Glycolipids, Glycerophospholipids, sphingophospholipids, Lysosomal Storage Disorders

Glycolipids

• Glycolipids are ceramide derivatives.
• Ceramide = fatty acid + sphingosine = (Serine + Palmitoyl CoA)

• Glycolipids = Ceramide +
• A carbohydrate group.
• A fatty acid.
• An alcohol.

Types of Glycolipids

• Cerebrosides:
• Ceramide + monosaccharide (glucose or galactose).
• Galactocerebroside → Neural tissues.
• Glucocerebroside → Extra-neural tissues.
• Side (ceramide) + Bro (single → mono)

• Globosides:
• Ceramide + oligosaccharide (glucose + galactose)
• Lactosylceramide
• Side (ceramide), O (oligo)

• Gangliosides:
• ganglioside → Side (ceramide), oligo (), Na (NANA)
• Globoside + NANA
• GM3 Ganglioside:
• Ceramide + oligosaccharide + NANA.
• The simplest ganglioside.
• GM2 Ganglioside:
• Ceramide + oligosaccharide + NANA + N-Acetyl Gal NH2
• (Galactose in GM3)
• GM1 Ganglioside:
• Ceramide + oligosaccharide + NANA + N-Acetyl Gal NH2 + galactose
• (attaches to N-Acetyl Gal NH2 in GM2)

Glycolipid Metabolism Disorders
(Lysosomal Storage Disorders)

Mnemonics for Glycosphingolipidosis

• GF:
• No mental retardation in Gaucher's and Fabry's disease.

• KGF:
• No Cherry red spot in Krabbe's, Gaucher's, and Fabry's disease.

• Tay Sach's and Krabbe's disease:
• No organomegaly.

Cherry Red Spot Disorders

• Seen in:
• GM1 gangliosidosis
• Tay-Sachs disease
• Niemann Pick disease

 

• Not seen in Gaucher

GM1 Gangliosidosis:

• Absence of Beta Galactosidase.

• GM1 - Galactose = GM2

GM2 Gangliosidosis / Tay Sach’s

• Absence of β Hexosaminidase A / Galactosaminidase
• catalyze GM2 - NGAL ⇏ GM3
• ⇒ GM2 (↑↑)

• Tay Sachs’s Disease
• Hexosaminidase A
• GM2 ganglioside accumulation

• Sandhoff diseases
• Hexosaminidase A + B
• Same as Tay–Sachs + hyperacusis + Globoside accumulation

• Key features:
• Neurological manifestations.
• Both have macrocephaly
• Exaggerated startle reflex - Tay Sachs’s Disease
• Cherry red spot on fundus examination.
• d/t lipid accumulation in ganglion cells.
• The fovea remains transparent as it lacks ganglion cells.

Onion Skin Appearance:

 

• Mnemonic:
• Onion → PSC exam
• PSC (Primary Sclerosing) kk padikan Sleep (SLE, Spleen) kalanj Tea (Tay) kudich BP (HTN) kuutti → Kidappilayi (CIDP)
• but Wings (ewing) vannu
• Lysosomes with onion-skin appearance - Tay sach’s
• Paccinian corpuscles

• Seen in:
• Chronic inflammatory demyelinating polyneuropathy (Biopsy)
• Primary sclerosing cholangitis (Biopsy)
• SLE, spleen (Gross)
• Ewing's sarcoma (X-ray)
• Tay sach's disease (Electron microscopy)
• Malignant hypertension (Biopsy).

Benign Hypertension

 

Associated Condition	Benign Hypertension	Malignant Hypertension
Feature	Benign Nephrosclerosis	Malignant Nephrosclerosis
Histological Finding	Pink, homogenous hyaline thickening of vessel wall	Concentric laminated thickening of vessel wall
Appearance/Result	Luminal narrowing	Onion skin appearance

GM3 Gangliosidosis / Sialidosis:

• Absence of Neuraminidase.
• GM3 - NANA = Globoside

• Presents with:
• Generalised swelling.
• Neurological manifestations.
• Organomegaly.

Fabry's Disease:

• Alpha girl (α gal) like fabric (fabrys) → searched whole globe (globoside) for fabric (fabrys) with cross (maltease cross) → last full rashes (angiokeratoma), CKD and Early MI → lens opaque ayi (lenticular opacities)

• X-linked recessive inherited disorder.

• Absence of Alpha Galactosidase.
• Globoside - Galactose = Cerebrosides
• Globoside / Ceramide accumulates.

• Clinical features:
• Reddish purple spots/angiokeratomas.
• Proteinuria.
• Chronic kidney disease (CKD).
• Early myocardial infarction.

• Maltase cross in urinary sediments

• No mental retardation.

• No cherry red spot.

Vortex Keratopathy / Cornea verticillata

• Whorl like/Spindle pattern

• Also seen in Queen () Ami () Tame () with Netram () in Indian () Fabric () dress
• Chloroquine
• Amiodarone
• Tamoxifene
• Netarsudil (Rho kinase ⛔),
• Indomethacin
• Fabry’s disease
• Phenothiazines

• NOT Methotrexate

Gaucher's Disease:

ERT Available For:

• Gaucher

• Pompe

• Fabry

• MPS I (Hurler), II (Hunter), IV (Morquio)

• Niemann Pick (recently)

Farber's Disease:

• Absence of Ceramidase
• Splits Ceramide → sphingosine + fatty acids.

• Manifests as a granulomatous condition.

• Features:
• Painful subcutaneous nodules.
• CKD.
• Neurological manifestations.
• Organomegaly (including hepatosplenomegaly).
• Resemble RA

• Ceramic (ceramidase) kadayile Farmer (Farber) nu RA ()

Tangier's Disease:

• Characterised by orange-coloured tonsils.

• Cholesterol esters accumulate in extrahepatic tissues, causing:
• Greyish-orange tonsils.
• Hepatosplenomegaly.
• Mononeuritis multiplex.

• ABC students drink Tang → don't get A1 → cant multiply

• Caused by a mutation in ABC1 (ATP Binding Cassette transporter 1).

• Key Characteristic:
• Significantly reduced levels of apo A1→ very low HDL levels.

Profile Component	Level
HDL	↓↓
LDL	↓
TAG	↑
Total Cholesterol	Normal/Low
Apo A1	↓↓

Wolman's Disease:

• Caused by a defect of Acid lipase.
• Note: Pompe's Disease → Acid maltase defect.

• Characterised by adrenal calcification.

Krabbe Disease

• Galactocerebrosidase (β-galactosidase)
• Same as GM1 gangliosidoses

Features

• Gross developmental delay

• Opisthotonus posture with clenched fists

• Globoid cells (white matter of brain)

• CN II atrophy

• Thalamic hyperdensity

• Mnemonic:
• kraBBe → β Galactosidase
• Crab HEAD Globe (Globoid) → Galactus (Galactosidase) → brain symptoms
• Boatil irunn Galaxyde (β Galactosidase) muttayi njandinu (Crab) koduth

Niemann–Pick A Disease

• [Neimann-Pick B = No CNS involvement]

• Sphingomyelinase

• Cherry red spot (CRS) on macula

• Foamy macrophages

• HSM

• Zebra body inclusions

• Mnemonic: Pick a Sac Common:
• P → Progressive Neurodegeneration
• S → Spots - cherry red
• Pick → Foamy Liver → Foam cells, Hepatomegaly
• Pick Sphik → Sphingomyelin
• Pick Zebra

Metachromatic Leukodystrophy

Tigroid appearance of brain seen in

Feature	Pelizaeus–Merzbacher	Metachromatic Leukodystrophy
Inheritance	X-linked recessive	Autosomal recessive (white matter involvement).
Defect	PLP1 gene	Arylsulfatase A
Myelin problem	Hypomyelination	Demyelination
Hallmark	• Early nystagmus	• Sulfatides accumulation • Peripheral nerves involved • Metachromasia • Cherry red spot
Mnemonic	Merzbacker → mess in the back → 💩 → look like tiger	• Central and peripheral demyelination • Ataxia, dementia

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Aryl suphatase

• Metachromatic leukodystrophy
• Enzyme: Arylsulfatase A
• CNS involvement present

• Maroteaux-Lamy
• Enzyme: Arylsulfatase B
• No CNS involvement

Key Diagnostic Approach (Algorithm Summary):

• Mnemonic:
• Cherry (CRS) Sac (Tay sac) nnu Pick (Neiman Pic) cheythapo → Crab (Krabbe) nu MR (MR in all 3) vann
• No Cherry in KGF (Krabbe, Gaucher, Fabrys)
• No MR in GF (Gauchers, Fabrys)
• No Organomegaly in Krabbe and Sac

1. Check for Organomegaly: Hepatosplenomegaly in Gaucher’s, Niemann-Pick.
• Present:
• Cherry Red Spot (CRS) + Mental Retardation (MR)
• Neimann–Pick Disease
• CRS - / MR -
• Gaucher Disease
• Mnemonic: Pick () a foamy liver (HSM) and wrap in Gauze (Gauchers)
• Absent:
• CRS + / MR +
• Tay–Sachs or Sandhoff Disease
• GM2 gangliosidosis
• CRS - / MR +
• Krabbe Disease
• Opisthotonus, clenched fists, globoid cells, no hepatosplenomegaly
• CRS - / MR -
• Check for Maltese Cross in urine:
• Present → Fabry Disease
• Angiokeratomas, lenticular opacities
• Absent → Metachromatic Leukodystrophy
• Demyelination, ataxia