STEPTRACKERGENETICS + PATHOLOGY | RECESSIVE & X-LINKED | HIGH-YIELD REVIEW

Autosomal Recessive & X-Linked Diseases

Recessive diseases are mostly missing enzymes; X-linked recessive ones show in boys through carrier mothers. Cystic fibrosis is the model to know cold.

FOCUS ON

Cystic fibrosis: CFTR (ch 7), most often ΔF508 → misfolded protein degraded → ↓ Cl⁻ secretion, ↑ Na⁺/water reabsorption in airways → thick mucus; ↑ sweat Cl⁻ (sweat gland CFTR reabsorbs Cl⁻). XLR list: "Oblivious Female Will Often Give Her Boys Her x-Linked Disorders" — OTC, Fabry, Wiskott-Aldrich, ocular albinism, G6PD, Hunter, Bruton, hemophilia A/B, Lesch-Nyhan, Duchenne/Becker.

DISEASE

DEFECT

FEATURES

CLUE · TREATMENT

Cystic fibrosis

AR · CFTR ch 7

ATP-gated Cl⁻ channel; ΔF508 = misfolding (in-frame deletion of Phe)

Meconium ileus, recurrent Pseudomonas/S aureus pneumonia, bronchiectasis, pancreatic insufficiency (ADEK deficiency), infertility (absent vas deferens), nasal polyps, clubbing

Sweat Cl⁻ > 60 mmol/L · ↑ nasal transepithelial potential · CFTR modulators (ivacaftor, lumacaftor)

Sickle cell disease

AR · HBB

Glu → Val at β6 → HbS polymerizes when deoxygenated

Vaso-occlusion, hemolysis, autosplenectomy, osteomyelitis (Salmonella)

Hydroxyurea ↑ HbF

Hemochromatosis

AR · HFE C282Y

↑ Intestinal iron absorption (↓ hepcidin)

"Bronze diabetes", cirrhosis, HCC, cardiomyopathy, arthropathy, hypogonadism

Phlebotomy

Wilson disease

AR · ATP7B

Can't excrete copper into bile or load ceruloplasmin

Liver disease, Kayser-Fleischer rings, basal ganglia (parkinsonism, psychiatric)

↓ Ceruloplasmin · penicillamine, trientine, zinc

Spinal muscular atrophy

AR · SMN1

Anterior horn cell degeneration

Floppy baby, tongue fasciculations

Nusinersen, gene therapy

Duchenne muscular dystrophy

XR · dystrophin

Frameshift → absent dystrophin

Onset < 5 y, Gowers sign, calf pseudohypertrophy, dilated cardiomyopathy

See 5.09

Hemophilia A / B

Factor VIII / factor IX deficiency

Hemarthroses, deep tissue bleeding; ↑ PTT, normal PT

Factor replacement; emicizumab (A)

G6PD deficiency

↓ NADPH → RBCs can't handle oxidants

Hemolysis after fava beans, sulfa, primaquine, infection; Heinz bodies, bite cells

Malaria protection

Bruton agammaglobulinemia

XR · BTK

B cells can't mature

Recurrent bacterial infections after 6 months, absent tonsils, ↓ all Igs

IVIG

Fabry disease

XR · α-galactosidase A

Ceramide trihexoside buildup

Burning pain in hands/feet, angiokeratomas, hypohidrosis, CKD, cardiomyopathy, stroke

Enzyme replacement

Rett syndrome

XD · MECP2

Almost always de novo; lethal in most males

Girl develops normally to 1–4 y, then regression, loss of speech, stereotyped hand-wringing, seizures, microcephaly

—

Recessive enzyme diseases

Most inborn errors of metabolism

PKU, galactosemia, glycogen and lysosomal storage diseases (except Fabry, Hunter = XR)

"Enzyme deficiency → usually AR"

Mechanism — cystic fibrosis in each organ

ΔF508 misfoldsDegraded in ER

→

Airway↓ Cl⁻ out, ↑ Na⁺ in → dry mucus

→

Pancreas, bile ducts, vasPlugged ducts

→

Sweat ductCl⁻ not reabsorbed → salty sweat

In sweat glands CFTR normally reabsorbs Cl⁻; everywhere else it secretes Cl⁻ — which is why sweat is the diagnostic fluid.

X-linked recessive checklist

DISEASE

DEFECT

HALLMARK

OTC deficiency

Urea cycle

Hyperammonemia, orotic acid

Wiskott-Aldrich

WAS protein

Eczema, thrombocytopenia, infections

Hunter

Iduronate sulfatase

MPS, no corneal clouding

Lesch-Nyhan

HGPRT

Self-mutilation, gout

Ocular albinism

GPR143

Low vision, normal skin

How it's tested

COMMON CONFUSIONMost lysosomal storage diseases are AR — Fabry and Hunter are the X-linked exceptions.

THE TRAPInfertility in a man with CF is obstructive — absent vas deferens; sperm production is normal. Women have thick cervical mucus but can conceive.

YOUR APPROACHMale-only pattern via mothers → XLR list; enzyme deficiency → probably AR; then organ clues → specific disease.

If you see… think…

Newborn with meconium ileus → cystic fibrosis

Salty-tasting baby, failure to thrive, recurrent pneumonia → CF (sweat Cl⁻ test)

Man with CF and azoospermia → congenital bilateral absence of vas deferens

Diabetes, bronze skin, cirrhosis → hereditary hemochromatosis (HFE)

Kayser-Fleischer rings + low ceruloplasmin → Wilson (ATP7B)

Girl regressing at age 2 with hand-wringing → Rett (MECP2)

Boy with burning hands, angiokeratomas, proteinuria → Fabry

Eczema, petechiae, recurrent infections in a boy → Wiskott-Aldrich

Hemolysis after fava beans → G6PD deficiency

Isolated ↑ PTT and hemarthrosis in a boy → hemophilia A or B