List of Select Genetic Disorders

7/31/2019 List of Select Genetic Disorders

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Disease Category Pathogenesis / Heredity Pathology, CardinalSymptoms

Cystic Fibrosis Autosomal Recessive. CFTRgene defect on Chrom 7 ------>

No Cl-

transport and failure tohydrate mucous secretions (noNaCl transport) ------>

excessively viscous mucoid

exocrine secretions

Meconium ileus (caused bythick, mucoid meconium),

respiratorybronchiectasis,Pseudomonas pneumonia, pancreatic

insufficiency, hypertonic (high

Cl-concentration) sweat.

FanconiAnemia

Autosomal

Recessive congenitalpancytopenia.

Normocytic anemia with

neutropenia.

Short stature, microcephaly,

hypogenitalism, strabismus, anomalies of

the thumbs, radii, and kidneys, mental

retardation, and microphthalmia.

Hartnup'sDisease

Autosomal Recessive. Defect

in GI uptake of neutral amino

acids ------> malabsorptionoftryptophan(niacinprecursor) ------> niacindeficiency among other things.

Pellagra-like syndrome(diarrhea, dementia,

dermatitis), light-sensitive skinrash, temporary cerebellar

ataxia.

Kartagener'sSyndrome

Autosomal Recessive. Defectin dynein arms ------> lost

motility ofcilia

Recurrent sinopulmonaryinfections (due to impaired

ciliary tract).Situs inversus

,due to impaired ciliary motionduring embryogenesis: lateral

transposition of lungs,

abdominal and thoracic visceraare on opposite sides of the

body as normal. Possible

dextrocardia, male sterility.

PyruvateDehydrogenaseDeficiency

Autosomal

Recessive. PyruvateDehydrogenase deficiency ------> buildup of lactate andpyruvate ------> lactic

acidosis.

Neurologic defects.

Treatment: Increase intake

ofketogenic nutrients (leucine, lysine)

------> increase formation of Acetyl-CoA

from other sources.

XerodermaPigmentosum

Autosomal Recessive. Defectin DNA repair, inability to

repair thymine

Dry skin, melanomas, pre-malignant lesions, other

cancers. Ophthalmic and


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dimers resulting from UV-lightexposure ------> excessiveskin damage and skin cancer.

neurologic abnormalities.

Familial

Hypercholesterolemia

Autosoma

lDominantDisorders

Autosomal Dominant. LDL-

Receptor defect.

Heterozygous: accelerated

atherosclerosis. Homozygous:accelerated atherosclerosis, MIby age 35, xanthomas.

HereditaryHemorrhagicTelangiectasia(Osler-Weber-RenduSyndrome)

Autosomal

Dominant

Disorders

Autosomal Dominant. Telangiectasias of skin andmucous membranes.

Hereditary

Spherocytosis

Autosoma

lDominantDisorders

Autosomal Dominant. Band-

3 deficiency in RBCmembrane ------> sphericalshape to cells. Other RBC

structural enzyme deficiencies

can cause it, too.

Sequestration of spherocytes in

spleen ------> hemolyticanemia.

Huntington'sDisease

Autosoma

l

DominantDisorders

Autosomal Dominant, 100%penetrance.

Genetic defect on Chrom 4 ------> atrophy

of caudate nuclei, putamen, frontal cortex.

Progressive dementia with

onset in adulthood, choreiform

movements, athetosis.

Marfan'sSyndrome

Autosomal

Dominant

Disorders

AutosomalDominant. Fibrillin deficiency------> faulty scaffolding in

connective tissue (elastin hasno anchor).

Arachnodactyly, dissectingaortic aneurysms, ectopialentis (subluxation of lens),mitral valve prolapse.

Neurofibromatosis (VonRecklinghausenDisease)

Autosoma

l

DominantDisorders

Autosomal Dominant. NF1gene defect (no GTPaseprotein) ------> dysregulationofRas tumor-suppressor

protein.

Multiple neurofibromas (Caf

au Lait spots) which may

become malignant,Lischnodules (pigmentedhamartomas of the iris).

Increased risk for tumors:

pheochromocytoma, Wilms tumor,

Rhabdomyosarcoma, leukemias.

TuberousSclerosis

Autosoma

l

Dominant

Autosomal Dominant. Tubers (glial nodules),seizures, mental retardation.

Associated with adenoma


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Disorders sebaceum (facial lesion),

myocardial

rhabdomyomas,renalangiomyolipomas.

Von Hippel-LindauSyndrome

AutosomalDominant

Disorders

Autosomal Dominant, shortarm of chromosome 3. Samegenetic region is associated

with incidence ofrenal cellcarcinoma.

(1) Hemangioblastomas ofcerebellum, medulla, or retina,(2) adenomas, (3) cysts in

visceral organs. High risk for

renal cell carcinoma.

CongenitalFructoseIntolerance

Carbohyd

rate

Metabolis

m Defect

Autosomal

Recessive. AldolaseB deficiency ------> buildupofFructose-1-Phosphate intissues ------> inhibit

glycogenolysis andgluconeogenesis.

Severe hypoglycemia.Treatment:Remove fructose

from diet.

Galactosemia Carbohydrate

Metabolism Defect

Autosomal Recessive. Inability

to convert galactose to glucose

------> accumulation ofgalactose in many tissues.

(1) Classic form: Galactose-1-

phosphate

Uridyltransferase deficiency.

(2) Rarer

form: Galactokinase deficiency.

Failure to thrive, infantile

cataracts, mental retardation.

Progressive hepaticfailure, cirrhosis, death.

Galactokinase-deficiency: infantile

cataracts are prominent.

Treatment: in either case,remove

galactose from diet.

AngelmanSyndrome

Chromos

omal

Deletion of part of short arm

ofchromosome 15, maternalcopy. An example ofgenomic

imprinting.

Mental retardation, ataxic gait,

seizures.Inappropriatelaughter.

Cri du ChatSyndrome

Chromos

omal5p-, deletion of the long arm ofchromosome 5.

"Cry of the cat." Severe mental

retardation, microcephaly, cat-

like cry. Low birth-weight,round-face, hypertelorism

(wide-set eyes), low-set ears,

epicanthal folds.

DownSyndrome

(Trisomy 21)

Chromos

omalTrisomy 21, with riskincreasing with maternal age.

Familial form (no age-associated risk) is

Most common cause of mental

retardation. Will see epicanthal

folds, simiancrease, brushfield spots in


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translocationt(21,x) in aminority of cases.

eyes. Associated

syndromes: congenital heartdisease, leukemia,prematureAlzheimer's disease (samemorphological changes).

Edward'sSyndrome

(Trisomy 18)

Chromosomal

Trisomy 18 Mental retardation,micrognathia, rocker-bottomfeet, congenital heart disease,flexion deformities of fingers.Death by 1 year old.

Patau'sSyndrome

(Trisomy 13)

Chromos

omalTrisomy 13 Mental retardation,

microphthalmia, cleft lip andpalate, polydactyly, rocker-bottom feet, congenital heart

disease. Similar to and moresevere than Edward'sSyndrome. Death by 1 year

old.

Prader-WilliSyndrome

Chromosomal

Deletion of part of short armofchromosome 15, paternalcopy. An example ofgenomic

imprinting.

Mental retardation, shortstature, hypotonia, obesity and

huge appetite after infancy.

Small hands and feet,

hypogonadism.

Fragile-X

Syndrome

Chromos

omalSex

chromosome

Progressively longer tandem

repeats on the long arm of theX-chromosome. The longer the

number of repeats, the worse

the syndrome. Tandem repeats

tend to accumulate throughgenerations.

Second most common cause

ofmental retardation next toDown Syndrome. Macro-

orchidism (enlarged testes) in

males.

Klinefelter'sSyndrome(XXY)

Chromos

omal

Sex

chromosome

Non-disjunction of the sex

chromosome during AnaphaseI of meiosis ------> Trisomy

(47,XXY)

Hypogonadism, tall stature,

gynecomastia. Mild mentalretardation. Usually not

diagnosed until after puberty.

One Barr body seen on buccalsmear.

Turner'sSyndrome (XO)

Chromos

omal

Sex

chromosome

Non-disjunction of the sex

chromosome during AnaphaseI of meiosis ------> Monosomy

(45,X)

Streak gonads, primary

amenorrhea, webbed neck,short stature, coarctation ofAorta, infantile genitalia.Nomental retardation. No Barr


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bodies visible on buccal smear.

XXX Syndrome Chromosomal

Sex

chromosome

Trisomy (47,XXX) and othermultiple X-chromosome

abnormalities.

Usually phenotypically normal.May see menstrual

abnormalities or mild mental

retardation in some cases.

Ehlers-DanlosSyndrome

Connectiv

e Tissue

disease

Various defects in collagen

synthesis.

Type-I: Autosomaldominant, mildest

form.

Type-IV: autosomaldominant. Defect in

reticular collagen (type-

III) Type-VI: autosomal-

recessive.

Type-VII: Defect incollagen type I

Type-IX: X-linkedrecessive

Laxity of joints,

hyperextensibility of skin, poor

wound healing, aneurysms.

Type-I: Diaphragmatichernia. Common,normal life-expectancy.

Type-IV: Ecchymoses,arterial

rupture.Dangerousdueto rupture aneurysms.

Type-VI: Retinaldetachment, cornealrupture

OsteogenesisImperfecta

Connectiv

e tissue

disease

Defects in Collagen TypeI formation.

Multiple fractures after

birth,blue sclerae, thin skin,

progressive deafness in sometypes (due to abnormal middle

ear ossicles).

Type-I is most common;Type-II is most

severe; Type-IVis mildest form.

Cori's Disease

(Glycogen Storage

Disease Type III)

Glycogen

Storage

Disease

Autosomal

Recessive. Debranchingenzyme deficiency (can onlybreak down linear chains ofglycogen, not at branch points)

------> accumulate glycogen inliver, heart, skeletal muscle.

Stunted growth, hepatomegaly,

hypoglycemia.

McArdle'sDisease

(Glycogen Storage

Disease Type V)

Glycogen

Storage

Disease

Autosomal Recessive. musclephosphorylase deficiency(cannot utilize glycogen inskeletal muscle) ------>

accumulation of glycogen in

Muscle cramps, muscle

weakness, easy fatigability.

Myoglobinuria with strenuousexercise.


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Disease y

Phagocyte

Deficiency

formation of peroxides and

superoxides ------> no

oxidative burst in phagocytes.

especially StaphAureusandAspergillus spp. B

and T cells usually remainnormal.

ChronicMucocutaneousCandidiasis

Immunedeficiency

T-Cell

Deficiency

T-Cell deficiency specificto Candida.

Selectiverecurrent Candidainfections.Treat with anti-fungal drugs.

Job's Syndrome Immunedeficienc

y

Phagocyte

Deficiency

A failure to produce gamma-Interferon by T-Helper cells,leading to an increase in TH2cells (no negative feedback) ---

---> excessively high levels

ofIgE.

High histamine levels,

eosinophilia.

Recurrent cold(non-inflammatory)

Staphylococcal abscesses(resul

ting from high histamine),eczema.

Selective IgADeficiency

Immune

deficiency

B-Cell

Deficiency

IgA deficiency may be due to a

failure of heavy-chain geneswitching.

The most common congenital

immune deficiency. There alsoexists selective IgM and IgG

deficiencies, but they are less

common.

SevereCombined

Immunodeficiency (SCID)

Immune

deficienc

yCombined

Deficiency

Autosomal

Recessive. Adenosine

Deaminase deficiency ------>accumulation ofdATP ------>inhibit ribonucleotide

reductase ------> decrease inDNA precursors

Severe deficiency in both

humoral and cellular immunity,

due to impaired DNAsynthesis. Bone marrow

transplant may be helpful in

treatment.

Thymic Aplasia(DiGeorgeSyndrome)

Immune

deficiency

T-Cell

Deficiency

Failure of development of

the 3rd and 4th PharyngealPouches ------> agenesis of thethymus and parathyroid glands.

T-Cell deficiency from nothymus. Hypocalcemictetany from primaryparathyroid deficiency.

Wiskott-AldrichSyndrome

Immune

deficienc

y

Combined

Deficiency

Inability to mount

initial IgM response to thecapsular polysaccharides ofpyogenic bacteria.

In infancy, recurrent pyogenic

infections, eczema,

thrombocytopenia, excessivebleeding. IgG levels remain

normal.

X-Linked Immune X-Linked. Mutation in gene Recurrent pyogenic infections


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Agammaglobulinemia(Bruton'sDisease)

deficienc

y

B-Cell

Deficiency

coding for tyrosinekinase causes failure of Pre-Bcells to differentiate into B-Cells.

after 6 months (when maternal

antibodies wear off). Can treat

with polyspecific gammaglobulin preparations.

Fabry's Disease Lysosomal Storage

Disease

X-Linked Recessive. alpha-Galactosidase A deficiency ------> buildup ofceramidetrihexoside in body tissues.

Angiokeratomas (skin lesions)over lower trunk, fever, severe

burning pain in extremities,

cardiovascular andcerebrovascular involvement.

Gaucher'sDisease

Lysosoma

l Storage

Disease

Autosomal

Recessive. Glucocerebrosidase deficiency ------>accumulation of

glucocerebrosides

(gangliosides, sphingolipids) inlysosomes throughout the

body.

Type-I: Adult form.80% of cases, retain

partial activity.Hepatosplenomegaly,

erosion of femoral

head, mild anemia.Normal lifespan with

treatment.

Type-II: Infantile form.Severe CNS

involvement. Deathbefore age 1.

Type-III: Juvenileform. Onset in early

childhood, involving

both CNS and viscera,

but less severe thanType II.

Niemann-PickLipidosis

Lysosoma

l Storage

Disease

Autosomal

Recessive. Sphingomyelinasedeficiency ------> accumulationof sphingomyelin in

phagocytes.

Sphingomyelin-

containingfoamy histiocytes inreticuloendo-thelial system andspleen. Hepatosplenomegaly,

anemia, fever, sometimes CNS

deterioration. Death by age 3.

Hunter's

Syndrome

Lysosoma

l StorageDisease

X-Linked Recessive. L-

iduronosulfatesulfatase deficiency ------>buildupofmucopolysaccharides (heparan sulfate and dermatan

sulfate)

Similar to but less severe than

Hurler Syndrome.Hepatosplenomegaly,

micrognathia, retinaldegeneration, joint stiffness,

mild retardation, cardiac

lesions.


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Hurler'sSyndrome

Lysosoma

l Storage

Disease

Autosomal Recessive. alpha-L-iduronidase deficiency ------> accumulationofmucopolysaccharides(heparan sulfate, dermatan sulfate)

in heart, brain, liver, otherorgans.

Gargoyle-like facies,

progressive mental

deterioration, stubby fingers,death by age 10. Similar to

Hunter's Syndrome.

Tay-SachsDisease

Lysosoma

l StorageDisease

Autosomal

Recessive. HexosaminidaseA deficiency ------>accumulation of

GM2 ganglioside in neurons.

CNS degeneration,

retardation, cherry red-spot ofmacula, blindness (amaurosis).

Death before age 4.

Albinism NitrogenMetabolis

m Defect

AutosomalRecessive. Tyrosinase deficien

cy ------> inability tosynthesize melanin fromtyrosine. Can result from a lack

of migration of neural crest

cells.

Depigmentation, pink eyes,increased risk of skin cancer.

Alkaptonuria NitrogenMetabolis

m Defect

Autosomal

Recessive. HomogentisicOxidase deficiency (inabilityto metabolize Phe and Tyr) ------> buildup and urinary

excretion ofhomogentisic

acid.

Urine turns dark and black on

standing, ochronosis(darkpigmentation of fibrous and

cartilage tissues), ochronoticarthritis, cardiac valve

involvement. Disease is

generally benign.

Homocystinuria NitrogenMetabolis

m Defect

Autosomal

Recessive. Cystathioninesynthase defect (eitherdeficiency, or lost affinity for

pyridoxine, Vit. B6) ------>

buildup of homocystine anddeficiency of cysteine.

Mental retardation, ectopia

lentis, sparse blond hair, genu

valgum, failure to thrive,thromboembolic episodes, fatty

changes of liver.

Treatment: Cysteine supplementation, give

excess pyridoxine to compensate for lost

pyridoxine affinity.

Lesch-NyhanSyndrome

NitrogenMetabolis

m Defect

X-LinkedRecessive. Hypoxanthine-

GuaninePhosphoribosyltransferase(HGPRT) deficiency ------>no salvage pathway for purine

re-synthesis ------> buildup of

Hyperuricemia (gout), mentalretardation, self-mutilation

(autistic behavior),

choreoathetosis, spasticity.


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purine metabolites

Maple SyrupUrine Disease

NitrogenMetabolis

m Defect

Autosomal Recessive.Deficiency ofbranched chainketo-acid decarboxylase ------

> no degradation of branched-chain amino acids ------>buildup ofisoleucine, valine,leucine.

Severe CNS defects, mentalretardation, death. Person

smells like maple syrup or

burnt sugar. Treatment:removethe amino acids from diet.

Phenylketonuria (PKU)

Nitrogen

Metabolis

m Defect

Autosomal

Recessive. Phenylalaninehydroxylase deficiency(cannot break down Phe nor

make Tyr) ------> buildup ofphenylalanine, phenyl ketones

(phenylacetate, phenyl lactate,phenylpyruvate) in bodytissues and CNS.

Symptoms result from

accumulation of phenylalanine

itself. Mental deterioration,

hypopigmentation (blond hair

and blue eyes), mousy bodyodor (from phenylacetic acid in

urine and sweat).Treatment: remove phenylalanine from

diet.

Glucose-6-PhosphateDehydrogenase(G6PD)Deficiency

RBCDisease

X-Linked Recessive. Glucose-

6-Phosphate Dehydrogenase(G6PD) deficiency ------> nohexose monophosphate shunt ------> deficiency in NADPH ---

---> inability to

maintain glutathione in

reduced form, in RBC's

Susceptibility to oxidativedamage to RBC's, leading

tohemolytic anemia. Can beelicited by drugs (primaquine,sulfonamides, aspirin), fava

beans (favism). More prevalentin blacks.

Glycolyticenzymedeficiencies

RBC

Disease

Autosomal Recessive. Defect

in hexokinase, glucose-

phosphate isomerase, aldolase,triose-phosphate isomerase,

phosphate-glycerate kinase, or

enolase. Any enzyme inglycolysis pathway.

Hemolytic anemia resultsfrom any defect in the

glycolysis pathway, as RBC'sdepend on glycolysis for

energy.

AutosomalRecessive

PolycysticKidney Disease(ARPKD)

Renal Autosomal Recessive. Numerous, diffuse bilateral

cysts formed in the collecting

ducts. Associated with hepaticfibrosis.

Bartter'sSyndrome

Renal Juxtaglomerular CellHyperplasia, leading

to primary hyper-reninemia.

Elevated renin and aldosterone,hypokalemic alkalosis.Nohypertension.


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Fanconi'sSyndrome TypeI

(Child-onset

cystinosis)

Renal Autosomal Recessive.

Deficient resorption in

proximal tubules.

(1) Cystine deposition

throughout body, cystinuria.

(2) Defective tubularresorption leads to amino-

aciduria, polyuria, glycosuria,

chronicacidosis;Hypophosphatemia andVitamin-D-resistantRickets.

Fanconi'sSyndrome II

(Adult-onset)

Renal Autosomal Recessive.

Defective resorption in

proximal tubules.

Similar to Fanconi Syndrome

Type I, but without the

cystinosis. Adult

onset osteomalacia, amino-aciduria, polyuria, glycosuria.

AutosomalDominantPolycysticKidney Disease(ADPKD)

RenalAutosomal

Dominant

Disorders

Autosomal Dominant. Numerous, disparate,heterogenous renal cystsoccurring bilaterally. Onset in

adult life. Associated with liver

cysts.

List of Select Genetic Disorders

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