Materiały źródłowe

• #1 Diagnosing & Testing Rett Syndrome | International Rett Syndrome Foundation

  https://www.rettsyndrome.org/about-rett-syndrome/diagnosing-and-testing-rett-syndrome/

  Rett syndrome is a clinical diagnosis involving the evaluation of specific clinical symptoms, such as developmental delays and specific behavioral signs. Genetic testing can then confirm variants in the MECP2 gene and support the diagnosis. […] Diagnosing Rett syndrome (RTT) is based on clinical observation of symptoms. This includes a period of developmental regression typically emerging between 6 to 18 months of age which guides clinicians toward further evaluation. Due to the complexity of the disorder, a thorough assessment of developmental history, physical signs, and behavioral symptoms is essential. […] Genetic testing plays a crucial role in supporting the RTT diagnosis by identifying mutations in the MECP2 gene. […] Diagnosing Rett syndrome, also known as Typical or Classic RTT, involves assessing a combination of core symptoms, such as slowed growth, loss of motor skills, and impaired communication, which typically appear between six and 18 months of age.

• #1 Rett Syndrome – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/congenital-neurologic-anomalies/rett-syndrome

  Diagnosis of Rett syndrome is made clinically by observing symptoms and signs during the child’s early growth and development. […] Genetic testing for the MECP2 gene mutation on the X chromosome (Xq28) and for other potentially confounding genetic mutations is used to complement the clinical diagnosis. […] Explicit guidelines are used to confirm the clinical diagnosis of Rett syndrome. […] The required diagnostic criteria are all of the following: A period of regression followed by recovery or stabilization (critical criterion), all main criteria, and all exclusion criteria. […] The main diagnostic criteria are loss of all or part of purposeful hand skills, repetitive hand movements (such as wringing or squeezing, clapping or rubbing), loss of all or part of spoken language, and gait abnormalities including toe-walking or an unsteady, wide-based, stiff-legged walk.

• #2 How do healthcare providers diagnose Rett syndrome? | NICHD – Eunice Kennedy Shriver National Institute of Child Health and Human Development

  http://www.nichd.nih.gov/health/topics/rett/conditioninfo/diagnosed

  Genetic evaluation of a blood sample can identify whether a child has one of the known mutations that cause Rett syndrome. Even if a child has a mutation of the Methylcytosine-binding protein 2 (MECP2) gene (which also occurs in other conditions), the symptoms of Rett syndrome may not always be present, so healthcare providers also need to evaluate the child’s symptoms to confirm a diagnosis. […] A child must meet the following five necessary criteria to be diagnosed with classic Rett syndrome: A pattern of development, regression, then recovery or stabilization; Partial or complete loss of purposeful hand skills such as grasping with fingers, reaching for things, or touching things on purpose; Partial or complete loss of spoken language; Repetitive hand movements, such as wringing the hands, washing, squeezing, clapping, or rubbing; Gait abnormalities, including walking on toes or with an unsteady, wide-based, stiff-legged gait.

• #3 How do healthcare providers diagnose Rett syndrome? | NICHD – Eunice Kennedy Shriver National Institute of Child Health and Human Development

  http://www.nichd.nih.gov/health/topics/rett/conditioninfo/diagnosed

  A slowing of head growth between 3 months and 4 years of age, leading to acquired microcephaly, is also characteristic of Rett syndrome and calls for a diagnosis to be considered. […] After a blood test to confirm a child’s genetic makeup, a healthcare provider may diagnose the child with atypical Rett syndrome if the child demonstrates development, followed by regression and then recovery or stabilization. In addition, the healthcare provider will confirm at least two of the other four main criteria, and five of the 11 supportive criteria before making a diagnosis. […] Sometimes Rett syndrome is misdiagnosed as regressive autism, cerebral palsy, or nonspecific developmental delays.

• #4 Rett Syndrome – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/congenital-neurologic-anomalies/rett-syndrome

  The exclusion diagnostic criteria are the presence of other disorders that cause similar symptoms, including traumatic brain injury, grossly abnormal psychomotor development during the first 6 months of life, neurometabolic disease, and severe infection causing neurologic problems. […] The supportive diagnostic criteria include awake breathing disturbances; scoliosis or kyphosis; awake bruxism; abnormal sleep patterns; cold, small hands and feet in relation to height; peripheral vasomotor disturbances; growth retardation; abnormal muscle tone; intense eye communication („eye pointing”); inappropriate laughing or screaming; and decreased response to pain.

• #5 Rett syndrome | Better Health Channel

  https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/rett-syndrome

  How is Rett syndrome diagnosed? […] A diagnosis of typical Rett syndrome requires five symptoms of decline: […] A diagnosis of atypical Rett syndrome requires a period of regression (returning to a less developed state) during the first five years of life, followed by recovery or stabilisation, and at least two of the other four symptoms for a diagnosis of typical Rett syndrome. […] A genetic test that reveals a change in the MECP2 gene is used to confirm a diagnosis that has already been determined or is already suspected by a medical professional. The genetic test on its own is not enough to confirm Rett syndrome, as this change in the MECP2 gene is also seen in other conditions.

• #6 What is Rett syndrome

  https://www.autismempowerment.org/understanding-autism/signs-symptoms/rett-syndrome/

  Supportive criteria are not required for a diagnosis of Rett syndrome but may occur in some individuals. […] In addition to the main diagnostic criteria, a number of specific conditions enable physicians to rule out a diagnosis of Rett syndrome. […] These are referred to as exclusion criteria. Children with any one of the following criteria do not have Rett syndrome: brain injury secondary to trauma, neurometabolic disease, severe infection that causes neurological problems; and grossly abnormal psychomotor development in the first 6 months of life.

• #7 Fact Sheet 3: Diagnosis of Rett syndrome – RETT Syndrome Association of Australia

  https://rettaustralia.org.au/about-rett-syndrome/selected-resources-specific-to-rett-syndrome/fact-sheets/fact-sheet-3-diagnosis-of-rett-syndrome/

  Even though mutations in the MECP2 gene have been found to cause Rett syndrome, diagnosis of the condition is based on an individual meeting certain criteria. There are two broad diagnostic groups in Rett syndrome, typical and atypical. Detection of a mutation in the MECP2 gene simply confirms the diagnosis that was made according to the criteria. A diagnosis of Rett syndrome can be made when there is NO mutation in the MECP2 gene. […] The five criteria that now must all be met for an individual to receive a diagnosis of typical or classical Rett syndrome are: A period of regression during the first 5 years of life followed by recovery or stability. Children start off normally then go backwards in their development. Partial or complete loss of acquired purposeful hand skills. Partial or complete loss of acquired spoken language. Persons with Rett syndrome may have developed to a babbling stage with their speech or may have been speaking in words or sentences, before the loss of such. Impaired ability to coordinate walking or an absence of the ability to walk. Stereotypic repetitive hand movements such as wringing/squeezing, clapping/tapping, mouthing, washing/rubbing. […] One or more symptoms such as irregular breathing, sleep disturbances, abnormal muscle tone, curvature of the spine, bouts of screaming, teeth grinding, cold and small hands and/or feet, growth retardation and an intense eye gaze, may also be evident.

• #8 Rett syndrome – Diagnosis & treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/rett-syndrome/diagnosis-treatment/drc-20377233

  Diagnosing Rett syndrome involves careful observation of your child’s growth and development and answering questions about medical and family history. The diagnosis is usually considered when slowing of head growth is noticed or loss of skills or developmental milestones occurs. […] For a diagnosis of Rett syndrome, other conditions with similar symptoms must be ruled out. […] If your child’s health care provider suspects Rett syndrome after evaluation, genetic testing (DNA analysis) may be needed to confirm the diagnosis. The test requires drawing a small amount of blood from a vein in your child’s arm. The blood is then sent to a lab, where the DNA is examined for clues about the cause and severity of the disorder. Testing for changes in the MEPC2 gene confirms the diagnosis. Genetic counseling can help you understand gene changes and their effects.

• #9 Rett Syndrome | National Institute of Neurological Disorders and Stroke

  https://www.ninds.nih.gov/health-information/disorders/rett-syndrome

  Doctors diagnose Rett syndrome by observing signs and symptoms during the child’s early growth and development and conducting ongoing evaluations of the child’s physical and neurological status. […] Scientists have developed a genetic test to find MECP2 mutations to complement observations and diagnosis by doctors. To confirm a diagnosis of Rett syndrome, families should consult a pediatric neurologist, clinical geneticist, or developmental pediatrician.

• #10 What is Rett syndrome

  https://www.autismempowerment.org/understanding-autism/signs-symptoms/rett-syndrome/

  Doctors clinically diagnose Rett syndrome by observing signs and symptoms during the child’s early growth and development, and conducting ongoing evaluations of the child’s physical and neurological status. […] Scientists have developed a genetic test to complement the clinical diagnosis, which involves searching for the MECP2 mutation on the child’s X chromosome. […] A pediatric neurologist, clinical geneticist, or developmental pediatrician should be consulted to confirm the clinical diagnosis of Rett syndrome. […] The physician will use a highly specific set of guidelines that are divided into three types of clinical criteria: main, supportive, and exclusion. […] Examples of main diagnostic criteria or symptoms include partial or complete loss of acquired purposeful hand skills, partial or complete loss of acquired spoken language, repetitive hand movements (such has hand wringing or squeezing, clapping or rubbing), and gait abnormalities, including toe-walking or an unsteady, wide-based, stiff-legged walk.

• #11 Understanding Rett Syndrome | International Rett Syndrome Foundation

  https://www.rettsyndrome.org/about-rett-syndrome/understanding-rett-syndrome/

  Rett syndrome is considered a clinical diagnosis. Diagnosis involves a clinical evaluation by a doctor, genetic testing, and observing early developmental signs in infancy based on a list of diagnostic criteria created by Rett clinical experts. […] Early diagnosis is essential for effective management and support. Unfortunately, individuals often receive incorrect or delayed diagnoses because in its early stages, RTT shares many clinical symptoms with other, more common neurological and developmental disorders like autism, cerebral palsy, and epilepsy.

• #12 Diagnosing & Testing Rett Syndrome | International Rett Syndrome Foundation

  https://www.rettsyndrome.org/about-rett-syndrome/diagnosing-and-testing-rett-syndrome/

  Genetic testing plays a critical role in supporting a clinical diagnosis of Rett syndrome by identifying the specific mutation present in the MECP2 gene. This testing not only provides diagnostic certainty but also helps families understand the specific mutation affecting their child, enabling access to targeted resources and care options.

• #13 Rett syndrome: Genetics, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/rett-syndrome-genetics-clinical-features-and-diagnosis

  Rett syndrome (RTT) is a severe neurodevelopmental disorder that occurs almost exclusively in females. […] This topic will review the genetics, clinical features, and diagnosis of Rett syndrome. […] In most patients, RTT is caused by pathogenic variants in the MECP2 gene, which maps to Xq28 and encodes methyl-CpG binding protein 2 (MeCP2). […] Pathogenic variants in MECP2 have been detected in approximately 95 percent of classic sporadic RTT cases and 75 percent of atypical RTT cases. […] There are three types of pathogenic variants in MECP2: missense, frameshift, and nonsense. The type of mutation may affect phenotypic expression. […] The diagnosis of Rett syndrome involves clinical diagnostic criteria and genetic confirmation.

• #14 Orphanet: Rett syndrome

  https://www.orpha.net/en/disease/detail/778

  A rare severe, X-linked, neurodevelopmental disorder characterized by rapid developmental regression in infancy, partial or complete loss of purposeful hand movements, loss of speech, gait abnormalities, and stereotypic hand movements, commonly associated with deceleration of head growth, severe intellectual disability, seizures, and breathing abnormalities. The disorder has a progressive clinical course and may associate various comorbidities including gastrointestinal diseases, scoliosis, and behavioral disorders. […] The clinical diagnosis of RTT is based on consensus clinical criteria. These include one necessary criteria i.e. presence of regression plus four main criteria that are absolutely required for the diagnosis of typical RTT that include (i) partial or complete loss of acquired purposeful hand skills, (ii) partial or complete loss of acquired spoken language, (iii) gait abnormalities, (iv) stereotypic hand movements. Genetic testing identifies variants in MECP2 in 95-97% of individuals with typical RTT, but is not mandatory for RTT diagnosis.

• #15 Rett syndrome

  https://www.nhs.uk/conditions/rett-syndrome/

  Rett syndrome is usually diagnosed based on your child’s symptoms, and by ruling out other more common disorders. […] A diagnosis of Rett syndrome may not be made straight away because the syndrome is so rare, and symptoms do not tend to appear until a child is between 6 and 18 months old. […] A genetic blood test can be used to identify if the genetic mutation is responsible for Rett syndrome. If a change is found in the MECP2 gene, it can help confirm the diagnosis, but failing to find it does not necessarily rule out the syndrome.

• #16 About Rett Syndrome, Symptoms, Causes, Diagnosis and Treatments

  https://reverserett.org/about-rett-syndrome/

  Rett syndrome is a clinical diagnosis given by a physician based on the child’s history and symptoms. An MECP2 mutation confirms a Rett diagnosis but is not required. In other words, it is possible to have a diagnosis of Rett without genetic confirmation or the other way around an individual can have an MECP2 mutation without a clinical diagnosis of Rett syndrome. […] If your child’s symptoms are consistent with Rett syndrome but your child has tested negative for an MECP2 mutation, please ensure that testing included sequencing all four exons of MECP2 and that deletion testing was done as well (sometimes called MLPA). […] Although Rett syndrome remains a clinical diagnosis based on the child’s symptoms and history, the identification of MECP2 has made DNA testing and confirmation possible for affected individuals and their families. To date, approximately 95% of girls with a clinical diagnosis of Rett have a confirmed MECP2 mutation.

• #17 Diagnosis of Rett SyndromeEnvelope icon

  https://rettsyndromenews.com/rett-syndrome-diagnosis/

  The essential criteria must be present for the physician to reach a diagnosis of Rett syndrome. […] Genetic testing through a simple blood sample can be used to confirm the diagnosis of Rett syndrome. […] Most cases of Rett syndrome are caused by a mutation in the MECP2 gene, which provides instructions for making a protein of the same name. However, mutations in the MECP2 gene also can cause other disorders, so physical examination is required for a diagnosis. […] Prenatal diagnosis through amniocentesis, which involves testing a sample of the amniotic fluid surrounding a fetus, can be used to identify a Rett-causing mutation before birth. […] A genetic test also can be used to detect mutations in other genes, including CDKL5 and FOXG1. These genes have been linked to atypical types of the disease, for which symptoms do not meet all the diagnostic criteria for Rett syndrome.

• #18 Genetic Testing for Rett Syndrome AHS – M2088 | Providers | Blue Cross NC

  https://www.bluecrossnc.com/providers/policies-guidelines-codes/commercial/laboratory/updates/genetic-testing-for-rett-syndrome

  Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder that occurs almost exclusively in females and is usually caused by mutations in the methyl CpG binding protein 2 (MECP2) gene (Amir et al., 1999). […] BCBSNC will provide coverage for genetic testing for Rett syndrome when it is determined the medical criteria or reimbursement guidelines below are met. […] For a child with developmental delay/intellectual disability and signs/symptoms of Rett syndrome (RTT), but for whom there is uncertainty in the clinical diagnosis, genetic testing of MECP2, CDKL5, and/or FOXG1 to confirm a diagnosis of RTT is considered medically necessary. […] For all other situations not described above (e.g., prenatal screening, testing of family members), genetic testing for RTT is not covered.

• #19 Rett Syndrome Workup: Laboratory Studies, Barium Swallow or Overnight pH Probe Study, Neuroimaging

  https://emedicine.medscape.com/article/916377-workup

  Females who meet the clinical diagnostic criteria for Rett syndrome (RS) should undergo genetic testing. Several laboratories provide diagnostic sequencing of the MECP2 gene; details on how to order this testing are available from the International Rett Syndrome Foundation (IRSF). Patients with positive MECP2 mutational gene analysis need no further diagnostic testing. […] Patients in whom no MECP2 mutation is found should undergo other diagnostic tests aimed at identifying other possible causes of their signs and symptoms. Such tests may include the following: Serum lactate, ammonia, pyruvate, and amino acids, Urinary organic acids, Chromosomal studies, including specific tests for Angelman syndrome (chromosome 15), Urinary tests for uroporphobilinogen to rule out intermittent porphyria (rarely helpful).

• #20 Rett Syndrome Workup: Laboratory Studies, Barium Swallow or Overnight pH Probe Study, Neuroimaging

  https://emedicine.medscape.com/article/916377-workup

  Neuroimaging may be useful. Magnetic resonance imaging (MRI) may help include or exclude other causes of a patients signs and symptoms. […] Findings on electrocardiography (ECG) may include an inverted T wave and a prolonged QT interval. […] Abnormal results on electroencephalography (EEG) are common. […] Auditory brainstem-evoked response testing generally demonstrates normal hearing with a delayed conduction time. […] Electroretinography (ERG), in conjunction with EEG and the continued decline observed children with infantile neuronal ceroid lipofuscinosis, can help differentiate RS from infantile neuronal ceroid lipofuscinosis. […] Polygraphic respiratory recordings may demonstrate a pattern of disorganized breathing characterized by periods of apnea or hyperventilation and significant oxygen desaturation and clinical cyanosis.

• #21 Rett Syndrome | Children’s Hospital of Philadelphia

  https://www.chop.edu/conditions-diseases/rett-syndrome

  Diagnostic evaluation of Rett syndrome usually begins with the identification of characteristic symptoms of the disorder, along with a comprehensive medical history and physical examination. […] At Childrens Hospital of Philadelphia (CHOP), clinical experts use a variety of diagnostic tests to confirm a Rett syndrome diagnosis and identify symptoms that may require treatment. Tests may include: Genetic testing to identify mutations of the MECP2 gene and confirm the clinical diagnosis […] Neurological testing such as an electroencephalogram (EEG), which evaluates the electrical activity in the brain and can detect seizure disorders […] Imaging tests such as an X-ray or MRI to examine bones, organs and other structures in the body […] Pulmonary function tests and cardiac function tests including electrocardiography (EKG) to determine how well the childs lungs and heart are working.

• #22 Glossary & FAQs | International Rett Syndrome Foundation

  https://www.rettsyndrome.org/about-rett-syndrome/glossary-and-faqs/

  Rett syndrome is considered a clinical diagnosis. Unfortunately, individuals often receive incorrect or delayed diagnosis because in its early stages, RTT shares many clinical symptoms with other, more common neurological and developmental disorders like autism, cerebral palsy, and epilepsy. […] To confirm a Rett syndrome diagnosis, a doctor will evaluate an individual based on a list of diagnostic criteria created by Rett clinical experts. The diagnosis will be either typical RTT where all clinical criteria are met or atypical RTT where only some of the criteria are met. Genetic testing can confirm the clinical diagnosis; however, the presence of a MECP2 mutation without the clinical features is not sufficient for a diagnosis of RTT.

• #23 Risk Factors for Late Diagnosis of Rett Syndrome | Pediatric Neurology Briefs

  https://pediatricneurologybriefs.com/articles/10.15844/pedneurbriefs-29-5-5

  Investigators at Emory University, Atlanta, GA; Stony Brook, New York; University of California, San Diego; and other centers determined the type of physician who makes the Rett syndrome (RTT) diagnosis and identified risk factors for delayed diagnosis. […] Among 919 classic and 166 atypical female RTT participants recruited between 2006 and 2014, the median age at diagnosis was 2.7 years (range 2.0-4.1) in classic and 3.8 years (range 2.3-6.9) in atypical RTT. […] Pediatricians rarely made the diagnosis of classic RTT (5.2%), but the proportion increased since 2006. […] Odds of a pediatrician making the diagnosis of classical RTT were higher if a child stopped responding to parental interaction, and lower if they had gastroesophageal reflux, specific stereopathies, or if they lost babbling or ability to follow commands.

• #24 Rett Syndrome Diagnosis and Disease Progression

  https://www.ajmc.com/view/rett-syndrome-diagnosis-and-disease-progression

  The typical age [of diagnosis] is around 3 years old. Right now, we base it on a clinical diagnosis. That means we review the developmental history, and [determine] if they have the regression in hand function, regression in communication, the hand stereotypies, the repetitive hand movements, and the problems with their ambulation or the absence of ambulation. Those 4 features define classic Rett syndrome. […] You can also have atypical Rett syndrome, where you have at least 2 of those 4 with some clear evidence of regression, but you may not have all 4 features. There are some criteria that you could use to help support the diagnosis of atypical Rett syndrome. […] The genetic mutation in MECP2 is found in 90% to 95% of patients with classic Rett syndrome, but only in 40% to 70% of patients with atypical Rett syndrome. You can have Rett syndrome without an MECP2 mutation.

• #25 Risk Factors for Late Diagnosis of Rett Syndrome | Pediatric Neurology Briefs

  https://pediatricneurologybriefs.com/articles/10.15844/pedneurbriefs-29-5-5

  Late diagnosis risk factors were delay in fine motor skills, late onset of supportive features (GE reflux, bruxism, breath-holding, hyperventilation, self-abuse) and normal head circumference; 33% with microcephaly before 2.5 years were diagnosed with RTT after the median age of 2.7 years. […] Age of RTT diagnosis has improved among subspecialists, and pediatricians made the diagnosis of classic RTT more frequently since 2006. […] The absence of some characteristic clinical signs, especially head circumference deceleration, should not lead to delay in diagnosis. […] Early diagnosis is important in family planning, and emphasis on intervention services.

• #26 Trends in the Diagnosis of Rett Syndrome in Australia | Pediatric Research

  https://www.nature.com/articles/pr2011179

  Modifications to diagnostic criteria and introduction of genetic testing have likely affected the pattern and timing of Rett syndrome diagnosis. […] The median age of Rett syndrome diagnosis decreased from 4.5 y if diagnosed before 2000 to 3.5 y if diagnosed after 1999. […] Earlier age of diagnosis may result in families experiencing less stress and emotional strain compared with those with delayed diagnosis. […] Changes in clinical practice resulting both from modifications to diagnostic criteria and the introduction of genetic testing have likely affected the pattern and timing of RTT diagnosis. […] The age at diagnosis decreased from a median of 4.5 y before 1999 to 3.5 y afterward. […] The change in cumulative risk before and after 1999 shows a clear increase in the risk of RTT diagnosis and a parallel decrease in age of diagnosis. […] An earlier diagnosis is important for families in that it provides them with the ability to come to terms with the cause of their child’s symptoms, to have a label for their child’s condition, obtain earlier access to appropriate services, and receive support from within parents’ organizations.

• #27 Genetic Testing for Rett Syndrome

  https://member.myhealthtoolkitks.com/web/public/brands/medicalpolicy/external-policies/genetic-testing-for-rett-syndrome/

  Genetic Testing for Rett Syndrome – CAM 347 […] For a child with developmental delay/intellectual disability and signs/symptoms of Rett syndrome (RTT), but for whom there is uncertainty in the clinical diagnosis, genetic testing of MECP2, CDKL5, and/or FOXG1 to confirm a diagnosis of RTT is considered MEDICALLY NECESSARY. […] For all other situations not described above (e.g., prenatal screening, testing of family members), genetic testing for RTT is therefore considered NOT MEDICALLY NECESSARY. […] Confirmation of the genetic diagnosis can improve the medical management of the patient. It can also end the diagnostic odyssey, provide a general idea of prognosis for the patient, and/or provide closure to the family. […] Of the clinical criteria for RTT, loss of hand skills was the most significant clinical predictor of a positive genetic test for mutations of a MECP gene in females. Gait abnormalities and stereotypic hand movements were also strong predictors of a positive genetic test for mutations of MECP. Language delay is the least specific of the major criteria.

• #28 Technological Improvements in the Genetic Diagnosis of Rett Syndrome Spectrum Disorders

  https://www.mdpi.com/1422-0067/22/19/10375

  According to recent studies, approximately 95% of patients with typical RTT and 75% of patients with atypical RTT (especially those with the Zappella variant) have pathogenic variants in MECP2. […] Since its association with RTT, MECP2 has been studied by direct sequencing (by Sanger sequencing) and gene dosage analysis (by multiplex ligation-dependent probe amplification (MLPA), qPCR, and FISH) to obtain a molecular confirmation of the clinical diagnosis. […] The arrival of next generation sequencing (NGS) has allowed us to simultaneously sequence multiple genes in the same experiment. […] NGS approaches can target anything from a set of specific genes (gene panels) to the whole genome. […] The overall diagnostic yield when applying WES to patients affected with pediatric rare diseases is 28% on average.

• #29 Technological Improvements in the Genetic Diagnosis of Rett Syndrome Spectrum Disorders

  https://www.mdpi.com/1422-0067/22/19/10375

  The higher diagnostic yield in WES studies focused only on patients with RTT spectrum disorders, usually above 60%, when compared to general NGS data, usually around 28–40%, could be explained due to the thorough phenotypic characterization of the patients included in these studies. […] NGS has identified more than 90 novel causative genes of RTT spectrum disorders over the past 7 years. […] The current list of RTT spectrum genes is especially enriched in chromatin modulators and genes involved in synaptic function. […] The fact that the dysfunction of different interconnected genes can give rise to such similar phenotypes suggests the implication of common pathways in the pathophysiology of the disease, but these mechanisms currently remain unknown.

• #30 Genetic Testing for Rett Syndrome

  https://member.myhealthtoolkitks.com/web/public/brands/medicalpolicy/external-policies/genetic-testing-for-rett-syndrome/

  Recent expert opinion in the United Kingdom concluded that genetic testing for all children with unexplained global developmental delay (GDD) should be first-line if an exogenous cause is not already established. All patients, irrespective of severity of GDD, should have investigations for treatable conditions. […] Vidal et al. (2017) have utilized next generation sequencing (NGS) in a total of 1577 patients with RTT-like clinical diagnoses or patients with potential RTT genetic mutations as determined previously by Sanger Sequencing. Of the 1577 patients with RTT-like clinical diagnoses, the NGS method was able to confirm the RTT diagnosis in 477 patients (about 30%). […] Vidal et al. (2019) used multiplex ligation-dependent probe amplification (MLPA) in the MECP2 gene of 21 RTT patients to identify deletions of varying sizes; these researchers identified both total and partial deletions of the MECP2 gene in each patient, with identified partial deletions ranging from 1,235 bp to 85 kb.

• #31 Genetic Testing for Rett Syndrome

  https://www.myhealthtoolkit.com/web/public/brands/medicalpolicyhb/external-policies/genetic-testing-for-rett-syndrome/

  Vidal et al. (2017) have utilized next generation sequencing (NGS) in a total of 1,577 patients with RTT-like clinical diagnoses or patients with potential RTT genetic mutations as determined previously by Sanger Sequencing. Of the 1,577 patients with RTT-like clinical diagnoses, the NGS method was able to confirm the RTT diagnosis in 477 patients (about 30%). Further, Positive results were found in 30% by Sanger sequencing, 23% with a custom panel, 24% with a commercial panel and 32% with whole exome sequencing, suggesting that NGS is a competitive diagnostic RTT tool compared to the aforementioned methods. […] Khajuria et al. (2020) included seventy-two classical Rett syndrome (RTT) female patients in a cohort study to analyze exons two-four of MECP2 gene by Sanger sequencing for sequence variations followed by deletion/duplication analysis using Multiplex Ligation-dependent Probe Amplification (MLPA). Through Sanger Sequencing, MECP2 sequence variations were identified in 90.3% of patients. With further evaluation using MLPA, large deletions of MECP2 were identified in 9.7% of the patients, which were negative on DNA sequencing. MLPA analysis increased the detection rate of MECP2 sequence variants identified in patients from 90.3% to 98.6%. The authors emphasize that „MLPA analysis of MECP2 is crucial and needs to be performed in classical RTT patients. Large deletions can be missed using DNA sequencing and reaffirms the view that large MECP2 deletions are an important cause of classical RTT.

• #32 Genetic Testing for Rett Syndrome

  https://member.myhealthtoolkitks.com/web/public/brands/medicalpolicy/external-policies/genetic-testing-for-rett-syndrome/

  Seventy-two classical Rett syndrome (RTT) female patients were included in a cohort study by Khajuria et al. (2020) to analyze exons two-four of MECP2 gene by Sanger sequencing for sequence variations followed by deletion/duplication analysis using Multiplex Ligation-dependent Probe Amplification (MLPA). Patients were defined as classical when they showed signs of partial or complete loss of acquired purposeful hand skills, partial or complete loss of acquired spoken language, gait abnormalities, impaired or absence of ability to walk, and stereotypic hand movements. Through Sanger Sequencing, MECP2 sequence variations were identified in 90.3% of patients. With further evaluation using MLPA, large deletions of MECP2 were identified in 9.7% of the patients, which were negative on DNA sequencing. MLPA analysis increased the detection rate of MECP2 sequence variants identified in patients from 90.3% to 98.6%. The authors emphasize that „MLPA analysis of MECP2 is crucial and needs to be performed in classical RTT patients. Large deletions can be missed using DNA sequencing and reaffirms the view that large MECP2 deletions are an important cause of classical RTT.

• #33 Orphanet: Rett syndrome

  https://www.orpha.net/en/disease/detail/778

  Differential diagnosis includes autism spectrum disorder; Angelman syndrome in which early development before 6 months is abnormal; CDKL5 deficient disorders in which early onset seizures are distinctive from RTT; FOXG1 syndrome in which congenital microcephaly and corpus callosum abnormalities are not usually found in RTT. […] Prenatal screening should be discussed in families with a proband having a pathogenic mutation.

• #34 Rett Syndrome Diagnosis and Disease Progression

  https://www.ajmc.com/view/rett-syndrome-diagnosis-and-disease-progression

  The question is if there can be a delay in diagnosis or misdiagnosis for our Rett patients. Yes, there are some disorders that could look similar to Rett syndrome, including cerebral palsy or Angelman syndrome. […] The question is, who helps to manage the diagnosis of Rett syndrome? Is it a single clinician? Is it the primary care provider? Or are there sub-specialists involved? […] The predominant group that manages Rett syndrome are child neurologists, as it presents in childhood initially. Theyre the group that [usually] makes the diagnosis, although geneticists make the diagnosis in many cases. Developmental pediatricians might make the diagnosis because they also will be following the same kids because of their developmental regression. […] We have some guidelines, published in 2020, that could help the pediatrician know what features to monitor for on a routine basis.

• #35

• #36 Diagnosing Rett Syndrome | CheckRare

  https://checkrare.com/47387-2/

  Jana von Hehn, PhD, Chief Scientific Officer of the Rett Syndrome Research Trust, discusses the challenges of diagnosing Rett syndrome. […] Confidently diagnosing Rett syndrome in patients younger than 2 years of age may be challenging; again, the symptom profile is highly variable. […] The average age of patients with typical Rett syndrome at the time of diagnosis is 2.5 years; however, as genetic testing becomes more prevalent, earlier diagnostic confirmation may be possible in the future. […] The average age of diagnosis for patients with atypical Rett syndrome is 3.8 years. […] Since the mutations are not inherited, family history does not play a role in diagnosis. Rather, it is based almost solely on presentation and recognition of the symptomatic pattern. […] Two specific criteria can exclude a diagnosis of Rett syndrome (typical or atypical): (1) brain injury secondary to trauma (peri-or postnatally), neurometabolic disease, or severe infection causing neurologic problems and (2) grossly abnormal psychomotor development in the first 6 months of life. […] The differential diagnosis includes Angelman syndrome, a rare genetic and neurological disorder characterized by severe developmental delays and learning disabilities, ataxia, and absence or near absence of speech.

• #37 Burden, Screening and Diagnosis of Rett Syndrome | Masters of Pediatrics

  https://mastersofpediatrics.com/articles/burden-screening-and-diagnosis-of-rett-syndrome/

  Pediatric neurologists, clinical geneticists, or developmental pediatricians should be consulted to confirm the diagnosis of RTT and may order additional testing to assist with diagnosis, including magnetic resonance imaging or computerized tomography scans, eye exams, and electroencephalograms. […] Approximately 95% of reported cases of Rett syndrome can be attributed to inherited mutations of the methyl-CpG-binding protein 2 (MECP2) gene. Mutations in this gene impact neuron development and axodendritic connections, which are closely related to the clinical presentation of the disease. A positive finding of a mutation of the MEPC2 gene confirms RTT diagnosis.

• #38 Rett Syndrome Diagnosis, Treatment & Future Research

  https://www.mastermindbehavior.com/post/rett-syndrome-diagnosis

  The key to managing Rett syndrome effectively lies in early diagnosis, comprehensive treatment planning, and regular monitoring of symptoms. […] Recognizing Rett Syndrome among pediatric providers is critical, especially with the availability of the first disease-specific therapy. […] This focus on early recognition and diagnosis is crucial for timely intervention and management of Rett syndrome.

• #39 Information for Families with a Recent Diagnosis of Rett Syndrome

  https://reverserett.org/recently-diagnosed/

  Getting a Rett syndrome diagnosis is one of the hardest things you’ll ever face. […] Research has made exciting progress. The mutated gene that causes Rett is known, so we have a clear target to attack. […] Many families are relieved to get the diagnosis. Uncertainty is replaced with a sense of empowerment that you can now get involved and help accelerate cures. […] In March 2023, the FDA approved DAYBUE as a treatment for Rett syndrome. […] Please register with us. It takes only a minute. This will give you access to our research updates, and information about webinars and other activities. […] Join the Rett Syndrome Global Registry and help us to advance cures. The information you possess about your child is priceless. […] Rett syndrome is a serious, lifelong neurological disorder that is caused by random mutations in a gene called MECP2. Diagnosed primarily in girls, symptoms typically appear in toddlerhood. […] Rett syndrome stands apart from other neurological disorders due to the dramatic reversibility of symptoms in animal models. Our confidence that Rett syndrome is curable guides our every decision.

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