LIPID STORAGE DISEASES

Presented by,

DR. AHMAD JAN

Student M. Phil

Chemical Pathology

FPGMI Lahore

LipidsLipids Lipids are fat-like substances that are Lipids are fat-like substances that are

important parts of the membranes important parts of the membranes found within and between each cell found within and between each cell and in the myelin sheath that coats and in the myelin sheath that coats and protects the nerves.  Lipids include and protects the nerves.  Lipids include oils, fatty acids, waxes, steroids (such oils, fatty acids, waxes, steroids (such as cholesterol and estrogen), and other as cholesterol and estrogen), and other related compounds. related compounds.

Why lipids are important-Why lipids are important-

Lipids are important to the body because;-

1) Important constituent of the cell membranes.

2) Helps in the absorption of fat soluble vitamins.

3) Maintains membrane fluidity.

4) Acts as a thermal insulator and cellular metabolic regulator.

5) Hormone synthesis.

6) Organ padding.

•

Lipid storage diseasesLipid storage diseases

Lipid storage diseases, or lipidoses, are a group of Lipid storage diseases, or lipidoses, are a group of inherited metabolic disorders in which harmful inherited metabolic disorders in which harmful amounts of fatty materials called lipids amounts of fatty materials called lipids accumulate in some of the body's cells and accumulate in some of the body's cells and tissues. People with these disorders either do not tissues. People with these disorders either do not produce enough of one of the enzymes needed to produce enough of one of the enzymes needed to metabolize lipids, or they produce enzymes that metabolize lipids, or they produce enzymes that do not work properly. Over time, this excessive do not work properly. Over time, this excessive storage of fats can cause permanent cellular and storage of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow.nervous system, liver, spleen, and bone marrow.

InheritanceInheritance

Lipid storage diseases can be inherited two Lipid storage diseases can be inherited two waysways

1. Autosomal recessive inheritance occurs when 1. Autosomal recessive inheritance occurs when both parents carry and pass on a copy of the both parents carry and pass on a copy of the faulty but none of the parents show symptoms of faulty but none of the parents show symptoms of disease.disease.

2. X-linked recessive (or sex linked) inheritance 2. X-linked recessive (or sex linked) inheritance occurs when the mother carries the affected occurs when the mother carries the affected gene on the X chromosome that determines the gene on the X chromosome that determines the child’s gender and passes it to her son.child’s gender and passes it to her son.

PathophysiologyPathophysiology Because glycosphingolipids are essential Because glycosphingolipids are essential

components of all cell membranes, inability to components of all cell membranes, inability to degrade these substances and their subsequent degrade these substances and their subsequent accumulation results in physiologic and accumulation results in physiologic and morphologic alterations of specific tissues and morphologic alterations of specific tissues and organs that lead to characteristic clinical organs that lead to characteristic clinical manifestations. In particular, progressive manifestations. In particular, progressive lysosomal accumulation of glycosphingolipids in lysosomal accumulation of glycosphingolipids in the central nervous system can lead to a the central nervous system can lead to a neurodegenerative course; whereas, storage in neurodegenerative course; whereas, storage in visceral cells can lead to organomegaly, skeletal visceral cells can lead to organomegaly, skeletal abnormalities, bone marrow dysfunction, abnormalities, bone marrow dysfunction, pulmonary infiltration, and other manifestations.pulmonary infiltration, and other manifestations.

Types of lipid storage Types of lipid storage diseasesdiseases

Niemann pick diseaseNiemann pick disease Fabry diseaseFabry disease Farbers diseaseFarbers disease GangliosidosisGangliosidosis Krabbe diseaseKrabbe disease Metachromatic leukodystrophyMetachromatic leukodystrophy Wolmans diseaseWolmans disease

Gaucher diseaseGaucher disease most common of the lipid storage diseasesmost common of the lipid storage diseases CauseCause caused by a deficiency of the enzyme caused by a deficiency of the enzyme

glucocerebrosidase.glucocerebrosidase. Resulting in accumulation of glucocereboside in Resulting in accumulation of glucocereboside in

spleen ,liver, kidneys,lungs,brain and bone marrow.spleen ,liver, kidneys,lungs,brain and bone marrow. CLINICAL FEATURESCLINICAL FEATURES Type 1Type 1 (non neuropathic form ) (non neuropathic form )

May be asymptomatic.May be asymptomatic. Begin early in lifeBegin early in life Bruise easilyBruise easily FatigueFatigue

HepatomegallyHepatomegally SpleenomegallySpleenomegally Brain not affectedBrain not affected

Type 2 Type 2 (acute infantile neuropathic )(acute infantile neuropathic ) Begins within three months of birth.Begins within three months of birth. Poor ability to suck and swallow.Poor ability to suck and swallow. Abnormal eye movements.Abnormal eye movements. Extensive and progressive brain damage.Extensive and progressive brain damage. Spasticity, Seizures and Limb rigidity.Spasticity, Seizures and Limb rigidity. Hepatomegally and SplenomegallyHepatomegally and Splenomegally..

Type 3 Type 3 (chronic neuropathic )(chronic neuropathic ) Can begin at any time in child hood Can begin at any time in child hood

or even inadult hood but milder or even inadult hood but milder neurologic symptoms as compared to neurologic symptoms as compared to type two.type two.

Respiratory problems.Respiratory problems. Anemia.Anemia. Skeletal problems.Skeletal problems. TreatmentTreatment For type 1 and most type 3 patients, For type 1 and most type 3 patients,

enzyme replacement treatment given enzyme replacement treatment given

intravenously every two weeks can intravenously every two weeks can dramatically decrease liver and spleen size, dramatically decrease liver and spleen size, reduce skeletal abnormalities and other reduce skeletal abnormalities and other manifestations.manifestations.

bone marrow transplantation cures the non-bone marrow transplantation cures the non-neurological manifestations.neurological manifestations.

Blood transfusion for anemia.Blood transfusion for anemia. Splenectomy (rarely )Splenectomy (rarely ) No effective treatment for brain damage.No effective treatment for brain damage.

PrognosisPrognosis Type 1: may live well into adulthood.Type 1: may live well into adulthood. Type 2: usuallyo teen age die before age two.Type 2: usuallyo teen age die before age two. Type 3: live to teen age.Type 3: live to teen age.

Niemann-Pick diseaseNiemann-Pick disease CauseCause Niemann-Pick types A and B result from Niemann-Pick types A and B result from

accumulation of the fatty substance called accumulation of the fatty substance called sphingomyelin, due to deficiency of an sphingomyelin, due to deficiency of an enzyme called sphingomyelinaseenzyme called sphingomyelinase..

Resulting in accumulation of Resulting in accumulation of sphingomyelin in liver,spleen, bone sphingomyelin in liver,spleen, bone marrow,lungs and in some patients in marrow,lungs and in some patients in brain.brain.

Type AType A Infants are normal at birth but at age of Infants are normal at birth but at age of

six years develop:six years develop: SplenomegallySplenomegally HepatomegallyHepatomegally Swollen lymph nodesSwollen lymph nodes Profound brain damage Profound brain damage

(atraxia,spasticity,slurred speech,loss of (atraxia,spasticity,slurred speech,loss of muscle tone )muscle tone )

AnemiaAnemia Susceptible to recurrent infectionsSusceptible to recurrent infections..

Type BType B enlargement of the liver and spleen enlargement of the liver and spleen

characteristically occurs in the pre-teen characteristically occurs in the pre-teen years.  years.  Most patients also develop ataxia, Most patients also develop ataxia, peripheral neuropathy, and pulmonary peripheral neuropathy, and pulmonary difficulties progress with age. difficulties progress with age. Brain is generally not Brain is generally not affected.affected.

TreatmentTreatment There is currently no cure for Niemann-There is currently no cure for Niemann-

Pick disease.  Treatment is supportive.Pick disease.  Treatment is supportive.

FABRY DISEASEFABRY DISEASE The only X-linked lipid storage disease.The only X-linked lipid storage disease. Predominantly affecting males.Predominantly affecting males.

CauseCause Deficiency of enzyme alpha galactosidase.Deficiency of enzyme alpha galactosidase. Resulting in accumulation of globosides in nervous Resulting in accumulation of globosides in nervous

tissue,eyes,kidneysand cardiovascular system.tissue,eyes,kidneysand cardiovascular system.

Clinical featuresClinical features Burning pain in arms and legsBurning pain in arms and legs CardiomegallyCardiomegally FeverFever Renal impairmentRenal impairment

Angiokeratomas (small,non cancerous, Angiokeratomas (small,non cancerous, reddish purple elevated spots on skin ) on reddish purple elevated spots on skin ) on lower part of trunklower part of trunk..

TreatmentTreatment Enzyme replacement therapyEnzyme replacement therapy Phenytoin or carbamazepine for painPhenytoin or carbamazepine for pain Dialysis or renal transplant.Dialysis or renal transplant.

AngiokeratomasAngiokeratomas

Farber’s diseaseFarber’s disease CauseCause Deficiency of the enzyme called ceramidase.Deficiency of the enzyme called ceramidase. Resulting in accumulation of ceramide in joints , Resulting in accumulation of ceramide in joints ,

tissues and central nervous system.tissues and central nervous system.

Clinical featuresClinical features DyspneaDyspnea DysphagiaDysphagia VomitingVomiting ArthritisArthritis HorsenessHorseness XenthemasXenthemas Joint contracturesJoint contractures

TreatmentTreatment no specific treatment for Farber’s no specific treatment for Farber’s

disease. disease.  Most children with the disease die by Most children with the disease die by

age 2.age 2.

Krabbé diseaseKrabbé disease CauseCause deficiency of the enzyme beta galactactosidase.deficiency of the enzyme beta galactactosidase. Resulting in accumulation of galactocerebrosides Resulting in accumulation of galactocerebrosides

in white matter of CNS and peripheral nerves.in white matter of CNS and peripheral nerves.

Clinical featuresClinical features Onset usually before age 6 monthsOnset usually before age 6 months HypertoniaHypertonia SeizuresSeizures SpasticitySpasticity IrritabilityIrritability Optic atrophy and blindness Optic atrophy and blindness

DiagnosisDiagnosis Characteristic grouping of cells into Characteristic grouping of cells into

globoid bodies in white matter of globoid bodies in white matter of brain.brain.

Demyelination of nerves and Demyelination of nerves and degeneration and destruction of brain degeneration and destruction of brain cells.cells.

TreatmentTreatment No specific treatmentNo specific treatment Bone marrow tranasplantation helpful Bone marrow tranasplantation helpful

in some patients.in some patients.

Metachromatic Metachromatic leukodystrophyleukodystrophy

CauseCause Due to deficiency of enzyme arylsulfatase A.Due to deficiency of enzyme arylsulfatase A. Resulting in accumulation of sulfatides in CNS, Resulting in accumulation of sulfatides in CNS,

peripheral nerves and kidneys.peripheral nerves and kidneys.

Clinical featuresClinical features Normal at birthNormal at birth Develop difficulty in walking and tendency to fall Develop difficulty in walking and tendency to fall

followed by intermittent pain in arms and legs.followed by intermittent pain in arms and legs. Progressive loss of vision leading to blindness.Progressive loss of vision leading to blindness. Developmental delays.Developmental delays. Dementia.Dementia.

TteatmentTteatment Treatment is symptomatic and supportiveTreatment is symptomatic and supportive.. Bone marrow transplantation may delay Bone marrow transplantation may delay

progression of the disease in some progression of the disease in some casses.casses.

GangliosidosisGangliosidosis

Two groupsTwo groups 11. . GM 1 Gangliosidosis5GM 1 Gangliosidosis5 CauseCause Due to deficiency of enzyme beta Due to deficiency of enzyme beta

galactosidasegalactosidase Resulting in abnormal storage of acidic Resulting in abnormal storage of acidic

lipid materials particularly in nerve cells of lipid materials particularly in nerve cells of central and periphel nervous system.central and periphel nervous system.

TypesTypes a) a) InfantileInfantile NeurodegerationNeurodegeration SeizuresSeizures HepatosplenomegallyHepatosplenomegally Coarsning of fascial featuresCoarsning of fascial features Skeletal irregularitesSkeletal irregularites Distended abdomenDistended abdomen DeafnessDeafness BlindnessBlindness

Adult typeAdult type AtrophyAtrophy DystoniaDystonia Corneal cloudingCorneal clouding Angiokeratomas on lower part of trunkAngiokeratomas on lower part of trunk..

GM 2 GangliosidosisGM 2 Gangliosidosis CauseCause Due to deficiency of enzyme beta hexosaminidase.Due to deficiency of enzyme beta hexosaminidase.

TypesTypes 1. 1. Tay-Sachs diseaseTay-Sachs disease CauseCause Due to deficiency of enzyme beta hexosaminidase Due to deficiency of enzyme beta hexosaminidase

A.A. Resulting in accumulation of gangliosides in nerve Resulting in accumulation of gangliosides in nerve

cells.cells. Clinical featuresClinical features Initially normal Initially normal Sign and symptoms begin at age of six monthsSign and symptoms begin at age of six months

Rapid and progressive neurodegenerationRapid and progressive neurodegeneration Cherry red spots in retinasCherry red spots in retinas Dementia Dementia DeafnessDeafness BlindnessBlindness SeizuresSeizures TreatmentTreatment No specific treatmentNo specific treatment Symptomatic and supportiveSymptomatic and supportive Anticonvulsants for seizuressAnticonvulsants for seizuress

2. 2. Sandhoff diseaseSandhoff disease CauseCause Due to deficiency of enzyme beta Due to deficiency of enzyme beta

hexosaminidase A and B.hexosaminidase A and B. Resulting in accumulation of gangliosides Resulting in accumulation of gangliosides

and globosides in nerve cells.and globosides in nerve cells. Clinical featuresClinical features Same as Tay-sachs disease plus visceral Same as Tay-sachs disease plus visceral

involvement i.e hepatosplenomegally.involvement i.e hepatosplenomegally. TreatmentTreatment Same as Tay-sachs disease.Same as Tay-sachs disease.

DiagnosisDiagnosis Diagnosis is made through clinical Diagnosis is made through clinical

examination, biopsy, genetic testing, examination, biopsy, genetic testing, molecular analysis of cells or tissues, molecular analysis of cells or tissues, and enzyme assays (testing a variety and enzyme assays (testing a variety of cells or body fluids for enzyme of cells or body fluids for enzyme deficiency).  In some forms of the deficiency).  In some forms of the disorder, a urine analysis can identify disorder, a urine analysis can identify the presence of stored material.the presence of stored material.

ReferencesReferences Lehninger,principles of biochemistry.Lehninger,principles of biochemistry. Stryer,biochemistry.sStryer,biochemistry.s Lppincott’s,biochemistry.Lppincott’s,biochemistry. Tietz,clinicil chemistry.Tietz,clinicil chemistry. CMDT by Lawrence.CMDT by Lawrence. Online resourcesOnline resources http://www.ninds.nih.govhttp://www.ninds.nih.gov http://emedicine.medscape.comhttp://emedicine.medscape.com http://www.sharecare.comhttp://www.sharecare.com http://www.britannica.comhttp://www.britannica.com