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Paediatric Biochemistry > Disaccharidases Deficiences > Flashcards

Disaccharidases Deficiences Flashcards

1
Q

How do Disaccharidase deficiency lead to Pathology?

A
  • Increased osmotic load in small bowel
  • Increased carbohydrate substrate
  • Production of fatty acids, acetate, butyrate, hydrogen gas
  • Bowel distention, abdominal pain, diarrhoea
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1
Q

How does dissacharidase deficiency commonly occur?

A
  • Most commonly secondary to GI diseas.
  • Isolated enzyme defect is rare
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2
Q

Why are biochemical tests not preferred for diagnosis of disacharidase deficiency?

A
  • Poor diagnostic performance
  • Challenging
  • Rarely performed
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3
Q

What are the types of Lactase Deficiency?

A

Primary

  • Congenital
  • Acquired
  • Developmental (related to Prematurity)

Secondary

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4
Q

What are features of congenital lactase deficiency?

A
  • Rare, autosomal recessive disorder
  • Severe presentation
  • Histology and other enzymes normal
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5
Q

What are features of Acquired lactase deficiency?

A
  • Lactase falls with age
  • Genetic basis
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6
Q

What causes secondary lactase deficiency?

A

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
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7
Q

How is the diagnosis of lactase deficiency made?

A
  1. Clinical​​
    • Symptoms resolve after lactose avoidance
    • Formal lactose provocative test
  2. Hydrogen breath test​​
    • Histological examination
    • Enzyme analysis
    • Relies on biopsy quality
  3. Small bowel biopsy
  4. Genetic testing
    • ​​Primary enzyme deficiency
  5. Analysis of faeces
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8
Q

What are tests for faecal analysis?

A

Tests using Faecal reducing substances

  1. Benedict’s test
    • Reduction of Cu2+ ions
    • Colour change noted
    • Detects all sugars
  2. Thin layer chromatography
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9
Q

What are limitations of tests using faeal reducing substances?

A
  • 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
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10
Q

What is Classic Galactosaemia (GALT Deficiency)?

A
  • 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
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11
Q

What are the enzymes affects in Classic Galactosaemia?

A

Affects

  • Glucokinase
  • Galactose-1-Phosphate Uridyl Transferase
  • UDP-Epimerase
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12
Q

What is the biochemistry of Classical Galactosaemia?

A
  • Elevated liver enzymes
  • Jaundice (unconjugated or mixed)
  • Abnormal Clotting
  • Amino Acids (Tyrosine, Phenylalanine, Methionine)
  • Renal Tubular Disease (Acidosis, Amino aciduria)
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13
Q

What are diagnostic tests for Galactosaemia?

A
  • Urine tests for galactose (Dipstick, Benedict’s reducing substances)
  • Urine sugar chromatography
  • Beutler test (qualitative GALT activity in erythrocytes)
  • Urine galactitol
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14
Q

Which tests have been withdrawn in most centres?

A

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
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15
Q

What are limitations of the Beutler test for analysis for Gal-1-PUT?

A

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
16
Q

What are the features of Urine Galactitol?

A

Benefits

  • Useful if patient transfused
  • Also detects galactokinase deficiency

Limitations

  • GC-MS so unsuitable for rapid screen
17
Q

What are features of the newborn screening of Galactosaemia?

A

Included in Irish NBS programme but not recommended by UK National

  • Analysis of Galactose and Gal-1-P
  • GALT enzyme activity second line test
18
Q

What are limitations of screening for Galactosaemia?

A
  • Does not prevent long-term problems caused by galactosaemia
  • Identifies mild variants
  • Many cases present before screening result is available
19
Q

How does Galactosaemia get picked up by the UK newborn screening?

A

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
20
Q

What is the treatment for Galactosaemia?

A
  • 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
21
Q

What are the long term outcomes for Galactosaemia?

A

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
22
Q

What are the non classical Galactosaemias?

A
  • Mild GALT deficiency
  • Galactokinase deficiency
  • Uridine diphosphate galactose 4’-epimerase deficiency (GALE)
23
Q

What are features of mild GALT Deficiency?

A
  • 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
24
Q

What are features of Galactokinase deficiency?

A
  • Clinically well in neonatal period
  • Cataracts
  • Most patients have no other features
  • Some cases with long-term complications
  • GALT (Beutler test) is normal
  • Urine galactitol used
25
Q

What are features of Uridine diphosphate galactose 4’-epimerase deficiency (GALE)?

A
  • Benign to severe neonatal disease
  • Improve on low galactose/lactose feed
  • ↑Gal-1-P on some NBS programmes
  • RBC GALE activity
  • Gene mutation analysis
26
Q

What are causes of Hereditary Fructose Intolerance?

A
  • Aldolase B deficiency
  • Fructose-1,6-bisphosphatase deficiency
27
Q

What are symptoms of Aldolase B deficiency?

A
  • GI pain
  • Vomiting
  • If untreated, progresses to Lethargy, Coma, Convulsions
28
Q

What is the biochemistry of Aldolase B deficiency?

A
  • Abnormal LFTs
  • Renal tubular dysfunction
29
Q

What are investigations for Aldolase B deficiency?

A
  • Based on clinical and nutritional history. Onset of symptoms with weaning
  • Genetics testing mainly
  • Fructose tolerance test
30
Q

What is the treatment for Aldolase B deficiency?

A

Resolution with withdrawal of fructose. Children avoid fructose-containing foods (‘neurotic’)

31
Q

How are results intepreted for the Fructose Intolerance test?

A
  • Normal Enzyme Activity: ↑ Glucose and PO4
  • Impaired aldolase: ↓ Glucose and PO4
32
Q

What is the GLUT-1 channel?

A

GLUT1 facilitates transport of glucose across blood brain barrier

33
Q

What is the biochemistry of Fructose-1,6-bisphosphatse deficiency?

A
  • Decreased Gluconeogenesis
  • Increased NADH/NAD
  • Increase Lactate
  • Increased Glycerol
  • Decreased glucose when fasting or glycogen stores or low (neonates)
34
Q

What is the treatment for Fructose-1,6-bisphosphatse deficiency?

A
  • Avoid Fasting particularly during illness
  • Regular carbohydrate feeds
35
Q

What can deficiency in GLUT1 lead to ?

A
  • Severe epilepsy
  • Complex movement disorder
  • Developmental delay
  • Milder variants have movement disorder or late-onset epilepsy
36
Q

How is diagnosis of Glucose transporter-1 deficiency made?

A
  • Low CSF/blood glucose ratio. Can also be meningitis so check CSF cell count
  • Genetic confirmation required
37
Q

What is the treatment of Glucose transporter-1 deficiency?

A

Ketogenic diet

  • Ketones cross BBB acting as an alternative fuel

Paediatric Biochemistry (31 decks)

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