31.3 Intellectual Disability
1131
Disorder
Pathophysiology
Clinical Features and Behavioral Phenotype
Tuberous sclerosis
complex 1
and 2
Benign tumors (hamartomas) and
malformations (hamartias) of
central nervous system (CNS),
skin, kidney, heart; dominant;
1/10,000 births; 50% TSC 1,
9q34; 50% TSC 2, 16p13
Epilepsy, autism, hyperactivity, impulsivity, aggression; spectrum of
intellectual disability from none (30%) to profound; self-injurious
behaviors, sleep disturbances
Neurofibromatosis
type 1 (NF1)
1/2,500–1/4,000; male
=
female;
autosomal dominant; 50% new
mutations; more than 90%
paternal NF1 allele mutated;
NFl
gene 17q11.2; gene product
is neurofibromin thought to be
tumor suppressor gene
Variable manifestations; café au lait spots, cutaneous neurofibromas,
Lisch nodules; short stature and macrocephaly in 30–45
Half with speech and language difficulties; 10% with moderate
to profound intellectual disability; verbal IQ
>
performance IQ;
distractible, impulsive, hyperactive, anxious; possibly associated with
increased incidence of mood and anxiety disorders
Lesch-Nyhan
syndrome
Defect in hypoxanthine guanine
phosphoribosyl-transferase
with accumulation of uric
acid; Xq26–27; recessive; rare
(1/10,000–1/38,000)
Ataxia, chorea, kidney failure, gout
Often severe self-biting behavior; aggression; anxiety; mild to moderate
intellectual disability
Galactosemia
Defect in galactose-1-phosphate
uridyltransferase or galactokinase
or empiramase; autosomal
recessive; 1/62,000 births in the
U.S.
Vomiting in early infancy, jaundice, hepatosplenomegaly; later cataracts,
weight loss, food refusal, increased intracranial pressure and increased
risk for sepsis, ovarian failure, failure to thrive, renal tubular damage
Possible intellectual disability even with treatment, visuospatial deficits,
language disorders, reports of increased behavioral problems, anxiety,
social withdrawal, and shyness
Phenylketonuria
Defect in phenylalanine hydroxylase
(PAH) or cofactor (biopterin) with
accumulation of phenylalanine;
approximately 1/11,500 births;
varies with geographical location;
gene for PAH, 12q22–24.1;
autosomal recessive
Symptoms absent neonatally, later development of seizures (25%
generalized), fair skin, blue eyes, blond hair, rash
Untreated: mild to profound intellectual disability, language delay,
destructiveness, self-injury, hyperactivity
Hurler’s syndrome 1/100,000; deficiency in
a
-L-
iduronidase activity; autosomal
recessive
Early onset; short stature, hepatosplenomegaly; hirsutism, corneal
clouding, death before age 10 years, dwarfism, coarse facial features,
recurrent respiratory infections
Moderate-to-severe intellectual disability, anxious, fearful, rarely
aggressive
Hunter’s syndrome 1/100,000, X-linked recessive;
iduronate sulfatase deficiency;
X q28
Normal infancy; symptom onset at age 2–4 years; typical coarse faces
with flat nasal bridge, flaring nostrils; hearing loss, ataxia, hernia
common; enlarged liver and spleen, joint stiffness, recurrent infections,
growth retardation, cardiovascular abnormality
Hyperactivity, intellectual disability by 2 years; speech delay; loss
of speech at 8–10 years; restless, aggressive, inattentive, sleep
abnormalities; apathetic, sedentary with disease progression
Fetal alcohol
syndrome
Maternal alcohol consumption
(trimester lll
>
ll
>
l); 1/3,000 live
births in Western countries; 1/300
with fetal alcohol effects
Microcephaly, short stature, midface hypoplasia, short palpebral fissure,
thin upper lip, retrognathia in infancy, micrognathia in adolescence,
hypoplastic long or smooth philtrum
Mild to moderate intellectual disability, irritability, inattention, memory
impairment
(Table by B. H. King, M.D., R. M. Hodapp, Ph.D., and E. M. Dykens, Ph.D.)
Table 31.3-4
Syndromes with Intellectual Disability and Behavioral Phenotypes (
continued
)
Children with profound intellectual disability require con-
stant supervision and are severely limited in both communication
and motor skills. By adulthood, some speech development may
be present, and simple self-help skills may be acquired. Clinical
features frequently observed in populations with intellectual dis-
ability either in isolation or as part of a mental disorder, include
hyperactivity, low frustration tolerance, aggression, affective insta-
bility, repetitive and stereotypic motor behaviors, and self-injuri-
ous behaviors. Self-injurious behaviors occur more frequently and
with greater intensity in more severe intellectual disability.
Dylan was a full-term infant, the second child born to his
42-year-old mother, a medical technician, and 48-year-old father,
a high school basketball coach. The pregnancy was unremarkable,
and Dylan’s sister, who was two years older, was healthy and devel-
oping normally. The family lived in a rural town in the Midwest.
Dylan was an extremely fussy, active newborn with extended peri-
ods of crying that the pediatrician labeled classic colic. As a newborn,
it was noticed that Dylan seemed to have large ears and strabismus,
which the pediatrician said would probably resolve spontaneously. At
