Metabolic disorders and screening Flashcards
What are the patterns of inheritence of metabolic disorders?
Chromosomal
Mendelian:
- Polygenic
- Monogenic
What may deficient enzyme activity be due to?
Deficient enzyme activity may be due to lack of enzyme or reduced enzyme activity due to defects of post-translational modification, assembly or transportation or to defects of cofactor activation.
What can deficient enzyme activity lead to?
Lack of end product
Build-up of precursors
Abnormal, often toxic metabolites
What are the screening criteria for inherited metabolic disorders?
- Important health problem
- Accepted treatment
- Facilities for diagnosis and treatment
- Latent or early symptomatic stage
- Suitable test or examination
- Test should be acceptable to the population
- Natural history understood
- Agreed policy on whom to treat as patients
- Economically balanced
- Continuing process
What is phenylketonuria (PKU)?
Phenylalanine hydroxylase deficiency
What are the features of classic PKU?
Disadvantage: IQ<50
Common: 1:5000 to 1:15000
Test: Blood Phe
Gene: >400 mutations
Treatment: Effective
What is the heel prick test?
5-8 days of life (in UK).
Heel prick capillary from posterior medial third of foot.
Blood spotted onto Guthrie card (thick filter paper).
What is congenital hypothyroidism?
Incidence 1:4000 (wrong on handout)
Inherited in only 15%
Usually dysgenesis/agenesis of thyroid gland
Not always detected clinically
Based on high TSH (in UK)
PPV+ve c.60-70%
What does the Guthrie heel prick test test for?
- PKU from 1969
- Congenital hypothyroidism added 1970
- Sickle cell disease added 2006
- Cystic fibrosis added 2007
- Medium chain AcylCoA dehydrogenase (MCADD) added 2009
What should you consider in hyperammonaemia with metabolic acidosis and high anion gap?
Organic acidurias
The most important involve the complex metabolism of the branched chain amino acids (leucine, isoleucine and valine).
What is the presentation of organic acidurias in neonates?
Unusual odour
Lethargy, feeding problems, truncal hypotonia/limb hypertonia, myoclonic jerks.
Hyperammonaemia with metabolic acidosis and high anion gap (not lactate).
Hypocalcaemia
Neutropenia, thrombopenia, pancytopenia
What is Reye’s Syndrome?
Recurrent episodes of ketoacidotic coma, cerebral abnormalities.
Vomiting, lethargy, increasing confusion, seizures, decerebration, respiratory arrest.
Triggered by: e.g. salicylates, antiemetics, valproate.
What is investigated in Reye’s Syndrome?
Collect during acute episode:
Plasma/blood ammonia
Plasma/urine amino acid
Urine organic acids
Plasma/blood glucose and lactate
Stays abnormal in remission:
Blood spot carnitine profile
What are signs of mitochondrial fatty acid β-oxidation?
Hypoketotic hypoglycaemia, hepatomegaly and cardiomyopathy.
What are laboratory findings of mitochondrial fatty acid beta-oxidation?
(Blood ketones)
Urine organic acids
Blood spot acylcarnitine profile
What are carbohydrate disorders?
Galactosaemia:
3 known disorders of galactose metabolism. Of these galactose-1-phoshate uridyl transferase (Gal-1-PUT) is the most severe and the most common. Raised gal-1-phosphate causes liver and kidney disease.
Presents with vomiting, diarrhoea, conjugated hyperbilirubinaemia, hepatomegaly, hypoglycaemia and sepsis.
Why can galactosaemia lead to cataracts?
Galactitiol is formed by the action of aldolase on gal-1-phosphate leading to bilaterial cataracts.
What are lab findings of galactosaemia?
Urine reducing substances
Red cell Gal-1-PUT
How does glycogen storage disease type 1 present?
Hepatomegaly
Nephromegaly
Hypoglycaemia
Lactic acidosis
Neutropenia
What are mitochondrial diseases?
Any organ, any age, any inheritance. mtDNA is small cf to nuclear DNA.
Heteroplasmy means that clinical manifestations become evident at a certain threshold of mutant DNA.
Mitochondrial DNA is maternally inherited – although nuclear genomes plays a huge role in mitochondrial function.
What is the pathophysiology of mitochondrial diseases?
Defective ATP production leads to multisystem disease especially affecting organs with a high energy requirement such as brain, muscle, kidney, retina and endocrine organs.
Which mitochondrial disorder presents at birth?
Barth: Cardiomyopathy, neutropenia, myopathy
Which mitochondiral disease presents between the ages of 5-15?
MELAS (mitochondrial encephalopathy, lactic acids and stroke-like episodes)
Which mitochondrial disorder presents between the ages of 12-30?
Kearns-Sayre
Chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia.
What are laboratory findings of mitochondrial disorders?
Elevated lactate (alanine): After periods of fasting (e.g. overnight), before and after meals.
CSF lactate/pyruvate – deproteinised at bedside.
CSF protein (raised in Kearns-Sayre syndrome)
CK
Muscle biopsy
Mitochondrial DNA analysis (not so useful in children)
What are congenital disorders of glycosylation?
Defect of post-translational protein glycosylation.
Multisystem disorders associated with cardiomyopathy, osteopenia, hepatomegaly and (in some cases) dysmorphia facial or otherwise.
E.g. CDG type 1a - abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction.
What is the prognosis of congenital disorders of glycosylation?
Mortality 20% in first year.
What are laboratory findings of congenital disorders of glycosylation?
Transferrin glycoforms (serum)
What are peroxisomal disorders?
Metabolism of very long chain fatty acids and biosynthesis of complex phospholipids.
What are signs and symptoms of peroxisomal disorders in neonates?
Severe muscular hypotonia
Seizures
Hepatic dysfunction including mixed hyperbilirubinaemia
Dysmorphic signs
What are signs and symptoms of peroxisomal disorders in infants?
Retinopathy often leading to early blindness, sensorineural deafness, hepatic dysfunction, mental deficiency, ftt, dysmorphic signs.
Bony changes involve a large fontanel which only closes after the first birthday, osteopenia of long bones, and often calcified stippling especially in the patellar region.
What are lab investigations for peroxisomal disorders?
Very long chain fatty acid profile
What are lysosomal storage disorders?
Intraorganelle substrate accumulation leading to organomagaly (connective tissue, solid organs, cartilage, bone and nervous tissue) with consequent dysmorphia.
What are lab investigations for lysosomal storage disorders?
Urine mucopolysaccharides and/or oligosaccharides
Leucocyte enzyme activities
What is the treatment for lysosomal disorders?
Bone marrow transplant
Exogenous enzyme
