Disaccharidases Deficiences Flashcards
How do Disaccharidase deficiency lead to Pathology?
- Increased osmotic load in small bowel
- Increased carbohydrate substrate
- Production of fatty acids, acetate, butyrate, hydrogen gas
- Bowel distention, abdominal pain, diarrhoea
How does dissacharidase deficiency commonly occur?
- Most commonly secondary to GI diseas.
- Isolated enzyme defect is rare
Why are biochemical tests not preferred for diagnosis of disacharidase deficiency?
- Poor diagnostic performance
- Challenging
- Rarely performed
What are the types of Lactase Deficiency?
Primary
- Congenital
- Acquired
- Developmental (related to Prematurity)
Secondary
What are features of congenital lactase deficiency?
- Rare, autosomal recessive disorder
- Severe presentation
- Histology and other enzymes normal
What are features of Acquired lactase deficiency?
- Lactase falls with age
- Genetic basis
What causes secondary lactase deficiency?
Intestinal Disease
- Flattening of villi causing lactose malabsorption
- Bacterial overgrowth in small intestine resulting in lactose fermentation
- Other disaccharidases affected but less reserve of lactase
How is the diagnosis of lactase deficiency made?
-
Clinical
- Symptoms resolve after lactose avoidance
- Formal lactose provocative test
-
Hydrogen breath test
- Histological examination
- Enzyme analysis
- Relies on biopsy quality
- Small bowel biopsy
-
Genetic testing
- Primary enzyme deficiency
- Analysis of faeces
What are tests for faecal analysis?
Tests using Faecal reducing substances
- Benedict’s test
- Reduction of Cu2+ ions
- Colour change noted
- Detects all sugars
- Thin layer chromatography
What are limitations of tests using faeal reducing substances?
- Lack of sensitivity and specificity
- Quality of the sample (uniformity, timing)
- False negative results: Bacterial degradation of disaccharides on sample storage
- False positive results: Lactose may be present in unaffected patients with diarrhoea
- Subjective
- Technical difficulties: IQC, EQA, UKAS
- Most UK laboratories have withdrawn the tests
What is Classic Galactosaemia (GALT Deficiency)?
- Autosomal Recessive condition
- Leads to severe liver and renal disease which develop at a few days of life. Can cause hypoglycaemia rarely
- Can also cause progressive neurological disease possibly due to Gal-1-P and galactitol
- Cataracts caused by increased galactitol in lens
- Withdrawal of lactose improves Symptoms. If left untreated, can cause sepsis (E.Coli), death
What are the enzymes affects in Classic Galactosaemia?
Affects
- Glucokinase
- Galactose-1-Phosphate Uridyl Transferase
- UDP-Epimerase
What is the biochemistry of Classical Galactosaemia?
- Elevated liver enzymes
- Jaundice (unconjugated or mixed)
- Abnormal Clotting
- Amino Acids (Tyrosine, Phenylalanine, Methionine)
- Renal Tubular Disease (Acidosis, Amino aciduria)
What are diagnostic tests for Galactosaemia?
- Urine tests for galactose (Dipstick, Benedict’s reducing substances)
- Urine sugar chromatography
- Beutler test (qualitative GALT activity in erythrocytes)
- Urine galactitol
Which tests have been withdrawn in most centres?
Urine tests for galactose (Dipstick, Benedict’s reducing substances)
- Dip-stick tests detect glucose (may be positive in galactosaemia)
- Benedict’s is non-specific
- Relies on dietary intake
- Technical difficulties (IQC, EQA, UKAS)
Urine Sugar Chromatography
- Relies on dietary intake
- Time taken for assay
- Subjective
- Technical difficulties
What are limitations of the Beutler test for analysis for Gal-1-PUT?
False Positive
- K-EDTA anticoagulant
- Delayed analysis
- Glucose-6-phosphate dehydrogenase deficiency can also be picked up
False Negative
- Transfused red blood cells
- Variant alleles
What are the features of Urine Galactitol?
Benefits
- Useful if patient transfused
- Also detects galactokinase deficiency
Limitations
- GC-MS so unsuitable for rapid screen
What are features of the newborn screening of Galactosaemia?
Included in Irish NBS programme but not recommended by UK National
- Analysis of Galactose and Gal-1-P
- GALT enzyme activity second line test
What are limitations of screening for Galactosaemia?
- Does not prevent long-term problems caused by galactosaemia
- Identifies mild variants
- Many cases present before screening result is available
How does Galactosaemia get picked up by the UK newborn screening?
Galactosaemia leads to ↑phenylalanine,↑tyrosine, and ↑methionine so inadvertently detected by newborn screening
- Phe/Tyr ratio <1 show no PKU
- ↑phenylalanine, ↑tyrosine, ↑methionine suggest liver disease
- No increase in succinylacetone which means no Tyrosinaemia type 1
What is the treatment for Galactosaemia?
- Life-long dietary restriction of galactose
- Avoid all animal milk and breast milk
- Avoid milk in processed foods
- Some hard cheeses are low in galactose
- Non-dairy galactose ?significance
- < endogenously produced galactose
What are the long term outcomes for Galactosaemia?
Low lactose/galactose feed leads to resolution of acute neonatal symptoms. Less success with long-term outcome
Cognitive impairment
- Low IQ
- Abnormalities on brain MRI
Bone health
- Nutritional deficiency
- Low bone mineral density
Gonadal impairment
- Primary ovarian insufficiency
- Sub-fertility in males and females – HRT given
What are the non classical Galactosaemias?
- Mild GALT deficiency
- Galactokinase deficiency
- Uridine diphosphate galactose 4’-epimerase deficiency (GALE)
What are features of mild GALT Deficiency?
- Duarte mutation
- Identified by borderline Beutler test and mutation analysis
- Urine galactitol
- Detected in some NBS programmes or incidentally
- Mild phenotoype, may be asymptomatic
- Benefit of galactose restriction unclear
