1.

ASD

Autism spectrum disorder (ASD) manifests in early childhood and is characterized by qualitative abnormalities in social interactions, markedly
aberrant communication skills, and restricted repetitive behaviors, interests, and activities (RRBs). ASD is the broad current designation for a
group of conditions with deficits in social interaction and communication and RRBs. ASD includes a variety of disorders that have been called
autistic disorder, pervasive developmental disorder, Asperger syndrome, Rett syndrome, and fragile X syndrome

History
Behavioral and developmental features that suggest autism include the following:
 Developmental regression
 Absence of protodeclarative pointing
 Abnormal reactions to environmental stimuli
 Abnormal social interactions
 Absence of symbolic play
 Repetitive and stereotyped behavior
Developmental regression
Between 13% and 48% of people with autism have apparently normal development until age 15-30 months, when they lose verbal and
nonverbal communication skills. These individuals may have an innate vulnerability to develop autism. Although regression may be
precipitated by an environmental event (eg, immune or toxic exposures), more likely it is coincidental with other environmental events.
Protodeclarative pointing
Protodeclarative pointing is the use of the index finger to indicate an item of interest to another person. Toddlers typically learn to use
protodeclarative pointing to communicate their concern for an object to others. The absence of this behavior is predictive of a later diagnosis of
autism. [111, 112]
The presence of protodeclarative pointing can be assessed by interview of the parent or caregiver. Screening questions include "Does your
child ever use his or her index finger to point, to indicate interest in something?" A negative response to this question suggests the need for a
specialized assessment for possible pervasive developmental disorder.
Environmental stimuli
In contrast to toddlers with delayed or normal development, toddlers with autism spectrum disorder are much more interested in geometric
patterns. Toddlers who prefer dynamic geometric patterns to participating in physical activities such as dance merit referral for evaluation for
possible autism spectrum disorder. [113]
Parents of children with autism report unusual responses to environmental stimuli, including excessive reaction or an unexpected lack of
reaction to sensory input. Certain sounds (eg, vacuum cleaners or motorcycles) may elicit incessant screaming. Playing a radio, stereo, or
television at a loud level may appear to produce hyperacusis, a condition in which ordinary sounds produce excessive auditory stimulation of a
painful magnitude. Sometimes parents must rearrange the family routine so that the child is absent during noisy housekeeping activities.
Children with autistic disorder may also display exaggerated responses or rage to everyday sensory stimuli, such as bright lights or touching.
Social interactions
Individuals with autism may display a lack of appropriate interaction with family members. [114] Moreover, difficulties in social interactions are
common. Children may have problems making friends and understanding the social intentions of other children and may instead show
attachments to objects not normally considered child oriented. Although children with autistic disorder may want to have friendships with other
children, their actions may actually drive away these potential companions. They may also exhibit inappropriate friendliness and lack of
awareness of personal space.
Isolation likely increases in adolescence and young adulthood. Interviews with a representative sample of 725 youths with autism (mean age
19.2 y) determined that the majority had not in the preceding year gotten together with friends or even spoken with a friend on the
telephone. [115]
High pain threshold
An absence of typical responses to pain and physical injury may also be noted. Rather than crying and running to a parent when cut or bruised,
the child may display no change in behavior. Sometimes, parents do not realize that a child with autistic disorder is hurt until they observe the
lesion. Parents often report that they need to ask the child if something is wrong when the child's mood changes, and may need to examine the
child's body to detect injury.
Language
Speech abnormalities are common. They take the form of language delays and deviations. Pronominal reversals are common, including saying
"you" instead of "I." Some speech habits, such as repeating words and sentences after someone else says them, using language only the child
understands, or saying things whose meaning is not clear, may occur not only in autism but in other disorders as well.
Play
Baron-Cohen and colleagues demonstrated that the absence of symbolic play in infants and toddlers is highly predictive of a later diagnosis of
autism. Therefore, screening for the presence of symbolic play is a key component of the routine assessment of well babies. The absence of
normal pretend play indicates the need for referral for specialized developmental assessment for autism and other developmental disabilities.

Response to febrile illnesses

Children with autism may be particularly vulnerable to develop infections and febrile illnesses due to immunologic problems. By seeking
pediatric intervention promptly at the onset of infections and febrile illnesses, parents may be able to abort sequelae of chronic infections.
During a febrile illness, children with autistic disorder may show a decrease in behavioral abnormalities that plague the parents when the child
is well (eg, self-injurious behaviors, aggression toward others, property destruction, temper tantrums, hyperactivity).
This inhibition of negative behaviors may occur with various febrile illnesses, including ear infections, upper respiratory tract infections, and
childhood illnesses. (A parent may say, "When he is suddenly an angel, I know that he has an ear infection.") The recovery of the child from
the febrile illness may be accompanied by an abrupt return of the child's usual problematic behaviors.
Autism Screening Checklist
The higher the total score for items 5-10, 12, and 13 on the Autism screening checklist, the more likely that an autism spectrum disorder is
present.
Speech, Behavioral, Occupational, and Physical Therapies
Therapies that are reported to help some individuals with autism include the following:
 Assisted communication - Using keyboards, letter boards, word boards, and other devices (eg, the Picture Exchange Communication
System [149] ), with the assistance of a therapist
 Auditory integration training - A procedure in which the individual listens to specially prepared sounds through headphones
 Sensory integration therapy - A treatment for motor and sensory motor problems typically administered by occupational therapists
 Exercise and physical therapy - Exercise is often therapeutic for individuals with autistic disorder; a regular program of activity
prescribed by a physical therapist may be helpful
Cogntive behavior therapy (CBT)
Cognitive behavior therapy (CBT) is a technique that has been valuable for people with anxiety disorders, including social anxiety disorder.
Individuals with ASD and social anxiety underwent CBT to adress negative thoughts and social situations provoking anxiety to develop
effective behavioral techniques. In addition to the traditional CBT for people with social anxiety without ASD, people with social anxiety and
ASD were also provided social skills training. Thus, CBT represents a promising psychological treatment for people with ASD and social
anxiety. [153]
Family therapy
Living with a person with ASD can be stressful for family members. Talking therapy to ameliorate conflicts among people with ASD and other
family members has been reported to be beneficial to people with ASD and to family members. Research is needed to assess family therapy for
people with ASD.

Simultaneous treatment with two or more antipsychotics may be beneficial to treat agitation/irritability, physical aggression, and self-injurious
behaviors of patients with ASD, particularly moderately to severely ill males with autism and intellectual disability.

Same with Asperger

2. Rett syndrome

Rett syndrome (RS) is a neurodevelopmental disorder that occurs almost exclusively in females and has a typically degenerative course. It is
related to various mutations on the MECP2 gene, which codes for methyl-CpG binding protein-2 (MECP2). Recent studies suggest that
MECP2 is expressed in neurons and glial cells and that it will someday be possible to reverse the disorder even after birth when behavioral
symptoms occur. [1]
Signs and symptoms
RS progresses through 4 stages, typically reached at the following ages:
 Stage I - Developmental arrest (6-18 months)
 Stage II - Rapid deterioration or regression (1-4 years)
 Stage III - Pseudostationary (2-10 years)
 Stage IV - Late motor deterioration (>10 years)
The history varies according to the clinical stage. Common symptoms reported include the following:
 Stage I - Gross motor development delay, disinterest in play, and loss of eye contact; hypotonia; hand wringing; unusual placidity and
calmness; vague and nonspecific early symptoms; breath-holding spells
 Stage II - Deterioration; autisticlike behavior; stereotypic hand movements during wakefulness; breathing irregularities; seizures and
vacant spells that resemble seizures; sleep disorders, intermittent strabismus, and irritability
 Stage III - Some improvement in behavior, hand use, and communication skills; good eye contact and attempts to communicate intent;
continued mental impairment and hand stereotypies; increasing rigidity, bruxism, and involuntary tongue movements; motor
dysfunction and seizures; continued breathing irregularities; poor weight gain despite good appetite; difficult feeding and some degree
of oral motor dysfunction
 Stage IV - No additional deterioration of cognitive skills, communication skills, or hand skills; increased motor problems; cessation of
walking; possible reduction of seizure frequency
Physical findings also vary according to the clinical stage of the disorder. Common findings on physical examination include the following:
 Stage I - Gross motor development delay; loss of eye contact; deceleration of head, weight, and height growth; hypotonia; hand
wringing; abnormal placidity and calmness; no cutaneous findings on Wood lamp examination
 Stage II - Autisticlike behavior; midline hand wringing, clapping, hand washing, or hand-to-mouth movements; episodes of
hyperventilation or breath-holding; seizures and vacant spells that resemble seizures; intermittent strabismus and irritability
 Stage III - Hand stereotypies, rigidity, hyperventilation, breath holding, bruxism, involuntary tongue movements, poor weight gain, and
scoliosis
 Stage IV - Dystonia, rigidity, muscle wasting, quadriparesis, scoliosis or kyphoscoliosis, loss of ambulation, growth retardation,
hyperventilation, and seizures; improved frequency and intensity of hand movements; preserved eye contact

RS is a genetic disorder of neurodevelopmental arrest rather than a progressive process. The gene is located on the X chromosome. Females
with a single mutated MECP2 gene are more likely to survive because 1 X chromosome is activated randomly in each cell.
The symptoms and severity of RS may depend on both the percentage of activated defective genes and the type of mutation. Multiple mutation
types have been found in the 3 coding regions of the MECP2 gene, with most of them causing truncations and missense proteins. Mutations
have been found in as many as 80% of analyzed cases of classic RS. The MECP2 protein may act as a transcriptional repressor or activator,
depending on the target gene with which it associates. [1, 18]
The mutations that cause RS are almost all sporadic. In families with a girl who has RS, the increased risk of having a second girl with the
syndrome is reportedly less than 0.4%. However, recurrence in families can occur through mechanisms such as germline mosaicism.
About 70% of RS cases are due to 4 missense mutations (ie, R106W, R133C, T158M, R306C) and 4 nonsense protein-truncating mutations (ie,
R168X, R255X, R270X, R294X), which are large deletions that cause significant gene destruction, resulting in greater severity. Another
cluster of mutations near the end of the gene abrogate only the very end of the protein (C-terminal truncations). Physical therapy and speech
therapy may result in intragroup differences, causing different outcomes. [19]
RS is the first human disease determined to be caused by defects in a protein that regulates gene expression through interaction with
methylated DNA. Accordingly, it involves abnormal chromatin structure, with broad-ranging effects on expression of genes that are otherwise
not mutated. The normal MECP2 gene encodes the MECP2 protein, which binds to methylated DNA in conjunction with a corepressor. This
causes activation of histone deacetylase.
Mutations in the MECP2 gene produce loss of function of this protein and unregulated expression of the genes that it normally affects, some of
which appear to be crucial in nervous system development beyond the initial stages. Although the nervous system is the primary site, the
specific target genes are not known. Astrocyte function is abnormal in RS, presumably owing to dysfunction of the MECP2 gene.

RS generally becomes clinically evident by age 2-4 years; however, the underlying neurodevelopmental arrest probably starts in children aged
6-18 months or younger.
Most patients identified are female because the disease is X-linked. Many males with RS are believed to die in utero.

Survival rates decline in individuals older than 10 years; the 35-year survival rate is 70%. Death may be sudden and often is secondary
to pneumonia. Risk factors include seizures, loss of mobility, and difficulties with swallowing. The life expectancy is more favorable in
patients with RS than in other individuals with profound intellectual disability, which is associated with a 35-year survival rate of only 27%.

Classic Rett syndrome

Necessary criteria for the diagnosis of classic RS are as follows:
 Apparently normal prenatal and perinatal period
 Apparently normal development through at least the first 5-6 months of life
 Normal head circumference at birth
 Deceleration of head growth (age, 3 months to 3 years)
 Loss of acquired skills (age, 3 months to 3 years), including learned purposeful hand skills, acquired babble or learned words, and
communicative abilities
  Appearance of obvious mental deficiency
 Appearance successively of intense hand stereotypies, including hand wringing or squeezing; hand washing, patting, or rubbing; and
hand mouthing or tongue pulling
 Gait abnormalities among ambulant girls, including gait apraxia, dyspraxia, or both, as well as jerky truncal ataxia, body dyspraxia, or
both
 Diagnosis is tentative until the individual is aged 2-5 years
Supportive criteria for the diagnosis of classic RS are as follows:
 Breathing dysfunction, including periodic apnea during wakefulness, intermittent hyperventilation, breath-holding spells, and forced
expulsion of air or saliva
 Bloating or marked air swallowing
 Electroencephalographic (EEG) abnormalities, including slow waking background and intermittent rhythmic slowing (3-5 Hz) and
epileptiform discharges, with or without clinical seizures
 Epilepsy (various seizure forms)
 Spastic signs, later muscle wasting, or dystonic traits
 Peripheral vasomotor disturbances
 Neurogenic scoliosis
 Hypotrophic small and cold feet
 Growth retardation
Exclusion criteria for the diagnosis of classic RS are as follows:
 Organomegaly or other signs of storage disease
 Retinopathy or optic atrophy
 Microcephaly at birth
 Presence of identifiable metabolic or other neurodegenerative disorder
 Acquired neurologic disorder resulting from severe infections, head trauma, or toxic ingestion
 Evidence of intrauterine growth retardation
 Evidence of perinatally acquired brain dama

3. Asperger syndrome

Asperger syndrome (also referred to as Asperger disorder) is a term applied to a form of autism spectrum disorder (ASD) It is characterized by
persistent impairment in social interactions and by repetitive behavior patterns and restricted interests. Although in the past this syndrome was
commonly considered a separate diagnosis, it is now subsumed under the diagnosis of ASD in the American Psychiatric
Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
Asperger syndrome is generally evident in children older than age 3 years and occurs most often in males The estimated male-to-female ratio is
approximately 4:1
Children with this syndrome typically exhibit a limited capacity for spontaneous social interactions, a failure to develop friendships, and a
limited number of intense and highly focused interests.
People with Asperger syndrome may have certain communication problems, including poor nonverbal communication and pedantic speech,
but many of them have good cognitive and verbal skills. Physical symptoms may include early childhood motor delays, clumsiness, fine motor
difficulty, gait anomalies, and odd movements.

Asperger syndrome is a term applied to a condition characterized by persistent impairment in social interactions and by repetitive behavior
patterns and restricted interests. Once generally regarded as a discrete disorder, it is categorized as a form of autism spectrum disorder (ASD)
in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). [1]
Signs and symptoms
In DSM-5, the diagnosis of ASD encompasses the following 4 previously separate diagnoses [1] :
 Autism
 Asperger disorder
 Childhood disintegrative disorder
 Pervasive developmental disorder not otherwise specified
This change in nosology reflects a scientific consensus that these are not separate disorders but, rather, forms of a single disorder characterized
by different levels of severity with respect to the following 2 core symptom areas, both of which are required for a diagnosis of ASD:
 Impairments in social communication and social interaction, including all three of the following:
o Deficits in social-emotional reciprocity
o Deficits in developing and maintaining relationships
o Deficits in nonverbal communicative behaviors in social interactions
 Restricted, repetitive patterns of behavior, interests, or activities, including two or more of the following:
o Repetitive movement or speech or use of objects
o Insistence on sameness, unwavering adherence to routines, or ritualized patterns of behavior
o Highly restricted, fixated interests with abnormal strength or focus
o Increased or decreased response to sensory input

Individual clinical characteristics are denoted through the use of specifiers, as follows:
 With or without accompanying intellectual impairment
 With or without accompanying language impairment
 Associated with a known medical or genetic condition or environmental factor
 Associated with another neurodevelopmental, mental, or behavioral disorder
 With catatonia

Diagnosis
Neuropsychological testing should focus on simple and complex problem-solving tasks, using tests and scales such as the following:
 Wisconsin Card Sorting Test
 Trail-Making Test
  Stanford-Binet Scale
Genetic tests that may be useful include the following:
 Chromosomal microarray (CMA), or array comparative genomic hybridization (aCGH)
 Karyotyping
 Fragile X (FMR1 molecular studies)
 Methylation studies
 Methyl-CpG-binding protein (MECP2) analysis [5]
 Phosphatase and tensin (PTEN) homolog testing [6]
 Specific gene sequencing when a particular syndrome is suspected

In Asperger syndrome, the clinical manifestations presumably reflect alterations in brain development resulting from interactions between
multiple genes, epigenetic factors affecting gene expression, and exposure to environmental factors. [9] Gaigg and Bowler hypothesized that
impairments in the connections between the amygdala and associated structures of the brain may play a role in the pathogenesis of Asperger
symptoms.

Clinical presentation

History
Parents should be interviewed about prenatal history and maternal health factors that may have affected the pregnancy. The clinician should
conduct a thorough evaluation of social behaviors, language, interests, routines, physical coordination, and sensory sensitivity, starting from
birth. The history is likely to elicit the following:
 Social problems
 Communication abnormalities
 Speech and hearing abnormalities
 Sensory sensitivity
Social problems
Children with Asperger syndrome may have difficulties with peer relations and may be rejected by other children. Adolescents with the
syndrome commonly experience depression and loneliness. [19]
Outside the realm of immediate family members, an affected child may exhibit inappropriate attempts to initiate social interaction and to make
friends. Whereas children with Asperger syndrome may have great anxiety about demonstrating genuine desires for friendship to peers, they
may be taught by family members to express their love for their parents through multiple rehearsals over the years.
Alternatively, an affected child may not display affection to parents or other family members. A lack of bonding and warmth with parents and
other guardians may seem apparent, typically resulting from the child’s lack of social skills.
Children with Asperger syndrome exhibit peculiar and narrow interests, excluding other activities. These interests may take precedence over
their relationships with their family, school, and community.
Separations from parents because of work and divorce may be particularly stressful for these children. Changing homes, communities, and
neighborhoods may also exacerbate anxiety, depression, and other psychological disturbances.

Communication abnormalities
Use of gestures is frequently limited in people with Asperger syndrome, and body language or nonverbal communication may be awkward and
inappropriate. Facial expressions may be absent or inappropriate. Pragmatic errors are commonly produced by children with Asperger
syndrome in response to questions.

Sensory sensitivity
Children with Asperger syndrome may show abnormal sensitivity to sound, touch, taste, sight, smell, pain, and temperature. For example, they
may demonstrate either extreme or diminished sensitivity to pain. They may be particularly sensitive to the texture of foods.

Speech and hearing abnormalities

Children affected by Asperger syndrome demonstrate several abnormalities in speech and language, including pedantic speech and oddities in
pitch, intonation, prosody, and rhythm. Miscomprehension of language nuance (eg, literal interpretations of figures of speech) is common.
Individuals often exhibit practical speech problems, including inability to use language in social contexts, insensitivity about interrupting
others, and irrelevant commentary. Speech may be unusually formal or used in idiosyncratic ways that others do not understand. Individuals
may vocalize their thoughts without censoring. Personal remarks inappropriate to most social environments may be uttered routinely.

In addition to the conditions listed in the differential diagnosis, other disorders to consider include the following:
Basic phonologic processing disorder, Catatonia, Dyslexia, Hearing impairment, Hyperlexia, Nonverbal learning disability, Personality
disorder, Physical abuse, Pragmatic language disorder, Right cerebral hemisphere damage or dysfunction, Schizoid personality, Semantic-
pragmatic processing disorder, Sensory integration disorder, Triple X syndrome, Endocrine disorders, Audiovisual disorders, Collagen
disorders

Differential Diagnoses
 Adrenal Hypoplasia
 Attachment Disorders
 Birth Trauma
 Child Abuse & Neglect: Posttraumatic Stress Disorder
 Child Sexual Abuse
 Cognitive Deficits
 Conduct Disorder
 Dissociative Identity Disorder
 Fetal Alcohol Syndrome
 Fragile X Syndrome
 Hearing Impairment
 Pediatric Generalized Anxiety Disorder
 Pediatric Intellectual Disability
 Pediatric Obsessive-Compulsive Disorder
  Rett Syndrome

Prognosis
People with Asperger syndrome tend to have a better prognosis when they receive support from family members who are knowledgeable about
the disorder. These individuals may be taught specific social guidelines, but the underlying social impairment is believed to be lifelong.
Individuals with Asperger syndrome appear to have a normal lifespan; however, they seem to endure an increased prevalence of comorbid
psychiatric maladies (eg, depression, mood disorders, obsessive-compulsive disorder [OCD], and Tourette disorder). Comorbid psychiatric
disorders, when present, significantly affect the prognosis.
Depression and hypomania are especially common among adolescents and adults with Asperger syndrome, particularly those with a family
history of these conditions. (Caregivers of persons with Asperger syndrome may be prone to depression as well.)

Therapy

- Reinforcement of Appropriate Social Behaviors

- Implementation of Communication and Language Strategies
- Relaxation Therapy
- Encouragement of Special Skills
- Career Counseling and Orientation
- Management of Comorbid Conditions

interventions should not be prescribed in the absence of an indication. Agents that may be considered include the following:
 Second-generation antipsychotics – riperidone, paliperidone, ariprazole
 Selective serotonin reuptake inhibitors (SSRIs) – fluvoxamine, sertraline
 Other psychiatric medications (eg, atomoxetine and guanfacine) – guanfacine, atomoxetine.