5% ( 134 – 136 ); however, tic disorders may be more frequent than the prevalence reported because many patients with tics do not seek medical attention ( 136 ).

The prevalence of tics in FXS differs among studies. Tics were reported in 16% of 152 people with FXS in a cohort study in the United States. Tic disorders are characterized by involuntary or semi-voluntary, sudden, brief and rapid, recurrent, repetitive, non-rhythmic, unpredictable, meaningless and stereotyped motor movements, such as, eye blinking, shoulder shrugging and throat clearing or sounds produced by moving air through the nose, mouth or throat (phonic or vocal tics) including swearing and complex expressions ( 136 ). Tics are not constant and appear in the background of normal motor activity, except for extremely severe cases ( 137 ). Tics disorders appear before 18 years of age and occur before taking stimulant medications in those FXS, however, tics may be unmasked or worsened by stimulants. An important step in the approach to the patient with tics is to rule out secondary causes of tics disorders. Drugs including stimulants, antidepressants, antihistamine and antiepileptic's may cause tics; tics disappear with the interruption of these medications ( 137 ). Treatment is not always necessary and only severe cases should be treated preferably with monotherapy at low doses ( 138 , 139 ). Usually clonidine or guanfacine use in FXS is effective for tics in FXS; however, most of the time tics are not severe and do not need medication treatment. Aripiprazole or risperidone may sometimes be helpful to treat tics in FXS ( 139 ).

2.10. Other Problems

Toileting issues are one of the most challenging problems for patients and their families. The problems include bowel and bladder control, washing and wiping abilities, and inclination to be toilet trained. Nearly half (48.8%) ( 140 ) of children with FXS had toileting problems and the time they were toilet-trained was delayed compared to the normal population. A study of functional skills of individuals with FXS showed that the majority of females with FXS could demonstrate toileting skills by age 11 to 15 years, while males by age 15 to 20 ( 141 ).

We must take into consideration that toilet training is a challenging task for parents even in typically developed children. The guidelines for toilet training for children with FXS are not different from those of typical children. The most important step is to start the training when the child is ready; the appropriate time to initiate the training should be based on developmental and behavioral milestones achievements rather than chronological age ( 142 ). Physicians should initiate conversations about this issue with the parents at a young age (∼1 year of age), it is also important to discuss with the family how to assess the child's readiness for toilet training in order to avoid maladaptive behaviors among other psychological problems associated with failed toileting training. Special concerns for children with FXS may be due to their increased anxiety, slow learning skills, sensory sensitivity and defensiveness ( 142 ). The steps for toilet training are deciding what words to use, picking a potty-chair, helping the child recognize signs of needing to use the potty-chair, making trips to the potty-chair as a routine, and encouraging the use of the potty-chair ( 143 ). Positive reinforcement, extinction, and a star-chart can be used as strategies in the training. During the training accidents should be expected, the parents should address these events lightly and avoid upsetting comments and negative reinforcement. Punishment and scolding will only make the training harder and may increase the time needed for toilet training. Creating a routine pattern and patience are keys to success in the training.

Other common problems in children with FXS mentioned by caregivers and physicians are sensory processing and integration issues. Sensory processing and integration have major roles in human development ( 144 ). Individuals with FXS have an enhanced sympathetic response to sensory stimuli ( 145 ), and the feel of a potty-chair. The sensation of evacuation is often anxiety provoking to children with FXS such that they may avoid these stimuli.

The sensory process has two important components which are sensory discrimination and sensory modulation. Sensory discrimination is the process in which sensory stimuli are distinguished, given their meaning and use. Problems with sensory discrimination can cause poor recognition and interpretation of sensory stimuli, which in turn may result in difficulties in sensory-motor skill development, such as, brushing teeth, climbing or riding a bike, being a picky eater, etc. Sensory modulation is how the sensory stimuli are used and responded to. Problems with this process can cause hyper-response, over-activity, poor attention and poor coping. The most common sensory modulation difficulty reported in FXS is hyperarousal. Examples of the processing problem are difficulty tolerating bright lights and loud noises, crowded places overstimulation, difficulty making good eye contact, and trouble tolerating certain clothes. These problems are related to a lack of normal habituation to a sensory stimulus seen in both electrodermal studies ( 145 ) and even on Functional Magnetic Resonance Imaging (fMRI) studies to recurrent direct or indirect eye contact ( 146 ).

To attain full assessment and treatment plans, a team approach is needed. The team usually includes occupational therapists, physical therapists, speech therapists, educators, psychologists, and physicians. The team can be adjusted for each individual's problems. There are many tools that have been proven useful and reliable for assessing an individual's condition such as the Sensory Profile questionnaire, the Sensory Processing Measure questionnaire, the Movement Assessment Battery for Children, the Quick Neurological Screening Test and the Berg Balance Scale ( 146 ). It is recommended that children with FXS should receive routine assessments from occupational therapists and receive occupational therapy at least twice a week during early development ( 66 ). The treatments are individualized for each patient's medical problem.

3. Discussion

Clinicians need to know that those with FXS are at risk for a wide range of medical problems other than ID, ADHD, and ASD that are so common in FXS. The diagnosis and treatment of the medical problems in FXS are described here and the treatment of behavioral problems are described elsewhere including the use of targeted treatments to reverse the cognitive and behavioral problems ( 147 , 148 ). Many of the medical problems in FXS, such as OM, MVP, GERD, hernias, joint dislocation, and flat feet are related to the connective tissue problems inherent in the syndrome. These connective tissue problems are related to the lack of FMRP on the structure of the elastin fibrils in the skin, heart, vessels and organs ( 149 ). These changes also relate to the soft and velvet like skin seen in FXS. Improvements in the looseness of connective tissue in FXS have been reported with the use of minocycline, a targeted treatment that lowers Matrix Metallopeptidase 9 (MMP9) levels. In FXS minocycline has been shown to be efficacious for behavior in children. Minocycline has also been used to treat aortic aneurisms because of the effects of pulling together connective tissue in cardiology studies so it may be helpful for dilated aortas in FXS, although this is rarely a problem. Most of these problems are treated symptomatically as described above and the response is usually good to such treatment ( Table 1 ). It is likely that the most severe medical problem in FXS, seizures, will also improve with targeted treatments, although the response to standard anticonvulsants is good as described above. The key to this treatment is early and aggressive intervention because ongoing seizures will further exacerbate ID and ASD severity. The future looks bright for not only reversing the cognitive and behavioral problems but also many of the medical problems of FXS with targeted treatments ( 150 ).

Acknowledgements

This work was supported by the NIH diversity supplement for the NICHD (HD036071), and also supported by grants from the National Fragile X Foundation and IDDRC (MIND Institute Intellectual and Developmental Disability) grant U54 HD 0791250.

Conflict of Interest:

Dr. Randi J Hagerman has received funding from Novartis, Roche, Alcobra and Neuren for carrying out treatment studies in fragile X syndrome, autism and Down syndrome. She has also consulted with Roche/Genentech and Novartis for treatment studies in fragile X syndrome.

Fragile X syndrome: clinical presentation, pathology and treatment.

• Salcedo-Arellano, María Jimena ;
• Hagerman, Randi J ;
• Martínez-Cerdeño, Verónica

Published Web Location

Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.

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Fragile X Syndrome: Diagnosis, Treatment, and Research

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Human cytogenetics is about 40 years old. I find it intriguing when people can watch the evolution of significant life events. My grandmother, in her 90s, can tell about the evolution of aircraft, from the Wright Brothers to the present. Human cytogenetics isn't as significant as the discovery of flight—or is it? Cytogenetics is a major part of the foundation for our understanding of many aspects of clinical medicine, molecular genetics, and the Human Genome Project. In the fall of 1997, the American Medical Association is planning a major conference on genetic medicine because fewer than one in 10 physicians have confidence in their ability to provide genetic counseling.

Fragile X syndrome (FXS) is just one of several X-linked mental retardation (XLMR) syndromes. The finding of a cytogenetic abnormality in an XLMR syndrome and thus the syndrome's name, occurred in 1969. My career in cytogenetics began in 1974. Thus, except

Schmidt MA. Fragile X Syndrome: Diagnosis, Treatment, and Research. JAMA. 1997;277(14):1169. doi:10.1001/jama.1997.03540380083039

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• Published: 07 July 2023

Phenotypic variability to medication management: an update on fragile X syndrome

• Nasser A. Elhawary   ORCID: orcid.org/0000-0002-9137-351X 1 ,
• Imad A. AlJahdali 2 ,
• Iman S. Abumansour 1 ,
• Zohor A. Azher 1 ,
• Alaa H. Falemban 3 ,
• Wefaq M. Madani 4 ,
• Wafaa Alosaimi 5 ,
• Ghydda Alghamdi 1 &
• Ikhlas A. Sindi 6 , 7  

Human Genomics volume  17 , Article number:  60 ( 2023 ) Cite this article

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This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome’s variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000–7000 men and 1 in 4000–6000 women worldwide. FXS is associated with the  fragile X messenger ribonucleoprotein 1  ( FMR1 ) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene’s promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of  FMR1  mutations and FXS’s variable expressivity by regulating the pathophysiological mechanisms related to the syndrome’s behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.

Fragile X syndrome (FXS, MIM 300624) is an X-linked dominant disorder affecting approximately 1 in 5000–7000 men and 1 in 4000–6000 women worldwide [ 1 ]. Currently, it is the second leading cause of intellectual disability (ID) (2.4% of all ID cases), surpassed only by Down syndrome, the leading cause of inherited ID, and the leading cause of ID in male individuals [ 1 , 2 , 3 ].

FXS is caused by a CGG trinucleotide repeat expansion in the  FMR1  (MIM 309550). The typical number of CGG repeats in the FMR1 gene ranges from 5 to 44. Individuals with > 200 CGG repeats are considered to have a full FMR1 mutation, also known as a fragile site [ 4 ]. More than 99% of individuals diagnosed with FXS have the full mutation [ 5 ]. The presence of 55–200 repeats is considered an  FMR1 premutation, which is associated with fragile X-associated tremor/ataxia syndrome (FXTAS, MIM 300623) [ 6 , 7 ] and, in female individuals, with fragile X-associated premature ovarian insufficiency (FXPOI; MIM 311360) [ 8 , 9 ]. Several reports have shown that AGG interruptions within the  FMR1  gene also contribute to FXS [ 10 ]. The number of AGG interruptions and the length of uninterrupted CGG repeats at the 3' end of  FMR1  have correlated with repeat instability during transmission from parent to a child [ 11 ]. Maternal alleles with no AGG interruptions confer the greatest risk for unstable transmission of the CGG repeats [ 11 ].

The  FMR1  gene encodes the fragile X messenger ribonucleoprotein (FMRP), commonly found in the brain and essential for normal cognitive development and female reproductive function. FMRP can bind to ribosomes and regulate the translation of many mRNAs in postsynaptic neurons, which is critical for neurological development and function [ 12 , 13 , 14 , 15 ]. It has also been shown to bind to multiple ion channels to regulate their activity [ 16 ].

In mammals, cytosine methylation frequently occurs in the linear DNA sequence where DNA methyltransferases (DNMT) add methyl groups to a cytosine adjacent to guanine in a 5'-3' direction (a CpG island). DNA demethylation causes the replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C). DNA methylation is a major epigenetic modification that regulates transcription [ 17 ], and hypermethylation of this CpG island silences transcription of the  FMR1  gene [ 18 ]. The full FXS mutation is associated with hypermethylation of a CpG island, proximal to the CGG repeat, in the promoter of the  FMR1  gene. As a consequence, FMRP is not produced, and the absence or low expression of FMRP leads to FXS [ 19 ].

FXS is molecularly diagnosed based on relevant X chromosome abnormalities and alterations in the  FMR1  gene and is clinically diagnosed based on a wide spectrum of the physical, central nervous system, and neuropsychiatric/developmental features. Most male individuals with FXS cannot perform basic activities of daily living, e.g., feeding, ambulating, toileting, maintaining personal hygiene/grooming, and dressing. Female patients are often more self-reliant but frequently exhibit learning difficulties [ 20 ]. Although there is no recognized cure for FXS, psychosocial interventions, educational interventions, and drug treatment can help manage some aspects of the disorder [ 21 , 22 , 23 ].

The early history of FXS

FXS, also known as Martin–Bell syndrome, was first described in 1943 by Martin and Bell as a form of ID following an X-linked pattern of inheritance [ 24 ]. Martin and Bell suggested X-linked inheritance because they observed that male children were more severely affected than their female counterparts. A family case study also suggested that FXS impaired brain development (likely the prefrontal cortex) since most patients had speech difficulty and ID [ 24 ]. Lubs first reported a fragile site at Chromosome Xq27.3 that segregated with ID in the late 1960s [ 25 ]. The association between this fragile site (FRAXA) and X-linked ID was confirmed two decades later [ 4 ]. Around the same time as Lub's discovery, Escalante et al. [ 26 ] noted the association of macroorchidism with X-linked mental retardation. Molecular analysis of 105 simplexes and 18 multiplex families later revealed no association between FRAXA and autism, ruling out Xq27.3 as a candidate region for autism [ 27 ]. Gross et al., however, have reported that the distinctive behavioral phenotypes of FXS-linked synaptic plasticity are consistent with autism spectrum disorder (ASD), self-injurious and stereotypic behavior, aggression, anxiety, impulsivity, hyperactivity, and attention deficit [ 28 ].

Epidemiology

In Europe and North America, the prevalence of the full FXS mutation estimates at approximately 1/5000 male and 1/4000–8000 female individuals in the general population [ 14 , 29 , 30 , 31 ]. Differences in haplotype frequencies and founder effects among different racial and ethnic populations can also affect the prevalence of FXS [ 32 ]. Newborn screening of 36,124 boys in the United States identified the full mutation in every 1 in 5,161 of the boys [ 30 ]; similarly, screening of 24,449 neonates in Québec, Canada, identified the full mutation in 1 in 6,209 boys [ 31 ]. The prevalence of the full mutation in male individuals is higher in Hispanic countries such as Chile (6.7%) [ 33 ], Spain (6.4%) [ 34 , 35 , 36 ], and Colombia (4.82%) [ 37 ]. Among 574 developmentally disabled French individuals, the prevalence of FXS was 1.9% (11/574) overall and 2.5% (10/403) in male individuals; only one case of FXS was detected among the 171 girls tested (0.6%) [ 38 ]. In 504 mentally disabled Iranian patients, full  FMR1  mutations were found in 19 (15.3%) of 124 unrelated families and in 13 (3.4%) of 384 consanguineous families [ 39 ]. Zhang et al. [ 40 ] have found a lower prevalence of FXS in a large-scale screening of 51,661 Chinese newborns (1/9,371 in males and 1/2,943 in females) than in Caucasians [ 1 , 14 , 29 ]. In the same study, they also found 33 children cohort of 33 children diagnosed with developmental delay. Among 237 Thai boys with a developmental delay of unknown cause in Southern Asia, 16 (6.8%) were found to have a full  FMR1  mutation, and four were reported to have a premutation [ 41 ]. The prevalence of FXS in Indonesia ranged from 0.9% to 1.9% among the ID population and was higher (6.15%) among the ASD population [ 42 ]. In Malaysia, with 2108 children with developmental disabilities from mixed ethnicities, the FXS full mutation was reported as 70 (3.6%) in males and 3 (2.4%) in females [ 43 ]. The prevalence of FXS in Pakistan was estimated to be 19/1,000 children for severe ID and 65/1000 children for mild ID [ 44 ]. In Northern Africa, the prevalence of FXS was 7.6% in 200 Tunisian boys with ID [ 45 ].

A global meta-analysis found that the prevalence of the FMR1 premutation ranges from 1 in 250–813 male individuals to 1 in 110–270 female individuals [ 1 ], much higher than the prevalence of the full mutation. In one study of male newborn screening in Spain, the prevalence of the premutation (1 in 1,233 male infants) was about ten times higher than the prevalence of the full mutation (1 in 2,466 male infants) [ 34 ]. It is noteworthy that the prevalence of the premutation is highest in Colombia and Israel (1 in 100 female individuals) and lowest in Japan (1 in 1,674 female individuals) [ 46 ]. In Saudi Arabia, screening of 94 cases with undiagnosed mental retardation found an even higher prevalence of the premutation: 6.4 in 100 female individuals and 7.86 in 100 male individuals [ 47 ]. In Egyptian males with ID, autistic-like features, and behavioral difficulties ( n  = 92), Rafeat et al. [ 48 ] found a prevalence of 37%, 0.03%, and 0.07% in premutation, gray zone (45–55 CGG repeats), and full mutation, respectively.

Clinical characteristics of FXS

At birth, the physical features associated with FXS are usually not apparent and affect children's height, weight, and head circumference within normal ranges [ 49 ]. Neonates show no clinical signs except for hypotonia, which is common among the general population [ 50 ]. Many of the major clinical characteristics of boys with FXS, summarized in Table 1 [ 51 , 52 , 53 , 54 ], become clearer during the first year of life, and diagnosis is often made around 2–3 years of life, particularly alongside the development of language delays [ 54 , 55 ]. Figure  1 shows the most prominent clinical characteristics of the condition at each stage of life, from infancy to old age.

Clinical characteristics of fragile X syndrome A specific to infancy and early childhood and B spanning from infancy to old age. Adapted from [ 14 ]

The clinical presentation of FXS varies, as some primary and secondary clinical characteristics are more common than others (Table 1 ). The presentation also differs between girls and boys. For example, 85% of male patients but only 60% of female patients have ID [ 49 ]. In males, the characteristic phenotype also includes post-pubertal macroorchidism (i.e., enlarged testes), a prominent lower jaw, a narrow-elongated face, and large anteverted ears [ 49 , 57 ]. Notably, however, 25% of male adults diagnosed with FXS do not have the distinctive facial characteristics associated with the condition [ 52 ]. Both girls and boys diagnosed with FXS tend to have connective tissue anomalies that can lead to heart disease (e.g., mitral valve prolapses) and are atypically short but otherwise have a normal physical appearance. Overall, the clinical presentation of FXS is less observable and more variable in female individuals than in their male counterparts [ 58 ].

Brain imaging abnormalities

Almost 74% of FXS patients have been shown to have electroencephalogram (EEG) abnormalities, such as focal spikes originating from several anatomic parts. However, 35% of children with FXS report remission of EEG abnormalities by age 7 or 8 [ 59 ]. Additionally, patients with FXS have abnormal brain MRI scans. Notable defects include elevated cortical complexity, increased whole lobar and cortical thickness volume, and diffuse atrophy [ 60 ]. The anomalies can be associated with an undeveloped spine, increased spine length and density, and reduced pruning. Moreover, patients with FXS are at high risk of developing mesial temporal sclerosis, enlarged fourth ventricles, and hippocampal complications [ 61 ]. MRI abnormalities are also negatively associated with cognitive performance among children diagnosed with FXS [ 62 ].

Comorbid and overlapping conditions

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are commonly comorbid conditions in individuals with FXS. Research has shown that about 60% of boys with the full FMR1 mutation are co-diagnosed with ASD or ADHD [ 14 , 63 , 64 , 65 ]. Furthermore, compared to boys without FXS, boys diagnosed with FXS have higher rates of ASD, ADHD, and anxiety [ 66 ]. Additional research suggests that ASD symptoms appear during early childhood in 50–60% of male FXS patients and 20% of female FXS patients [ 67 , 68 ]. Although FXS and ASD affect overlapping neurobiological pathways, clinical trials have shown that the two disorders do not respond equally to the same treatment, suggesting different molecular mechanisms underlying the shared symptomatology [ 69 ].

The co-occurrence of FXS with other genetic conditions has been occasionally reported; the full FMR1 mutation was described in a few Down syndrome cases [ 3 ] and in five female fetuses with mosaic Turner syndrome (45,X0/46,XX) [ 70 ]. Also, an autistic ID was found to be affected by FXS while having pathological MED12 variants of X-linked MED12 (MIM 300188) [ 71 ]. However, the autistic features in FXS are not due to a double genetic cause but can instead be attributed to the variable phenotypic spectrum of the syndrome. Although the co-occurrence of Duchenne muscular dystrophy (DMD) with non-contiguous genetic entities' mutational events is extremely rare, an unrecognized association of X-linked DMD (MIM 310200) with ASD was previously reported [ 72 ]. The dystrophin protein 71 (Dp71) is widely expressed in the brain, and learning difficulties and cognitive impairments are also prevalent in DMD patients [ 73 , 74 ]. Moreover, the  MYT1L  gene (MIM 616521) is associated with obesity, epilepsy, speech delay, and aggression, and PPP2R5D  (MIM 601646) gene is correlated with neurodevelopmental disorder. Therefore, Tabolacci et al. [ 75 ] have recently described three unrelated cases of FXS co-occurrence with DMD,  PPP2R5D , and  MYT1L  genetic conditions.

FMR1 gene interactions of  FMR1  and co-expressed genes

We analyzed the potential protein–protein interaction (PPI) network to predict functional interactions between proteins using the STRING database ( https://string-db.org ). Figure  2 presents the  FMR1  protein network interactions with STRING software. The FMRP protein network showed significantly more interactions among themselves ( P  value = 8.68e−10) than would be expected for random proteins of the same size and degree of distribution drawn from the genome. Such an enrichment indicates that the proteins are partially biologically connected.

Protein–protein interactions predicted by STRING ( https://string-db.org/ ). Strong interactions were predicted between  FMR1  and ten co-expressed proteins. Colored nodes ( n  = 11) represent proteins and the first shell of interactors (average node degree = 6.91). Edges represent specific and meaningful protein–protein associations ( n  = 38) (i.e., proteins jointly contribute to a shared function)

Functional enrichment analysis

Table 2 highlights the functional enrichment of FMRP and related proteins in biological processes, including the regulation of translation and modulation of synaptic transmission (GO:0099578) and regulation of gene silencing by miRNAs (GO:2000637), cellular components, including dendritic filopodium, and dendritic spine neck (GO:1902737/Dendritic spine neck), and cytoplasmic stress granule (GO:0010494). Furthermore, KEGG pathway analysis revealed the RNA transport (hsa03013), and protein domains revealed the fragile-X 1 protein core C-terminal (PF12235) (Table 2 ).

Molecular and phenotypic variability

Mutations in the  FMR1  gene due to the CGG repetition can result in several conditions, e.g., ID, FXPOI, FXTAS, autism, Parkinson’s disease, developmental delays, other cognitive deficits, and even fragile X-associated neuropsychiatric disorders (FXAND) [ 53 , 76 , 77 ]. So, FXAND refers to the neuropsychiatric problems that typically occur at an earlier age than FXTAS. Hence, the  FMR1 premutation would exhibit variable expressivity and be associated with a wide spectrum of clinical phenotypes [ 78 ].

Mosaicism has been reported as a source of phenotypic variability in FXS patients of both sexes, with a higher frequency in male patients [ 78 ]. The prevalence of mosaicism in male FXS patients varies greatly, from 12 to 41% in the general population [ 79 ]. Notably, in individuals with FXS, mosaicism can be either in the size of the CGG repeat expansion or in hypermethylation of the CpG island [ 80 ]. A recent study has evaluated alterations in FMR1 function due to both types of mosaicism [ 78 ]. Because mosaic individuals with FXS produce some FMRP, they have milder cognitive and behavioral deficits than non-mosaic individuals with FXS [ 81 , 82 ].

Mosaicism of size

Mosaicism of size is described as the presence of both the full FMR1 mutation and the FMR1 premutation in some cells [ 79 ]. Approximately 50% of individuals with FXS are estimated to have this type of mosaicism [ 83 ]. FXS patients with mosaicism of size have higher IQ scores than those without mosaicism [ 84 ]. Although decreases in the number of CGG repeats (from full mutation to premutation and from premutation to normal size) are widely reported between generations, a retraction from full mutation to normal size appears to be sporadic [ 79 , 85 , 86 ]. In these cases, shortening of the CGG repeat expansion occurs post-zygotically due to the excision of many trinucleotides, giving rise to some alleles of normal size [ 86 ]. Baker et al. [ 87 ] reported that FXS patients with mosaicism of size had less aggressive behavior than FXS patients without this type of mosaicism. Mosaicism of size has also been associated with a higher risk of developing FXTAS [ 18 ].

Mosaicism of hypermethylation

Epigenetic silencing of the  FMR1  gene in individuals with the full FMRI mutation is characterized by DNA methylation of the promoter region and modification of histones [ 88 ].  FMR1  silencing takes place at about 11 weeks of gestation and seems related to histone H3 dimethylation, which is mediated by DNA-RNA duplex formation between the CGG repeat region of  FMR1  and its mRNA counterpart [ 89 ]. In mosaicism of hypermethylation, some cells exhibit hypermethylation, and others do not. In cells in which fully mutated or premutated alleles are not methylated, the  FMR1  gene is transcriptionally active and can be expressed [ 90 , 91 , 92 , 93 , 94 , 95 ]. In male individuals, the most frequent presentation of mosaicism is non-methylation of alleles with partial mutations and either methylation or non-methylation of alleles with full mutations (i.e., a combination of mosaicism of size and mosaicism of methylation) [ 14 ].

Modifier genes

In several monogenic disorders, modifier genes have an important effect on the pathophysiological mechanisms regulating penetrance and expressivity [ 96 ]. A genetic variant can modify the phenotypic effects of other variants in many ways, including through epistasis and genetic interactions [ 97 , 98 ]. Several studies have investigated modifier genes and their relationship with behavioral features of the FXS phenotype (e.g., epilepsy, aggression, autistic features) [ 99 , 100 , 101 , 102 , 103 ]. One study found that the Val66Met polymorphism in the  brain-derived neurotrophic factor  ( BDNF ) gene may lessen the epilepsy phenotype in FXS patients, as this polymorphism can affect cerebral anatomy [ 104 ] and fragile X-associated neuropsychiatric disorders (FXAND) [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. Evidence has been conflicting on whether variations in genes such as  SLC6A4 (MIM 182138), MAOA (MIM 309850) ,  and  COMT (MIM 116790) genes affect the severity of aggression, self-injury, and stereotypic behaviors in males with FXS [ 108 ]. However, Crawford et al. [ 103 ] recently reported that only  COMT , and not  SLC6A4  or MAOA , can affect dopamine levels in the brain, contributing to variability in challenging and repetitive behaviors in male FXS patients.

Molecular diagnostic testing

Although most parents notice some developmental delay during an affected child’s first year, FXS diagnosis may be delayed to 36 months. Diagnostic testing previously focused on karyotyping peripheral blood lymphocytes to determine if the X chromosome contained FRAXA [ 64 , 109 ]. However, the test required advanced technical skills, and the results were challenging to interpret. Fluorescence in situ hybridization (FISH) later became the standard cytogenetic test for diagnosing FXS, given its high accuracy and reliability, but this has been replaced today by FMR1 DNA test. The American Academy of Pediatrics ( https://www.aap.org/ ) recommends testing all individuals with ID, global developmental delay, or a family history of the full FMR1 mutation or the FMR1 premutation (Table 3 ).

Many additional molecular diagnostic techniques have recently been developed for FXS [ 110 ]. Low-cost PCR using asymmetric oligonucleotide primers that anneal to the CGG motif in  FMR1  can screen individuals at high risk of FXS [ 35 , 37 , 111 ], and Southern blotting can be used as a confirmatory test [ 112 ]. Triplet repeat-primed PCR has also been recently introduced, allowing real-time magnification of the CGG repeats and full-length  FMR1  alleles [ 113 ], and DNA methylation analysis can be used to determine methylation patterns in some male patients [ 112 ]. To help determine which patients might benefit from molecular diagnostic testing for FXS, Lubala et al. [ 114 ] have developed an evidence-based clinical checklist for physicians (Table 3 ).

For prenatal molecular diagnosis, PCR-based  FMR1  testing is available using amniotic fluid samples (i.e., amniocytes) or chorionic villi samples. Current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) encourage couples to have  FMR1  prenatal testing to facilitate early diagnosis. Notably, women with a personal history of isolated cognitive impairment, developmental delay, inexplicable ID, autism, elevated levels of the follicle-stimulating hormone after 40 years of age, idiopathic familial primary ovarian failure, isolated cerebellar ataxia accompanied with tremor, or FXS-related disorders are encouraged to have  FMR1  prenatal testing [ 13 ]. Importantly, there is also a need to perform AGG trinucleotide repeat genotyping [ 51 ], which can establish the magnitude of AGG interruptions within  FMR1  CGG repeats. This is especially important among women with a small premutation or borderline allele [ 52 ], as maternal alleles with no AGG repeats are at the greatest risk for  FMR1  CGG repeat instability and transmission [ 11 ]. Preconception is an ideal time for potential parents to request FXS testing or screening to make reasonable and evidence-based decisions about their reproductive health.

Current and emerging therapeutic approaches

FXS currently has no cure, as no genetic manipulation, medical intervention, or medication has been shown to reverse the full impact of a lack of FMRP during fetal development [ 115 ]. However, pharmacological treatment aims to improve behavioral symptoms linked to FXS [ 115 , 116 ], with sympatholytics, stimulants, antipsychotics, anxiolytics, and antidepressants being some of the most effective medications used for this purpose. Table 4 presents pharmacologic agents commonly used to treat some FXS phenotypes or have shown promise in recent clinical studies.

Metformin , a biguanide antidiabetic agent, is a safe and effective therapy for type 2 diabetes and weight loss worldwide. Preclinical studies found metformin to be a modulator of the mGluR/mTORC1-ERK cascade in animal models of FXS [ 118 , 120 ]. Metformin could correct social deficits, repetitive behaviors, macroorchidism, aberrant dendritic spine morphology, and exaggerated long-term depression of synaptic transmission in the adult FXS mice model (fmr1-/y mice) [ 120 , 121 ]. Moreover, Dy and colleagues reported the first clinical data demonstrating metformin’s effectiveness in treating seven children with FXS for at least six months [ 118 ]. The FXS patients had improved weight and eating behaviors and experienced positive behavioral changes in irritability, social avoidance, and aggression [ 118 ].

Sertraline , a selective serotonin reuptake inhibitor (SSRI), was the first antidepressant to treat anxiety in patients with FXS, including those as young as 2–3 years old starting in 2–3 years of life [ 69 , 122 ]. SSRIs are described to stimulate neurogenesis, increase BDNF in FXS [ 123 ], and enhance dopamine levels in the striatum [ 124 ]. Both of these strengths can be very important for young children with FXS who have evidence of oxidative stress [ 125 ]. Metabolomic studies demonstrate the downregulation of the enzymes leading to serotonin production from tryptophan in the blood of patients with idiopathic ASD, including those with FXS [ 126 , 127 ].

Minocycline

Minocycline , a tetracycline antibiotic used to treat acne in adolescence, has been reported to decrease matrix metallopeptidase-9 (MMP9) level that is too high in FXS [ 128 , 129 ]. MMP9 regulates synaptic formation (GSK3β, Arc, STEP, Map1B, αCaMKII), central nervous system development, and neural plasticity [ 130 ]. The cross between an MMP9 knockout mouse with an  fmr1  knockout mouse led to the rescue of the FXS phenotype in the offspring emphasizing the importance of the MMP9 pathway in the phenotype of FXS [ 127 , 131 ].

Lovastatin , a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (also known as a statin), inhibits the RAS-MAPK-ERK1/2 activation pathway. In the FMR1 knockout mouse model, this has been shown to normalize the excess protein synthesis and prevent epileptogenesis, a functional consequence of increased protein synthesis in FXS [ 132 ]. In addition, they rescued the seizure phenotype in the live knockout mouse. These studies have encouraged clinical trials of lovastatin (10–40 mg/day) combined with a treatment of a parent-implemented language intervention in youth with FXS aged 10 to 17 years [ 133 ].

Acamprosate

Acamprosate  is a drug approved for maintaining abstinence in adults from alcohol. However, acamprosate has recently been focused on due to its potential pleiotropic effects impacting glutamate and GABA neurotransmission. A 10-week acamprosate clinical trial in 12 children with FXS ages 6 to 17 years showed improvements in social behavior and inattention/hyperactivity in 75% (9 children) of the study participants [ 134 ]. A multicenter controlled trial of acamprosate was carried out in individuals with FXS ( http://www.clinicaltrials.gov ; NCT01911455).

Cannabidiol

Cannabidiol (CBD) , an herbal drug supplement extracted from cannabis plants, is mainly related to anxiety, cognition, movement disorders, and pain. In 2018, CBD was approved by the United States Food and Drug Administration to treat two epilepsy disorders. CBD represents a promising treatment to address comorbidities in FXS, e.g., epilepsy and cognitive impairment [ 135 ]. In humans, no clinical improvement with Huntington’s disease was shown [ 136 ], while clinical neuroprotection of CBD in general Parkinson’s was observed with no psychiatric comorbidity [ 137 ]. The transdermal gel of CBD was applied to children with FXS and showed efficacy in reducing anxiety and improving other behavioral measures [ 138 ]. Palumbo et al. [ 119 ] have recently reviewed the potential mechanisms for benefit from CBD treatment. Thus, the drug affects DNA methylation, serotonin 5HT-1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D2/D3 receptor signaling, which may help restore synaptic homeostasis in patients with FXS [ 119 ]. In many countries, CBD is legally sold at  marijuana  stores or online and is thus available for clinical use.

Other therapeutic approaches

Several supplements, additional medications, and a gene editing approach have also been used or proposed to be used as a treatment for various clinical and molecular characteristics of FXS.  Folic acid  is an important micronutrient that facilitates the hydroxylation and methylation of neurotransmitters. Its therapeutic effects include improved speech, language, and motor coordination among patients with FXS [ 139 ]. L-acetylcarnitine has been used alongside methylphenidate or mixed amphetamine salts to treat co-morbid ADHD in FXS patients [ 140 ]. Treatment of  fmr1 KO  mice with the metabotropic glutamate receptor (mGluR) antagonist ‘2-methyl-6-(phenylethynyl) pyridine’ resulted in suppression of the audiogenic seizure phenotype [ 141 ] and rescue of dendritic spine morphology in the  fmr1 KO  mouse [ 142 ]. Moreover, mGluR antagonists can target features of macroorchidism, hippocampus atrophy, protein synthesis, and dendritic spine morphology [ 143 ]. Despite their promise, mGluR antagonists are still experimental drugs that must be comprehensively investigated in clinical trials to establish their efficacy [ 144 ].

CRISPR/Cas9 gene therapy

Epigenetic modifying drugs can only transiently and modestly induce FMR1 reactivation in the presence of the expanded CGG repeat. Thus, gene replacements in gene therapy approaches are the most suitable option for those disorders caused by loss-of-function (LoF) mutations. In contrast, the gene replacement approach is not an option in gain-of-function (GoF) mutations to reduce the gene expression of the mutant target genes [ 145 , 146 ]. The recent discovery of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 strategies [ 147 , 148 , 149 , 150 , 151 ] has been developed to correct disease-causing mutations mammalian genome of living organisms [ 89 , 152 , 153 , 154 , 155 , 156 ].

CRISPR/Cas9 system has been applied for genome editing in both GoF and LoF mutations by inducing double-stranded DNA (dsDNA) at specific loci. Cas9 can inactivate alleles with GoF mutations by inserting indels at sites associated with a single guide RNA (sgRNA) to form double-stranded breaks [ 157 , 158 , 159 , 160 , 161 ]. Thus, CRISPR/Cas9 has been applied to efficiently and directly demethylate the FMR1 triplet expansions [ 113 ]. A great development of nuclease defective Cas9 (dCas9) has been implemented to allow its binding to target genomic DNA sequences, creating steric hindrance that prevents the activity of other DNA-binding proteins such as endogenous transcription factors and RNA polymerase II and therefore interfering with gene expression (CRISPR interference) [ 162 ]. Thus, dCas9 has been fused to the catalytic domain of DNMT3A [ 163 , 164 ] and ten-eleven translocation (TET) proteins to methylate and demethylate DNA [ 165 ]. Finally, dCas9 fusion to an engineered reverse transcriptase makes it possible to rewrite new genetic information into a specified DNA site.

This review discussed the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of FXS. It also highlights the molecular mechanisms underlying the syndrome’s variable expressivity and summarizes several emerging, promising therapeutic strategies. Importantly, the content of this review can inform future public health studies on FXS and provide clinicians with evidence-based information about FXS and its genetic and clinical implications for patients and their primary caregivers.

Availability of data and materials

The data sets analyzed during the current study are available from the corresponding author.

Abbreviations

American College of Medical Genetics and Genomics

American College of Obstetricians and Gynecologists

Attention Deficit Hyperactive Disorder

Attention deficit hyperactivity disorder

Autism spectrum disorder

Catechol-o-methyltransferase

Clustered regularly interspaced short palindromic repeats

Nuclear defective Cas9

Duchenne muscular dystrophy

DNA methyltransferase

Electroencephalogram

False discovery rate

Fragile X mental retardation 1 gene

Fragile X messenger ribonucleoprotein

Follicle-stimulating hormone

Fragile X associated psychiatric disorders

Fragile X-associated premature ovarian insufficiency

Fragile X syndrome

Fragile X-associated tremor/ataxia syndrome

Gene ontology

Gain-of-function

Intellectual disability

Kyoto Encyclopedia of Genes and Genomes

Loss of function

5-Methylcytosine

Monoamine oxidase

Metabotropic glutamate receptor

Magnetic resonance image

Myelin transcription factor 1-like

Protein–protein interaction

Protein phosphatase 2, regulatory subunit B (B56) delta

Single guide RNA

Solute carrier family 6 (neurotransmitter transporter), member 4

Ten-eleven translocation

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Acknowledgements

The authors are grateful to the Batterjee Medical College, Jeddah, Saudi Arabia, for the technical and financial support to publish this work. The authors would like to thank the Saudi Digital Library, Umm Al-Qura University for providing the updated scientific periodicals to achieve this work.

This work was technically and financially supported by the Batterjee Medical College, Jeddah, Saudi Arabia for publishing this work.

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Imad A. AlJahdali

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Alaa H. Falemban

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Wefaq M. Madani

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The study conception and design were initiated by NAE. Material preparation, data collection, and analysis were performed by NAE, IAA, ISA, ZAA, AHF, IAS, WA, WMM, and GA. Protein–protein interactions and functional enrichment analysis were done by NAE. Current and therapeutic approaches were reviewed by NAE, and AHF. Figures and tables were prepared by NAE, WA, WMM, and GA. The first draft of the review article was written by NAE, ISA, WA, ZAA, and AHF. All authors reviewed and approved the final version of the manuscript.

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Elhawary, N.A., AlJahdali, I.A., Abumansour, I.S. et al. Phenotypic variability to medication management: an update on fragile X syndrome. Hum Genomics 17 , 60 (2023). https://doi.org/10.1186/s40246-023-00507-2

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DOI : https://doi.org/10.1186/s40246-023-00507-2

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• Fragile X syndrome (FXS)
• Clinical features
• Variable expressivity
• CGG trinucleotide repeat
• DNA methylation
• CRISPR/Cas9

Human Genomics

ISSN: 1479-7364

• General enquiries: [email protected]

Differences of clinicopathological characteristics and outcomes of IgA nephropathy patients with and without nephrotic syndrome

• Nephrology - Original Paper
• Published: 02 April 2024

Cite this article

• Naya Huang 1 , 2 ,
• Jianbo Li 1 , 2 ,
• Zhen Ai 1 , 2 ,
• Lin Guo 1 , 2 ,
• Wei Chen 1 , 2 &
• Qinghua Liu   ORCID: orcid.org/0000-0002-6385-5482 1 , 2  

To evaluate the differences in clinicopathological features and outcomes of IgA nephropathy (IgAN) patients with and without nephrotic syndrome.

In this retrospective cohort study, IgAN patients from January 2006 to December 2011 in the First Affiliated Hospital of Sun Yat-sen University were enrolled and followed up to Dec 31, 2013. Logistic and Cox regression were conducted to evaluate the associated factors of nephrotic syndrome (NS) and its relation with outcomes of creatinine doubling and progression to end-stage kidney disease (ESKD).

A total of 1413 patients with IgAN were enrolled in this study, 57 (4.0%) of whom exhibited NS. Meanwhile, 13 (22.8%) of NS IgAN patients had minimal change disease (MCD). Logistic regression showed that more presence of hypertension, less glomerular sclerosis, less tubular atrophy/interstitial fibrosis, and lower density of IgA deposition in mesangial region were significantly associated with NS IgAN that were independent of age and gender. In addition, a total of 921 patients (890 with non-NS IgAN and 31 with NS IgAN) were followed up to Dec 31, 2013. After adjusting for age, sex, baseline estimated glomerular rate, hypertension and hemoglobin, no significant difference was observed in outcomes of serum creatinine doubling and ESKD between patients with or without NS IgAN.

Conclusions

Prevalence of NS IgAN patients was 4.0%, and 22.8% of them had MCD. Patients with NS IgAN had more severe clinical but less severe pathological features. However, outcomes of serum creatinine doubling and ESKD were not significantly different between patients with or without NS IgAN.

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Data availability

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Acknowledgements

We thank all my colleagues in Sun Yat-sen University for their excellent data collection. We thank Xueqing Yu and Qiongqiong Yang for their help in the data curation and instruction for the project, Wenfang Chen and Shicong Yang for their help with reviewing renal biopsies. All authors have approved to the submitted paper for publication.

This work was supported by grants from the Natural Science Foundation of Guangdong Province (2023A1515012477), National Natural Science Foundation of China (82200820), Guangzhou Science and Technology Project (202201011483), Key Laboratory of National Health Commission, and Key Laboratory of Nephrology, Guangdong Province, Guangzhou, China (2020B1212060028), and 5010 Clinical Program of Sun Yat-Sen University (No. 2017007) and National Key Research and Development Project of China (No. 2021YFC2501302). Natural Science Foundation of Guangdong Province,2023A1515012477,Qinghua Liu,National Natural Science Foundation of China,82200820,Naya Huang, Guangzhou Municipal Science and Technology Project,202201011483,Naya Huang, Key Laboratory of Nephrology, Guangdong Province,2020B1212060028,5010 Clinical Program of Sun Yat-Sen University,2017007,National Major Science and Technology Projects of China,2021YFC2501302,Wei Chen

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Naya Huang, Jianbo Li, Zhen Ai, Lin Guo, Wei Chen & Qinghua Liu

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Conceptualization: Qinghua Liu and Wei Chen; data curation: Naya Huang and Jianbo Li; formal analysis: Naya Huang and Lin Guo; funding acquisition: Qinghua Liu; investigation: Naya Huang; methodology:, Naya Huang; project administration: Qinghua Liu and Wei Chen; resources: Qinghua Liu and Wei Chen; software: Naya Huang and Jianbo Li; supervision: Qinghua Liu and Wei Chen; validation: Naya Huang; visualization: Naya Huang; writing original draft: Naya Huang, Jianbo Li, and Lin Guo; writing—review and editing: Naya Huang, Jianbo Li, Qinghua Liu, and Wei Chen.

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Huang, N., Li, J., Ai, Z. et al. Differences of clinicopathological characteristics and outcomes of IgA nephropathy patients with and without nephrotic syndrome. Int Urol Nephrol (2024). https://doi.org/10.1007/s11255-024-04040-6

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Received : 16 September 2023

Accepted : 16 March 2024

Published : 02 April 2024

DOI : https://doi.org/10.1007/s11255-024-04040-6

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