LIPID STORAGE DISEASES Presented by, DR. AHMAD JAN Student M. Phil Chemical Pathology FPGMI Lahore
Lipids Lipids are fat-like substances that are important parts of the membranes found within and between each cell and in the myelin sheath that coats and protects the nerves. Lipids include oils, fatty acids, waxes, steroids (such as cholesterol and estrogen), and other related compounds.
Why lipids are important- Lipids are important to the body because;- • Important constituent of the cell membranes. • Helps in the absorption of fat soluble vitamins. • Maintains membrane fluidity. • Acts as a thermal insulator and cellular metabolic regulator. • Hormone synthesis. • Organ padding. •
Lipid storage diseases Lipid storage diseases, or lipidoses, are a group of inherited metabolic disorders in which harmful amounts of fatty materials called lipids accumulate in some of the bodys cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize lipids, or they produce enzymes that do not work properly. Over time, this excessive storage of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow.
Inheritance Lipid storage diseases can be inherited two ways 1. Autosomal recessive inheritance occurs when both parents carry and pass on a copy of the faulty but none of the parents show symptoms of disease. 2. X-linked recessive (or sex linked) inheritance occurs when the mother carries the affected gene on the X chromosome that determines the child’s gender and passes it to her son.
Pathophysiology Because glycosphingolipids are essential components of all cell membranes, inability to degrade these substances and their subsequent accumulation results in physiologic and morphologic alterations of specific tissues and organs that lead to characteristic clinical manifestations. In particular, progressive lysosomal accumulation of glycosphingolipids in the central nervous system can lead to a neurodegenerative course; whereas, storage in visceral cells can lead to organomegaly, skeletal abnormalities, bone marrow dysfunction, pulmonary infiltration, and other manifestations.
Gaucher disease most common of the lipid storage diseases Cause caused by a deficiency of the enzyme glucocerebrosidase. Resulting in accumulation of glucocereboside in spleen ,liver, kidneys,lungs,brain and bone marrow. CLINICAL FEATURES Type 1 (non neuropathic form ) May be asymptomatic. Begin early in life Bruise easily Fatigue
Hepatomegally Spleenomegally Brain not affected Type 2 (acute infantile neuropathic ) Begins within three months of birth. Poor ability to suck and swallow. Abnormal eye movements. Extensive and progressive brain damage. Spasticity, Seizures and Limb rigidity. Hepatomegally and Splenomegally.
Type 3 (chronic neuropathic ) Can begin at any time in child hood or even inadult hood but milder neurologic symptoms as compared to type two. Respiratory problems. Anemia. Skeletal problems. Treatment For type 1 and most type 3 patients, enzyme replacement treatment given
intravenously every two weeks can dramatically decrease liver and spleen size, reduce skeletal abnormalities and other manifestations. bone marrow transplantation cures the non- neurological manifestations. Blood transfusion for anemia. Splenectomy (rarely ) No effective treatment for brain damage. Prognosis Type 1: may live well into adulthood. Type 2: usuallyo teen age die before age two. Type 3: live to teen age.
Niemann-Pick disease Cause Niemann-Pick types A and B result from accumulation of the fatty substance called sphingomyelin, due to deficiency of an enzyme called sphingomyelinase. Resulting in accumulation of sphingomyelin in liver,spleen, bone marrow,lungs and in some patients in brain.
Type A Infants are normal at birth but at age of six years develop: Splenomegally Hepatomegally Swollen lymph nodes Profound brain damage (atraxia,spasticity,slurred speech,loss of muscle tone ) Anemia Susceptible to recurrent infections.
Type B enlargement of the liver and spleen characteristically occurs in the pre-teen years. Most patients also develop ataxia, peripheral neuropathy, and pulmonary difficulties progress with age. Brain is generally not affected. Treatment There is currently no cure for Niemann-Pick disease. Treatment is supportive.
FABRY DISEASE The only X-linked lipid storage disease. Predominantly affecting males. Cause Deficiency of enzyme alpha galactosidase. Resulting in accumulation of globosides in nervous tissue,eyes,kidneysand cardiovascular system. Clinical features Burning pain in arms and legs Cardiomegally Fever Renal impairment
Angiokeratomas (small,non cancerous, reddish purple elevated spots on skin ) on lower part of trunk. Treatment Enzyme replacement therapy Phenytoin or carbamazepine for pain Dialysis or renal transplant.
Farber’s disease Cause Deficiency of the enzyme called ceramidase. Resulting in accumulation of ceramide in joints , tissues and central nervous system. Clinical features Dyspnea Dysphagia Vomiting Arthritis Horseness Xenthemas Joint contractures
Treatment no specific treatment for Farber’s disease. Most children with the disease die by age 2.
Krabbé disease Cause deficiency of the enzyme beta galactactosidase. Resulting in accumulation of galactocerebrosides in white matter of CNS and peripheral nerves. Clinical features Onset usually before age 6 months Hypertonia Seizures Spasticity Irritability Optic atrophy and blindness
Diagnosis Characteristic grouping of cells into globoid bodies in white matter of brain. Demyelination of nerves and degeneration and destruction of brain cells. Treatment No specific treatment Bone marrow tranasplantation helpful in some patients.
Metachromatic leukodystrophy Cause Due to deficiency of enzyme arylsulfatase A. Resulting in accumulation of sulfatides in CNS, peripheral nerves and kidneys. Clinical features Normal at birth Develop difficulty in walking and tendency to fall followed by intermittent pain in arms and legs. Progressive loss of vision leading to blindness. Developmental delays. Dementia.
Tteatment Treatment is symptomatic and supportive. Bone marrow transplantation may delay progression of the disease in some casses.
Gangliosidosis Two groups 1. GM 1 Gangliosidosis5 Cause Due to deficiency of enzyme beta galactosidase Resulting in abnormal storage of acidic lipid materials particularly in nerve cells of central and periphel nervous system.
Types a) Infantile Neurodegeration Seizures Hepatosplenomegally Coarsning of fascial features Skeletal irregularites Distended abdomen Deafness Blindness
Adult type Atrophy Dystonia Corneal clouding Angiokeratomas on lower part of trunk.
GM 2 Gangliosidosis Cause Due to deficiency of enzyme beta hexosaminidase. Types 1. Tay-Sachs disease Cause Due to deficiency of enzyme beta hexosaminidase A. Resulting in accumulation of gangliosides in nerve cells. Clinical features Initially normal Sign and symptoms begin at age of six months
Rapid and progressive neurodegeneration Cherry red spots in retinas Dementia Deafness Blindness Seizures Treatment No specific treatment Symptomatic and supportive Anticonvulsants for seizuress
2. Sandhoff disease Cause Due to deficiency of enzyme beta hexosaminidase A and B. Resulting in accumulation of gangliosides and globosides in nerve cells. Clinical features Same as Tay-sachs disease plus visceral involvement i.e hepatosplenomegally. Treatment Same as Tay-sachs disease.
Diagnosis Diagnosis is made through clinical examination, biopsy, genetic testing, molecular analysis of cells or tissues, and enzyme assays (testing a variety of cells or body fluids for enzyme deficiency). In some forms of the disorder, a urine analysis can identify the presence of stored material.
References Lehninger,principles of biochemistry. Stryer,biochemistry.s Lppincott’s,biochemistry. Tietz,clinicil chemistry. CMDT by Lawrence. Online resources http://www.ninds.nih.gov http://emedicine.medscape.com http://www.sharecare.com http://www.britannica.com