Intellectual Disability (ID) Joel Charrow, MD

Intelligence is what the IQ tests measure.

The Wechsler Intelligence Scale for Children Full Scale IQ (“General Intelligence”) Verbal IQ Information (facts) Vocabulary (definitions) Arithmetic (word problems) Comprehension (social understanding) Similarities Performance IQ (Visual-spatial) Picture completion Block design (copy block arrangements from models and pictures) Object assembly (puzzles) Picture arrangement (order cartoons to tell a story) Coding (use symbols to code and decode, with a key)

“Mental Age” IQ = x 100 Chronologic Age

34.1% 34.1% 13.6% 13.6% 2.1% 2.1%

} 5 Approximate Percentage of Intellectually Disabled Population Severity of Intellectual Disability IQ Mild (“educable”) 50 - 70 75 Moderate (“trainable”) 35 - 50 20 Severe 20 - 35 } 5 Profound < 20

} } Mild 50-70 Moderate 35-49 Severe 20-34 Profound <20 Severe

} } } } } Frequency Size exaggerated Profound <20 Severe 20-34 Moderate 35-49 Mild 50-70

Why should we care what causes ID? There may be treatment (1 -2%) It’s important to know the course and prognosis Genetic counseling and family planning!

Everyone has a family.

Recurrence Risks for Intellectual Disability When the couple has not had any children When the couple has had one intellectually disabled child Risk Risk Both parents normal <1% Both parents normal 3 - 5.5% Both parents normal, intellectually disabled aunt or uncle Both parents normal, intellectually disabled aunt or uncle 2.5% 13% One parent intellectually disabled and one parent normal, with one intellectually disabled aunt or uncle 24% One parent intellectually disabled 20%

How common is intellectual disability? 3% of the population is intellectually disabled (~7,000,000 people) < 0.1% has cystic fibrosis < 0.01% has PKU < 0.2% of African Americans have sickle cell disease

Origin of Severe Intellectual Disability Prenatal Origin Perinatal Origin Postnatal Origin Unknown

Origin of Severe Intellectual Disability Single Gene Chromosomal Malformational

Karyotype Resolution Standard karyotype (550 – 850 bands) has relatively low resolution: 3 – 8 MB

Array Based Comparative Genomic Hybridization (aCGH) DNA fragments from known chromosomal locations are bound to a glass slide to form an array. The DNA in each circle (clone), contains DNA from a specific, known chromosomal location, and is physically bound to the slide. The DNA clones are selected to cover the entire genome at approximately even intervals. Chromosome regions of particular interest (e.g., known genes or microdeletion regions) are represented by clones that are closer together on the chromosome. Microarray with Genomic Clones

Array Based Comparative Genomic Hybridization (aCGH) DNA from the patient is fragmented and labeled with a fluorescent tag (e.g., green). “Control” DNA fragments from a different person is labeled with a fluorescent tag with a different color (e.g., red). The DNA fragments from the patient and the control are hybridized to the DNA in the array.

Array Based Comparative Genomic Hybridization (aCGH) Patient DNA Microarray with Genomic Clones Normal: ratio 0.8 – 1.2 Control DNA

Array Based Comparative Genomic Hybridization (aCGH) Patient DNA Microarray with Genomic Clones Loss: ratio <0.8 Normal: ratio 0.8-1.2 Control DNA

Array Based Comparative Genomic Hybridization (aCGH) Patient DNA Microarray with Genomic Clones Loss: ratio <0.8 Normal: ratio 0.8-1.2 Gain: ratio >1.2 Control DNA

Array Based Comparative Genomic Hybridization (aCGH)

Array Based Comparative Genomic Hybridization (aCGH)

Abnormal Microarray

Karyotype vs. Array CGH Density Resolution Karyotype 550 – 850 bands 3 – 8 MB 44K Array 42,494 probes 24 – 43 KB spacing 1M Array 963,029 probes 1.8 – 2.1 KB spacing

Origin of Severe Intellectual Disability Single Gene Chromosomal Malformational

The FMR1 Gene CpG island Trinucleotide repeat 5' 3' ... CGG CGG CGG CGG CGG CGG ...

Expansion of Trinucleotide Repeat # of Repeats Phenotype Normal 28 Normal Premutation 50 - 200 Normal Full Mutation > 200 Intellectually Disabled* *Penetrance of ID in females is ~53%

Risk of Intellectual Disability in Child # of Repeats in Mother Frequency of Full Mutation Son Daughter* 61 - 70 16% 8% 4% 71 - 80 70% 35% 18% > 81 100% 50% 26% *Penetrance of ID in daughters is ~53%

The Sherman Paradox Premutation 8% Transmitting male 4% 0% 50% 28% Full mutation Normal repeat length 16% 37% % refers to risk of ID

Expansion of Trinucleotide Repeats in FMR-1 Premutations: Meiotically unstable in oogenesis - tend to expand Mitotically stable (post-fertilization) Full mutations: Mitotically unstable (post-fertilization) - leads to mosaicism for size of expanded repeat

Single Gene Noonan Syndrome Autosomal dominant

Incontinentia Pigmenti Single Gene (X-linked dominant, lethal in males) Single Gene

Brachman - De Lange Syndrome (Usually sporadic; Nipped-B-Like gene)

Origin of Severe Intellectual Disability Single Gene Chromosomal Malformational

Causes of Severe Intellectual Disability (Summary of three studies) Percent Multiple congenital anomalies 13 - 20 Isolated CNS malformations 2 - 15 Neural tube defects 3 Hydrocephalus 2 - 5 Microcephaly 5 Moser et al., in Emery and Rimoin, 1990

Meningomyelocele / Spina Bifida From: KL Moore, TVN Persaud, K Shiota: Color atlas of clinical embryology. W.B. Saunders Company, Philadelphia, 1994.

Anencephaly/Encephalocele

Congenital Malformations Percent of Cases Unknown 60 Multifactorial 20 Single Genes 7 Teratogens Chromosome abnormalities 6

Causes of Severe Intellectual Disability (Summary of three studies) Perinatal (and unidentified prenatal) causes 16 - 32 Infectious diseases 3 - 9 Postnatal brain injury (non-infectious) 1 - 4 Unclassified 4 - 12 Percent Moser et al., in Emery and Rimoin, 1990

Deterioration IQ Degeneration Time

I-cell disease (Mucolipidosis II)

History & Physical IQ > 50 Familial ID? IQ < 50 Prenatal Onset - chromosomal - MCA - CNS malformation - teratogens Postnatal Onset - infection - metabolic - trauma Perinatal Onset - infection - asphyxia

Frequency of Minor and Major Anomalies Only 1 Only 2 3 or More 1 or More Patient Group Minor Major Minor Major Minor Major Minor Major Intellectually Disabled 24 18 18 10 32 2 74 30 “Normal” 20 7 2 22 7 Smith & Bostian (1964) J Pediatr 65:189-196