A Systematic Approach to Mental Retardation

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A Systematic Approach to Mental Retardation

• Moshe Frydman MD,
• The Danek Gertner Institute of Human Genetics,
  the Chaim Sheba Medical Center

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American Association on Mental Retardation, 1992
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American Association on Mental Retardation, 1992
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Mental Retardation Prevalence

• Assumptions
• The average IQ in the population is 100
• Intelligence follows a normal distribution
• 15 IQ points equal one standard deviation

• Under these assumptions
• 2.3 will have an IQ between 50 and 70
• 0.38 of the population will have an IQ lt50

1.14 of all school children in the US, are
retarded
Massey McDermott, MMWR 4161-65, 1995
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FAQs in Mental retardation
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Some causes of mental retardation

• Unknown 30-50

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Down syndrome 1/600 Kleinfelter
1/800 males Triple X
1/800 females Turner
1/5000 females Trisomy 18
1/3500 Trisomy 13
1/5000 TOTAL 1/285
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Down syndrome
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Microdeletions Examples
Williams syndrome del7p11 Velo-cardio-facial
syndrome del22q12 Prader Willy and Angelman
syndromes del15q11 Tricho-Rhino-Phalangeal
syndrome del8q21 Smith-Magenis
syndrome del17p Lyssencephaly syndrome
del17q Sotos syndrome del5q
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Velo-cardio-facial syndrome (Shprintzen-DiGeorge
syndrome)
Cardiac malformations Thymic hypoplasia Cleft
soft palate Hypocalcemia 22q deletion
CATCH-22
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Models for VCFS
Chromosome 22
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WS RT
Wiliams Syndrome
Rubinstein Taybi syndrome
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Telomere structure
Unique telomere region (site of FISH probes)
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Subtelomeric rearrangements A frequent cause
of idiopathic mental retardation (10.6)
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Telomer painting
Chromosome 1
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Monosomy 1pter
Motor retardation 100 Severe mental
retardation 96 Seizures 75 Specific facial
dysmorphy 100
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????? ???? ????? ?? ???????? X
142 ??????? ?????? ???? ????????? X 12 ???? ??
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(RSK, ATRX, ARX) 83 ?????? ?? XLMR ???? ???????
????? ????????? 1/3 ????? ????? ???? ?? ??????
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Fragile X
?????? 1/4000 ?????? 1/7000 ??????
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Fragile X Main findings
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Fragile X Molecular basis
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Russel Silver Syn.
Noonan syndrome
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  sclerosis)
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????? ?????? ??????? ? PDD

• ?. ????? ?????? ??????? ?????? 3-6.
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Inborn Errors of Metabolism

• Functional disorders
• Failure to thrive
• Poor feeding
• Vomiting
• Diarrhea
• Developmental delay
• Behavioral changes
• Hypo/hypertonicity
• Seizures
• Deafness neurosensory
• Respiratory Distress
• Apnea

• Physical Findings
• Jaundice
• Hepato/splenomegaly
• Facial dysmorphism
• Eye findings Cataract,
  Retinopathy, etc.
• Abnormal Hair
• Abnormal odor
• Macroglossia

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Clinical findings
Gingival hypertrophy (GM1 gangliosidosis
Flag sign of protein malnutrition (Lysinurgic
(Dibasic) aminoaciduria)
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Cherry-red spot
Tay Sachs Disease Neimann- Pick Disease Infantile
Gaucher Disease Lipofuscinosis (NCL)
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Smith-Lemli-Opitz Syndrome (SLO)

• Microcephaly
• FTT
• Mental Retardation
• Structural brain anomalies
• Facial dysmorphism
• Syndactily of toes
• Genital anomalies
• Early death

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Smith Lemli OpitzDiagnosis
Plasma 7-dehydrocholesterol
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Carbohydrate Deficient Glycoprotein Syndromes
(CDG)

• Normal Perinatal period
• Strabismus
• Developmental delay/CP
• Brain CT
• Large cisterna magna
• Cerebellar hypoplasia/atrophy

Neurometabolic studies NORMAL Diganosis Serum
Isotransferrin
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Isotransferrins Measured by Isoelectric Focussing
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CDG Type 3 Fucosilation failure
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Peroxisomal DisordersInfantile Refusm
DiseaseNeonatal AdrenoleukodystorphyZellweger/Ze
llweger like
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Recommendations for work-up

• Hx of pregnancy, delivery and early years
• Three generation pedigree
• Detailed physical examination
• Anthropometric and photographic documentation
• Standard karyotyping and fragile X test
• Brain imaging
• Routine and directed tests (Metabolic and
  other)
• Periodic follow-up

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Prader- Willi
Angelman
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Mental Retardation Routine

• 500-band karyotype
• Fragile X (DNA test)
• Thyroid hormones
• CBC, including blood smear and supravital staining

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Complete blood count (CBC)

• Pancytopenia, leukopenia or leukocytosis
• Inclusion Bodies (RBC or WBC)

• GM1
• Galactosialidosis
• MLD
• ML-II
• Alpha Thalassemia Mental Retardation

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Inborn errors of metabolismRoutine biochemistry

• Glucose
• Na, K, Cl, HCO3
• BUN, creatinine
• Uric acid
• AST, ALT, GGT
• Bilirubin
• Alk. Phosphatase
• Ca, P

• CPK, LDH
• Cholesterol
• Triglycerides
• HDL
• B12 Folate

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Inborn Errors of Metabolism?????? ????????, ???
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Inborn Errors of Metabolism ?????? ???????? ???
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Inborn Errors of Metabolism ?????? ???????? ???
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• MRIMRS ???
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• ERGVEP, BERA, EMGNCT
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• ?????? ?????????? ????????? (EM)

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Sturge-Weber
Lyssencephaly
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Genetic Intervention Benfits to patients

• Medications and other treatment modalities
• Surgical and specialist interventions
• Presymptomatic recognition of complications
• Educational planning
• Limiting unnecessary tests
• Extention of work-up to family at risk