Deciphering the neurology of Deciphering the neurology of rare inborn errors of

rare inborn errors of metabolismmetabolismwith a focus on organic with a focus on organic acidemias and fatty acid

acidemias and fatty acid oxidation disordersoxidation disorders

Andrea Gropman, M.D., FAAP, FACMGProfessor, George Washington University of the Health SciencesAttending, Children’s National Medical Center

Goals

0Discuss the major neurological features of FAOs and OAs0 Seizures0 Muscle disease0 Developmental delay/MR

Fatty Oxidation Disorders (FODs)

0Genetic disorders in which the body is unable to oxidize (breakdown) fatty acids to make energy 0 Enzyme deficiency0 Inherited disorder

Fatty acid oxidation disorders0 Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency 0 Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency 0 Short-chain acyl-CoA dehydrogenase (SCAD) deficiency 0 Multiple acyl-CoA dehydrogenase (MAD) deficiency (= Glutaric

aciduria type II, GA II) 0 Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency 0 Trifunctional protein deficiency 0 Carnitine palmitoyl-transferase I (CPT I) deficiency 0 Carnitine palmitoyl-transferase II (CPT II) deficiency 0 Carnitine acylcarnitine translocase deficiency 0 Primary (systemic) carnitine deficiency

How does it cause symptoms

0Energy from fat keeps us going when our bodies run low of their main source of energy, sugar (glucose)

0Our bodies rely on fat when we don’t eat for a period of time such as an overnight fast

0When 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

0Glucose is a good source of energy but there is a limited amount available

0Once the glucose is gone, the body tries to use fat without success

0This leads to low blood sugar, called hypoglycemia, and to the build up of harmful substances in the blood

Fatty acid oxidation defects

0Risk: cause recurrent disturbances of brain function 0 The neurological symptoms attributed to

0Hypoglycemia0Hypoketonemia 0Effects of potentially toxic organic acids

0 Symptoms occur during fasting

Fatty acid oxidation defects

0Symptoms0 Drowsiness0 Stupor and coma occur during acute metabolic crises0 Seizures0 Long term neurological effects

0Muscle tone0Cognition/thinking

Organic acidurias:

0Result From: 0Deficiencies of mitochondrial enzymes that

metabolize CoA activated carboxylic acids0derived from amino acid breakdown.

0Neurological Symptoms0Encephalopathy

0Changes in level of consciousness0Seizures

0Episodic metabolic acidosis 0caused by build up of toxic metabolites 0Disturbance of mitochondrial energy production

Organic acidurias

0Treatment0 Dietary restriction of the amino acids that cannot be

broken down0 Prevention protein catabolism0 Supplementation with carnitine and or glycine to form

less toxic intermediate conjugates0 Supplementation with biotin/vitamin to act as a co-

factor for mitochondrial carboxylase enzymes

Neurological complications

0Fatty acid oxidation disorders0 Hypotonia0 Seizures

0due to hypoglycemia0 Developmental delay or

mental retardation0 Muscle disease

0VLCAD0VLCHAD0LCHAD

0Organic acidemias0 Tone abnormalites

0Hypotonia0Hypertonia

0 Seizures0 Developmental delay or

mental retardation0 Movement disorders

Short and Long term Neurological consequences of FAOs and OAs

0Hypotonia0 Low muscle tone0 Results in delayed gross, fine and speech milestones0 Usually trunk muscles0 Improves with therapy

Short and Long term Neurological consequences of FAOs and OAs

0Hypertonia0 High resting muscle tone0 Muscles are contracted and stiff0 Prevents movements0 Using limb muscles0 Stretching therapies0 Medications0 Surgeries

0Tendon releases and transfers

Short and Long term Neurological consequences of FAOs and OAs

0Movement disorders0 Fixed postures0 Interfere with purposeful movement0 Writhing or rapid movements0 May be induced by purposeful movement

Short and Long term Neurological consequences of FAOs and OAs

0Seizures0 Single event that may be provoked

0Hypoglycemia0Hyperammonemia

0 Repetitive events0Focal0generalized

Short and Long term Neurological consequences of FAOs and OAs

0Developmental delay/mental retardation0 Variable degrees0 Disorder affects brain

0Hypoglycemia0Seizures0Repeated injury

Short and Long term Neurological consequences of FAOs

0Muscle weakness0 At rest0 After exercise

Hypotonia

0Medical term used to describe decreased muscle tone0 the amount of resistance to movement in a muscle

0It is not the same as muscle weakness, although the two conditions can co-exist 

0Not a specific medical disorder0It can be a condition on its own or it can be

associated with another problem where there is progressive loss of muscle tone

Hypotonia

0Hypotonia can be caused by a variety of conditions 0 Central nervous system (brain and muscle)0 Muscle disorders0 Genetic disorders

0 It is usually first noticed during infancy0 Floppy infant0 Poor head control0 Weak suck and swallow

Hypotonia

Clinical aspects of hypotonia

0Can involve only the trunk or trunk and extremities 0Delayed Motor skills (requires strength and

movement against gravity)0Hypermobile or hyperflexible joints0Drooling and speech difficulties

Clinical manifestations of hypotonia

0Poor tendon reflexes0Decreased strength0Decreased activity tolerance0Rounded shoulder posture and curved back when

sitting

Infantile hypotonia0Floppy, rag doll0Difficulty with feeding

0 Mouth muscles cannot maintain a proper suck-swallow pattern or a good breastfeeding latch

0Hypotonic infants are late in 0 Lifting their heads while lying on their stomachs0 Rolling over0 Lifting themselves into a sitting position0 Sitting without falling over0 Balancing0 Crawling0 Walking independently

Hypotonia and motor delays

0Delayed developmental milestones0 degree of delay can vary widely

0Motor skills are particularly susceptible to the low-tone disability

Hypotonia and motor delays

0They can be divided into two areas0 gross motor skills0 fine motor skills0 Fine motor skills delays

0grasping a toy 0 transferring a small object from hand to hand0pointing out objects0 following movement with the eyes0self feeding

Speech delays and hypotonia

0Speak later than their peers0appear to understand a large vocabulary0 can obey simple commands

0Difficulties with muscles in the mouth and jaw 0 inhibit proper pronunciation0discourage experimentation with word

combination and sentence-forming0Feeding difficulties0Chewing0Textures0Mouth play

Hypotonia versus weakness

0The low muscle tone associated with hypotonia is often confused with low muscle strength0 Muscle tone is the ability of the muscle to respond to a

stretch 0 The child with low tone has muscles that are

0slow to initiate a muscle contraction0contract very slowly in response to a stimulus0cannot maintain a contraction

0 Muscles remain loose and very stretchy

Workup for hypotonia

0Computerized tomography (CT) scans0Magnetic resonance imaging (MRI) scans0Blood tests

0 CPK

0Electromyography (EMG) 0Muscle and nerve biopsy

Hypotonia

0Often evaluated by physical and occupational therapists through a series of exercises designed to assess developmental progress, or observation of physical interactions

0Hypotonic child has difficulty deciphering his spatial location0develop recognizable coping mechanisms

0 locking the knees while attempting to walk0 tendency to observe the physical activity of those around

them for a long time before attempting to imitate

Different names for hypotonia

0Low Muscle Tone 0Benign Congenital Hypotonia 0Congenital Hypotonia 0Congenital Muscle Hypotonia 0Congenital Muscle Weakness 0Amyotonia Congenita 0Floppy Baby Syndrome 0 Infantile Hypotonia

Management and treatment

0No known treatment or cure for most (or perhaps all) causes of hypotonia

0The outcome depends on the underlying disease0 In some cases, muscle tone improves over time0Patient 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 hypotonia0Physical therapy can improve fine motor control and

overall body strength0Occupational therapy to assist with fine motor skill

development and hand control, and speech-language therapy can help breathing, speech, and swallowing difficulties

0Therapy for infants and young children may also include sensory stimulation programs

0Ankle/foot orthoses are sometimes used for weak ankle muscles

0Toddlers and children with speech difficulties may benefit greatly by using sign language or picture exchange

Hypotonia

0Diagnostic tests 0 CT or MRI scan of the brain0 EMG to evaluate nerve and muscle function0 EEG to measure electrical activity in the brain may also

be necessary

Treatment

0Once a diagnosis has been made0 underlying condition is treated first0 followed by symptomatic and supportive therapy for the

hypotonia

Hypertonia

0Abnormal increase in the tightness of muscle tone 0Reduced ability of a muscle to stretch

0 increased stiffness

0Accompanied by spasticity

Causes of hypertonia

0Damage to upper motor neurons 0 Causes hypertonia0 Spasticity (overactive reflexes)0 Rigidity (constant muscle contractions)

Hypertonia

0Other names for hypertonia0 Cerebral palsy0 Hemiparesis0 Quadriparesis0 Hemiplegia0 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

0The medical syndrome of recurrent, unprovoked seizures is termed epilepsy

0A single seizure is not yet epilepsy0A “spell” may be a seizure or may be something else

0 Movement disorder0 GERD0 Sleep disorder

Things that go bump in the night: Spells, seizures, and epilepsies

0A seizure 0 Temporary abnormal electrophysiologic phenomenon

of the brain0Results in abnormal synchronization of electrical neuronal

activity0 Can manifest as

0Alteration in mental state/awareness0Tonic or clonic movements0Convulsions0Various other psychic symptoms (such as déjà vu or jamais

vu

Seizures0Cause involuntary changes in

0 body movement0 Function0 Sensation0 Awareness0 behavior

0Can last from0 few seconds 0 status epilepticus, a continuous seizure that will not

stop without intervention0Seizure is often associated with a sudden and

involuntary contraction of a group of muscles

Seizures

0A seizure can also be as subtle as 0 Marching numbness of a part of the body0 A brief loss of memory0 Sparkling or flashes0 Sensing an unpleasant odor0 A strange sensation in the stomach 0 Sensation of fear

Seizures

0Seizures are typically classified as 0 Motor0 Sensory0 Autonomic0 Emotional/cognitive

Seizures

0Symptoms 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

0A person having a tonic-clonic seizure may cry out, lose consciousness and fall to the ground, and convulse, often violently

Seizures

0Complex partial seizure 0 Person may appear confused or dazed 0 not be able to respond to questions or direction

0Sometimes, the only clue that a person is having an absence seizure0 Rapid blinking0 Mouthing movements 0 Few seconds of staring into space

Hypoglycemia and seizures

0Hypoglycemia0 Lower than normal level of glucose (sugar) in the blood

0Why is this important?0 Brain metabolism depends primarily on glucose for fuel

in most circumstances0 A limited amount of glucose can be made from glycogen

stored in astrocytes, but it is used up within minutes0 Brain is dependent on a continual supply of glucose

diffusing from the blood into central nervous system and into the neurons themselves

Hypoglycemia

0Caused by a continuing demand for glucose by brain and other organs0 Results from the primary biochemical defect of fatty-

acid oxidation since fats cannot be broken down efficiently

0Treatment0 Avoidance of catabolism (more break down)

0Requires the use of fatty acids except in FAOs0L-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)

0Seizures may occur as the glucose falls further0 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

0Brief or mild hypoglycemia produces no lasting effects on the brain0 Can temporarily alter brain responses to additional

hypoglycemia

0Prolonged, severe hypoglycemia can produce lasting damage of a wide range0 Impairment of cognitive function, motor control, or even

consciousness

Hypoglycemia and seizures

0The likelihood of permanent brain damage from any given instance of severe hypoglycemia is difficult to estimate

0Depends on a many factors 0 Age0 Underlying disorder0 Recent blood and brain glucose concurrent0 Problems such as hypoxia0 Availability of alternative fuels

Hypoglycemia, symptoms

0Abnormal thinking, impaired judgement

0anxiety, moodiness, depression, crying

0 irritability, combativeness

0Personality change, emotional lability

0Fatigue, weakness, apathy, lethargy, daydreaming, sleep

0Confusion, amnesia, dizziness, delirium

0Staring, "glassy" look, blurred vision, double vision

Hypoglycemia, symptoms

0Automatic behavior, also known as automatism 0Difficulty speaking, slurred speech 0Ataxia, incoordination, sometimes mistaken for

"drunkenness" 0Focal or general motor deficit, paralysis,

hemiparesis 0Paresthesia, headache 0Stupor, coma, abnormal breathing 0Generalized or focal seizures

Management of hypoglycemic seizures

0Failure to administer glucose would be harmful to the patient

0Recurrent seizures0 Anti-epilepsy drugs

0Give single drug at lowest concentration if possible0Careful with certain conditions

0 Drug treatment geared towards whether focal, generalized, etc.0Trileptal, Keppra, Zonergran, Lamictal, Depakote, Klonopin,

Dilantin, Tegretol

Movement disorders-Organic acidemias

0Dystonia0 Abnormal fixed posture of an extremity (arms or legs,

neck)0 sustained muscle contraction0 resulting in abnormal posture

0Chorea0 Fast, dance like movements of the distal extremities

(fingers and toes)

0Athetosis0 Slow, writhing movements of the extremities

Movement disorders-Organic acidemias

0Patient may have combination of movement disorders at baseline or with special circumstances0 Stress0 Illness0 Attempt at purposeful movement

FAOs and Muscle disease0SCAD0VLCAD0LCHAD

0Symptoms0 Weakness0 Pain/cramps0 Exercise intolerance0 Red urine0 Muscle breakdown0 rhabdomyolysis

Rhabdomyolysis

0Elevations of CPK

FAOs with muscle disease0SCAD

0 Hypotonia 0 metabolic acidosis0 NBS:

0elevated C4 0UOA have elevated ethylmalonic acid

0 Common mild variants of ? Significance

FAOs with muscle disease

0LCHAD0 Cardiomyopathy0 hypotonia,0 rhabdomyolysis 0 moms have HELLP syndrome0 NBS

0Acylcarnitine profile with elevated C14-OH,C16-OH ,C18-OH and C18:1-OH

FAOs with muscle disease

0VLCAD0 Cardiomyopathy0 hepatomegaly,0 SIDS 0 Rhabdomyolysis0 Acylcarnitine profile:

0Elevations of C14:1and C14:1/ C12:1

General management guidelines-medical

0Fatty acid oxidation0 Provide brain fuel

0Glucose0Calories0Sick day management

0Organic acidurias0 Provide brain fuel

0Calories0Glucose and

nonprotein/fat0Sick day management

General management guidelines-medical

0Malignant hyperthermia0 Risk with anesthesia for surgery

0G tube0Orthopedic surgery to correct hypertonia0Dental work0Etc.

Management of metabolic disorders

0Mechanical assistance with basic life functions 0 breathing and feeding0 physical therapy to prevent muscle atrophy and

maintain joint mobility

0Treatments to improve neurological status 0 medication for a seizure disorder0 medicines or supplements to stabilize a metabolic

disorder0 surgery to help relieve the pressure from hydrocephalus

(increased fluid in the brain).

General management guidelines-therapies

0Physical therapy0 Large muscles, gross motor skills

0Occupational therapy0 Fine motor skills

0Speech therapy0 Speech articulation, communication

0Feeding therapy0 May be done by either speech or occupational therapist

Metabolic crisis0extreme sleepiness0behavior changes0 irritable mood0poor appetite0Other symptoms then follow:0fever0nausea0diarrhea0vomiting0hypoglycemia

Consequences of metabolic crises

0 If a metabolic crisis is not treated, a child with CTD can develop:0 • breathing problems0 • swelling of the brain0 • seizures0 • coma, sometimes leading to death0 Babies who are not treated may have other effects:0 • enlarged heart0 • enlarged liver0 • muscle weakness0 • anemia0 Repeated episodes of metabolic crisis can cause brain damage. This can result in0 learning problems or mental retardation.0 Symptoms of a metabolic crisis often happen after having nothing to eat for more0 than a few hours. Symptoms are also more likely when a child with CTD gets sick0 or has an infection.

Thank you for Thank you for your attentionyour attention

Questions? ? ?