Lysosomes and Lysomal Stroage Disease

Lysosomes function

Recycling center of the cell; degrade macromolecules into fatty acids, amino acids, nucleotides, monosaccharides

Lysosome acidity

pH ~4.5

Lysosomal hydrolases

Active only at acidic pH; responsible for intracellular digestion

LAMPs

Lysosomal membrane proteins defining lysosome identity

Lysosome morphology

Morphologically diverse; defined by biochemical properties rather than appearance

Lysosomal transporters

Transport sugars, amino acids, purines, pyrimidines, and other building blocks

Lysosomal enzyme trafficking origin

Hydrolases translated in ER and transported through Golgi

M6P signal

Mannose‑6‑phosphate added to lysosomal enzymes for targeting

GlcNAc‑1‑phosphotransferase subunits

GNPTAB encodes α/β catalytic subunits; GNPTG encodes γ subunit

GlcNAc‑1‑phosphotransferase function

Adds GlcNAc‑P to mannose residues on lysosomal enzymes

Uncovering enzyme

Removes GlcNAc to expose M6P

M6P receptor function

Binds M6P‑tagged enzymes in Golgi and directs them to lysosomes

Secreted lysosomal enzymes

Recovered by receptor‑mediated endocytosis

Glycocalyx turnover

Continuously remodeled via endocytosis and lysosomal degradation

Lysosomal storage disease definition

Genetic conditions due to lysosomal enzyme deficiencies causing substrate accumulation

LSD incidence

~1 in 6,000 collectively

LSD inheritance

Mostly autosomal recessive; exceptions: Hunter syndrome, Fabry disease (X‑linked)

LSD onset

Usually early childhood; adult variants exist

LSD tissue specificity

Depends on tissue distribution of stored substrate

Mucopolysaccharidoses stored substrate

Glycosaminoglycans (GAGs)

Mucopolysaccharidoses symptoms

Dysmorphic features, cardiovascular and skeletal abnormalities, mental retardation, early death

Hunter syndrome inheritance

X‑linked; almost all patients male

Oligosaccharidoses stored substrate

Glycans and oligosaccharides

Oligosaccharidoses symptoms

Similar to mucopolysaccharidoses

Sphingolipidoses stored substrate

Sphingolipids

Sphingolipidoses symptoms

Severe neurological degeneration; loss of motor and intellectual function

Examples of sphingolipidoses

Fabry, Niemann‑Pick, Gaucher, Metachromatic leukodystrophy, Tay‑Sachs

Mucolipidoses cause

Loss of phosphotransferase needed for M6P tagging

Mucolipidoses stored substrate

Multiple substrates accumulate

I‑cell disease inheritance

Autosomal recessive

I‑cell disease molecular defect

Phosphotransferase deficiency → no M6P tagging

I‑cell disease enzyme fate

Lysosomal enzymes secreted into extracellular fluids

I‑cell disease early sign

Impaired turnover of extracellular matrix

I‑cell disease clinical features

Skeletal deformities, hepatomegaly, coarse facial features, low nasal bridge, growth retardation, intellectual regression

I‑cell disease prognosis

Death in early childhood

Hurler disease enzyme deficiency

α‑L‑iduronidase deficiency

Hurler disease stored substrates

Dermatan sulfate and heparan sulfate GAGs; glycosphingolipids may also accumulate

Hurler disease severity

Varies with allelic heterogeneity (Hurler > Scheie)

Hurler disease symptoms

Skeletal deformities, coarse facies, hepatosplenomegaly, cardiac abnormalities, neuropathies

Hurler disease neurological symptoms

Intellectual disability, hearing loss, vision loss (severe cases)

Fabry disease inheritance

X‑linked

Fabry disease enzyme deficiency

α‑galactosidase A deficiency

Fabry disease stored substrate

Ceramide trihexoside (Gb3)

Fabry early symptoms

Tingling, numbness, burning pain in hands/feet (acroparesthesias)

Fabry vascular lesions

Angiokeratomas

Fabry organ involvement

Heart, kidney, brain → heart failure, renal failure, neurological deficits

Fabry cause of death

Uremia, myocardial infarction, pulmonary congestion (age 30–50)

Fabry treatment

Enzyme replacement therapy (ERT)

Fabry skin lesions

Angiokeratomas: dark red/purple, non‑blanchable

Fabry angiokeratoma distribution

Buttocks, groin, umbilicus, upper thighs

Fabry angiokeratoma onset

Adolescence or young adulthood

Fabry corneal finding

Cornea verticillata (“whorled” pattern)

Fabry corneal involvement

Does not impair vision

Fabry dysmorphic facies

Prominent ear lobules, periorbital fullness, bushy eyebrows, recessed forehead, generous nose, bulbous tip, supraorbital ridges, shallow midface, full lips

Fabry diagnostic criteria

Test any patient with family history or corneal verticillata

Fabry additional diagnostic triggers

Two+ features: decreased sweating, angiokeratomas, kidney failure history, acroparesthesias, heat/cold intolerance, unexplained cardiac hypertrophy

Fabry male diagnosis

WBC α‑gal activity <5% normal

Fabry female diagnosis

Mosaic; α‑gal may be low or normal

Fabry biomarkers

↑Gb3; ↑lysoGb3 (deacylated Gb3)

Fabry newborn screening

Detects mild mutations; many of unknown significance

Fabry pathogenesis

Gb3 deposition → multi‑organ dysfunction

Fabry epidemiology

Incidence 1/47,600–1/117,000; higher true prevalence

Fabry newborn screening Italy

1/3,100 newborns

Fabry newborn screening Taiwan

1/1,500 newborns; 86% cardiac variant

Fabry mutation count

~790 GLA mutations recorded

Fabry mutation types

~70% missense/nonsense; others include splicing, regulatory, deletions, insertions

Fabry phenotype variability

High variability even within families

Fabry common symptoms

Neuropathic pain, abdominal pain, headache, tinnitus, hearing loss, diarrhea, cardiovascular disease

Fabry female disease

Major organ involvement common; X‑linked but NOT recessive

Fabry management

Multidisciplinary: nephrology, neurology, cardiology, genetics, pain, pediatrics, psych, derm, ophthalmology

ERT drugs

Agalsidase alpha (EU), agalsidase beta (FDA)

ERT mechanism

Replace deficient α‑gal A; relies on M6P receptor uptake

ERT limitations

Does not treat neurologic forms

ERT outcomes

94% survival at 10 years; 81% event‑free

ERT cost

~$300,000/year

Fabry novel therapies

Chaperones, substrate reduction therapy, stem cell transplant, gene therapy

Pharmacological chaperones

Small molecules that stabilize mutant α‑gal A in ER