Block 5 Case 3

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ADHD: 3 primary symptoms: inattention, hyperactivity, impulsivity
ADHD: epidemiology: 4:1 boys:girls
3-7% of children
4% of adults
ADHD: diagnosis: Six or more symptoms of inattention.
Six or more symptoms of hyperactivity and impulsivity.

Must be present before age 7 and in two or more settings!
ADHD: 3 classifications: ADHD-C (80%): all 3 symptoms.

ADHD-I (15%): inattention

ADHD-HI (5%): hyperactive and impulsive
ADHD: 3 primary symptoms... onset and adult prognosis.: Hyperactivity: usually by 4yo and increases over 4 years. Usually disappears during adulthood.

Impulsivity: usually by 4yo and increases over 4 years. Persists during adulthood.

Inattention: usually by 9yo. Persists during adulthood.
ADHD: pharmacologic treatment: Pharmacologic is best: stimulants such as methylphenidate or dextroamphetamine.

Atomoxetine is an alternative.
ADHD: non-pharmacologic treatment: Behavior therapy, reduction of sugar intake, and combinations with drugs appear ineffective compared to drugs alone.
MR: 3 diagnostic criteria: Significantly below average IQ.

Major limitations in adaptive functioning in at least two skill areas.

Must begin before 18 yo.
MR: adaptive functioning skill areas: communication
self care
home living
social skills
use of community resources
self direction
academic skills
work
leisure
health
safety
MR: degrees of MR: Mild (85%): 50-70 IQ
Moderate (10%): 40-50 IQ
Severe (4%): 25-40 IQ
Profound (1%): below 25 IQ
MR: 3 most common causes: fetal alcohol syndrome
fragile X syndrome
Down's syndrome
PDD: stands for...: Pervasive developmental disorders.

Usually associated with some level of MR.
PDD: general symptoms: Impairment in certain developent:

Social interaction skills.
Communication skills.
Existance of stereotyped behavior, interests, activities.
PDD: includes what diseases ...: Autism
Rett's disorder
Childhood disintegrative disorder
Asperger's Disorder
PDD not otherwise specified
Rett's Disorder: brief summary: Initially normal development, but 5mo-4yo head growth slows.

Deterioration of hand skills, social skills. Ataxia, apraxia common. MR common.

1:10,000 females. FEMALE ONLY.
Childhood disintegrative disorder: brief summary: Marked deterioration after at least 2 years of normal development.

Losses in: language, social skills, bladder/bowel control, play, motor skills.

Can be confused with autism.
Asperger's disorder: brief summary: Severe and constant impairment of social interaction.

Unlike autism, no poor language development.

Appears after 3yo, 5:1 male:female.
PDD otherwise not specified: brief summary: Severe impairment in development of social communication AND

Stereotypical behavior, activities, interests AND

Critera are not met for other PDDs.
Differentiating Rett's from Autism...: Rett's has slowing of head growth, loss of previously mastered skills, poor coordination.
Differentiating Childhood disintegrative disorder from Autism...: Severe REGRESSION seen after 2 normal years, in autism abnormalities are seen at 1yo.
Differentiating Asperger's from Autism...: No delay in language skills in Asperger's.
Inborn errors of metabolism: neonatal symptoms: Lethargy, decreased feeding, tachypnea, seizures, abnormal muscle tone or posture
Inborn errors of metabolism: infant/child symptoms: MR or delay, attention deficits, organomegaly, neuro findings, skeletal abnormalities
Inborn errors of metabolism: general labs to order: CBC w/diff
Serum chems: glucose, ammonia, amino acids, lactate.
ABGs
Urinalysis: ketones, amino acids, organic acids
Inborn errors of metabolism: inheritance: Almost all autosomal recessive. Some are X linked.
Inborn errors of metabolism: carbohydrate metabolism related: Glycogen storage disease type I
Galactosemia
Inborn errors of metabolism: amino acid related: Phenylketonuria
Maple syrup urine disease
Inborn errors of metabolism: Organic acid related: Methylmalonicaciduria
Propionic aciduria
Inborn errors of metabolism: fatty acid related: Medium chain acyl-CoA dehydrogenase deficency
Inborn errors of metabolism: lysosomal storage diseases: Gaucher's disease
Hurler's syndrome
Inborn errors of metabolism: peroxisome defects: Zellweger syndrome
Glycogen storage disease I: incidence, pathophys, features, diagnosis, treatment: 1:100,000
Mutation in glucose-6-phosphatase
Hypoglycemia, metabolic acidosis
Liver biopsy or enzyme assay
Corn starch and continous overnight feeding
Galactosemia: incidence, pathophys, features, diagnosis, treatment: 1:40,000
Mutation in galactose-1-phosphate uridyltransferase or galactokinase epimerase
MR, growth failure, liver dysfunction, cataracts
Enzyme assays, galactose assay
Lactose free diet
Phenylketonuria: incidence, pathophys, features, diagnosis, treatment: 1:15,000
mutation in phenylalanine hydroxylase
MR, acquired microcephaly
serum phenylalanine concentration
diet low in phenylalanine
Maple syrup urine disease: incidence, pathophys, features, diagnosis, treatment: 1:150,000 higher in Mennonites
Mutation in alpha-ketoacid dehydrogenase
MR, encepholopathy, metabolic acidosis.
Serum amino acid and organic acid concentrations.
Dietary restriction of branched chain AAs.
Methylmalonicaciduria: incidence, pathophys, features, diagnosis, treatment: 1:20,000
mutation in methylmalonyl-CoA mutase
encephalopathy, metabolic acidosis, hyperammonemia
urine organic acid concetrations, enzyme assay
sodium bicarb, carnitine, B12, low protein diet
Propionic aciduria: incidence, pathophys, features, diagnosis, treatment: 1:50,000
mutation in propionyl-CoA carboxylase
hypoglycemia, encephalopathy, coma, sudden death
urine organic acid concentrations
regular feeding to avoid hypoglycemia and fasting
Gaucher's disease: incidence, pathophys, features, diagnosis, treatment: 1:60,000
mutation in b-glucocerebrosidase
coarse facial features, hepatosplenomegaly
Leukocyte b-glucocerebrosidase
bone marrow transplant or enzyme therapy
Zellweger syndrome: incidence, pathophys, features, diagnosis, treatment: 1:50,000
mutation in peroxisome membrane proteins
hypotonia, seizures, liver dysfunction
plasma fatty acid concentrations
no treatment available.
Tuberous sclerosis: hamartoma: Focal malformation resembling a neoplasm grossly and microscopically resulting from faulty development. Unlikely to compress or invade adjacent structures and grows at normal rate.

Can form in skin, brain, eye, kidney, heart and more.
Tuberous sclerosis: inheritance and epidemiology: autosomal dominant, but 50-70% are new mutations.

1:~15:000
Tuberous sclerosis: genetic loci: 9q34 "TSC1" -- similar to GTPase activator

16p13 "TSC2" -- hamartin, unknown fcn

Both mutations phenotypically the same.
Tuberous sclerosis: clinical manifestations: Benign tumors in various tissue.

Seizures, MR, behavioral problems, skin abnormalities.
Tuberous sclerosis: heart manifestations: rhabdomyomas, can cause HF or arrhythmias in newborns.

Seen in 47-67% of cases.
Tuberous sclerosis: CNS manifestations: Cortical tubers: may cause seizures

Subependymal nodules: near walls of ventricles, can be calicified

Subependymal giant cell astrocytomas (SEGA): 15% of patients, can block CSF and cause noncommunicating hydrocephalus.
Tuberous sclerosis: skin: adenoma sebaceum: shows up at 5-10 yo and consists of reddened nodules on face and sometimes forehead and neck.
Tuberous sclerosis: behavioral symptoms: aggression, rage, hyperactivity, attention deficit, acting out.
Tuberous sclerosis: misc symptoms: pitting in baby and adult teeth seen in 90% of patients.
Tuberous sclerosis: diagnostic criteria: Definate: 2 major OR
1 major 2 minor

Probable: 1 major and 1 minor

Possible: 1 major OR
2+ minors
Tuberous sclerosis: major diagnostic criteria: Facial angiofibromas
Ungual or periungual fibroma
Hypomelanotic macules
Shagreen patch
Retinal nodular harmartomas
Cortical tuber
Subependymal nodule
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma
Lymphangiomyomatosis
Renal angiomyolipoma
Tuberous sclerosis: minor diagnostic criteria: Dental pits
Hamartomatous rectal polyps
Bone cysts
Cerebral white matter migration lines
Gingival fibromas
Non-renal hamartoma
Retinal achromic patch
"confetti" skin lesions
Multiple renal cysts
Tuberous sclerosis: treatment: Focuses on symptoms.

Antiepileptic drugs and other behavioral drugs.

Surgery if lesions effect organs or are cosmetically bad.
Tuberous sclerosis: Prognosis: Prognosis variable depending on symptoms. Those with mild symptoms live long productive lives. Severe symptoms indicate a high probability (75%) of death before 25.
Autism: definition: PDD of early childhood.

Impairment in social skills, language development, and reptitive or stereotyped activities and interests especially inanimate objects.
Autism: epidemiology: 7:10,000

Onset by definition BEFORE age 3, but usually obvious earlier.

3:1 male:female

Genetic component
Autism: social signs: Lack of non-verbal behavior (posture, facial expression)

No peer relationships.

Lack of sharing, reciprocity.
Autism: communication signs: Delay of spoken langauge w/o other modes.

Unable to understand humor, irony.

Stereotypical repetition.
Autism: stereotyped behavior: Motor mannerisms (clapping, rocking, swaying)

Mimicing tv actors, lining things up over and over.

Self-injurous (head banging, wrist biting)

Distress over changes.
Autism: comorbid conditions: fragile X, tuberous sclerosis, congenital rubella syndrome, untreated PKU
Autism: genetics: Unknown but siblings with autism increase risk factors, monozygotic twins increase risk factors.
Autism: diagnosis: Testing: Childhood Autism Rating Scale (CARS) or other test

EEG since epilepsy common.

Serotonin levels elevated in 1/3.

Also test urine, blood for metabolic, do chromosome analysis, and get hearing testing.
Autism: general diagnostic criteria: 6 or more problems in:

Social interaction (at least 2)
Communication (at least 1)
Stereotypical Behavior (at least 1)

Cannot be better accounted for by Rett's or CDD.
Autism: social interaction criteria: Impairment in non-verbal behaviors: eye contact, facial expression, posture, gestures.
Failure to develop peer relationships.
Lack of sharing experiences with others.
Lack of social or emotional reciprocity.
Autism: communication criteria: Delay in development of spoken language without non-verbal compensation.
Inability to start and carry out conversation if language present.
Stereo/repetitive use of language.
Lack of imitative play for developmental level.
Autism: sterotypical behavior criteria: Encompassing preoccupation that is abnormal in intensity or focus.
Inflexible adherence to specific routines and rituals.
Stero/reptitive motor mannerisms (hand flapping etc)
Persistent preoccupation with parts of objects.
Autism: treatment: No cure.
Speech, behavioral and physical therapy.
Increased risk of seizure disorders may require medication.
Behavior may require medication (SSRI, stimulants, tricyclics)
Fragile X: pathophysiology: Trinucleotide mutation in FMR1 gene causes methylation of FMR gene. Gene product is key in mRNA translation in brain synapse, leading to clinical problems.
Fragile X: CGG repeats: 5-50: normal
50-200: pre-mutation
200+: mutation

More CGG repeats increase likelihood of methylation.
Fragile X: Sherman paradox: Further down a pedigree the gene travels, more likely clinical disease will result.
Fragile X: CGG expansion: Occurs during oogenesis only, not during spermatogenesis. So mothers with 1 premutation X pass a full mutation gene to their children 50% of the time.
Fragile X: epidemiology: Most common inherited cause of MR.
2nd most common genetic cause of MR after trisomy 21.
1:4000 males, 1:8000 females full mutation
1:250 males, 1:700 females premutation
Accounts for 10% of MR in males.
Fragile X: premutation carrier syndromes: Females: mild cognative or psychological disorders, 20% premature ovarian failure

Males > 50yo: tremor/ataxia syndrome
Fragile X: full mutation clinical symptoms in boys: 85% MR and autism-like symptoms.

IQ 35-70.

Seizures in 20%
Fragile X: physical signs: prominent ears, hyperextensible finger joints, long face with large mandible, macroorchidism at puberty. Signs unreliable except macroorchidism seen in 90% males.
Fragile X: full mutation clinical symptoms in girls: 50% have cognitive defects, usually milder than males.
Emotional problems ADHD, social anxiety and shyness common.
Fragile X: diagnosis: Genetic FMR1 DNA testing by PCR or southern blot.
Fragile X: treatment: Language and motor therapy.

Counseling for social issues.

Medications (SSRIs, stimulants, tricyclics)
PKU: pathophysiology: Mutation in chromosome 12q24.1 gene for phenylalanine hydroxylase -> phenylalanine cannot be converted to tyrosine.

Alternate pathways produce phenylpyruvic acid and phenylacetic acid which along with phenyalanine, accumulate in tissues.

This inhibits neutral amino acid transport into the brain.
PKU: inheritance: autosomal recessive
PKU: epidemiology: Autosomal recessive
1:~15,000 births
Over 400 possible mutations.
PKU: clinical findings: MR, especially if untreated.
Microcephaly (2/3)
Delayed speech
Seizures (1/4) & EEG abnormalities
Hyperactive DTRs
Musty odor
Usually fair skinned, haired, blue eyed.
Behavioral problems
General physical development normal
PKU: diagnosis: Diagnosed by neonatal screening, various methods such as Guthrie Bacterial Inhibition Assay.

If positive screen, test concentrations: >20mg/dL phenylalanine, high phenylpyruvic acid, and low tyrosine are diagnostic.
PKU: treatment: Restrict intake of phenylalanine: decrease total protein intake and supplement with essential amino acids.

Continue throughout life... stopping after developmental period does not cause MR but can cause some attention issues etc.
PKU: phenylalanine monitoring: 2-6 mg/dL if less than 12yo
2-15 mg/dL if older than 12yo

Testing
1st year: 1/week
1-12yo: 2/month
Over 12y: 1/month
If Pregnant: 2/week!
PKU: early diagnosis equals...: Long, normal life without MR. Only if diagnosed VERY early.
PKU: pregnant with PKU: Pregnant women with PKU need to maintain good metabolic control to prevent fetal damage (microcephaly, MR, congenital heart disease).
Phenobarbital: Class, Uses, MOA, Adverse effects: antiepileptic, sedative/hypnotic
Tonic-clonic seizures in children
Increases GABA affinity for its receptor, increasing Cl flow.
OD is fatal, uses P450 system, class D pregnancy!
Methylphenidate: trade name, class, uses, MOA, adverse effects: Ritalin
indirect sympathomimetic (stimulant)
Used in ADHD and narcolepsy.
Causes presynaptic release of norepinephrine and prevents reuptake of norepinephrine and dopamine.
Do NOT take with MAO inhibitors! Highly synergetic!
Glycine: class, uses, MOA: Spasmolytic
Used in seizures and isovaleric academia.
Inhibitory neurotransmitter increasing Cl- conductance... readily passes BBB.
Isovaleric acidemia: inheritance: autosomal recessive
chromosome 15q14-15
Isovaleric acidemia: pathophysiology: Deficency of isovaleryl-CoA dehydrogenase, part of leucine metabolism pathway.

Leads to build up of isovaleryl-CoA derivatives.
Isovaleric acidemia: epidemiology: 1:50,000 - 250,000
Isovaleric acidemia: clinical presentation: Neonate: poor feeding, vomiting, lethargy, seizures, coma.
Odor of "sweaty feet"
Failure to thrive, MR, other developmental delay if untreated.
Isovaleric acidemia: Labs: acidosis with anion gap.
hyperammonemia, glucose/calcium abnormalities common.
NO INCREASED LEUCINE LEVELS since it is irreversibly converted to isovaleryl-CoA
Isovaleric acidemia: diagnosis: Newborn screening shows elevated C5 acylcarnitine.

Isovalerylcarnitine and isovalerylglycine are the elevated in plasma, urine. Hallmark.
Isovaleric acidemia: treatment: Prevent metabolic crisis by increasing caloric intake and decreasing leucine intake.

Diet modifications require HIGH protein intake but without leucine to avoid catabolism.

Give glycine, which conjugates with isovaleryl-CoA, and carnitine which increases excretion of isovaleryl-carnitine complex.
Isovaleric acidemia: prognosis: 50% of newborns presenting with isovaleric acidemia die.

Most of the other 50% develop normally with treatment.
Isovaleric acidemia: glycine dose: 200-300 mg/kg daily

Divided into 3-4 doses.
Isovaleric acidemia: carnitine dose: 100 mg/kg/day

Divided into 3 doses/day
Newborn screening: purpose: To identify individuals at high risk of being effected by a disease that would benefit from early diagnosis and treatment.

MUST do confirmatory testing and eval on a positive patient.
Newborn screening: Tandem Mass Spectrometry: Screens for multiple compounds, takes 3 minutes, very cheap. A single elevated value can indicate various diseases so followup testing is required.
Newborn screening: Tandem Mass Spectrometry detects...: ~50 metabolic disorders incl:
aminoacidopathies
organicacidopathies
fatty acid oxidation disorders
Newborn screening: Tandem Mass Spectrometry does NOT detect...: CF, biotinidase deficency, G6PD deficency, OTC/CPS deficency, lysosomal storage, peroxisomal disorders and cholesterol metabolism disoders.
Newborn screening: epidemiology,: 1/2400 tested babies is positive for a disease.

20% PPV.
Very high sensitivity (conservative cutoffs).
Newborn screening: other diseases screened by besides using mass spect...: Congenital hypothyroidism
Galactosemia
Hemoglobinopathies
Congenital Adrenal Hyperplasia
Newborn hearing screen
Servies for patients with MR are provided by:: Department of Mental Health, Division of Mental Retardation and Developmental Disabilities (DMRDD)
Prospects for independant living by IQ:: Mild MR: can live independently, but benefit from some assistance
Moderate: Can go either way, some can live in community some require institutions.
Profound MR: ALL require institutions. I M O
Foster care: predictors of entering system: Poverty (#1), poorly educated parents, single parenthood, parental substance abuse, lack of social support, family violence, homelessness.
Foster care: stated goals: Provide substitute care for childrens taken from parents.
Establish a permanent home for them.
Help them adjust to placement and monitor progress.
Foster care: placement %s: 3% voluntarily placed
97% placed by court order due to abuse or neglect
Foster care: funds provided: 0-6: $227
6-13: $256
13-18: $298

$150 clothing allowance/yr
Foster care: medical issues: Much more likely to have medical issues than normal children:

Growth, developmental, and mental health issues.

All children entering foster care should undergo evaluation.
Seizures: general causes: Metabolic disorders
Trauma
Tumors or other lesions
Vascular disease
Degenerative disorders
Infectious diseases
Seizures: types of partial seizures: Involve one part of brain.

Simple partial (SPS): focal. motor, sensory, autonomic symptoms.

Complex partial (CPS): impaired consciousness, repetitive motor behaviors
Seizures: types of generalized: Large sections of both hemispheres involved. Nearly always impaired consciousness.

Types: tonic-clonic (grand mal), absence (petit mal), myoclonic.
Seizures: absence seizures: Petit mal.

May have impaired consciousness, extremely brief... patient may be unaware it happened!

Usually begins in childhood, ends by age 20.
Seizures: myoclonic seizures: Single or multiple myclonic jerks... shock-like contraction of muscle groups.
Seizures: tonic-clonic: Grand mal.

Tonic phase: sudden loss of consciousness. Respiration arrested... usually lasts <1min then moves to clonic.

Clonic phase: Jerking of musculature, lasts 2-3min then moves to flaccid coma.
Seizures: treatment: AEDs. Start with monotherapy and move to polytherapy if 2 monotherapies fail.

Most effective agents: carbamazepine, phenytoin, valproic acid.

Other treatments include surgery, vagal nerve stimulation.
Concept of Penetrance: Proportion of people with a mutant autosomal dominant gene that show a phenotype.

Complete: anyone with bad gene shows symptoms.

Incomplete/reduced: some with the bad gene show no symptoms.
X-linked disorders: manifesting heterozygotes: In female carriers of a recessive X-linked gene symptoms manifest, due to inactivation of one of the X chromosomes... the healthy one.
Concept of Imprinting: Differential expression of a gene depending on if it came from mother or father.

Achieved by methylation of promotor (turns off transcription) or acetylation of histones (turns on gene). Both reversible.
Diseases linked to Imprinting: Prader-Willi syndrome vs. Angelman syndrome.

Both caused by microdeletion at 15q11-q13. If deletion is on father's chromosome, PWS, if on maternal, AS.
Prader-Willi syndrome: symptoms: Obesity, hypogonadism, mild to moderate MR.
Angelman syndrome: symptoms: Microcephaly, ataxic gait, seizures, inappropriate laughter, severe MR
Concept of uniparental disomy: Both chromosomes come from 1 parent, due to meiotic nondisjuction leading to trisomy and subsequent rescue returning to disomy.
Diseases linked to uniparental disomy: Prader-Willi if 2 copies of chromosome 15 from mother... lack of paternal chromosome.
Angelman syndrome if 2 copies of chromosome 15 from father... lack of maternal chromosome.
Concept of mitochrondrial inheritance: mtDNA is all inherited from the mother on a circular self-replicating chromosome.

mtDNA diseases disproportionately effect metabolically active tissue, ie brain and muscle.
Concept of X-chromosome inactivation: Mosaicism resulting from random inactivation of a maternal or paternal X-chromosome. Half cells have maternal, have paternal activated.
Concept of somatic mosaicism: Individual with more than one genetically distinct cell line, due to mutations after fertilization resulting in some normal cells, some with mutation.
Concept of germ line mosaicism: Mutation in embryonic cell line resulting in a healthy individual with mutant sperm/eggs that pass disease to offspring.
Concept of nucleotide repeat expansion disorders: Repeats go above a threshold, cause disorder expression. More repeats = more phenotype severity (Anticipation).
Hurler's syndrome: incidence, pathophysiology, features, diagnosis, treatment: 1:100,000
Mutation in alpha-1-iduronidase
Coarse facial features and hepatosplenomegaly
Leukocyte a-1-iduronidase assay
Bone marrow transplant

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