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Rett Syndrome

What Rett’s Syndrome?

You read or heard Rett’s Syndrome as part of the broader autism spectrum disorder or pervasive developmental disorders. But what exactly is Rett’s Syndrome?

Rett Syndrome (RTT) is a neurodevelopmenal disorder that affects girls almost exclusively. It is characterized by normal early growth and development followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability.[1] This disorder is included under the ICD-10’s Pervasive Developmental Disorders category and was formerly included in the DSM-IV list of developmental disorders but was now removed under the DSM-5 because of its molecular causes.[2][3] The disorder was identified by Dr. Andreas Rett, an Austrian physician who first described it in a journal article in 1966. It was not until after a second article about the disorder, published in 1983 by Swedish researcher Dr. Bengt Hagberg, that the disorder was generally recognized.[1][4] Rett Syndrome is almost exclusively affects females but has also been found in male patients.[2]

What causes Rett Syndrome?

Rett Syndrome is genetic. It is caused by mutations in the gene MECP2 located on the X chromosome, and can arise sporadically or from germline mutations. In less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. Rett syndrome was initially diagnosed by clinical observation, but the diagnosis is definitive when there is a genetic defect in the MECP2 gene. In some very rare cases, no known mutated gene can be found suggesting changes in MECP2 that are not identified by presently used techniques or mutations in other genes that may result in clinical similarities.[2]  Neurotransmitter (brain chemicals that regulate brain and body functions) deficits are also causes of Rett Syndrome like pontine noradrenergic deficits caused by genetic loss of MECP2 changes the properties of cells in the locus coeruleus, the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus[2][5][6], and midbrain dopaminergic disturbances where dopamine synthesized by nuclei located in the mesencephalon is dysregulated.[2]

What are the signs and symptoms of Rett Syndrome?

Initial development is normal. Onset occurs between 6 and 18 months of age.[1][2] During this time there are subtle developmental deviations and early indicators of Rett syndrome. A period of developmental stagnation is followed by developmental regression where language and motor milestones regress, purposeful hand use is lost, and acquired deceleration in the rate of head growth (resulting in microcephaly in some) is seen. Hand stereotypes are typical, and breathing irregularities such as hyperventilation, breathholding, or sighing are seen in many. Early on, autistic-like behavior may be seen.[2] However, closer scrutiny reveals disturbance of the normal spontaneous limb and body movements that are thought to be regulated in the brainstem. The brief period of developmental progress is followed by stagnation and regression of previously acquired skills. During regression, some features are similar to those of autism. It is, hence, easy to mistakenly diagnose Rett syndrome for autism.[2][7]

Occasionally, Rett Syndrome shares a lot of symptoms with autism and cerebral palsy, making it difficult to diagnose and rule out from other disorders.

Signs of Rett syndrome that are similar to autism[2]:

  • incontinence
  • screaming fits
  • inconsolable crying
  • breath holding, hyperventilation & air swallowing
  • avoidance of eye contact
  • lack of social/emotional reciprocity
  • markedly impaired use of nonverbal behaviors to regulate social interaction
  • loss of speech
  • sensory problems

Signs of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion could rarely be made)[2]:

Rett Syndrome also has stages and is divided into 4 stages[1]:

Stage I (Early Onset) – typically begins between 6 and 18 months of age. This stage is often overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first. The infant may begin to show less eye contact and have reduced interest in toys. There may be delays in gross motor skills such as sitting or crawling. Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can continue for more than a year.[1]

Stage II (Rapid Destructive Stage) – usually begins between ages 1 and 4 and may last for weeks or months. Its onset may be rapid or gradual as the child loses purposeful hand skills and spoken language. Characteristic hand movements such as wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth often begin during this stage. The child may hold the hands clasped behind the back or held at the sides, with random touching, grasping, and releasing. The movements continue while the child is awake but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing usually improves during sleep. Some girls also display autistic-like symptoms such as loss of social interaction and communication. Walking may be unsteady and initiating motor movements can be difficult. Slowed head growth is usually noticed during this stage.[1]

Stage III (Plateau or Pseudo-stationary Stage) – usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this stage. However, there may be improvement in behavior, with less irritability, crying, and autistic-like features. A girl in stage III may show more interest in her surroundings and her alertness, attention span, and communication skills may improve. Many girls remain in this stage for most of their lives.[1]

Stage IV (Late Motor Deterioration Stage) – can last for years or decades. Prominent features include reduced mobility, curvature of the spine (scoliosis) and muscle weakness, rigidity, spasticity, and increased muscle tone with abnormal posturing of an arm, leg, or top part of the body. Girls who were previously able to walk may stop walking. Cognition, communication, or hand skills generally do not decline in stage IV. Repetitive hand movements may decrease and eye gaze usually improves.[1]

Image courtesy of bryanking.net. A girl with Rett Syndrome has scoliosis as one of its symptoms.

Image courtesy of dealwithautism.com

How is Rett Syndrome diagnosed?

Diagnosing Rett syndrome involves careful observation of your child’s growth and development and answering questions about her or his medical and family history.[8]

Your child may also have certain tests to identify conditions that can cause some of the same symptoms as Rett syndrome. Some of these conditions include[8]:

  • Other genetic disorders
  • Autism
  • Cerebral palsy
  • Hearing or vision problems
  • Epilepsy
  • Disorders that cause the brain or body to break down (degeneration disorders)
  • Brain disorders caused by trauma or infection
  • Prenatal brain damage

What tests your child needs depends on particular signs and symptoms. Tests may include[8]:

  • Blood tests
  • Urine tests
  • Tests to measure the speed of impulses through a nerve (nerve conduction studies)
  • Imaging tests such as magnetic resonance imaging (MRI) or computerized tomography (CT) scans
  • Hearing tests
  • Eye and vision exams
  • Brain activity tests (electroencephalograms, also called EEGs)

Genetic testing[8] is also done to rule out Rett Syndrome by seeing if there is a broken or mutated MECP2.

There is also a criteria for diagnosing Rett Syndrome.

The criteria required for a diagnosis of Rett syndrome include[8]:

  • Apparently normal development for the first five months after birth
  • Normal head circumference at birth, followed by a slowing of the rate of head growth between the ages of 5 months and 4 years
  • Severely reduced language skills
  • Loss of hand skills and development of repetitive hand movements between the ages of 5 months and 30 months
  • Loss of interaction with others (though this often improves later)
  • An unsteady walk or poorly controlled torso movements
  • Severely impaired ability to communicate and move normally

How is Rett Syndrome managed?

There is no cure for Rett Syndrome,  but studies have shown that restoring MECP2 function may lead to a cure.[2][9] One area of research is in the use of Insulin-like Growth Factor 1 (IGF-1), which has been shown to partially reverse signs in MeCP2 mutant mice.[2][10] Other therapeutic intervention is to counter the neuroexcitotoxic effect of increased spinal fluid levels of a neurotransmitter called glutamate and increased NMDA receptors in the brain of young Rett girls.[2][11] Dextromethorphan, an antagonist of the NMDA receptor in those below the age of 10 years, is also used.[2]

Treatment of Rett syndrome includes:

Because of the increased risk of sudden cardiac death, when long QT syndrome is found on an annual screening EKG it is treated with an anti-arrhythmic such as a beta-blocker. There is some evidence that phenytoin may be more effective than a beta-blocker.[2][12]

What is the outcome for Rett Syndrome?

Despite the difficulties with symptoms, many individuals with Rett syndrome continue to live well into middle age and beyond.  Because the disorder is rare, very little is known about long-term prognosis and life expectancy.  While there are women in their 40s and 50s with the disorder, currently it is not possible to make reliable estimates about life expectancy beyond age 40.[1]

How common is Rett Syndrome?

Rett Syndrome is a rare disease. The incidence of Rett Syndrome is estimated at 1 in 10,000 females.[13]

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(C) Tomy/Takara. Licca-chan doll.

But why Rett Syndrome is more common in girls than boys?

Though Rett Syndrome is a genetic and developmental disorder, it occurs more in girls than boys.

Girls have two X chromosomes in every cell. If they have Rett syndrome, some of the cells will use the defective gene. Other cells will use the healthy genes which will help to make up for the cells using the defective gene.[14]

However, boys only have one X chromosome in every cell. They lack the extra X chromosome that can protect their bodies from being completely overcome by the disorder. Therefore boys with the cell mutation that causes Rett syndrome often die before or shortly after birth.[14]

Image courtesy of rettsyndrome.org.

Because Rett Syndrome is a rare yet one of the most debilitating genetic and developmental disorders, awareness and acceptance of Rett Syndrome is spread around the world. October is designated as Rett Syndrome awareness month and violet is the color symbol of RTT. Despite difficulties associated with Rett, girls ho have it deserve to live a good life, cared for, and be respected.

Reference:

  1. http://www.ninds.nih.gov/disorders/rett/detail_rett.htm
  2. https://en.wikipedia.org/wiki/Rett_syndrome
  3. Abbeduto, Leonard; Ozonoff, Susan; Thurman, Angela John; McDuffie, Angela; Schweitzer, Julie. Hales, Robert; Yudofsky, Stuart; Robert, Laura Weiss, eds. Chapter 8. Neurodevelopmental Disorders, The American Psychiatric Publishing Textbook of Psychiatry (6 ed.). Arlington, VA: American Psychiatric Publishing. ISBN 978-1-58562-444-7. Retrieved 11 March 2015.
  4. Rett A (September 1966). “[On a unusual brain atrophy syndrome in hyperammonemia in childhood]”. Wien Med Wochenschr (in German) 116 (37): 723–6. PMID 5300597.
  5. Hokfelt T, Martensson R, Bjorklund A, Kleinau S, Goldstein M (1984). “Distribution maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain”. In A. Bjorklund and T. Hokfelt. Handbook of Chemical Neuroanatomy. Classical Transmitters in the CNS, Part I 2. New York: Elsevier. pp. 277–379.
  6. Berridge, Craig W; Waterhouse, Barry D (2003). “The locus coeruleus–noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes”. Brain Research Reviews 42 (1): 33–84. doi:10.1016/S0165-0173(03)00143-7. PMID 12668290.
  7. Jessica Wright (12 April 2013). “Clinical research: Rett symptoms emerge early, gradually”. SFARI.org. Retrieved 6 April 2014.
  8. http://www.mayoclinic.org/diseases-conditions/rett-syndrome/basics/tests-diagnosis/con-20028086
  9. “Autism-like disorder ‘reversible'”, BBC News, 8 February 2007.
  10. Tropea, D.; Giacometti, E.; Wilson, N. R.; Beard, C.; McCurry, C.; Fu, D. D.; Flannery, R.; Jaenisch, R.; Sur, M. (2009). “Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice”. Proceedings of the National Academy of Sciences 106 (6): 2029–34. doi:10.1073/pnas.0812394106. PMC 2644158. PMID 19208815.
  11. Blue, ME; Naidu, S; Johnston, MV (1999). “Development of amino acid receptors in frontal cortex from girls with Rett syndrome”. Annals of neurology 45 (4): 541–5. doi:10.1002/1531-8249(199904)45:43.0.CO;2-2. PMID 10211484.
  12. McCauley MD, Wang T, Mike E et al. (December 2011). “Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome”. Science Translational Medicine 3 (113): 113ra125. doi:10.1126/scitranslmed.3002982. PMC 3633081. PMID 22174313.
  13. http://www.rsrt.org/rett-and-mecp2-disorders/rett-syndrome/
  14. http://www.mychildwithoutlimits.org/understand/rett-syndrome/who-does-rett-syndrome-affect/

Further Reading:

  1. https://www.rettsyndrome.org/
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Autism-Related Disorders and the DSM-5 Change

Autism Spectrum Disorder is a general umbrella term for a neurodevelopmental condition with deficits in social interaction and communication, stereotyped or repetitive behaviors and interests, sensory issues, and in some cases, cognitive delays.[1] IT is called an “umbrella” because it encompasses some of the neurodevelopmental disorders with the same symptoms in a continuum. They are as follows (from severe to mild):

  • Rett’s Syndrome
  • Autistic Disorder
  • Childhood Disintegrative Disorder
  • Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS)
  • Atypical Autism
  • Asperger’s Syndrome

The “common” autism that most of us know is the Autistic disorder, where the child who has it has all the classic symptoms of autism and is non-verbal. But there are also “milder” versions or milder disorders similar to the autistic disorder like Asperger’s syndrome and a genetic disorder similar also to autism like Rett’s syndrome (for my general article in autism, click here). However, due to the overlapping symptoms and misuse of these disorders led the American Psychiatric Association revised their Diagnostic and Statistical Manual of Mental Disorders (DSM) and remove these autism-related disorders and instead absorbed them into the umbrella term “autism spectrum disorder.”[2] However, the World Health Organization’s disease manual, International Classification of Diseases (ICD), did not remove these disorders, but placed them under the general category of “Pervasive Developmental Disorders.”[3]

DSM-IV (the fourth edition) has this list of autism and its related disorders[4]:

The following is the ICD-10’s equivalent of autism spectrum disorders[3]:
F84 Pervasive developmental disorders
  • F84.0 Childhood autism
  • F84.1 Atypical autism
    • .10 Atypicality in age of onset
    • .11 Atypicality in symptomatology
    • .12 Atypicality in both age of onset and symptomatology
  • F84.2 Rett’s syndrome
  • F84.3 Other childhood disintegrative disorder

F84.4 Overactive disorder associated with mental retardation and stereotyped movements

  • F84.5 Asperger’s syndrome
  • F84.8 Other pervasive developmental disorders
  • F84.9 Pervasive developmental disorder, unspecified

Whereas, the DSM-5 has now its criteria for autism spectrum disorders, according to severity[5]:

Autism Spectrum Disorder           299.00 (F84.0)

Diagnostic Criteria

A.      Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text):

1.       Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions.

2.       Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication.

3.       Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers.

Specify current severity:

Severity is based on social communication impairments and restricted repetitive patterns of behavior (see Table 2).

B.      Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive; see text):

1.       Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic phrases).

2.       Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat food every day).

3.       Highly restricted, fixated interests that are abnormal in intensity or focus (e.g, strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interest).

4.       Hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement).

Specify current severity:

Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Table 2).

C.      Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life).

D.      Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.

E.       These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level.

Note: Individuals with a well-established DSM-IV diagnosis of autistic disorder, Asperger’s disorder, or pervasive developmental disorder not otherwise specified should be given the diagnosis of autism spectrum disorder. Individuals who have marked deficits in social communication, but whose symptoms do not otherwise meet criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder.

Specify if:
With or without accompanying intellectual impairment
With or without accompanying language impairment
Associated with a known medical or genetic condition or environmental factor
(Coding note: Use additional code to identify the associated medical or genetic condition.)
Associated with another neurodevelopmental, mental, or behavioral disorder
(Coding note: Use additional code[s] to identify the associated neurodevelopmental, mental, or behavioral disorder[s].)
With catatonia (refer to the criteria for catatonia associated with another mental disorder, pp. 119-120, for definition) (Coding note: Use additional code 293.89 [F06.1] catatonia associated with autism spectrum disorder to indicate the presence of the comorbid catatonia.)

Table 2  Severity levels for autism spectrum disorder

Severity level Social communication Restricted, repetitive behaviors
Level 3
“Requiring very substantial support”
Severe deficits in verbal and nonverbal social communication skills cause severe impairments in functioning, very limited initiation of social interactions, and minimal response to social overtures from others. For example, a person with few words of intelligible speech who rarely initiates interaction and, when he or she does, makes unusual approaches to meet needs only and responds to only very direct social approaches
Inflexibility of behavior, extreme difficulty coping with change, or other restricted/repetitive behaviors markedly interfere with functioning in all spheres. Great distress/difficulty changing focus or action.
Level 2
“Requiring substantial support”
Marked deficits in verbal and nonverbal social communication skills; social impairments apparent even with supports in place; limited initiation of social interactions; and reduced or  abnormal responses to social overtures from others. For example, a person who speaks simple sentences, whose interaction is limited  to narrow special interests, and how has markedly odd nonverbal communication.
Inflexibility of behavior, difficulty coping with change, or other restricted/repetitive behaviors appear frequently enough to be obvious to the casual observer and interfere with functioning in  a variety of contexts. Distress and/or difficulty changing focus or action.
Level 1
“Requiring support”
Without supports in place, deficits in social communication cause noticeable impairments. Difficulty initiating social interactions, and clear examples of atypical or unsuccessful response to social overtures of others. May appear to have decreased interest in social interactions. For example, a person who is able to speak in full sentences and engages in communication but whose to- and-fro conversation with others fails, and whose attempts to make friends are odd and typically unsuccessful.
Inflexibility of behavior causes significant interference with functioning in one or more contexts. Difficulty switching between activities. Problems of organization and planning hamper independence

Hmmm… But what’s the implication of removing milder forms of autism in the DSM-5?

The separate diagnoses of autistic disorder, PDD-NOS, and Asperger syndrome is no longer applicable. Meaning, only the autism spectrum disorder (ASD) is applied regardless of severity. ASD is the new single diagnosis of all forms of autism. The DSM also removed Rett’s syndrome because it is a genetic/chromosomal disorder and is similar to other chromosomal disorders like fragile X syndrome, tuberous sclerosis, or Down syndrome[6] and it has a known molecular etiology.[6][7] However, there will be a conflict when the DSM is compared to the ICD, where Rett’s syndrome is still under pervasive developmental disorders, and Asperger’s syndrome is not yet removed. Overlapping diagnoses of ASD or PDD will be still common.

Another problem that DSM-5 changes may bring is the acceptance among people with milder forms of autism. Since disorders like Asperger’s and PDD-NOS are eliminated, they are now confused with autistic disorder; some people even protested against the DSM’s changes. Patients and parents alike became anxious about these change. This anxiety ranges from a mild concern on the part of some parents to angry protest: More than 8,000 people signed an online petition circulated by the Global and Regional Asperger’s Syndrome Partnership; another petition sponsored by Asperger’s Association of New England received 5,400 signatures.[8]

But why is the DSM-5 has changed criteria for diagnosing ASD (if it causes confusion and anxiety to the autism community)?

Experts from APA have this explanation about DSM-5 changes in a Slate magazine article:

The logic behind the changes seems sound. “There wasn’t any evidence after 17 years that [the DSM-IV diagnoses] reflected reality,” says Bryan King, director of Seattle Children’s Autism Center, who served on the APA task force charged with revamping the diagnosis. “There was no consistency in the way Asperger’s or PDD-NOS was applied.” In fact, a 2011 study by Catherine Lord (another member of the task force) and more than 35 colleagues reported, “In these 12 university-based sites, with research clinicians selected for their expertise in ASD and trained in using standardized instruments, there was great variation in how best-estimate clinical diagnoses within the autism spectrum (i.e., autistic disorder, PDD-NOS, Asperger’s disorder) were assigned to individual children.”[8]

This argument sounds right, but some experts don’t agree because milder forms of autism has more subtle symptoms than the autistic disorder, and most countries don’t even recognize milder autism forms because people with these conditions can be verbal and independent (but still with social and communication deficits).

Another quote from Slate[8]:

Certain states provide services for children diagnosed with autism but not for those diagnosed with Asperger’s. “It was difficult to get kids with Asperger’s services because their deficits can be subtle, so they were left on their own to some degree,” says Matthew Siegel, director of the Developmental Disorders Program at Spring Harbor Hospital in Maine. And it’s not just those with Asperger’s who have been shortchanged by the current system, says Stewart Newman, who treats kids from all parts of the spectrum at Mind Matters PC in Oregon. He has spent many hours advocating for his patients with educators who had “a lack of clarity about what the diagnosis of PDD-NOS in particular meant, and how the children should be characterized for special services.”

Parents of children with autistic disorder are now worried about integrating higher functioning children with the low functioning ones; hence, blurring of the distinction of the severe and milder form of autism spectrum disorders.

Parents of lower-functioning kids are also concerned about how the influx of high-functioning individuals will affect the public’s perception of autism—mainly because they feel autism is a serious disorder that people should associate with profound disability. One mother commented online that “the proposed DSM change would diminish the enormity of the challenges that those with moderate to severe autism have.” Ursitti, who has a daughter with Asperger’s and a son with severe autism, feels this is already happening: “If we have this national perspective that autism is a blessing, that it’s not a crisis, the ones who will lose out are the expensive ones, the severe ones. Legislators focus on the cheapest option, and celebration is cheaper than treatment.”[8]

That parent’s comment is right, this change may lessen the severity of autism symptoms and may forget the classic autism and will only recognize milder forms of autism.

Not good. But somehow, the DSM has its autism spectrum severity scale from 1 (mild) to 3 (severe).

What is my opinion about the DSM-5 change?

I really do not know my standing about the changes in the DSM-5. But I find the ICD-10 more accurate than the DSM-5. I wish APA never eliminated autism-related disorders and integrated them into the umbrella of ASD, though I slightly agree with their elimination of Rett’s syndrome because it is chromosomal, but it has still autism-like symptoms. But with the removal of autism-related disorders, laymen will never know milder forms of autism (particularly in my native Philippines) and also the public will never know the internal struggles of people with milder autism and other pervasive developmental disorders and may only trivialize people with autism as either mutes or eccentric geeks, without seeing

Reference:

  1. https://en.wikipedia.org/wiki/Autism_spectrum
  2. http://www.dsm5.org/Documents/Autism%20Spectrum%20Disorder%20Fact%20Sheet.pdf
  3. http://www.who.int/classifications/icd/en/GRNBOOK.pdf?ua=1
  4. https://en.wikipedia.org/wiki/DSM-IV_codes
  5. https://www.autismspeaks.org/what-autism/diagnosis/dsm-5-diagnostic-criteria
  6. https://en.wikipedia.org/wiki/Rett_syndrome
  7. Abbeduto, Leonard; Ozonoff, Susan; Thurman, Angela John; McDuffie, Angela; Schweitzer, Julie. Hales, Robert; Yudofsky, Stuart; Robert, Laura Weiss, eds. Chapter 8. Neurodevelopmental Disorders, The American Psychiatric Publishing Textbook of Psychiatry (6 ed.). Arlington, VA: American Psychiatric Publishing. ISBN 978-1-58562-444-7. Retrieved 11 March 2015.
  8. http://www.slate.com/articles/health_and_science/medical_examiner/2013/05/autism_spectrum_diagnoses_the_dsm_5_eliminates_asperger_s_and_pdd_nos.html

Further Reading:

  1. http://raisingchildren.net.au/articles/dsm-5_changes_to_autism_diagnosis.html