MBLD Diseases
Disease
Down Syndrome
Cause
Trisomy 21
Edwards Syndrome
Trisomy 18
Patau Syndrome
Trisomy 13
Turner Syndrome
Monosomy X
Klinefelter Syndrome
47, XXY
Complete Hyaditiform
Mole (CHM)
Diploid Paternal Genome
Tall, breast development,
hypogonadism, high pitched voice
Miscarriage
Ovarian Teratoma
Diploid Maternal Genome
Miscarriage
-
Prader-Willi Syndrome
15q11-13 deletion/silencing of
SNRPN paternal gene
-
Angelman Syndrome
15q11-13 deletion/silencing of
UBE3A maternal gene
-
incidence = 1/15,000
Beckwith-Wiedemann
Syndrome
Paternal trisomy of 11p15.5 OR
paternal uniparental disomy on 11
(maternal copy of the gene replaced
with extra copy of the paternal one)
OR paternal duplication of 11p15.5
OR translocations/mutations
involving maternal 11p15
Autosomal dominant disorder
Mental retardation, obesity,
polyphagia, small hands/feet (and
you know what they say about
people with small hands/feet)
Intellectual deficiency, absent
speech, small head, paroxysmal
laughter and seizures
Overgrowth due to overactive
IGF-2, macroglossia (enlarged
tongue), visceromegaly (enlarged
organs), hypoglycemia
Usually diagnosed due to
infertility, incidence = 1/1000
1-2% undergo malignant
transformation to
choriocarcinomas
1% undergo malignant
transformation to squamous cell
carcinoma
incidence = 1/15,000
-
1000x increased risk of
childhood tumours, incidence =
1/13,700
High plasma cholesterol due to
abnormal LDLs, xanthomas on
skin
Didn’t say but
I’d assume
limiting your fat
Much more likely to a heart
attack, usually die in 30s,
incidence = 1/500
Hypercholesterolaemia
Symptoms
Mental retardation, abundant
neck skin, simian crease,
epicanthic folds and flat face
Prominent occiput and rocker
bottomed feet, overlapping
fingers
Treatment
-
Microphthalmia, cleft lips+palate,
post axial polydactyl
Short stature, thick neck,
infertility, broad (small) chest
with wide-spaced nipples
-
-
Hormone
therapy can
improve
growth
-
Notes
Will develop Alzheimer’s Disease
by middle age. Affects genes
DYRK1A and DSCR1
18 (eighteen) starts with E and
so does Edward (memory tool).
90% mortality by 2 years old,
incidence = 1/5000
Rarely live beyond 1 year,
incidence = 1/8000
Most dies in utero, some cases
are mosaic, incidence = 1/2000
Albinism
Achondroplasia
Marfan Syndrome
Defect in metabolism of melanin
(related to the genes OCA2 – P
gene, OCA3 – TYRP1, and OCA4 –
MATP)
Mutation in FGFR3 gene on 4p
(gly380arg)
Mutation on FBN1 on chr 15
Pale
Large head, may have respiratory
problems
Tall, long limbs, spidery fingers
(arachnodactyly), dislocation of
lens, risk of aortic dissection
Thick mucus clogs pancreas,
pulmonary problems, F508del
causes deletion of nucleotide
binding domain #1 therefore
preventing Cl- from exiting the cell
and causing mucus dehydration
intake?
-
-
*Cystic Fibrosis*
Mutation in CFTR gene on 7q31.2
(27 exons over 188 kb), most due
to missense mutation
Hereditary
Hemochromatosis
Mutation in the HFE gene
Excessive accumulation of iron
causing tissue damage
Healthy diet?
Duchenne Muscular
Dystrophy
X-linked recessive disorder,
mutation in the dystrophin gene at
Xp21
Progressive weakness/loss of
muscle, Gower sign (must use
hands to stand up)
Becker Muscular
Dystrophy
X-linked recessive disorder,
mutation in the dystrophin gene at
Xp21, different mutant alleles at
same locus as DMD (allelic
heterogeneity)
Autosomal dominant disorder, IT15
gene (aka HTT or the Huntingtin
gene) contains more CAG repeats
on exon 1 than normal (>40, 36-39
at risk)
Same as DMD but milder
(chairbound by 25, live to 50),
later onset
Steroids for
ambulation,
ventilation, and
now gene
therapy
Same as DMD
from what I
understand
*Huntington’s
Disease*
Midlife psychiatric disturbances,
motor impairment (coordination,
fidgeting, balance issues, trouble
speaking/swallowing), and
cognitive decline (memory,
Control
infections,
replace
pancreatic
enzymes, gene
therapy, and
Kalydeco (in
the G551D
subset)
-
Can have locus heterogeneity
(same disease from different
mutations)
Incidence = 1/25,000,
homozygous is lethal
Associated with paternal age,
incidence = 1/5000, dominant
negative fashion
Incidence = 1/2000, 10% have
meconium ileus at birth and need
surgery, males infertile due to no
vas deferens, diagnose with NaCl
sweat test, lung disease most
variable aspect, MBL2 (mannose
binding lectin) and TGF-beta1
are associated with worse lung
function (Robbins Basic
Pathology p248-250), blood
taken on newborns to test for CF
(heel prick)
“Bronze diabetes”, most common
autosomal recessive disorder,
non-penetrance (not everyone
displays symptoms)
Most bedridden by 15, death by
20, most common/severe
muscular dystrophy, high
creatine kinase levels in blood,
usually frameshift mutation
Incidence = 1/20,000, usually
mutations are in-frame
Juvenile form possible, 100%
penetrant by age 70, incidence =
4-7/100,000, HTT has large
network of interacting proteins
such as CBP (transcription) and
anxiety, depression, awareness)
Myotonic Dystrophy
(DM1)
Mutation in DMPK (myotonin
kinase) on chr 19 (affects Ca2+
homeostasis), mutation is CTG
trinucleotide expansion in 3’ UTR
Myotonic Dystrophy
(DM2)
Mutation in ZNF9 (zinc finger)
gene, mutation is CCTG is
tetranucleotide expansion (7511,000 copies) in intron 1
Mutation in FMR1 gene (encodes
FMRP), mutation is CGG
trinucleotide expansion in the 5’
UTR
Fragile X Syndrome
HAP1 and HIP1 (intracellular
signaling, cleaved N-terminus of
mHTT is super toxic (affects
metabolism, gene expression,
transport, and signal
transduction)
Incidence = 1/8000, exhibit
variable expression and
anticipation, usually die in 50s, 537 copies of CTG is normal (>50
causes the disease)
Difficulty relaxing contracted
muscles, muscle wasting,
susceptible to cataracts,
hypogonadism, male frontal
baldness, and cardiac arrhythmia
(and mental deterioration)
Same as DM1 except does not
show congenital form
-
-
ZNF9 is a DNA-binding protein
and is not related in any way to
DM1 or its proteins
Males have mental retardation,
macroorchidism (large testes),
and tall stature with long face.
Women (carriers) have mild
mental retardation (only 30%
show this), learning disabilities,
and shyness. All show
impulsiveness, hand flapping, and
hyperactivity
-
Incidence = 1/4000 in males and
1/8000 in females, anticipation,
most common single gene cause
of autism, 5-50 CGG repeats
normal (55-200 is permutation
and >200 is full mutation), FMRP
is an RNA-binding protein
(involved in synaptic plasticity)