FTM1 Diseases and Disorders

mneumonic for autosomal dominant disorders

MAN OF HAM

MAN OF HAM

Marfan, Achondroplasia, Neurofibromatosis Type I

Osteogeneis Imperfecta, Familial Hypercholesterolemia

Huntington’s, Acute Intermittent Porphoria, Myotonic Distrophy

familial hypercholesterolemia (FHC) inheritance pattern

Autosomal Dominant (homozygous —> child onset or heterozygous —> adult onset)

familial hypercholesterolemia (FHC) gene

LDLR deficiency or APOB

familial hypercholesterolemia mode of transmission

haploinsufficiency, allelic heterogeneity, locus heterogeneity

familial hypercholesterolemia clinical features

• high serum cholesterol leading to atherosclerosis and CVD

• xanthoma (cholesterol depositions on tendons, ankles, wrists knee)

• xanthelasma (cholesterol depositions on eyelids)

huntington disease inheritance pattern

autosomal dominant (90% cases adult onset, high penetrance)

huntington disease gene

huntintin (HTT)

huntington disease mode of transmission

gain of function, triple repeat expansion disorder (CAG in exon → expanded tract of glutamine in protein which accumulates in neurons → neuronal death), displays anticipation

huntington disease clinical features

atrophy basal ganglia and cerebral cortex → involuntary movements, chorea, rigidity, cognitive decline

age of onset: 30-50

myotonic dystrophy inheritance pattern

autosomal dominant

myotonic dystrophy gene

DMPK

myotonic dystrophy mode of transmission

triplet repeat expansion disorder, anticipation, pleiotropy, gain of function

myotonic dystrophy clinical features

myotonia, muscle wasting, cataracts, conduction/endocrine issues

marfan syndrome inheritance pattern

autosomal dominant

marfan syndrome gene

FBN1 (encodes connective tissue protein)

marfan syndrome mode of transmission

haploinsufficiency and dominant negative forms

pleiotropic phenotype

de novo

marfan syndrome clinical features

chest wall looks caved in (pectus excavatum)

tall stature, arachnodactyly, wasting of muscles, hypermobile joints

risk of heart defect, endocrine changes, myotonia

eye lens subluxation (dislocation of lens)

osteogenesis imperfecta (brittle bone disease) inheritance pattern

autosomal dominant

osteogenesis imperfecta gene

COL1A1 & COL1A2

osteogenesis imperfecta mode of transmission

haploinsufficiency (50% collagen formed),

dominant negative forms (more severe, low functional collagen),

de novo

pleiotropy

osteogenesis imperfecta clinical features

frequent fractures, brittle bones, peridontal weakness

blue sclera

achondroplasia inheritance (Dwarfism) pattern

autosomal dominant

achondroplasia gene

FGFR3 - fibroblast growth factor receptor 3

achondroplasia mode of transmission

gain of function (point mutation - Gly380Arg), unregulated tyrosine kinase signalling, 100% penetrance

mutation hot spot (de novo)

homozygosity is not compatible with life

achondroplasia clinical features

premature ossification of bone growth plates = disproportionate short statutre

shortening of long bones (trunk)

facial dysmorphology

neurofibromatosis type I inheritance patterns

autosomal dominant

neurofibromatosis type I gene

NF1

neurofibromatosis type I mode of transmission

loss of heterozygosity, mutation hot spot (50% are inherited, 50% are de novo mutation), allelic heterogeneity

high penetrance, variable expressivity (second mutation may cause loss of all functional NF1 → cancer)

neurofibromatosis type I clinical features

neurofibromas (benign tumors)

café au lait spots

lisch nodules of eye

acute intermittent porphyria (AIP) inheritance pattern

autosomal dominant

acute intermittent pophyria mode of transmission

heme (enzyme) synthesis deficiency

acute intermittent porphyria clinical features

anxiety, nausea, severe abdominal pain, constipation, diarrhea, purple-red urine (accumultion of heme synthesis precursors

autosomal recessive mnemonic

Can Somebody Please Take HEr HOme, Girl Always Shits

Can Somebody Please Take HEr HOme, Girl Always Shits

Cystic Fibrosis, Sickle-Cell, Phenylketonvia, Tay-Sachs, HEmochromatosis, HOmcystinuria, Galactosemia, Alpha-1-Antitrypsin deficiency, SCID

Cystic Fibrosis (CF) inheritance pattern

autosomal recessive

Cystic Fibrosis Gene

CFTR

CF mode of transmission

pseudo-dominance

compound heterozygosity

variable expression

CF clinical features

salty sweat

recurrent respiratory infections (pneumonia)

infertility (male and female)

meconium ileus, abdominal distension, bilious vomiting

malabsorption, fatty stools

chronic inflammation and tissue damage of intestines, pancreas, lungs

Sickle-Cell disease inheritance pattern

autosomal recessive

Sickle-Cell Disease gene

HBB

Sickle-Cell Disease mode of transmission

point mutation (Glu6Val, gene encoding beta-globin)

gain of function

pseudo-dominance

Sickle Cell disease clinical features

anemia, sickle-shaped RBCs, vaso-occlusive crises of pain, migraines, organ death (lack of O2 to organ)

carriers may have crises under extreme settings,alleles show co-dominance

Phenylketonuria (PKU) inheritance pattern

autosomal recessive

Phenylketonuria gene

PAH

Phenylketonuria mode of transmission

loss of function (haploinsufficiency), allelic heterogeneity, compound heterozygoute

Phenylketonuria clinical features

irreversible brain damage, severe intellectual disability

PKU management

low Phe diet (inability to convert phenylalanine to tyrosine)

Tay-Sachs inheritance pattern

autosomal recessive

Tay-Sachs gene

HEXA

Tay-Sachs mode of transmission

Tay-Sachs clinical features

Hemochromatosis (iron overload disorder) inheritence pattern

autosomal recessive

Hemochromatosis gene

HFE

Hemochromatosis mode of transmission

delayed age of onset (30-40 in males, older in females)

incomplete penetrance

pseudo-dominance

variable expression (more severe in males, due to X/Y differences)

Hemochromatosis (iron overload disorder) clinical features

fatigue, weakness

joint pain

liver disease

metallic hyperpigmentation

endocrine dysfunction

cardiac issues

Homcystinuria inheritance pattern

autosomal recessive

Homcystinuria gene

GALT

Homcystinuria mode of transmission

Homcystinuria clinical features

body shape resembles that of Marfan Syndrome (tall)

neurological and cardiovascular presentations (high levels of homocysteine interacts with connective tissue and disrupts it)

Galactosemia inheritance pattern

autosomal recessive

Galactosemia gene

GALT

Galactosemia clinical features

inability to degrade milk sugar (galactose)

liver damage, cataracts, intellectual disability (high galactose serum)

Galactosemia management

restriction of all milk sugars (incl breast milk)

Alpha-1-antitrypsin inheritance pattern

autosomal recessive

Alpha-1-antitrypsin deficiency gene

SERPINA1

Alpha-1-antitrypsin mode of transmission

adult onset

Alpha-1-antitrypsin clinical features

adult emphysema, liver damage in children

SCID inheritance pattern

autosomal recessive

SCID gene

ADA

SCID mode of transmission

accumulation of dATP is toxic to B and T cells, ADA deficiency in the purine degradation pathway

SCID clinical features

severe combined immune deficiency (build-up of adenosine)

Muscular Dystrophy disorders

Ducheene (severe) and Becker (milder) muscular dystrophy

Muscular Dystrophy inheritance pattern

X-linked recessive

Muscular Dystrophy gene

DMD (dystrophin)

Duchenne Muscular Dystrophy mode of transmission

manifesting heterozygote (in females) due to skewed X-inactivation (milder symptoms e.g. muscle weakness and elevated CK)

de novo

Duchenne muscular dystrophy clinical features

severe in childhood (wheelchair bound by adolescence)

pseudohypertrophic calves (muscle fibers replaced with adipose/connective tissue)

low reproductive fitness

Glucose 6-phosphate dehydrogenase deficiency inheritance pattern

X-linked recessive

Glucose 6-phosphate dehydrogenase deficiency gene

G6PD

Glucose 6-phosphate dehydrogenase deficiency clinical features

hemolysisis with triggers (primaquine/sulfa drugs)

Hemophelia A & B inheritance pattern

X-linked recessive

Hemophelia A gene

factor VIII

hemophilia mode of transmission

manifesting heterozygote (in women) due to skewed X-inactivation - milder symptoms

allelic heterogeneity

loss of function (incorrect splicing)

hemophilia clinical features

hemarthorisis (bleeding into joint cavity)

subcutaneous hematoma (blood pooling under skin of head)

easy bruising

Lesch-Nyhan Syndrome inheritance pattern

X-linked recessive

Lesch-Nyhan syndrome gene

HGPRTL

Lesch-Nyhan Syndrome Clinical Features

hyperuricemia, gout, self mutilation

Red-Green Color Blindness inheritance patter

X-linked recessive

X-linked SCID inheritance pattern

X-linked recessive

X-linked SCID gene

SCIDX1

X-linked SCID clinical features

poor T cell maturation, B cell dysfunction

constant infections

Y-linked disorders

mutations in SRY genes, HY histocompatibility antigen, hairy ears

Rett Syndrome inheritance pattern

X-linked dominant

Rett Syndrome clinical features

• loss of speech

• hand-wringing behavior

• autism-like features

lethal in males

Charcot-Marie tooth disease inheritance pattern

dominant, recessive, or X-linked patterns

Charcot-Marie tooth disease mode of transmission

locus heterogeneity