Inherited metabolic disorders Flashcards
What are the common characteristics of an inheritd metabolic disorder?
- under-diagnosed
- most autosomal recessive
- normal at birth, become symptomatic later (exacerbated by diet or illness)
- mimics sepsis but without known risk factors
- can lead a normal life if managed early before irreversible organ damage
How might a patient with an inherited metabolic disorder appear?
- non specific symptoms mimicking sepsis
- poor feeding, vomiting, lethargy, seizures, coma
- not responsive to glucose or calcium
How are patients investigated?
There are a few screening tests available
e.g. plasma ammonia, blood gas (acidosis), urine for metabolites
Specific tests
- blood tests
- tissue samples
How can amino acid disorders be subdivided?
TRANSPORT DISORDERS
- dibasic amino acids (cystinuria)
- neutral amino acids (Hartnup disease)
METABOLIC DISORDERS
- phenylalanine/tyrosine
- urea cycle defects
What is cystinuria?
Autosomal recessive inherited metabolic disorder
Disorder: defective cystine transporter which causes high levels of cystine in urine which crystallises to form stones
How do you manage cystinuria?
- In the symptomatic patient
- prevent stone formation: increased water intake, alkalisation
- lithotripsy (shock waves to break up stones), chelation (to sweep up excess cysteine)
How does phenylketonuria present?
Normal at birth
Gradually develop neurophysiological problems: microcephaly, low IQ, sezuires, tremors, impaired myelination
Blonde hair
Musty odour
Describe the MOA of phenyloketonuria
PKU
- Phenylalanine hydroxylase is deficient in PKU
- so phenylalanine builds up as its conversion to tyrosine is inhibited
- Tyrosine is needed to make melanins, fumarate and acetoacetate
Instead, phenylalanine is shunted into another pathway where it is converted to phenylpyruvate (toxic) by transaminase
How is phenylketonuria managed?
- Diet
- LDOPA ; Serotonin
(think about MOA: tyrosine is needed to make dopamine and NA, and tryptase which is the precursor of serotonin) - Carefully manage mothers with PKU as foetus affected too. National screening of neonates available
Early treatment reduces neuro impairment
This question is about urea cycle defects
What are the precursor molecules that are raised in urea cycle defects?
How do they present?
Hallmark on blood test?
Glutamine, glutamic acid, aspartic acid, glycine
Present soon after birth: lethargy, poor feeding, seizures, coma, death
If left untreated fatal
Hyperammonaemia, alkalosis, normal LFT
Describe the urea cycle
Protein catabolism produces amino acids glutamine, glutamic acid, aspartic acid and glycine. These form ammonia
Carmbamyl phosphate synthase converts this amonium to carbamyl phosphate which enters the urea cycle
Here it combines with omithin to form citrulline
Citrulline combines with aspartate to form argino-succinic acid (arginosuccinate synthase)
Argino-succinic acid is converted to argenine which is (a) converted to urea and excreted as urine (b) converted to omithine to replace it in step 2
How will a dysfunction in one of the enzymes in the urea cycle cause hyperammonaemia?
Will decrease urea production and reduce amount of omithin which together with carbamyl phosphate produce citrullline
If carbamyl phosphate is not being accepted into the urea cycle, conversion of ammonia to carbamyl phosphate will cease and ammonium will build up
Describe the management of UCD
- reduce dietary protein intake
- remove the excess ammonia (Levulose)
- remove the excess precursors: sodium benzoate will remove glycine and sodium phenylbutyrate will remove glutamate
- replace intermediates not being synthesised due to enzyme deficiency: citrulline, arginine
- liver transplant
This question is about glycogen storing disease 1 (GSD1)
What is the enzyme deficiency?
Glucose 6 phosphatase deficiency
- key enzyme in gluconeogenesis
How does GSD1 present?
- hypoglycaemia
- lactic acidosis
- lipidaemia
- hepatomegaly
- uricaemia
- neutropenic
- bruising
- renal disease
(short stature, obesity, hypotonia)
What is the management of GSD1?
- continuous feeds or corn starch
- limit other sugars: fructose, galactose, sucrose, maltose
- reduce uricaemia using Allopurinol
- statins for lipid control
- liver transplant
What is the disorder caused by a GAL1PUT deficiency called?
How does it present?
How is it managed?
Galactosaemia
- Galactose-1-phosphate uridyl transferase deficiency
Poor weight gain, prolonged jaundice, cataracts, hepatomegaly
Galactose free diet (dairy milk), advise soy milk
Give an example of an organic acid disorder?
- Maple syrup urine disease
- MCAD deficiency
What is MCAD deficiency?
Autosomal recessive organic acid disorder whereby there is a problem in fatty acid oxidation. Medium-chain Acetyl-CoA dehydrogenase is involved in mobilising fatty acids to produce energy
Why do patients with MCAD become really unwell?
When these patients are normo-glycaemic they are well
When they are unwell or fasting they quickly become hypoglycaemic which can be dangerous
This is because they cannot break down fatty acids to produce energy
How do MCAD deficiency patients present?
- in childhood
- hypoglycaemic, hypoketotic with liver function
- infection with vomiting may precede such an episode
- multiorgan failure, death
May have a history of vomiting and drowsiness (any signs of hypoglycaemia) which is relieved by sugary drinks
Which investigation result will prompt you to consider a diagnosis of MCAD deficiency?
Elevation of medium-chain acylcarnitines
- particularly C8 (largest spike)
- and C6, C10
Reduction in total carnitine, free carnitine: acyl carnitine ratio
How do you manage MCAD deficiency?
- avoid fasting
- consume slow release carbohydrates e.g. starch (to provide glucose overnight)
- supplement Carnitine
- Riboflavin: benefits some patients with electron transport chain deficiency
- Medic-Alert Bracelet
What are lysosomes?
- spherical vesicles containing >50 hydrolytics enzymes
- involved in phagocytosis, endocytosis and autophagy
- the stomach of the cell contains suicide bags or sacs and recycling unit
What are mucopolysaccharidoses?
State 3 diseases that fall under this category
How are they managed?
Inherited metabolic disorders caused by an absence or defect in enzymes needed to break down glycosaminoglycans
Hunters, Sanfilippo, Hurlers
Symptomatic treatment
What are the features of a patient with mucopolysaccharidoses
Gargoyle cells (fibroblast containing large deposits of mucopolysaccharide) Coarse facies Mental retardation Short stature Contractures Dystostosis multplexa
Give an example of a lipid storage disorder
Gangliosidosis Tay Sachs Gaucher Niemann Pick Mucolipidoses Lipofuscinosis
(These are lysosomal storage disorders)
What are signs of lysosomal storage disorders
Neuroregression
- seizures
- hepatosplenomegaly
- haematologic (anaemia)
- skeletal signs (pathological fractures)
- cherry red spot (in eye)
What is the treatment for lysosomal storage disorders?
- Enzyme replacement
- Liver transplant
How are mitochondrial disorders inherited?
What are they?
How do they present?
Inherited by maternal mitochondrial DNA
Respiratory chain defects cause problems in energy production
Brain, eye, heart and muscle problems
What is Leigh’s disease?
Subacute necrotising encephalomyelopathy
can cause loss of skills, epilepsy and problems with muscle function
What is the treatment and prognosis for mitochondrial disorder?
Symptomatic treatment
Death in early life
Describe the process of pronuclear transfer
- Egg with abnormal mitochondria fertilised by IVF
- Embryo with abnormal mitochondria is formed
- A donor egg with health mitochondria is used and the nuclear DNA from the abnormal cell is added to it
- This produces an embryo with healthy mitochondria with the nuclear DNA of its given mother
Give an example of a peroxisomal disorder that leads to production and decomposition of peroxide
- Zellwegers
- Refsum
- Adrenoleudystrophy
How do peroxisomal disorders cause disease ?
How are they managed?
Accumulation of very low chain fatty acids (VLCFAs) in adrenal glands and peripheral nerves
Cause import/export defects
Diet
Bone marrow transplantation
