Biochemical Genetics

Many of the genetic diseases are caused but mutation, alteration in the gene results in an abnormal production of the end products, metabolites, enzymes, aminoacids etc. This can be studied by a simple screening of urine, enzymes from cells or organic acids etc by an advance study of GC-MS, MSMS etc. All these fall under Biochemical genetics.

Screening For Metabolic Disorders

INTRODUCTION

Although inborn errors of metabolism are individually rare, collectively they are common. Yet many children with inherited metabolic diseases often remain undiagnosed or are not diagnosed enough to prevent irreversible damage. Furthermore, inherited metabolic disease may recur in the family.

Early & accurate diagnosis of metabolic disease is very important in determining patient outcome. Many of these disorders are now treatable by simple dietary measures, yet when undiagnosed and untreated, result in death or irreversible mental retardation.

Phenylketonuria, Galactosemia, and Maple Syrup Urine Disease are a few examples of disorders in which early diagnosis and introduction of therapy can prevent disorders otherwise there are severe outcomes. The clinician is presented with a difficult situation: clinical presentations for metabolic disease are often non-specific and shared with more common disorders of early infancy. When & how screening can be done?

The predominant clinical signs in infancy suggesting the possibility of metabolic disease are lethargy and poor feeding. Due to the importance of early diagnosis, the clinician should consider metabolic disease parallel with other considered diagnoses. Any child or adult with progressive developmental delays, dementia or neurological decline could benefit from metabolic screening. Should you have a patient with any of the clinical manifestations and initial laboratory findings listed below, then selective screening is indicated.

Indications for biochemical genetic testing

CLINICAL MANIFESTATIONS

Failure to thrive

Hepatomegaly

Vomiting

Coarse facial features

Diarrhea

Abnormal odor

Lethargy or coma

Dysmorphic features

Hypotonicity

Abnormal eye findings

Hypertonicity

Abnormal hair

Seizures

Macroglossia

Respiratory distress

Apnea

Jaundice

Progressive dementia

Progressive neurological deterioration

INITIAL HOSPITAL FINDINGS

Metabolic acidosis Hypoglycemia

Hyperammonemia Elevated liver enzymes

Nonglucose reducing sugar Ferric chloride test positive on urine

Ketonuria Neutropenia

Thrombocytopenia Anemia

Vacuolated lymphocytes on peripheral smear

PLEASE NOTE: Appropriate clinical interpretations of laboratory results require an accompanying clinical history.

Comprehensive screening

COMPREHENSIVE SCREEN:

Urine metabolic screen, Paper Chromatography

Urine organic acid analysis - by GC MS,

Urine and Plasma amino acid

URINE ORGANIC ACIDS:

Organic acid analysis by GC/MS will detect medium-chain acyl-CoA dehydrogenase deficiency (MCAD), Canavan disease, and primary and secondary organic acidemias that are not detectable by either metabolic screen or amino acid analysis. Altogether 120 organic acid disorders can be diagnosed by this method.

ENZYME ASSAYS:

A large variety of enzyme assays diagnostic for specific metabolic defects are offered. These assays are usually performed as a follow-up to positive screening tests or when clinical symptoms strongly suggest a specific disorder.

The chart below is meant to give a quick-scan of the characteristics of the Lysosomal Diseases.

Name

Enzyme Defect

Substance
Stored

Chromosome Location

A. Glycogenosis Disorders

Pompe Disease

Acid-a1,4-Glucosidase

Glycogen a 1-4 linked
Oligosaccharides

17

B. Glycolipidosis Disorders

GM1 Gangliodsidosis

Beta -Galactosidase

GM₁Ganliosides

3

Tay-Sachs Disease

Beta-Hexosaminidase A

GM₂Ganglioside

15

GM2 Gangliosidosis: AB Variant

GM₂ Activator Protein

GM₂Ganglioside

5

Sandhoff Disease

Beta-Hexosamindase A&B

GM₂Ganglioside

5

Fabry Disease

Alpha-Galactosidase A

Globosides

X

Gaucher Disease

Glucocerebrosidase

Glucosylceramide

1

Metachromatic Leukodystrophy

Arylsulfatase A

Sulphatides

22

Krabbe Disease

Galactosylceramidase

Galactocerebroside

14

Niemann-Pick, Types A and B

Acid Sphingomyelinase

Sphingomyelin

18

Niemann-Pick, Type C

Cholesterol Esterification Defect

Sphingomyelin

18

Niemann-Pick, Type D

Unknown

Sphingomyelin

18

Farber Disease

Acid Ceramidase

Ceramide

?

Wolman Disease

Acid Lipase

Cholesteryl
Esters

10

C. Mucopolysaccharide Disorders

Hurler Syndrome
(MPS IH)

Alpha-L-Iduronidase

Heparan & Dermatan Sulfates

4

Scheie Syndrome
(MPS IS)

Alpha-L-Iduronidase

Heparan & Dermatan Sulfates

4

Hurler-Scheie
(MPS IH/S)

Alpha-L-Iduronidase

Heparan & Dermatan Sulfates

4

Hunter Syndrome
(MPS II)

Iduronate Sulfatase

Heparan & Dermatan Sulfates

X

Sanfilippo A
(MPS IIIA)

Heparan N-Sulfatase

Heparan Sulfate

17

Sanfilippo B
(MPS IIIB)

Alpha-N-Acetylglucosaminidase

Heparan Sulfate

17

Sanfilippo C
(MPS IIIC)

Acetyl-CoA-Glucosaminide Acetyltransferase

Heparan Sulfate

14

Sanfilippo D
(MPS IIID)

N-Acetylglucosamine -6-Sulfatase

Heparan Sulfate

12

Morquio A
(MPS IVA)

Galactosamine-6-Sulfatase

Keratan Sulfate

16

Morquio B
(MPS IVB)

Beta-Galactosidase

Keratan Sulfate

3

Maroteaux-Lamy
(MPS VI)

Arylsulfatase B

Dermatan Sulfate

5

Sly Syndrome
(MPS VII)

Beta-Glucuronidase

?

7

D. Oligosaccharide/Glycoprotein Disorders

a-Mannosidosis

Alpha-Mannosidase

Mannose/Oligosaccharides

19

b-Mannosidosis

Beta-Mannosidase

Mannose/Oligosaccharides

4

Fucosidosis

Alpha-L-Fucosidase

Fucosyl Oligosaccharides

1

Asparylglucosaminuria

N-Aspartyl- b-Glucosaminidase

Asparylglucosamine
Asparagines

4

Sialidosis (Mucolipidosis I)

Alpha-Neuraminidase

Sialyloligosaccharides

20

Galactosialidosis
(Goldberg Syndrome)

Lysosomal Protective Protein Deficiency

Sialyloligosaccharides

20

Schindler Disease

Alpha-N-Acetyl- Galactosaminidase

?

22

E. Lysosomal Enzyme Transport Disorders

Mucolipidosis II (I-Cell Disease)

N-Acetylglucosamine-1- Phosphotransferase

Heparan Sulfate

4

Mucolipidosis III (Pseudo-Hurler Polydystrophy)

Same as ML II

4

F. Lysosomal Membrane Transport Disorders

Cystinosis

Cystine Transport Protein

Free Cystine

17

Salla Disease

Sialic Acid Transport Protein

Free Sialic Acid and
Glucuronic Acid

6

Infantile Sialic Acid Storage Disease

Sialic Acid Transport Protein

Free Sialic Acid and
Glucuronic Acid

6

G. Other

Batten Disease (Juvenile Neuronal Ceroid Lipofuscinosis)

Unknown

Lipofuscins

16

Infantile Neuronal Ceroid Lipofuscinosis

Palmitoyl-Protein Thioesterase

Lipofuscins

1

Mucolipidosis IV

Unknown

Gangliosides &
Hyaluronic Acid

?

Prosaposin

Saposins A, B, C or D

10

All LDS’s can be studied from Leucocytes, fibroblasts or plasma depending on the enzymes to be investigated.

Prenatal diagnosis for biochemical genetic disorders

Please directly contact the laboratory at +91 079 26921414/ 26921415. for more specific information regarding the condition in question and availability of desired testing.

Triple marker screening