Biochemistry For Medicshttp://www.namrata.co/

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By- Shivanee Dunneram

Lipid Storage Diseases

Lipid storage diseases

Presented by; Shivanee DunneramRoll no:18

Introduction

Tay Sach Disease

Gaucher Disease

Niemann Pick Disease

Other lipid storage Diseases

Table of contents

any of a group of relatively rare hereditary disorders of fat metabolism, characterized by the accumulation of distinctive types of lipids;

Gangliosides

cerebrosides, or

sphingomyelins, in various body structures.

Each type of lipid accumulates as a result of a defect in one of the several organic catalysts or enzymes that normally metabolize it inside the cell.

Introduction: lipid storage diseases or sphingolipidosis

Tay Sach Disease: Biomedical defect• This is an inborn error of metabolism due to failure of degradation of gangliosides. • The enzyme hexosaminidase A is deficient.composed of an α and β subunitsMutation in α subunit,15q23

HEXOSAMINIDASE A

Tay Sach disease: Inheritance

It is inherited as an autosomal recessive traits, with a predilection in the Ashkenazi Jewish population, where the carrier frequency is about 1/25.

Tay Sach Disease: Clinical Symptoms and classification

Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms. Infantile TSD

Birth: normal but develop Loss of motor skills Increased startle reaction Macullar pallor and retinal cherry red spot 5-6 months Decreased eye contact Hyperacusis Progressive development of idiocy and blindness are diagnostic of this disease and they are due to wide

spread injury to ganglion cells, in brain and retina.

Tay Sach Disease: Clinical symptoms and Classication

Juvenile TSD extremely rare presents itself in children between 2 - 10

years develop cognitive, motor, speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5–15 years.

Tay Sach Disease: Clinical symptoms and Classication

Adult/Late Onset TSD. rare form of the disorder occurs in patients in their 20s and

early 30s. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness

Diagnosis of Tay-Sach diseaseis usually suspected in an infant with neurologic features and a cherry-red spot.

Enzymatic Assays-Definitive diagnosis is by determination of the level of ß-hexosaminidase A in isolated blood leukocytes.

Fine needle Aspiration Cytology of brain tissue – can show the degree of neuronal degeneration. FNAC has a great potential for diagnosis and follow-up of Tay-Sachs disease

Prenatal screening-Future at-risk pregnancies for both disorders can be monitored by prenatal diagnosis by amniocentesis or chorionic villus sampling.

Carrier screening- Identification of carriers within families is also possible by ß-hexosaminidase A and B determination.

Treatment of Tay-Sach disease

No cure for this disease.

Symptomatic treatment is given.

Enzyme replacement therapy and Gene

therapy are under trial.

Gaucher disease

This disease is a multisystem lipidosis characterized by hematological

changes, organomegaly and skeletal involvement, manifested in the form of

bone pains and multiple fractures.

It is the most common genetic disorder among

Ashkenazi Jews.

It is the commonest Lysosomal storage disease.

Gaucher disease :Biochemical defect

• results from deficient activity of Lysosomal Hydrolase, β- Glucocerebrosidase.

• enzyme defect results in accumulation of undegraded glycolipid in the form of Glucosyl ceramide in the cells of reticuloendothelial system.

β- Glucocerebrosidase

GAUCHER DISEASE: CLINICAL FEATURES

There are three clinical subtypes• 1)Type-1- (from early childhood-

adulthood)• easy bruising due to thrombocytopenia,

chronic fatigue due to anemia, hepatomegaly

• Progressive enlargement of spleen• Clinical bone involvement in the form of

bone pains, or pathological fractures. 

GAUCHER DISEASE: CLINICAL FEATURES

Type 2- • less common,• characterized by neurodegeneration,

extreme visceral involvement • death within 2 years of life.  Type 3- • is intermediate in presentation to type 1 and

2.• Neurological involvement is there but

occurs later in life with decreased severity as compared to Type 2.

Gaucher disease: Laboratory Diagnosis

• Enzyme activity testing: A finding of less than 15% of mean normal activity is diagnostic.• Genotype testing: Molecular diagnosis can be helpful, Especially in Ashkenazi patients.• Complete blood count: • to assess the degree of cytopenia.• Liver function enzyme testing: the presence of jaundice or impaired hepatocellular synthetic function

Imaging studies Hip MRI may

be useful in revealing early avascular necrosis.

Ultrasonography

Skeletal radiography

Liver biopsy

TreatmentEnzyme replacement therapy(ERT)

by recombinant β- Glucocerebrosidase

is currently done.

Surgical Care:

Partial and total Splenectomy was once advocated in the treatment of patients with Gaucher disease.

Bone marrow transplant is also helpful.

Gene replacement is the permanent cure.

Niemann Pick disease: clinical significanceOccurs due to impaired degradation of shingomyelins.

There is deficiency of sphingomyelinase enzyme.

Due to non degradation, there is accumulation of shingomyelin in liver, spleen, bone marrow, and brain

Niemann Pick disease: Inheritance

• Is a congenital disease• Autosomal recessive in nature• There are 2 types: A and B• Type A: more common present in 1/40000

population• Type B: present in 1/80000 population• More common in Jewish population

Niemann Pick disease :Clinical manifestation

TypeA Niemann Pick disease: there is progressive mental retardation,

hepatosplenomegaly because of progressive accumulation of sphingomyelin• Children die within 2 years of lifeType B: there is no involvement of

brain but sphingomyelin is present in excessive amount in liver, spleen, and bone marrow.• Death occurs within 20 years of

life• Treatment: only symptomatic • treatment is given.

 Disease Enzyme Deficiency

Lipid Accumulating Clinical Symptoms

Tay Sach’s Disease Hexosaminidase A

GM2 Ganglioside Mental retardation, blindness, muscular weakness

Fabry's disease α-Galactosidase Globotriaosylceramide

Skin rash, kidney failure (full symptoms only in males; X-linked recessive).

Metachromatic leukodystrophy Arylsulfatase A Sulfogalactosylceramide

Mental retardation and Psychologic disturbances in adults; demyelination.

Krabbe's disease β-Galactosidase Galactosylceramide Mental retardation; myelin almost absent.

Gaucher's disease β -Glycosidase Glucosyl ceramide Enlarged liver and spleen, erosion of long bones, mental retardation in infants.

Niemann-Pick disease Sphingomyelinase

Sphigomyelin Enlarged liver and spleen, mental retardation; fatal in early life.

Farber's disease Ceramidase Ceramide Hoarseness, dermatitis, skeletal deformation, mental retardation; fatal in early life

References

Class notes

Internet