Transcript Neurological manifestations of FODs and Organic Acidemias

Goals
0 Discuss the major neurological features of FAOs and
OAs
0 Seizures
0 Muscle disease
0 Developmental delay/MR
Fatty Oxidation Disorders (FODs)
0 Genetic disorders in which the body is unable to
oxidize (breakdown) fatty acids to make energy
0 Enzyme deficiency
0 Inherited disorder
Fatty acid oxidation disorders
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Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency
Multiple acyl-CoA dehydrogenase (MAD) deficiency (= Glutaric
aciduria type II, GA II)
Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
Trifunctional protein deficiency
Carnitine palmitoyl-transferase I (CPT I) deficiency
Carnitine palmitoyl-transferase II (CPT II) deficiency
Carnitine acylcarnitine translocase deficiency
Primary (systemic) carnitine deficiency
How does it cause symptoms
0 Energy from fat keeps us going when our
bodies run low of their main source of energy,
sugar (glucose)
0 Our bodies rely on fat when we don’t eat for a
period of time such as an overnight fast
0 When an enzyme is missing or not working
well, the body cannot use fat for energy and
must rely solely on glucose
How does it cause symptoms
0 Glucose is a good source of energy but there is a
limited amount available
0 Once the glucose is gone, the body tries to use fat
without success
0 This leads to low blood sugar, called hypoglycemia,
and to the build up of harmful substances in the blood
Fatty acid oxidation defects
0 Risk: cause recurrent disturbances of brain function
0 The neurological symptoms attributed to
0 Hypoglycemia
0 Hypoketonemia
0 Effects of potentially toxic organic acids
0 Symptoms occur during fasting
Fatty acid oxidation defects
0 Symptoms
0 Drowsiness
0 Stupor and coma occur during acute metabolic crises
0 Seizures
0 Long term neurological effects
0 Muscle tone
0 Cognition/thinking
Organic acidurias:
0 Result From:
0 Deficiencies of mitochondrial enzymes that
metabolize CoA activated carboxylic acids
0 derived from amino acid breakdown.
0 Neurological Symptoms
0 Encephalopathy
0 Changes in level of consciousness
0 Seizures
0 Episodic metabolic acidosis
0 caused by build up of toxic metabolites
0 Disturbance of mitochondrial energy production
Organic acidurias
0 Treatment
0 Dietary restriction of the amino acids that cannot be
broken down
0 Prevention protein catabolism
0 Supplementation with carnitine and or glycine to form
less toxic intermediate conjugates
0 Supplementation with biotin/vitamin to act as a cofactor for mitochondrial carboxylase enzymes
Neurological complications
0 Fatty acid oxidation
disorders
0 Hypotonia
0 Seizures
0 due to hypoglycemia
0 Developmental delay or
mental retardation
0 Muscle disease
0 VLCAD
0 VLCHAD
0 LCHAD
0 Organic acidemias
0 Tone abnormalites
0 Hypotonia
0 Hypertonia
0 Seizures
0 Developmental delay or
mental retardation
0 Movement disorders
Short and Long term Neurological
consequences of FAOs and OAs
0 Hypotonia
0 Low muscle tone
0 Results in delayed gross, fine and speech milestones
0 Usually trunk muscles
0 Improves with therapy
Short and Long term Neurological
consequences of FAOs and OAs
0 Hypertonia
0 High resting muscle tone
0 Muscles are contracted and stiff
0 Prevents movements
0 Using limb muscles
0 Stretching therapies
0 Medications
0 Surgeries
0 Tendon releases and transfers
Short and Long term Neurological
consequences of FAOs and OAs
0 Movement disorders
0 Fixed postures
0 Interfere with purposeful movement
0 Writhing or rapid movements
0 May be induced by purposeful movement
Short and Long term Neurological
consequences of FAOs and OAs
0 Seizures
0 Single event that may be provoked
0 Hypoglycemia
0 Hyperammonemia
0 Repetitive events
0 Focal
0 generalized
Short and Long term Neurological
consequences of FAOs and OAs
0 Developmental delay/mental retardation
0 Variable degrees
0 Disorder affects brain
0 Hypoglycemia
0 Seizures
0 Repeated injury
Short and Long term Neurological
consequences of FAOs
0 Muscle weakness
0 At rest
0 After exercise
Hypotonia
0 Medical term used to describe decreased
muscle tone
0 the amount of resistance to movement in a muscle
0 It is not the same as muscle weakness,
although the two conditions can co-exist
0 Not a specific medical disorder
0 It can be a condition on its own or it can be
associated with another problem where there
is progressive loss of muscle tone
Hypotonia
0 Hypotonia can be caused by a variety of conditions
0 Central nervous system (brain and muscle)
0 Muscle disorders
0 Genetic disorders
0 It is usually first noticed during infancy
0 Floppy infant
0 Poor head control
0 Weak suck and swallow
Hypotonia
Clinical aspects of hypotonia
0 Can involve only the trunk or trunk and extremities
0 Delayed Motor skills (requires strength and
movement against gravity)
0 Hypermobile or hyperflexible joints
0 Drooling and speech difficulties
Clinical manifestations of hypotonia
0 Poor tendon reflexes
0 Decreased strength
0 Decreased activity tolerance
0 Rounded shoulder posture and curved back when
sitting
Infantile hypotonia
0 Floppy, rag doll
0 Difficulty with feeding
0 Mouth muscles cannot maintain a proper suck-swallow
pattern or a good breastfeeding latch
0 Hypotonic infants are late in
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Lifting their heads while lying on their stomachs
Rolling over
Lifting themselves into a sitting position
Sitting without falling over
Balancing
Crawling
Walking independently
Hypotonia and motor delays
0 Delayed developmental milestones
0 degree of delay can vary widely
0 Motor skills are particularly susceptible to the low-
tone disability
Hypotonia and motor delays
0 They can be divided into two areas
0 gross motor skills
0 fine motor skills
0 Fine motor skills delays
0 grasping a toy
0 transferring a small object from hand to hand
0 pointing out objects
0 following movement with the eyes
0 self feeding
Speech delays and hypotonia
0 Speak later than their peers
0 appear to understand a large vocabulary
0 can obey simple commands
0 Difficulties with muscles in the mouth and jaw
0 inhibit proper pronunciation
0 discourage experimentation with word
combination and sentence-forming
0 Feeding difficulties
0 Chewing
0 Textures
0 Mouth play
Hypotonia versus weakness
0 The low muscle tone associated with hypotonia is
often confused with low muscle strength
0 Muscle tone is the ability of the muscle to respond to a
stretch
0 The child with low tone has muscles that are
0 slow to initiate a muscle contraction
0 contract very slowly in response to a stimulus
0 cannot maintain a contraction
0 Muscles remain loose and very stretchy
Workup for hypotonia
0 Computerized tomography (CT) scans
0 Magnetic resonance imaging (MRI) scans
0 Blood tests
0 CPK
0 Electromyography (EMG)
0 Muscle and nerve biopsy
Hypotonia
0 Often evaluated by physical and occupational
therapists through a series of exercises
designed to assess developmental progress, or
observation of physical interactions
0 Hypotonic child has difficulty deciphering his
spatial location
0 develop recognizable coping mechanisms
0 locking the knees while attempting to walk
0 tendency to observe the physical activity of those around
them for a long time before attempting to imitate
Different names for hypotonia
0 Low Muscle Tone
0 Benign Congenital Hypotonia
0 Congenital Hypotonia
0 Congenital Muscle Hypotonia
0 Congenital Muscle Weakness
0 Amyotonia Congenita
0 Floppy Baby Syndrome
0 Infantile Hypotonia
Management and treatment
0 No known treatment or cure for most (or perhaps all)
causes of hypotonia
0 The outcome depends on the underlying disease
0 In some cases, muscle tone improves over time
0 Patient may learn or devise coping mechanisms that
enable him to overcome the most disabling aspects of
the disorder
Management of hypotonia
0 If the underlying cause is known, treatment is tailored
to the specific disease, followed by symptomatic and
supportive therapy for the hypotonia
0 In very severe cases, treatment may be primarily
supportive
Management of hypotonia
0 Physical therapy can improve fine motor control and
overall body strength
0 Occupational therapy to assist with fine motor skill
development and hand control, and speech-language
therapy can help breathing, speech, and swallowing
difficulties
0 Therapy for infants and young children may also
include sensory stimulation programs
0 Ankle/foot orthoses are sometimes used for weak
ankle muscles
0 Toddlers and children with speech difficulties may
benefit greatly by using sign language or picture
exchange
Hypotonia
0 Diagnostic tests
0 CT or MRI scan of the brain
0 EMG to evaluate nerve and muscle function
0 EEG to measure electrical activity in the brain may also
be necessary
Treatment
0 Once a diagnosis has been made
0 underlying condition is treated first
0 followed by symptomatic and supportive therapy for the
hypotonia
Hypertonia
0 Abnormal increase in the tightness of muscle tone
0 Reduced ability of a muscle to stretch
0 increased stiffness
0 Accompanied by spasticity
Causes of hypertonia
0 Damage to upper motor neurons
0 Causes hypertonia
0 Spasticity (overactive reflexes)
0 Rigidity (constant muscle contractions)
Hypertonia
0 Other names for hypertonia
0 Cerebral palsy
0 Hemiparesis
0 Quadriparesis
0 Hemiplegia
0 Diplegia
Damage of motor tracts in
hypertonia
Hypertonia
• Diagnostic tests
– CT or MRI scan of the brain
– EEG to measure electrical activity in the brain
may also be necessary
Diagnosis of hypertonia
Management of hypertonia
• Physical therapy can encourage stretching and prevent
contractures
• Occupational therapy to assist with fine motor skill
development and hand control, and speech-language
therapy can help breathing, speech, and swallowing
difficulties
• Ankle/foot orthoses are used to prevent contractures at
the heel cords
• Toddlers and children with speech difficulties may benefit
greatly by using sign language or picture exchange
Spells, seizures, and epilepsy
0 The medical syndrome of recurrent, unprovoked
seizures is termed epilepsy
0 A single seizure is not yet epilepsy
0 A “spell” may be a seizure or may be something else
0 Movement disorder
0 GERD
0 Sleep disorder
Things that go bump in the night:
Spells, seizures, and epilepsies
0 A seizure
0 Temporary abnormal electrophysiologic phenomenon of
the brain
0 Results in abnormal synchronization of electrical neuronal
activity
0 Can manifest as
0 Alteration in mental state/awareness
0 Tonic or clonic movements
0 Convulsions
0 Various other psychic symptoms (such as déjà vu or jamais
vu
Seizures
0 Cause involuntary changes in
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body movement
Function
Sensation
Awareness
behavior
0 Can last from
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0 status epilepticus, a continuous seizure that will not
stop without intervention
0 Seizure is often associated with a sudden and
involuntary contraction of a group of muscles
Seizures
0 A seizure can also be as subtle as
0 Marching numbness of a part of the body
0 A brief loss of memory
0 Sparkling or flashes
0 Sensing an unpleasant odor
0 A strange sensation in the stomach
0 Sensation of fear
Seizures
0 Seizures are typically classified as
0 Motor
0 Sensory
0 Autonomic
0 Emotional/cognitive
Seizures
0 Symptoms depend on where in the brain the
disturbance in electrical activity occurs
0 In children, seizures often happen in sleep or the
transition from sleep to wake
0 A person having a tonic-clonic seizure may cry out,
lose consciousness and fall to the ground, and
convulse, often violently
Seizures
0 Complex partial seizure
0 Person may appear confused or dazed
0 not be able to respond to questions or direction
0 Sometimes, the only clue that a person is having an
absence seizure
0 Rapid blinking
0 Mouthing movements
0 Few seconds of staring into space
Hypoglycemia and seizures
0 Hypoglycemia
0 Lower than normal level of glucose (sugar) in the blood
0 Why is this important?
0 Brain metabolism depends primarily on glucose for fuel
in most circumstances
0 A limited amount of glucose can be made from glycogen
stored in astrocytes, but it is used up within minutes
0 Brain is dependent on a continual supply of glucose
diffusing from the blood into central nervous system
and into the neurons themselves
Hypoglycemia
0 Caused by a continuing demand for glucose by
brain and other organs
0 Results from the primary biochemical defect of fatty-
acid oxidation since fats cannot be broken down
efficiently
0 Treatment
0 Avoidance of catabolism (more break down)
0 Requires the use of fatty acids except in FAOs
0 L-Carnitine supplementation
0 Some patients may benefit from medium-chain triglyceride
supplementation as a source of fat
Hypoglycemia and seizures
0 If the amount of glucose supplied by the blood falls,
the brain is one of the first organs affected
0 In most people, reduction of mental abilities occur
when the glucose falls below 65 mg/dl (3.6 mM)
Hypoglycemia and seizures
0 Impairment of action and judgement usually becomes
obvious below 40 mg/dl (2.2 mM)
0 Seizures may occur as the glucose falls further
0 As blood glucose levels fall below 10 mg/dl (0.55 mM),
most neurons become electrically silent and
nonfunctional, resulting in coma
Hypoglycemia and seizures
0 Brief or mild hypoglycemia produces no lasting effects
on the brain
0 Can temporarily alter brain responses to additional
hypoglycemia
0 Prolonged, severe hypoglycemia can produce lasting
damage of a wide range
0 Impairment of cognitive function, motor control, or even
consciousness
Hypoglycemia and seizures
0 The likelihood of permanent brain damage from any
given instance of severe hypoglycemia is difficult to
estimate
0 Depends on a many factors
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Age
Underlying disorder
Recent blood and brain glucose concurrent
Problems such as hypoxia
Availability of alternative fuels
Hypoglycemia, symptoms
0 Abnormal thinking,
impaired judgement
0 anxiety, moodiness,
depression, crying
0 irritability,
combativeness
0 Personality change,
emotional lability
0 Fatigue, weakness,
apathy, lethargy,
daydreaming, sleep
0 Confusion, amnesia,
dizziness, delirium
0 Staring, "glassy" look,
blurred vision, double
vision
Hypoglycemia, symptoms
0 Automatic behavior, also known as automatism
0 Difficulty speaking, slurred speech
0 Ataxia, incoordination, sometimes mistaken for
"drunkenness"
0 Focal or general motor deficit, paralysis,
hemiparesis
0 Paresthesia, headache
0 Stupor, coma, abnormal breathing
0 Generalized or focal seizures
Management of hypoglycemic
seizures
0 Failure to administer glucose would be harmful to the
patient
0 Recurrent seizures
0 Anti-epilepsy drugs
0 Give single drug at lowest concentration if possible
0 Careful with certain conditions
0 Drug treatment geared towards whether focal,
generalized, etc.
0 Trileptal, Keppra, Zonergran, Lamictal, Depakote, Klonopin,
Dilantin, Tegretol
Movement disorders-Organic
acidemias
0 Dystonia
0 Abnormal fixed posture of an extremity (arms or legs,
neck)
0 sustained muscle contraction
0 resulting in abnormal posture
0 Chorea
0 Fast, dance like movements of the distal extremities
(fingers and toes)
0 Athetosis
0 Slow, writhing movements of the extremities
Movement disorders-Organic
acidemias
0 Patient may have combination of movement disorders
at baseline or with special circumstances
0 Stress
0 Illness
0 Attempt at purposeful movement
FAOs and Muscle disease
0 SCAD
0 VLCAD
0 LCHAD
0 Symptoms
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Weakness
Pain/cramps
Exercise intolerance
Red urine
Muscle breakdown
rhabdomyolysis
Rhabdomyolysis
0 Elevations of CPK
FAOs with muscle disease
0 SCAD
0 Hypotonia
0 metabolic acidosis
0 NBS:
0 elevated C4
0 UOA have elevated ethylmalonic acid
0 Common mild variants of ? Significance
FAOs with muscle disease
0 LCHAD
0 Cardiomyopathy
0 hypotonia,
0 rhabdomyolysis
0 moms have HELLP syndrome
0 NBS
0 Acylcarnitine profile with elevated C14-OH,C16-OH ,C18-
OH and C18:1-OH
FAOs with muscle disease
0 VLCAD
0 Cardiomyopathy
0 hepatomegaly,
0 SIDS
0 Rhabdomyolysis
0 Acylcarnitine profile:
0 Elevations of C14:1and C14:1/ C12:1
General management guidelinesmedical
0 Fatty acid oxidation
0 Provide brain fuel
0 Organic acidurias
0 Provide brain fuel
0 Glucose
0 Calories
0 Calories
0 Glucose and
0 Sick day management
nonprotein/fat
0 Sick day management
General management guidelinesmedical
0 Malignant hyperthermia
0 Risk with anesthesia for surgery
0 G tube
0 Orthopedic surgery to correct hypertonia
0 Dental work
0 Etc.
Management of metabolic disorders
0 Mechanical assistance with basic life functions
0 breathing and feeding
0 physical therapy to prevent muscle atrophy and
maintain joint mobility
0 Treatments to improve neurological status
0 medication for a seizure disorder
0 medicines or supplements to stabilize a metabolic
disorder
0 surgery to help relieve the pressure from hydrocephalus
(increased fluid in the brain).
General management guidelinestherapies
0 Physical therapy
0 Large muscles, gross motor skills
0 Occupational therapy
0 Fine motor skills
0 Speech therapy
0 Speech articulation, communication
0 Feeding therapy
0 May be done by either speech or occupational therapist
Metabolic crisis
0 extreme sleepiness
0 behavior changes
0 irritable mood
0 poor appetite
0 Other symptoms then follow:
0 fever
0 nausea
0 diarrhea
0 vomiting
0 hypoglycemia
Consequences of metabolic crises
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If a metabolic crisis is not treated, a child with CTD can develop:
• breathing problems
• swelling of the brain
• seizures
• coma, sometimes leading to death
Babies who are not treated may have other effects:
• enlarged heart
• enlarged liver
• muscle weakness
• anemia
Repeated episodes of metabolic crisis can cause brain damage. This can result in
learning problems or mental retardation.
Symptoms of a metabolic crisis often happen after having nothing to eat for more
than a few hours. Symptoms are also more likely when a child with CTD gets sick
or has an infection.