Trigger Week 1

FRAGILE X SYNDROME

 First of all, congratulation for making it to second year medical student. Please ask questions, just attack anyone . We are here to help each other, not to compete with each other. It is a waste if we keep silence through out this PBL session. Lets proceed to our chairperson summary.

Summary

Anatomy of nervous system

Function of nervous system

Primary coordinating and controlling system of the body Monitors internal and external changes, analyse information, make conscious and unconscious decision, take appropriate action. Activities occur almost instantaneously through electrochemical impulses that flow from neuron to neuron.

Major parts of the brain

Brain is a part of CNS located in cranial cavities covered by meninges. Weight : 1450 grams. (average of adult brain) 1.Cerebellum 2. Diencephalon 3. Brain stem 4. Cerebellum

Meninges layer of brain.

cerebrum
1. Contains two cerebral hemisphere. 2. Seperated by superior longitudinal fissure but united at the base by corpus callosum. - Corpus callosum are the mass of nerve fibre. 3. Cortex outer layer of grey matter consist of sulcus and gyrus. 4. Inner white matter.

Insula deep to the lateral sulcus

Lobes and functional area

Function of cerebrum Higher center for the control of mental behaviour thought and conciousness moral sense,will, intellect speech,language and the special senses Motor cortex is the origin of all voluntary impulses controlling the skeletal muscles Sensory cortex is the final area for the reception of incoming sensory impulses

Internal Capsule
Internal Capsule -projection fibers carrying ascending & descending tracts to and from the (Cerebral cortex, brain stem & spinal cord) Beneath the corpus callosum are islands of grey matter Diencephalon ---thalamus & hypothalamus and pineal body Basal ganglia (nuclei) --- caudate & lentiform nuclei

Function of basal ganglia: modulate motor output from the cerebral cortex. Subconscious control of skeletal muscle tone coordination of learned movement patterns.

Diencephalon
Thalamus -The thalamus forms the major portion of the diencephalon, - lies on either side of the third ventricle It receives the sensory information from all parts of the body,(except olfaction) -filters the information, and passes the filtered portion to the cerebral cortex. Hypothalamus - One of the main functions of the hypothalamus is to keep the body physiologically balanced, also known as homeostasis.

The brain stem Composed of

Mid Brain Pons Medulla Oblongata Contains /functions Reticular activating system-for wakefulness reflex centers for sight & hearing nuclei of cranial nerves Nerve fibers forming bundles & tracts/pathways In the medulla are nuclei that regulate vital body functions such as heart rate, breathing, and gastrointestinal function. When it is damaged the person can no longer survive

Cerebrum (hind or small brain)

separated from pons and medulla by the fourth ventricle divided into 2 cerebellar hemispheres by a fold of dura mater- falx cerebelli Function: -Muscle coordination -Maintenance of balance -Equilibrium and posture Damage to the cerebellum usually results in jerky, uncoordinated movement. Without the cerebellum stabilizing the body, simple movements such as walking or balancing can become laborious and cumbersome

Ventricular system
Interconnected Cavities within the brain Contains the cerebrospinal fluid (CSF) Two LATERAL ventricles lie one in each cerebral hemisphere & connected to the THIRD ventricle that lies in the midline Fourth Ventricle lies between the pons and medulla

Blood supply
Two major arteries a) internal carotid artery b) Vertebrae artery c) Both anastomose to form circle of wills.

Pathophysiology of fragile x syndrome

 Caused by mutation fragile X mental retardation 1 (FMR1) gene number of CGG trinucleotide repeats; (normal : 29-31 ; premutation :55-200; full mutation > 200) Repeat expansion > 200; methylation CGG repeat expansion & FMR1 promoter -> silencing of the FMR1 gene & lack of its product; fragile X mental retardation protein (FMRP)

 Methylation of FMR1 -> constriction of X-chm -> appears fragile under the microscope

Normal function of FMR1 gene

Provide instruction for making a protein, FMRP

Normal function of FMRP

play a role in the development of connections between nerve cells (synapses), where cell-to-cell communication occurs. The synapses can change and adapt over time in response to experience (a characteristic called synaptic plasticity). help regulate synaptic plasticity, which is important for learning and memory. acts as a shuttle within cells by transporting molecules called messenger RNA (mRNA), which serve as the genetic blueprint for making proteins.

 Mutation of the fragile x mental retardation 1 (FMR1) gene onIncrease in number of CGG trinucleotide repeats X chromosome Methylation of FMR1 in chromosome band Xq27

PHYSIOLOGY OF NERVOUS SYSTEM

The three major levels of the CNS in human brain:

1.

Higher brain level eg. Cerebral cortex which store informations, Lower brain level eg. Hypothalamus which controls body temperature, sleep-and-wake pattern

2.

3.

Spinal cord level eg. Pain reflex, reflex against gravity, GI movements

MAJOR PARTS OF THE BRAIN

Cerebral hemisphere
2- hemispheres - connected primarily at the corpus callosum ( a distinct structure formed by axons passing from one side of the brain to the other ) do not necessarily correspond to the anatomical lobes of the brain Have a different functional role Certain functions are well developed (Specialization of function ) in one cerebral hemisphere than other 1. Cerebral lateralization ( cerebral dominance ) 2. CONTRALATERAL function of the cerebrum

CEREBRAL DOMINANCE OR LATERALIZATION

In most people, language &verbal skill: speech, writing & analytical ability are dominant in the Left hemisphere

*Spatial skill are

concentrated on the Right hemisphere e g. recognition of face, place & musical composing , singing.

Functional region of the cerebral cortex

Cerebral Cortex: 4- pairs of lobes are specialized for different activities

Cerebral cortex is specialized into functional areas: Sensory areas : Sensory Perception Motor areas : Movement Association areas : integration of informations

Summary of the function of Cerebral Cortex

Examine the cortex from a functional view-pointCan be divided into 3- specializations 1. Sensory areas : receive sensory inputs & translate it into perception ( awareness ) 2. Motor areas : which direct skeletal movement 3. Association areas : which integrate information from sensory & motor areas - can direct voluntary behaviors

PHYSIOLOGY OF NERVOUS SYSTEM

NERVOUS SYSTEM
THREE MAIN FUNCTIONS: SENSORY INPUT INTEGRATION DATA (only in the brain) MOTOR OUTPUT TWO MAJOR PART: 1. CNS 2. PNS

Structure and function of neurons

Neurons are highly specialized for the processing and transmission of cellular signals

SYNAPSES
A

synapse is a functional connection between neuron and a second cell. In CNS the second cell is neuron, whereas in PNS the second cell is an effector cell may be either neuron or within a muscle or gland.
Neuron-to-neuron

synapse involve connection of axon of one neuron to cell body, dendrite or axon, of the second neuron; known as axosomatic, axodendritic, axoaxonic respectively.
Neuron-to-muscle There

eg. NMJ

are TWO major types of synapses ie. Electrical and Chemical synapses respectively.

1-Electrical synapses Ionic current spreads directly from one cell to the another through gap junction. eg smooth muscle, cardiac muscle.
2-Chemical synapse Presynaptic & postsynaptic neurons are separated by the synaptic cleft (20-50nm space). Impulses cannot jump the cleft, thus the electrical presynaptic signal is converted into chemical signal (neurotransmitter) which in turn generate electrical postsynaptic signal. The process is one-way and requires a synaptic delay of 0.5msec.

SIGN AND SYMPTOM

Developmental delay:
Intellectual disability Speech delay Physical skills and co-ordination difficulties

Behavioural or emotional problems:

not attentive hyperactivite hand flapping and biting gaze aversion repetitive speech mimicry sensory problems such as aversion to touch, loud noises, bright lights and strong smells anxiety and mood instability with aggression and depression

Physical characteristics:
Male: large prominent ears long face large testicles high & broad forehead high arched palate and connective tissue problems-flat feet, loose joints, scoliosis Female: Similar, but less distinctive

Facial Features

Hyperextensible fingers

Diagnosis

DIAGNOSIS Molecular genetic testing of FMR1 gene - CGG trinucleotide seqence repated 6-50 times- normal person - more than 200 times+ hypermethylation- Fragile X Syndrome - between 50 to 200- carrier

 Polymerase Chain Reaction -analyse number of CGG repeat and methylation status using Southern Blot analysis - assessment of risk for premutation carrier & risk have affected children - Can't be use to diagnose FXS

Management

Medical Care
Based on patient basis Routine care involves treating the medical problems that these patients commonly experience, including
gastroesophageal reflux sinusitis, and otitis media

Medical Care
During infant and early childhood healthcare maintenance visits, focus examination on possible
hip dislocations hernias hypotonia

Consultations
Genetic specialist:
Genetic counseling are important to inform patients and families and to assist with family planning and reproducive decisions.

Speech and language therapist Occupational and physical therapist Behavioral intervention/modification team:
Specific areas of focus include social eye contact and stress reduction training.

Special education professional:

Consultation with a special education professional is appropriate to assess the level of cognitive functioning, attention deficit hyperactivity disorder (ADHD) symptoms, and aggressiveness and to initiate sensory integration therapy for behavior problems.

 Psychology or behavioral specialist:

This consultation is important to assist families with methods for decreasing negative behavior. Additionally, some patients with fragile X syndrome benefit from social skillsoriented therapy and individual counseling.

Neurologist
Consult a neurologist if seizures persist.

Cardiologist Otolaryngologist
Patients with chronic sinusitis and chronic otitis media require an evaluation by an otolaryngologist.

Ophthalmologist
An ophthalmologic referral is important for patients with strabismus.

Gastroenterologist

 Diet A special diet is indicated in infants with significant gastroesophageal reflux. In these patients, thickened feeds may decrease the incidence of reflux; otherwise, no special diet is indicated. Activity No limitations of activity are indicated.

 Trials of medications, such as fenobam, that act as mGluR5 antagonists are underway. Excess mGluR5 signaling occurs when FMRP is decreased or absent. Therefore, downregulation of mGluR5 may improve outcomes in patients with fragile X syndrome. Lithium also inhibits mGluR5 signaling (as well as other pathways) and may benefit patients with fragile X syndrome. Other trials with -aminobutyric acid agonists are underway.

COMPLICATION OF FRAGILE X SYNDROME

 Many people with this syndrome participate in an active lifestyle and enjoy good health no single health problem is exclusive to Fragile X individuals with this syndrome are more prone to a number of medical conditions

 Otitis Media
Common to boys This infection can cause intermittent hearing loss

Attention deficit hyperactivity disorder (ADHD)

Attention problems can interfere with all aspects of a childs life

 Autism
a person has delays or abnormalities prior to the age of 3 years in
social interaction in language as used in social communication in behaviour and interests and in symbolic or imaginative play

20-25% incidence of autism in people with Fragile X syndrome.

 Mitral Valve Prolapse (MVP)

manifested by an early systolic murmur caused by a valve that does not close properly. therefore, , blood in the heart does not flow smoothly occurs in approximately 50% of adult males

Seizures
occur approximately in 15-20% of children type of seizure may include absence episodes, partial motor, generalized (grand mal), or partial complex seizures

 Hernia
FXS patient may have weak connective tissue, increased risk of developing hernias This happens when an organ pushes through a weak spot or abnormal opening in tissue

Strabismus (lazy eye)

Risk Factor/Prevention

EpidemiOLOGY

 Most common known cause of inherited intellectual disability Affects both males and females Affects 1 in 5000 males Average age of FXS diagnosis in boys is 35-37 months

Co-Occurring Conditions and Characteristics

Males
Developmental Delay (DD) or Intellectual Disability (ID): 96% Attention Problems: 84% Anxiety: 70% Hyperactivity: 66% Autism: 46% Self-Injury: 41% Aggressiveness: 38% Seizures: 18% Depression: 12%

 Females
Attention Problems: 67% Developmental Delay or Intellectual Disability: 64% Anxiety: 56% Hyperactivity: 30% Depression: 22% Autism: 16% Aggressiveness: 14% Self-Injury: 10% Seizures: 7%

Epidemiology
United States Conservative estimates report that fragile X syndrome affects approximately 1 in 2500-4000 males and 1 in 7000-8000 females. The prevalence of female carrier status has been estimated to be as high as 1 in 130-250 population; the prevalence of male carrier status is estimated to be 1 in 250-800 population. As many as 10% of cases of previously undiagnosed mental retardation in males and 3% of cases of previously undiagnosed mental retardation in females are attributed to fragile X syndrome. International Exact frequency is unknown. However, data collected from England and Australia are comparable to data from the United States.

Risk Factors
Mental retardation or learning problems in boys or girls Boys with autistic-like behaviors Women with unexplained premature ovarian failure (POF), which causes menopause symptoms before the age of 40 Men or women with muscle tremors and balance problems over the age of 50, which can be a sign of fragile X-associated tremor/ataxia syndrome (FXTAS) Relatives with any of these signs

Risk Factor
Genetics
The main risk factor for FXS is having a parent with an FMR1 mutation. Most people who inherit a minor mutation, which is sometimes called a premutation, do not develop the symptoms and signs of FXS. A few premutated children may show signs that resemble autism. Others, primarily males, may develop a set of neurological symptoms called fragile X tremor ataxia syndrome in later adult life.

 Children of mothers with FMR1 premutations are at risk of inheriting a fully mutated FMR1 gene severe enough to cause symptomatic FXS. If a woman does not have symptoms and is a carrier of an FMR1 mutation or premutation, each child of hers has a 50% chance of inheriting that gene. Of the children that inherit that gene, boys are much more likely to develop symptoms than girls. The severity of the disorder may vary between different individuals.

 In general, each generation tends to have worse mutations and a higher risk of FXS than

the previous one.