Rett Syndrome: A Genetic Update and Clinical ... - ACS Publications

Subscriber access provided by READING UNIV

Review

Rett syndrome: A genetic update and clinical review focusing on comorbidities Wendy A. Gold, Rahul Krishnaraj, Carolyn Ellaway, and John Christodoulou ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00346 • Publication Date (Web): 29 Nov 2017 Downloaded from http://pubs.acs.org on December 1, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Chemical Neuroscience is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Chemical Neuroscience

Rett syndrome: A genetic update and clinical review focusing on comorbidities Wendy A Gold1,2, Rahul Krishnaraj1, Carolyn Ellaway2,3,4, John Christodoulou1,2,3,5 1

Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The

Children’s Hospital at Westmead, Sydney, NSW, Australia 2

Discipline of Child and Adolescent Health and 3Genetic Medicine, Sydney Medical School,

Sydney University, Sydney, NSW Australia 4

Genetic Metabolic Disorders Service, Western Sydney Genetics Program, The Children’s

Hospital at Westmead, Sydney, NSW, Australia 5

Neurodevelopmental Genomics Research Group, Murdoch Children’s Research Institute,

and Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, Australia

*Correspondence to Wendy Gold Genetic Metabolic Disorders Research Unit The Children’s Hospital at Westmead, Locked Bag 4001 Sydney, NSW, Australia Email: [email protected]

Key words: neurodevelopment, MECP2, CDKL5, FOXG1, Rett syndrome

1 ACS Paragon Plus Environment

ACS Chemical Neuroscience 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract Rett syndrome (RTT) is a unique neurodevelopmental disorder that primarily affects females resulting in severe cognitive and physical disabilities. Despite the commendable collective efforts of the research community to better understand the genetics and underlying biology of RTT, there is still no cure. However, in the past 50 years, since the first report of RTT, steady progress has been made in the accumulation of clinical and molecular information resulting in the identification of a number of genes associated with RTT and associated phenotypes, improved diagnostic criteria, natural history studies, curation of a number of databases capturing genotypic and phenotypic data, a number of promising clinical trials and exciting novel therapeutic options which are currently being tested in laboratory and clinical settings. This review focuses on the current knowledge of the clinical aspects of RTT, with particular attention being paid to clinical trials and the comorbidities of the disorder as well as the genetic aetiology and the recognition of new diseases genes.


Page 2 of 26

Page 3 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Introduction Rett syndrome (RTT, MIM 312750) is an X-linked neurodevelopmental disorder which mostly affects females and is the second most common cause of severe intellectual disability in females after Down syndrome. Since the first report of RTT by Andreas Rett in 1966 1, a tremendous effort has been made to better understand the disorder, facilitate diagnosis and identify a cure. Over the past 50 years, a number of pivotal discoveries have been made including the discovery of the major causative gene Methyl CpG binding protein 2 (MECP2) and refining of the clinical diagnostic criteria of the disorder to aid diagnosis. In the last decade additional disease genes have been associated with RTT and additional clinical phenotypes, further refinements of the diagnostic criteria have been made, novel therapeutics are being tested in clinical trials, and an overall better understanding of the full clinical spectrum of the disorder has been established to allow for improved treatment options and quality of life for patients with RTT.

Clinical Stages RTT is a neurodevelopmental disorder, which means that the course of the disorder changes over time when motor and cognitive development should be progressing. These changes can be evidenced by a sequence of “stages” which encapsulate specific changes in the girls as the disorder progresses. Girls with classical RTT have an apparently normal period of early development, and it is only at about 6-18 months of life when the early signs of the disorder start to emerge. In 1985 Hanefeld et al separated the progression of the disease into 4 distinct stages known as Stage I to Stage IV 2. Stage I is the early-onset stagnation period and appears between 6 and 18 months of age. Features include a delay or stagnation in development, where the girls stop meeting their expected developmental milestones. This is followed by Stage II, the rapid-developmental regression period where girls, between 1 and 4 years of age, lose acquired skills such as communication skills, including language and socialisation, as well as losing some fine and gross motor skills. In addition, deceleration of head growth may be noted 3. It is during this time, and sometimes before, that stereotypic hand movements, a hallmark of RTT, become apparent

4, 5

It is not uncommon for girls to

misdiagnosed with autism spectrum disorder 6, and with the latest update in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) catalogue, the distinction between the two disorders is made clear 7. There may be further loss of motor skills to adolescence, with 3 ACS Paragon Plus Environment


Page 4 of 26

Parkinsonian features becoming prevalent in many girls 8. Girls then enter the pseudostationary stage or stage III. In this post-regression stage, where the phenotype stabilizes, many girls actually develop an intense eye gaze and increased social awareness. They may also partially regain some of the skills lost during stage II. The last stage, stage IV, is known as the late motor deterioration stage and can last for years or decades. This stage is characterised by reduced mobility, muscle weakness, rigidity, and spasticity, with the development of dystonia and hand and foot deformities as they grow older. Walking may cease but eye gaze usually improves, repetitive hand movements may decrease and cognition, communication, or hand skills generally do not decline.

Overview and update on the clinical features of Rett syndrome As described above, RTT is recognised as a severe neurodevelopmental disorder characterized by the loss of language skills, fine and gross motor skills, communication skills, deceleration of head growth and the development of stereotypic hand movements occurring after a period of apparently normal development. However, the spectrum is broad, with girls developing comorbidities at different stages. Comorbidities often include seizures, breathing disturbances with hyperventilation and/or apnoeas, gastro-intestinal complications, gait disturbances and scoliosis, which in combination make the management of RTT very complex 9, 10.

Among the most characteristic features of RTT is the deceleration of head growth, which is frequently seen between 6 and 24 months of age and occurs in 80% of girls with RTT

11, 12

.

Most girls with RTT typically do start walking in their early years, albeit with an abnormal gait which is often described as dyspraxic. Of the girls that start walking, one third lose this skill as the disorder progresses 3.

Between 60-80% of girls develop seizures, usually towards the end of the regression period or post-regression, which in some can be difficult to control

13, 14

. Girls are commonly

plagued with gastrointestinal problems including gastro-oesophageal reflux, air swallowing with abdominal distension, and chronic constipation. Some girls experience abdominal pain due occasionally to gallbladder disease 15, 16. The lack of oral motor control frequently results in feeding difficulties, and poor weight gain, which may lead to nutritional deficiencies that require close monitoring and in some gastrostomy tube placement is required to maintain 4 ACS Paragon Plus Environment

Page 5 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


body weight and general health

10, 16

. Bone health is a major concern as most girls have

osteoporosis 17 and develop a scoliosis. Approximately 10% of girls with a scoliosis require surgical intervention 18, 19. Increased muscle tone associated with dystonia, contractures 10 and rigidity, along with other Parkinsonian features are common in the later stages of the disorder 8

. Girls with RTT commonly have breathing dysregulation, including hyperventilation and

breath holding episodes when awake. Overall survival and quality of life are improving in RTT with the development of guidelines for the management of specific comorbidities. Behavioural abnormalities have long been recognised as a fundamental feature of RTT, particularly autistic behaviour which arises during the period of regression 20, and can persist into the post-regression period

21-25

. A high prevalence of anxiety and mood disturbances,

such as repetitive self-injury, screaming episodes, abrupt mood changes, and inconsolable crying are also prevalent 26-33. Fear and anxiety are also common in RTT patients, with these behaviours being inversely associated with mutation type/disease severity. For example individuals with mutations resulting in a milder phenotype (p.Arg133Cys, p.Arg294*, and large deletions) are more likely to experience mood problems and higher levels of anxiety and those with mutations that cause a more severe phenotype (p.Thr158Met and p.Arg168*) 34

.

Although RTT is not considered a neurodegenerative disorder, recently it has been identified that for most mutation types, regardless of the initial severity of the mutation, clinical severity becomes progressively worse with age. This demonstrates that MECP2 mutation type is a strong predictor of disease severity, thus, careful attention needs to be applied to each comorbidity so that clinicians and families can better prepare for the needs of patients with RTT 35.

Genetic causes of RTT Since the first report in 1966, RTT has solely been diagnosed on a clinical basis. However, in 1999 the Zoghbi laboratory identified mutations in the MECP2 gene in RTT patients and sequencing of the MECP2 gene was included in the diagnosis

36

. Rarely, mutations in

MECP2 have been identified in isolated autistic spectrum disorder and syndromic intellectual disability. Further, not all patients with a clinical diagnosis of RTT have a mutation in MECP2 (or any other known gene) and are thus classed as mutation negative. In fact, some 5 ACS Paragon Plus Environment


Page 6 of 26

5% of patients who meet the diagnostic clinical criteria for classical RTT do not have mutations in MECP2, with the number of gene-negative patients being higher in atypical RTT cases 37. In addition, patients having a clinical phenotype that overlaps with RTT but do not fulfil the revised clinical diagnostic criteria are termed Rett-like, and include Angelman syndrome, Pitt-Hopkins syndrome and some epileptic encephalopathies. Given this information, it is now accepted that that diagnosis of RTT is based on both clinical and molecular findings.

Although the majority of RTT patients have mutations in the MECP2 gene, mutations in other genes are associated with RTT, including Cyclin-dependent kinase-like 5 (CDKL5), Forkhead box protein G1 (FOXG1), Myocyte-specific enhancer factor 2C (MEF2C) and Transcription factor 4 (TCF4) 38-40.

MECP2: MECP2 is a pleotropic protein abundantly expressed in the brain. It is a member of the methyl binding domain (MBD) family and is a key epigenetic modulator in the brain, controlling chromatin architecture and gene expression through binding to methylated DNA 41

. Mutations in MECP2 have been identified as the primary genetic cause of RTT

36

.

MECP2 plays an important role in neuronal development and function, through its ability to bind to methylated DNA and it interacts with co-regulatory transcription protein partners in neuronal cells. The overall mechanism of neuronal development through the mediation of MECP2 is still unclear, however, it is very clear that mutations in MECP2 impair neuronal development

42, 43

. There are extensive in vivo studies that highlight the importance of

MECP2 in neuronal development, dendritic branching and brain morphology and substantiate the genotype-phenotype connection between MECP2 and RTT

44-46

. Recent estimates

recognize that around 95% of classical RTT cases and 75% of atypical RTT cases have mutations in MECP2

47, 48

. To date over 900 unique mutations have been identified within

MECP2 with 518 being pathogenic or likely pathogenic, 206 being benign or likely benign and 211 VOUS (variants of unknown significance) variants (Figure 1) 49.

Figure 1. The distribution of pathogenicity of variants in MECP2, CDKL5, and FOXG1 genes.


Page 7 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The severity of the RTT phenotype depends on the nature of the mutation and almost any exonic deletion in the protein is considered pathogenic. Structural analysis of MeCP2 has highlighted three major domains within the protein; the methyl binding domain (MBD), the transcriptional repression domain (TRD) and the nuclear localization signal (NLS) domain. The majority of the mutations affecting these domains are pathogenic compared to mutations falling in other areas of the protein such as the C-terminal and N-terminal regions. Up to 60% of all the pathogenic mutations are located within the methyl-binding domain (MBD) and the transcriptional repression domain (TRD) with 8 major (hot spot) mutations dispersed along these regions accounting for approximately 47% of all the mutations (p.Arg106Trp, p.Arg133Cys,

p.Thr158Met,

p.Arg168*,

p.Arg255*,

p.Arg270*,

p.Arg294*,

and

p.Arg306Cys).

Truncation and missense mutations make up the majority of mutations with 104 of all the 110 truncation mutations being pathogenic and 70 of all the 252 missense variants being pathogenic. Intronic mutations are less common with 14 out of the total 43 intronic mutations being pathogenic. Variants in the 3’UTR and 5’UTR comprise a considerable proportion of the total variants (85, 60 and 5 respectively), however none of these have functional proof of pathogenicity 49. This data is depicted in Figure 2.

Figure 2. Number of variants in MECP2.

While the majority of RTT patients have mutations/deletions in the MECP2 gene

47

,

approximately 5% of classical RTT and 25% of variant RTT patients are MECP2 mutation negative 3.

CDKL5: The first reports that mutations in Cyclin-dependent kinase-like5 (CDKL5) were associated with RTT were published in 2004 50, 51 and since then many more cases have been reported with a total of 499 individuals (368 female and 66 male). Of this cohort, 209 individuals had pathogenic mutations (177 female and 31 male) with 159 individuals being 7 ACS Paragon Plus Environment


diagnosed with RTT (155 female and 4 male)

49

. To date over 255 unique mutations have

been identified within CDKL5, with 164 mutations being pathogenic or likely pathogenic, 65 being benign or likely benign based largely on in silico analyses and 26 Variants Of Unknown Significance (VOUS) (Figure 1) 49.

The common clinical characteristics associated with mutations in CDKL5 include early-onset seizures (typically by 3 months of age), severe intellectual disability and gross motor impairment. In addition, a facial gestalt has been described in patients with CDKL5 mutations, including a broad forehead, deep-set eyes, well-defined philtrum, tapered fingers and full lips

52

. A comprehensive phenotypic assessment of a large cohort of patients with

CDKL5 mutations has recently been published with the aim of determining whether these patients actually fall under the spectrum of RTT

52

. The study by Fehr et al., demonstrated

that almost 25% of their cohort of 86 patients with mutations in CDKL5 did not meet the Neul criteria for the early-onset seizure variant of RTT

52

. The authors thus proposed that

patients with mutations in CDKL5 should be considered a separate entity to RTT, rather than be a variant form of the disorder, and suggested it should be known as the CDKL5 disorder 52

.

FOXG1: A small number of patients diagnosed with RTT have mutations in the Forkhead box protein G1 (FOXG1) gene and diagnosed with the congenital variant of RTT. In 2008 two individuals were identified to have mutations in the FOXG1 gene who had been diagnosed with congenital RTT

53

. To date 59 patients have been reported with pathogenic

FOXG1 mutations (36 female and 23 male) with only 27 being diagnosed with atypical RTT (20 female and 7 male) 49. To date 44 unique mutations have been identified within FOXG1 with 41 being pathogenic or likely pathogenic, 2 being benign or likely benign and 1 VOUS (variants of unknown significance) variants (Figure 1)

49

. FOXG1 encodes a brain-specific

transcriptional repressor that is essential for early brain development. However, as was the case for CDKL5 mutations, there are features that are seen commonly in those with FOXG1 mutations, such as agenesis or hypoplasia of the corpus callosum, that has not been reported in individuals with MECP2 or CDKL5 mutations, and consequently it has been suggested that mutations in FOXG1 cause a clinical entity distinct from RTT 54.


Page 8 of 26

Page 9 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


MEF2C: The involvement of MEF2C in RTT was first reported in 2008

55

. It has

subsequently been estimated that around 2% of those with a RTT-like phenotype are caused by mutations in MEF2C

38, 56, 57

. MEF2C haplo-insufficiency syndrome, a disorder resulting

from the microdeletion of the 5q14.3 region, has been shown to exclusively affect neuronal function, with affected individuals having severe intellectual disability, seizures, hypotonia, and cerebral malformations

58

. The prevalence of stereotypic hand movements in MEF2C

syndrome is significant, prompting the suggestion that this disorder overlaps with RTT 57, 59. Interestingly, patients with MEF2C mutations also show reduced MECP2 and CDKL5 expression

56

. This phenotypic and genotypic connection has raised the possibility of a

common pathway or a convergence in separate pathways involving MECP2, CDKL5 and MEF2C, which may be impaired when any of these genes are dysfunctional. This has led to a strong interest in identifying such a pathway or convergence, which could be a potential target for therapeutic intervention.

The advent of whole-exome sequencing in the identification of novel disease-causing genes has been rapid and the subsequent results within RTT research has been notable with a handful of genes being investigated for their disease causing potential. These genes of interest include TCF4, ZNF238, EEF1A2, SLC35A2, EIF2B2, SHROOM4, STXBP1, SCN8A, IQSEC2, GABRD, SHANK3, PTPN4 and MFSD8

38, 60-65

. The list is not exhaustive and with

the increasing impact of next generation sequencing in this field, the list is expected to grow, incorporating new elements with the potential to improve clinical diagnosis of RTT. It should also be noted that these genes, although flagged as strong candidates for RTT, require further research and functional validation to substantiate their disease-causing role to justify their inclusion in routine clinical screening. Genotype-phenotype correlations of new disease genes Genotype-phenotype correlation studies of RTT patients and their MECP2 variants have been reported widely, although some disparity still exists which is largely attributed to skewed X chromosome inactivation (XCI) 47, 66-71.

Mutations in MECP2 are highly likely to be found in individuals with classic RTT, however other disease genes are starting to emerge in RTT and RTT-like patients. For example, Neul et al have recently reported the utility of being able to separate atypical RTT patients into 9 ACS Paragon Plus Environment


Page 10 of 26

subtypes based on their clinical severity score 3. A number of new disease genes have recently been suggested by whole exome sequencing which have been found to be associated with atypical RTT patients and patients with RTT-like features and some correlations are starting to emerge.

For example, a recent study by Olson et al, demonstrated that out of eleven MECP2-mutation negative patients with RTT-like features that underwent exome sequencing

64

, a number of

genotype-phenotype correlations could be drawn. Of significance, a novel frameshift mutation in the STXBP gene was found in an atypical RTT patient with neonatal onset epilepsy. Further analyses identified pathogenic mutations in the SCN8A and IQSEC2 genes in two patients who did not meet the formal selection criteria for typical RTT. Interestingly two other patients in this cohort who also did not fulfil the formal selection criteria for RTT were found to harbour a mutation in MECP2 and FOXG1 respectively. Of note, one patient was diagnosed with classic RTT but no pathogenic mutation was identified, not even in the canonical disease genes such as MECP2 64. The latter observation may be attributed to issues relating to the technology, or that other genetic causes of RTT are still unknown. As sequencing technology improves, there is hope that this may be resolved.

Genotypic-phenotypic correlations in RTT have been useful in uncovering new candidate genes with disease causing mutations. One such study conducted exome sequencing of 21 RTT patients of Spanish origin with no known mutations in MECP2, CDKL5 and FOXG1 uncovered de novo variants in 21 genes, 17 of which were not previously associated with neurodevelopmental disorders

72

. Of particular interest is a de novo variant identified in the

neuronal receptor, GABBR2 (c.1699G>A, p.Ala567Thr) in one of the patients. The wild type amino acid that is predicted to be mutated in GABBR2 is highly conserved among many animal species and has been predicted by in silico evaluation to be ‘potentially disease causing’. Although the researchers carried out functional studies in C. elegans, they could not demonstrate any neurological effects in this animal model harbouring the orthologous gbb-2 mutation. Despite the authors explicitly stating the patients met Neul’s revised clinical diagnostic criteria, they continued to classify the patients as ‘RTT-like’ or having ‘clinical features that resemble RTT cases, but did not provide detail as to the clinical picture that would allow independent assessment of whether these individuals fulfilled the clinical criteria for RTT. Interestingly, a more recent report also identified the same de novo missense variant (p.Ala567Thr) in GABBR2 in two mutation-negative atypical RTT patients 10 ACS Paragon Plus Environment

73

. In this study,

Page 11 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


functional analysis of the variant was carried out using a X. tropicalis model system to examine the pathogenicity, drawing on previous studies that tadpoles are a reliable model to study human behavioural phenotypes such as epilepsy. Their findings demonstrated that variants in GABBR2 mutant tadpoles caused aberrant swimming and increased seizure-like behaviours in a mutation-dependent manner

73

. The same variant has been reported in

another cohort of Portuguese patients with RTT-like phenotypes 62. Because the in silico and functional studies for this variant were conflicting, it remains to be determined whether this and other variants in this gene can indeed cause a RTT-like phenotype.

Thus, careful

consideration should to be taken when attempting to identify new disease genes, particularly in a complex disorder such as RTT, which include ensuring that patients have a confirmative diagnosis of RTT (ie they either meet the 2010 diagnostic criteria for typical or variant RTT 74

), using robust in silico prediction tools to determine whether variants are likely to be

pathogenic, as well as using disease appropriate experimental models.

Classification and diagnostic criteria The diverse and complicated clinical phenotype of RTT has resulted in revision of the clinical diagnostic criteria over the years to facilitate the identification of typical (classical) and atypical (variant) RTT cases. The first description of RTT in the English medical literature was reported by Hagberg and colleagues in 1983 established

20

and the first set of clinical criteria were

75, 76

. This was followed by a number of publications including reports of atypical

RTT, describing variations in severity of comorbidities, behaviour, prognosis and involvement of the autonomic nervous system. These atypical forms consist of the milder clinical form known as the Zappella variant or preserved speech variant where patients have some degree of speech 77; and the forme fruste variant, or more severe phenotypes, including the early onset seizure form (also known as the Hanefeld variant or early seizure variant), and the very early onset symptom variant known as the congenital variant. Other variants described in the early literature include the male variant and the late childhood regression variant 2.

To take into account the emerging atypical cases, simplification of the diagnosis was required and in 1994 primary and supportive criteria were developed to encompass the full range of clinical manifestations 78. Despite this, a requirement to revise the criteria was needed and in 2002, a new version was published which combined all three of the existing diagnostic 11 ACS Paragon Plus Environment


Page 12 of 26

criteria into a new version which recognised classical RTT and atypical RTT as two separate entities

79

. Finally in 2010, a further set of criteria were developed to further define and

simplify the diagnosis

74

. The Neul criteria are now the diagnostic criteria most commonly

used for the identification of new cases of RTT.

Over 95% of classical RTT cases and over 75% of atypical RTT cases have mutations in MECP2 3. According to the revised diagnostic criteria, for patients to be diagnosed with classical RTT they must have a period of developmental regression followed by recovery or stabilisation, partial or complete loss of acquired purposeful hand skills and speech, gait abnormalities and stereotypic hand movements. The diagnosis is excluded if there is a history of brain injury secondary to trauma, neurometabolic disease or severe neurological infections. The diagnosis is also excluded if there is grossly abnormal psychomotor development within the first six months of life 74.

Before the groundbreaking discovery that mutations in MECP2 caused RTT in 1999

36

, the

diagnosis of RTT was based purely on clinical diagnostic criteria, as no useful biomarkers of the disorder had been and remain to be identified. However, despite this discovery, due to the complex nature of the disorder, the diagnosis of RTT still relies to a large extent, on the clinical diagnostic criteria and the exclusion of differential diagnoses.

Multidisciplinary approach to managing RTT Treatment of RTT is purely symptomatic and supportive as there are no specific therapies currently available. The disorder is associated with a high prevalence of comorbidities 74. The management of these comorbidities requires a multidisciplinary approach to medical management. With multidisciplinary health care coordinated by a paediatrician, combined with symptomatic drug treatment, patients with RTT can enjoy a better quality of life and a considerably longer lifespan. Along with standard treatments such as antiepileptic drugs for seizures, preventative approaches are being incorporated into the treatment regimen to manage individual patient needs. This may include medical and surgical subspecialists such as a gastroenterologist to manage gastrointestinal dysmotility and chronic constipation, a neurologist to manage seizures, spasticity and movement disorders, an endocrinologist to monitor and manage bone health, an orthopaedic surgeon for monitoring and surgical 12 ACS Paragon Plus Environment

Page 13 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


management of scoliosis and a cardiologist to manage prolonged QTc interval. In addition allied health professionals play a vital role; a dietician to assess nutrition and feeding, a physiotherapist can work to improve mobility and muscle tone, an occupational therapist is required to assist with optimising hand function, control stereotypic hand movements and assist with equipment needs, a speech therapist to assist with feeding and communication including the use of augmentative communication devices and special education providers. In addition, alternate therapies such as hydrotherapy, massage therapy, hippotherapy and music therapy are also part of the multidisciplinary management program.

Clinical trials A number of clinical trials addressing the various comorbidities of RTT have been conducted over the years, however, to date, no therapeutic strategy has been translated into the clinic. This is not necessarily due to the lack of efficacy of these treatments, but rather to the confounding and complex nature of the disorder and in some cases study design flaws. To this end, valuable lessons have been learnt which may be taken under consideration in the existing and future trials. These trials include both observational and interventional designs, with the latter involving drug and dietary supplementation aimed at ameliorating specific comorbidities associated with the disorder.

Therapeutic agents with the potential capacity to improve patient motor skills and cognitive development have been tested in clinical trials which include bromocriptine80, naltrexone

81

,dextromethorphan, cerebrolysin82 and lovastatin. Cerebrolysin, naltrexone and lovastatin have also been tested for their ability to restore normal EEG function and reduce seizures as well as the compounds Trofinetide (previously known as NZ-2566), glatiramer acetate (Copyolymer-1 or Copazone) and triheptanoin (UX007) (https://clinicaltrials.gov/).

A

number of compounds including desipramine, lovastatin, glatiramer acetate and ketamine are, or have been, tested for their capacity to restore respiratory deficits such as apnoeas in RTT patients. The full-length form of insulin-like growth factor, recombinant human IGF-1 (hrIGF-1, Mecasermin or INCRELEX), has been successfully tested in a number of clinical trials. 13 ACS Paragon Plus Environment


These trials have established the safety of the drug and demonstrated improvement in a number of neurobehavioral parameters, specifically measures of anxiety and depression and a reduction in the incidence of apnoea

83, 84

. The success of these trials led to the design and

goals of the current trofinetide and sarizotan trials. Sarizotan, a selective serotonin (5-HT1A) receptor agonist and dopamine 2 (D2) receptor antagonist, is currently being tested in a randomized, double-blind, placebo-controlled study to evaluate its capacity to reduce respiratory deficits such as apnoea in patients with RTT. Trofinetide, a synthetic analogue derived from the tri-peptide of IGF-1, has previously been tested in a phase 2 randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study in patients between the ages of 16 and 45 years and is in the process of being set up for another phase 2 trial for paediatric (5‒15-year-old) patients. Both trials have the same primary outcomes measures to determine incidence of adverse events.

Poor growth is a common feature in RTT children, being evident as early as three months of age and may continue into adulthood 85. This is contributed to by feeding difficulties, oromotor dysfunction and digestive tract dysfunction. However additional neurological factors such as apraxia, hyperventilation and breath-holding, disrupted sleep and scoliosis contribute significantly. Increased calorie intake, improving feeding skills, and gastrostomy feeding tube placement are part of the clinical management of RTT patients. Dietary supplements have been tested in clinical trials. These include folic acid for overall clinical improvement86-88 , the ketogenic diet to address seizures, breathing disturbances and hand movements and growth,89 and L-carnitine to address general well-being, sleep efficiency, energy levels, communication skills and expressive speech 90, 91.The L-carnitine clinical trials showed improvement in two of the measured outcomes (the behavioural/social and orofacial/respiratory scales of the Rett Syndrome Motor Behavioural Assessment and the Patient Well-Being Index)90 , however, the effects were not as substantial as those reported earlier 92, 93, and to date no long-term studies have been reported using L-carnitine. In addition and more recently, ω-3 polyunsaturated fatty acids (PUFAs) have been tested in clinical trials supporting that the oral supplementation of these FDA approved oils could potentially be of therapeutic value for RTT patients. Two pilot studies of female patients with typical RTT showed that ω-3 PUFA oil treatment significantly reduced their levels of oxidative stress markers, and resulted in improved clinical severity scores94, 95.These were followed by two further studies, whereby patients showed improved ω-6/ω-3 ratios and 14 ACS Paragon Plus Environment

Page 14 of 26

Page 15 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


serum plasma lipid profiles (total cholesterol and triglycerides), and decreased PUFA peroxidation end products compared to the untreated RTT group 96 as well as improved biventricular myocardial systolic function 97.

The dietary supplements creatine98 , folate and betaine99 , ketogenic diet 89 and L-carnitine90, 91

have also been tested for the capacity to improve motor function and behaviour.

Of all the completed trials, although the outcomes tended to be variable, most studies showed improvements in at least one outcome measure, suggesting a need for follow-up studies to reexamine some of these compounds and their derivatives. Conducting clinical trials in rare disorders such as RTT has many challenges; however, lessons from past clinical trials together with new information from preclinical studies will enable clinical trials research to move forward to achieve effective therapeutic strategies for RTT.

Conclusions One of the most significant contributions to research in RTT is the proof of concept demonstration using Mecp2-deficient mice that RTT is reversible. This landmark achievement, whereby Mecp2 expression was restored in these mice, leading to a dramatic recovery from their ‘Rett-like phenotype’, has greatly increased the motivation of the RTT research community in finding a cure.

The paradigm shift that RTT is potentially a

reversible disorder, makes the notion of treatment tempting. Recent advances in applications such as next generation sequencing (whole exome and whole genome sequencing) and technologies that allow for the development of sophisticated model systems using induced pluripotent stem cells and CRISPR gene editing are rapidly advancing our understanding of the functional role of MeCP2 and the aetiology of RTT and guiding us closer to new therapeutic strategies.

However, the pursuit of all possible therapeutic options, and

increasing our understanding of the underlying biology of RTT is still warranted, so that we may identify ways in which to better alleviate the symptoms of RTT.

Author Contributions: Wendy A Gold, Rahul Krishnaraj, Carolyn Ellaway and John Christodoulou all researched and wrote sections of this review manuscript, with Wendy A Gold being the lead author. 15 ACS Paragon Plus Environment



Page 16 of 26

Page 17 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


References [1] Rett, A. (1966) [On a unusual brain atrophy syndrome in hyperammonemia in childhood], Wien Med Wochenschr 116, 723-726. [2] Hanefeld, F. (1985) The clinical pattern of the Rett syndrome, Brain Dev 7, 320-325. [3] Neul, J. L., Lane, J. B., Lee, H. S., Geerts, S., Barrish, J. O., Annese, F., Baggett, L. M., Barnes, K., Skinner, S. A., Motil, K. J., Glaze, D. G., Kaufmann, W. E., and Percy, A. K. (2014) Developmental delay in Rett syndrome: data from the natural history study, J Neurodev Disord 6, 20. [4] Temudo, T., Maciel, P., and Sequeiros, J. (2007) Abnormal movements in Rett syndrome are present before the regression period: a case study, Mov Disord 22, 2284-2287. [5] Einspieler, C., Kerr, A. M., and Prechtl, H. F. (2005) Is the early development of girls with Rett disorder really normal?, Pediatr Res 57, 696-700. [6] Young, D. J., Bebbington, A., Anderson, A., Ravine, D., Ellaway, C., Kulkarni, A., de Klerk, N., Kaufmann, W. E., and Leonard, H. (2008) The diagnosis of autism in a female: could it be Rett syndrome?, Eur J Pediatr 167, 661-669. [7] American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) ed., American Psychiatric Association, Arlington, United States. [8] Humphreys, P., and Barrowman, N. (2016) The Incidence and Evolution of Parkinsonian Rigidity in Rett Syndrome: A Pilot Study, Can J Neurol Sci 43, 567-573. [9] Hagberg, B., Anvret, M., and Wahlström, J. (1993) Rett Syndrome - Clinical and Biological Aspects Studies on 130 Swedish Females, Vol. 127, Cambridge University Press, . [10] Tarquinio, D. C., Hou, W., Neul, J. L., Kaufmann, W. E., Glaze, D. G., Motil, K. J., Skinner, S. A., Lee, H. S., and Percy, A. K. (2015) The Changing Face of Survival in Rett Syndrome and MECP2-Related Disorders, Pediatr Neurol 53, 402-411. [11] Tarquinio, D. C., Motil, K. J., Hou, W., Lee, H. S., Glaze, D. G., Skinner, S. A., Neul, J. L., Annese, F., McNair, L., Barrish, J. O., Geerts, S. P., Lane, J. B., and Percy, A. K. (2012) Growth failure and outcome in Rett syndrome: specific growth references, Neurology 79, 1653-1661. [12] Christodoulou, J., Grimm, A., Maher, T., and Bennetts, B. (2003) RettBASE: The IRSA MECP2 variation database-a new mutation database in evolution, Hum Mutat 21, 466-472. [13] Glaze, D. G., Percy, A. K., Skinner, S., Motil, K. J., Neul, J. L., Barrish, J. O., Lane, J. B., Geerts, S. P., Annese, F., Graham, J., McNair, L., and Lee, H. S. (2010) Epilepsy and the natural history of Rett syndrome, Neurology 74, 909-912. [14] Nissenkorn, A., Levy-Drummer, R. S., Bondi, O., Renieri, A., Villard, L., Mari, F., Mencarelli, M. A., Lo Rizzo, C., Meloni, I., Pineda, M., Armstrong, J., Clarke, A., Bahi-Buisson, N., Mejaski, B. V., Djuric, M., Craiu, D., Djukic, A., Pini, G., Bisgaard, A. M., Melegh, B., Vignoli, A., Russo, S., Anghelescu, C., Veneselli, E., Hayek, J., and Ben-Zeev, B. (2015) Epilepsy in Rett syndrome-lessons from the Rett networked database, Epilepsia 56, 569-576. [15] Freilinger, M., Bohm, M., Lanator, I., Vergesslich-Rothschild, K., Huber, W. D., Anderson, A., Wong, K., Baikie, G., Ravikumara, M., Downs, J., and Leonard, H. (2014) Prevalence, clinical investigation, and management of gallbladder disease in Rett syndrome, Dev Med Child Neurol 56, 756-762. [16] Motil, K. J., Caeg, E., Barrish, J. O., Geerts, S., Lane, J. B., Percy, A. K., Annese, F., McNair, L., Skinner, S. A., Lee, H. S., Neul, J. L., and Glaze, D. G. (2012) Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome, J Pediatr Gastroenterol Nutr 55, 292-298. [17] Jefferson, A., Leonard, H., Siafarikas, A., Woodhead, H., Fyfe, S., Ward, L. M., Munns, C., Motil, K., Tarquinio, D., Shapiro, J. R., Brismar, T., Ben-Zeev, B., Bisgaard, A. M., Coppola, G., Ellaway, C., Freilinger, M., Geerts, S., Humphreys, P., Jones, M., Lane, J., Larsson, G., Lotan, M., Percy, A., Pineda, M., Skinner, S., Syhler, B., Thompson, S., Weiss, B., Witt Engerstrom, I.,



and Downs, J. (2016) Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence, PLoS One 11, e0146824. [18] Downs, J., Torode, I., Wong, K., Ellaway, C., Elliott, E. J., Christodoulou, J., Jacoby, P., Thomson, M. R., Izatt, M. T., Askin, G. N., McPhee, B. I., Bridge, C., Cundy, P., and Leonard, H. (2016) The Natural History of Scoliosis in Females With Rett Syndrome, Spine (Phila Pa 1976) 41, 856-863. [19] Percy, A. K., Lee, H. S., Neul, J. L., Lane, J. B., Skinner, S. A., Geerts, S. P., Annese, F., Graham, J., McNair, L., Motil, K. J., Barrish, J. O., and Glaze, D. G. (2010) Profiling scoliosis in Rett syndrome, Pediatr Res 67, 435-439. [20] Hagberg, B., Aicardi, J., Dias, K., and Ramos, O. (1983) A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases, Ann Neurol 14, 471-479. [21] Kaufmann, W. E., Tierney, E., Rohde, C. A., Suarez-Pedraza, M. C., Clarke, M. A., Salorio, C. F., Bibat, G., Bukelis, I., Naram, D., Lanham, D. C., and Naidu, S. (2012) Social impairments in Rett syndrome: characteristics and relationship with clinical severity, J Intellect Disabil Res 56, 233-247. [22] Matson, J. L., Dempsey, T., and Wilkins, J. (2008) Rett syndrome in adults with severe intellectual disability: exploration of behavioral characteristics, Eur Psychiatry 23, 460-465. [23] Mount, R. H., Charman, T., Hastings, R. P., Reilly, S., and Cass, H. (2003) Features of autism in Rett syndrome and severe mental retardation, J Autism Dev Disord 33, 435-442. [24] Mount, R. H., Hastings, R. P., Reilly, S., Cass, H., and Charman, T. (2003) Towards a behavioral phenotype for Rett syndrome, Am J Ment Retard 108, 1-12. [25] Wulffaert, J., Van Berckelaer-Onnes, I. A., and Scholte, E. M. (2009) Autistic disorder symptoms in Rett syndrome, Autism 13, 567-581. [26] Cass, H., Reilly, S., Owen, L., Wisbeach, A., Weekes, L., Slonims, V., Wigram, T., and Charman, T. (2003) Findings from a multidisciplinary clinical case series of females with Rett syndrome, Dev Med Child Neurol 45, 325-337. [27] Cianfaglione, R., Clarke, A., Kerr, M., Hastings, R. P., Oliver, C., Moss, J., Heald, M., and Felce, D. (2015) A national survey of Rett syndrome: behavioural characteristics, J Neurodev Disord 7, 11. [28] Coleman, M., Brubaker, J., Hunter, K., and Smith, G. (1988) Rett syndrome: a survey of North American patients, J Ment Defic Res 32 ( Pt 2), 117-124. [29] Halbach, N. S., Smeets, E. E., Schrander-Stumpel, C. T., van Schrojenstein Lantman de Valk, H. H., Maaskant, M. A., and Curfs, L. M. (2008) Aging in people with specific genetic syndromes: Rett syndrome, Am J Med Genet A 146A, 1925-1932. [30] Mount, R. H., Charman, T., Hastings, R. P., Reilly, S., and Cass, H. (2002) The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome, J Child Psychol Psychiatry 43, 1099-1110. [31] Naidu, S., Murphy, M., Moser, H. W., and Rett, A. (1986) Rett syndrome--natural history in 70 cases, Am J Med Genet Suppl 1, 61-72. [32] Robertson, L., Hall, S. E., Jacoby, P., Ellaway, C., de Klerk, N., and Leonard, H. (2006) The association between behavior and genotype in Rett syndrome using the Australian Rett Syndrome Database, Am J Med Genet B Neuropsychiatr Genet 141B, 177-183. [33] Sansom, D., Krishnan, V. H., Corbett, J., and Kerr, A. (1993) Emotional and behavioural aspects of Rett syndrome, Dev Med Child Neurol 35, 340-345. [34] Anderson, A., Wong, K., Jacoby, P., Downs, J., and Leonard, H. (2014) Twenty years of surveillance in Rett syndrome: what does this tell us?, Orphanet J Rare Dis 9, 87. [35] Cuddapah, V. A., Pillai, R. B., Shekar, K. V., Lane, J. B., Motil, K. J., Skinner, S. A., Tarquinio, D. C., Glaze, D. G., McGwin, G., Kaufmann, W. E., Percy, A. K., Neul, J. L., and Olsen, M. L. (2014) Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome, J Med Genet 51, 152-158. 18 ACS Paragon Plus Environment

Page 18 of 26

Page 19 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


[36] Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., and Zoghbi, H. Y. (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2, Nat Genet 23, 185-188. [37] Dolce, A., Ben-Zeev, B., Naidu, S., and Kossoff, E. H. (2013) Rett syndrome and epilepsy: an update for child neurologists, Pediatr Neurol 48, 337-345. [38] Armani, R., Archer, H., Clarke, A., Vasudevan, P., Zweier, C., Ho, G., Williamson, S., Cloosterman, D., Yang, N., and Christodoulou, J. (2012) Transcription factor 4 and myocyte enhancer factor 2C mutations are not common causes of Rett syndrome, Am J Med Genet A 158A, 713-719. [39] Evans, J. C., Archer, H. L., Colley, J. P., Ravn, K., Nielsen, J. B., Kerr, A., Williams, E., Christodoulou, J., Gecz, J., Jardine, P. E., Wright, M. J., Pilz, D. T., Lazarou, L., Cooper, D. N., Sampson, J. R., Butler, R., Whatley, S. D., and Clarke, A. J. (2005) Early onset seizures and Rett-like features associated with mutations in CDKL5, Eur J Hum Genet 13, 1113-1120. [40] Philippe, C., Amsallem, D., Francannet, C., Lambert, L., Saunier, A., Verneau, F., and Jonveaux, P. (2010) Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females, J Med Genet 47, 59-65. [41] Zachariah, R. M., and Rastegar, M. (2012) Linking epigenetics to human disease and Rett syndrome: the emerging novel and challenging concepts in MeCP2 research, Neural Plast 2012, 415825. [42] Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T., Qin, J., and Zoghbi, H. Y. (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription, Science 320, 1224-1229. [43] Cohen, S., Gabel, H. W., Hemberg, M., Hutchinson, A. N., Sadacca, L. A., Ebert, D. H., Harmin, D. A., Greenberg, R. S., Verdine, V. K., Zhou, Z., Wetsel, W. C., West, A. E., and Greenberg, M. E. (2011) Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function, Neuron 72, 72-85. [44] Chen, R. Z., Akbarian, S., Tudor, M., and Jaenisch, R. (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice, Nat Genet 27, 327-331. [45] Guy, J., Gan, J., Selfridge, J., Cobb, S., and Bird, A. (2007) Reversal of neurological defects in a mouse model of Rett syndrome, Science 315, 1143-1147. [46] Belichenko, P. V., Wright, E. E., Belichenko, N. P., Masliah, E., Li, H. H., Mobley, W. C., and Francke, U. (2009) Widespread changes in dendritic and axonal morphology in Mecp2mutant mouse models of Rett syndrome: evidence for disruption of neuronal networks, J Comp Neurol 514, 240-258. [47] Neul, J. L., Fang, P., Barrish, J., Lane, J., Caeg, E. B., Smith, E. O., Zoghbi, H., Percy, A., and Glaze, D. G. (2008) Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome, Neurology 70, 1313-1321. [48] Percy, A. K., Lane, J. B., Childers, J., Skinner, S., Annese, F., Barrish, J., Caeg, E., Glaze, D. G., and MacLeod, P. (2007) Rett syndrome: North American database, J Child Neurol 22, 1338-1341. [49] Krishnaraj, R., Ho, G., and Christodoulou, J. (2017) RettBASE: Rett syndrome database update, Hum Mutat. [50] Tao, J., Van Esch, H., Hagedorn-Greiwe, M., Hoffmann, K., Moser, B., Raynaud, M., Sperner, J., Fryns, J. P., Schwinger, E., Gecz, J., Ropers, H. H., and Kalscheuer, V. M. (2004) Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation, Am J Hum Genet 75, 1149-1154. [51] Weaving, L. S., Christodoulou, J., Williamson, S. L., Friend, K. L., McKenzie, O. L., Archer, H., Evans, J., Clarke, A., Pelka, G. J., Tam, P. P., Watson, C., Lahooti, H., Ellaway, C. J., Bennetts, B., Leonard, H., and Gecz, J. (2004) Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation, Am J Hum Genet 75, 1079-1093. [52] Fehr, S., Wilson, M., Downs, J., Williams, S., Murgia, A., Sartori, S., Vecchi, M., Ho, G., Polli, R., Psoni, S., Bao, X., de Klerk, N., Leonard, H., and Christodoulou, J. (2013) The CDKL5 disorder



is an independent clinical entity associated with early-onset encephalopathy, Eur J Hum Genet 21, 266-273. [53] Ariani, F., Hayek, G., Rondinella, D., Artuso, R., Mencarelli, M. A., Spanhol-Rosseto, A., Pollazzon, M., Buoni, S., Spiga, O., Ricciardi, S., Meloni, I., Longo, I., Mari, F., Broccoli, V., Zappella, M., and Renieri, A. (2008) FOXG1 is responsible for the congenital variant of Rett syndrome, Am J Hum Genet 83, 89-93. [54] Pratt, D. W., Warner, J. V., and Williams, M. G. (2013) Genotyping FOXG1 Mutations in Patients with Clinical Evidence of the FOXG1 Syndrome, Mol Syndromol 3, 284-287. [55] Li, H., Radford, J. C., Ragusa, M. J., Shea, K. L., McKercher, S. R., Zaremba, J. D., Soussou, W., Nie, Z., Kang, Y. J., Nakanishi, N., Okamoto, S., Roberts, A. J., Schwarz, J. J., and Lipton, S. A. (2008) Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo, Proc Natl Acad Sci U S A 105, 9397-9402. [56] Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Cornelia, K., Ekici, A. B., Reis, A., and Rauch, A. (2010) Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression, Hum Mutat 31, 722-733. [57] Lambert, L., Bienvenu, T., Allou, L., Valduga, M., Echenne, B., Diebold, B., Mignot, C., Heron, D., Roth, V., Saunier, A., Moustaine, A., Jonveaux, P., and Philippe, C. (2012) MEF2C mutations are a rare cause of Rett or severe Rett-like encephalopathies, Clin Genet 82, 499-501. [58] Zweier, M., and Rauch, A. (2012) The MEF2C-Related and 5q14.3q15 Microdeletion Syndrome, Mol Syndromol 2, 164-170. [59] Le Meur, N., Holder-Espinasse, M., Jaillard, S., Goldenberg, A., Joriot, S., Amati-Bonneau, P., Guichet, A., Barth, M., Charollais, A., Journel, H., Auvin, S., Boucher, C., Kerckaert, J. P., David, V., Manouvrier-Hanu, S., Saugier-Veber, P., Frebourg, T., Dubourg, C., Andrieux, J., and Bonneau, D. (2010) MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations, J Med Genet 47, 22-29. [60] Craiu, D., Dragostin, O., Dica, A., Hoffman-Zacharska, D., Gos, M., Bastian, A. E., Gherghiceanu, M., Rolfs, A., Nahavandi, N., Craiu, M., and Iliescu, C. (2015) Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs, Eur J Paediatr Neurol 19, 78-86. [61] Hara, M., Ohba, C., Yamashita, Y., Saitsu, H., Matsumoto, N., and Matsuishi, T. (2015) De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient, Am J Med Genet A 167, 1593-1596. [62] Lopes, F., Barbosa, M., Ameur, A., Soares, G., de Sa, J., Dias, A. I., Oliveira, G., Cabral, P., Temudo, T., Calado, E., Cruz, I. F., Vieira, J. P., Oliveira, R., Esteves, S., Sauer, S., Jonasson, I., Syvanen, A. C., Gyllensten, U., Pinto, D., and Maciel, P. (2016) Identification of novel genetic causes of Rett syndrome-like phenotypes, J Med Genet 53, 190-199. [63] Okamoto, N., Miya, F., Tsunoda, T., Kato, M., Saitoh, S., Yamasaki, M., Shimizu, A., Torii, C., Kanemura, Y., and Kosaki, K. (2015) Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders, Clin Genet 88, 288-292. [64] Olson, H. E., Tambunan, D., LaCoursiere, C., Goldenberg, M., Pinsky, R., Martin, E., Ho, E., Khwaja, O., Kaufmann, W. E., and Poduri, A. (2015) Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome, Am J Med Genet A 167A, 20172025. [65] Williamson, S. L., Ellaway, C. J., Peters, G. B., Pelka, G. J., Tam, P. P., and Christodoulou, J. (2015) Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype, Eur J Hum Genet 23, 1171-1175.


Page 20 of 26

Page 21 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


[66] Amir, R. E., Van den Veyver, I. B., Schultz, R., Malicki, D. M., Tran, C. Q., Dahle, E. J., Philippi, A., Timar, L., Percy, A. K., Motil, K. J., Lichtarge, O., Smith, E. O., Glaze, D. G., and Zoghbi, H. Y. (2000) Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes, Ann Neurol 47, 670-679. [67] Bebbington, A., Anderson, A., Ravine, D., Fyfe, S., Pineda, M., de Klerk, N., Ben-Zeev, B., Yatawara, N., Percy, A., Kaufmann, W. E., and Leonard, H. (2008) Investigating genotypephenotype relationships in Rett syndrome using an international data set, Neurology 70, 868-875. [68] Bienvenu, T., Carrie, A., de Roux, N., Vinet, M. C., Jonveaux, P., Couvert, P., Villard, L., Arzimanoglou, A., Beldjord, C., Fontes, M., Tardieu, M., and Chelly, J. (2000) MECP2 mutations account for most cases of typical forms of Rett syndrome, Hum Mol Genet 9, 1377-1384. [69] Fabio, R. A., Colombo, B., Russo, S., Cogliati, F., Masciadri, M., Foglia, S., Antonietti, A., and Tavian, D. (2014) Recent insights into genotype-phenotype relationships in patients with Rett syndrome using a fine grain scale, Res Dev Disabil 35, 2976-2986. [70] Renieri, A., Meloni, I., Longo, I., Ariani, F., Mari, F., Pescucci, C., and Cambi, F. (2003) Rett syndrome: the complex nature of a monogenic disease, J Mol Med (Berl) 81, 346-354. [71] Schanen, C., Houwink, E. J., Dorrani, N., Lane, J., Everett, R., Feng, A., Cantor, R. M., and Percy, A. (2004) Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome, Am J Med Genet A 126A, 129-140. [72] Lucariello, M., Vidal, E., Vidal, S., Saez, M., Roa, L., Huertas, D., Pineda, M., Dalfo, E., Dopazo, J., Jurado, P., Armstrong, J., and Esteller, M. (2016) Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype, Hum Genet 135, 1343-1354. [73] Yoo, Y., Jung, J., Lee, Y. N., Lee, Y., Cho, H., Na, E., Hong, J., Kim, E., Lee, J. S., Lee, J. S., Hong, C., Park, S. Y., Wie, J., Miller, K., Shur, N., Clow, C., Ebel, R. S., DeBrosse, S. D., Henderson, L. B., Willaert, R., Castaldi, C., Tikhonova, I., Bilguvar, K., Mane, S., Kim, K. J., Hwang, Y. S., Lee, S. G., So, I., Lim, B. C., Choi, H. J., Seong, J. Y., Shin, Y. B., Jung, H., Chae, J. H., and Choi, M. (2017) GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy, Ann Neurol 82, 466-478. [74] Neul, J. L., Kaufmann, W. E., Glaze, D. G., Christodoulou, J., Clarke, A. J., Bahi-Buisson, N., Leonard, H., Bailey, M. E., Schanen, N. C., Zappella, M., Renieri, A., Huppke, P., Percy, A. K., and RettSearch, C. (2010) Rett syndrome: revised diagnostic criteria and nomenclature, Ann Neurol 68, 944-950. [75] NoAuthorsListed. (1988) Diagnostic criteria for Rett syndrome. The Rett Syndrome Diagnostic Criteria Work Group, Ann Neurol 23, 425-428. [76] Hagberg, B., Goutieres, F., Hanefeld, F., Rett, A., and Wilson, J. (1985) Rett syndrome: criteria for inclusion and exclusion, Brain Dev 7, 372-373. [77] Zappella, M. (1992) The Rett girls with preserved speech, Brain Dev 14, 98-101. [78] Hagberg, B. A., and Skjeldal, O. H. (1994) Rett variants: a suggested model for inclusion criteria, Pediatr Neurol 11, 5-11. [79] Hagberg, B., Hanefeld, F., Percy, A., and Skjeldal, O. (2002) An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001, Eur J Paediatr Neurol 6, 293-297. [80] Zappella, M. (1990) A double blind trial of bromocriptine in the Rett syndrome, Brain Dev 12, 148-150. [81] Percy, A. K., Glaze, D. G., Schultz, R. J., Zoghbi, H. Y., Williamson, D., Frost, J. D., Jr., Jankovic, J. J., del Junco, D., Skender, M., Waring, S., and et al. (1994) Rett syndrome: controlled study of an oral opiate antagonist, naltrexone, Ann Neurol 35, 464-470.



[82] Gorbachevskaya, N., Bashina, V., Gratchev, V., and Iznak, A. (2001) Cerebrolysin therapy in Rett syndrome: clinical and EEG mapping study, Brain Dev 23 Suppl 1, S90-93. [83] Pini, G., Bigoni, S., Engerstrom, I. W., Calabrese, O., Felloni, B., Scusa, M. F., Di Marco, P., Borelli, P., Bonuccelli, U., Julu, P. O., Nielsen, J. B., Morin, B., Hansen, S., Gobbi, G., Visconti, P., Pintaudi, M., Edvige, V., Romanelli, A., Bianchi, F., Casarano, M., Battini, R., Cioni, G., Ariani, F., Renieri, A., Benincasa, A., Delamont, R. S., Zappella, M., and group, E. (2012) Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases, Neuropediatrics 43, 37-43. [84] Khwaja, O. S., Ho, E., Barnes, K. V., O’Leary, H. M., Pereira, L. M., Finkelstein, Y., Nelson, C. A., Vogel-Farley, V., DeGregorio, G., Holm, I. A., Khatwa, U., Kapur, K., Alexander, M. E., Finnegan, D. M., Cantwell, N. G., Walco, A. C., Rappaport, L., Gregas, M., Fichorova, R. N., Shannon, M. W., Sur, M., and Kaufmann, W. E. (2014) Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome, Proceedings of the National Academy of Sciences 111, 45964601. [85] Schultz, R. J., Glaze, D. G., Motil, K. J., Armstrong, D. D., del Junco, D. J., Hubbard, C. R., and Percy, A. K. (1993) The pattern of growth failure in Rett syndrome, Am J Dis Child 147, 633637. [86] Temudo, T., Rios, M., Prior, C., Carrilho, I., Santos, M., Maciel, P., Sequeiros, J., Fonseca, M., Monteiro, J., Cabral, P., Vieira, J. P., Ormazabal, A., and Artuch, R. (2009) Evaluation of CSF neurotransmitters and folate in 25 patients with Rett disorder and effects of treatment, Brain Dev 31, 46-51. [87] Hagebeuk, E. E., Koelman, J. H., Duran, M., Abeling, N. G., Vyth, A., and Poll-The, B. T. (2011) Clinical and electroencephalographic effects of folinic acid treatment in Rett syndrome patients, J Child Neurol 26, 718-723. [88] Hagebeuk, E. E., Duran, M., Koelman, J. H., Abeling, N. G., Vyth, A., and Poll-The, B. T. (2012) Folinic acid supplementation in Rett syndrome patients does not influence the course of the disease: a randomized study, J Child Neurol 27, 304-309. [89] Haas, R. H., Rice, M. A., Trauner, D. A., and Merritt, T. A. (1986) Therapeutic effects of a ketogenic diet in Rett syndrome, Am J Med Genet Suppl 1, 225-246. [90] Ellaway, C., Williams, K., Leonard, H., Higgins, G., Wilcken, B., and Christodoulou, J. (1999) Rett syndrome: randomized controlled trial of L-carnitine, J Child Neurol 14, 162-167. [91] Ellaway, C. J., Peat, J., Williams, K., Leonard, H., and Christodoulou, J. (2001) Medium-term open label trial of L-carnitine in Rett syndrome, Brain Dev 23 Suppl 1, S85-89. [92] Plioplys, A. V., and Kasnicka, I. (1993) L-carnitine as a treatment for Rett syndrome, South Med J 86, 1411-1412. [93] Plochl, E., Sperl, W., Wermuth, B., and Colombo, J. P. (1996) [Carnitine deficiency and carnitine therapy in a patient with Rett syndrome], Klin Padiatr 208, 129-134. [94] De Felice, C., Ciccoli, L., Leoncini, S., Signorini, C., Rossi, M., Vannuccini, L., Guazzi, G., Latini, G., Comporti, M., Valacchi, G., and Hayek, J. (2009) Systemic oxidative stress in classic Rett syndrome, Free Radic Biol Med 47, 440-448. [95] Leoncini, S., De Felice, C., Signorini, C., Pecorelli, A., Durand, T., Valacchi, G., Ciccoli, L., and Hayek, J. (2011) Oxidative stress in Rett syndrome: natural history, genotype, and variants, Redox Rep 16, 145-153. [96] Signorini, C., De Felice, C., Leoncini, S., Durand, T., Galano, J. M., Cortelazzo, A., Zollo, G., Guerranti, R., Gonnelli, S., Caffarelli, C., Rossi, M., Pecorelli, A., Valacchi, G., Ciccoli, L., and Hayek, J. (2014) Altered erythrocyte membrane fatty acid profile in typical Rett syndrome: effects of omega-3 polyunsaturated fatty acid supplementation, Prostaglandins Leukot Essent Fatty Acids 91, 183-193. [97] Maffei, S., De Felice, C., Cannarile, P., Leoncini, S., Signorini, C., Pecorelli, A., Montomoli, B., Lunghetti, S., Ciccoli, L., Durand, T., Favilli, R., and Hayek, J. (2014) Effects of omega-3 PUFAs 22 ACS Paragon Plus Environment

Page 22 of 26

Page 23 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


supplementation on myocardial function and oxidative stress markers in typical Rett syndrome, Mediators Inflamm 2014, 983178. [98] Freilinger, M., Dunkler, D., Lanator, I., Item, C. B., Muhl, A., Fowler, B., and Bodamer, O. A. (2011) Effects of creatine supplementation in Rett syndrome: a randomized, placebocontrolled trial, J Dev Behav Pediatr 32, 454-460. [99] Glaze, D. G., Percy, A. K., Motil, K. J., Lane, J. B., Isaacs, J. S., Schultz, R. J., Barrish, J. O., Neul, J. L., O'Brien, W. E., and Smith, E. O. B. (2009) A Study of the Treatment of Rett Syndrome With Folate and Betaine, Journal of child neurology 24, 551-556.



Figure 1. The distribution of pathogenicity of variants in MECP2, CDKL5, and FOXG1 genes. 338x190mm (96 x 96 DPI)

ACS Paragon Plus Environment

Page 24 of 26

Page 25 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 2. Number of variants in MECP2. 338x190mm (96 x 96 DPI)



Rett syndrome (RTT) is a rare paediatric neurodevelopmental disorder predominantly caused by the X-linked Methyl-CpG-binding protein 2 (MECP2) gene. To date there still is no cure and the disorder is associated with a high prevalence of comorbidities whereby the management of these requires a multidisciplinary approach to medical management. Classification and diagnostic criteria have been revised a number of times over the years with the most comprehensive revision being published in 2010 to take into account the emerging atypical forms of RTT and simplification of diagnosis. The number of promising clinical trials and exciting novel therapeutic options currently being testing in laboratory and clinical settings are providing new hope to patients and families in finding a cure for this devastating disorder. 338x190mm (96 x 96 DPI)


Page 26 of 26

Rett Syndrome: A Genetic Update and Clinical ... - ACS Publications

Recommend Documents