Metabolics Flashcards
What are amino acids and how do we test for them?
- Building blocks of protein
- ~ 20 amino acids
Disease where you are unable to break down phenylalanine
PKU
Present at 6-12 months with developmental delay + seizures
Disease associated with elevated leucine
- Leucine is particularly toxic to the brain when levels are elevated
- Typically present in a coma at 7-10 days of life
- pH normal
- BSL normal
- No acidosis
- Maple syrup urine disease
What is the disease associated with tyrosine
Disease associated with elevated homocysteine?
- Homocysteinuria
- Typically tall, blondish
- Myopia + dislocated lens
In exams questions like to throw in + try trick you with Marfan’s
How do organic acidopathies / aciduria present?
- Severe acidosis
- Ketosis
- Hypoglycaemia
- Hyperammonemia
- Brain + liver affected
- Hepatitis
- Seizure
- Coma
What are the most common organic acids that we measure?
- Ketones: beta hydroxybuturate
- Lactate
- Homocysteine: buils up
How do you test for organic acids?
Urine sample
Blood (acyl carnitine profile) : picked up on guthrie card
What is on organic acid?
- Contains carbon chain + acid group
- NO amino group
If you take the amino group away from an amino acid you are left with an organic acid
What is a lysosome?
- Cell organelle
- Area where a series of enzyme reactions occur in the breaking down of cell compounds
- “Recycling centre for cells”
What are cell organelles
Lysosome
Mitochondria
Lysosomal storage disease presentation + examples
- Presentation: over a period of months - years have a deterioration with developmental regression
- Lysosomal storage diseases
- Mucopolysaccharidosis
- Sphingolipidoses
- Gaucher
- Gangliosidoses
- GM1
- GM2
- Krabbe
- Metachormatic leukodystrophy
- Niemann-Pick
- Fabry
- OIigosaccharidoses
- Sialidosis
- Lipid storage disorders
- Wolman
- Ceroid
How do we test for lysosomal storage diseases?
- Urine GAGs (glycose amino glycans)
- White cell enzyme test
Treatment of lysosomal storage diseases
Early bone marrow transplant
Lysosomal disease groups
- Mucopolysacharridosis / oligosacharridosis
- Course features
- Short, developmental delay
- Multiple infections
- Hurler, Hunter, Sanfilipino
- Sphingolipidosis
- Regression
- Tay Sachs (cherry red spot), Sandhoff
- Regression
- Leukodystrophy (more WHITE matter disease they GREY matter)
- Cause more motor defects due to white matter changes
- Metachromatic, Krabbe
- Cause more motor defects due to white matter changes
- Liver / spleen / blood
- Gaucher (splenomegaly, abdominal distension, anaemia, low Plt, multiple fractures)
- Neimann Pick
- Fabry
- Renal, cardiac, pain, strokes
What does the urea cycle do?
Converts nitrogen waste products (ammonia) into urea
How do we test for a urea cycle defect?
Serum ammonia
What is the most common urea cycle defect?
OTC deficiency - X linked recessive
In questions they tend to say a baby is born to a mother who is a vegetarian as she feels sick after every protein meal. Can also include details such as they had another child that died at age 4yrs of unknown cause.
1g protein / carbohydrates = XX kCal
1g fat = XX kCal
1g protein / carbohydrates = 4 kCal
1g fat = 9 kCal
What is fatty acid oxidation?
- Process where fatty acids are converted to ketones + reducing substances
How do kids with a fatty acid oxidation present
- Hypoglycaemia with NORMAL ketones after a period of starving
What is the classical MCADD presentation?
Previously well but then presents with 6-8 months with a vomiting illness + put to bed but then dies in his sleep
How do we test for fatty acid oxidation defects?
What test do you perform if you want to rule out adreno-leukodystrophy?
Very long chain fatty acids
What are common peroxismal disorders?
X-linked adrenoleukodystrophy
Zellwegger syndrome
Long chain fatty acid vs. medium chain fatty acid disorders
Medium chains 8-10 carbons long
Most of the food we eat is 16-20 carbon chains long therefore can be broken down
More severe presentation in LCFA usually present BSL 0.01 day 1 of life with cardiomyopathy + rhabdomyolysis + hypoglycaemia
Neonate presents with collapse + profround hypoglycaemia + cardiomyopathy + rhabdomyolysis
- Long chain fatty acid disorder
- Can be a spectrum of disease as well and present with late exercise induced rhabdomyolysis
What part of the mitochondria is involved in mitochondrial disorders?
Respiratory chain: where oxygen is broken down + free radicals produced
How do we test for mitochondrial disorders?
- Carbon + oxygen = energy + CO2
- Most common reason for mitochondria not working properly is low oxygen levels = production of lactic acid
- Tests:
- Lactic acid: organic acid
- Organic acids in urine
- Molecular mtDNA (ALL mitochondrial DNA is inherited from your mother)
- Codes for 13 proteins
- Nuclear DNA
Mitochondrial disorder presentation features
Any symptom in any organ due to mitochondria being everywhere!
A 7 yr old boy is referred to you from from ED post a seizure on the background of hyperactivity, inattention and worsening school performance + deterioration in his vision + hearing. His mother reports he was previously doing well at school in prep + grade 1 and put his behavioural change down to the arrival of his newborn sister.
Physical examination + MRI brain reveals….
Adrenoleukodystrophy
- X-linked recessive
- Defective ABCD1 gene
- Peroxisimal disorder resulting in the accumulation of saturated VLCFA’s + progressive dysfunction of the adrenal cortex + nervous system
Presentation
- Typically presents age 4-8yrs
- Seizure
- Hyperactivity, inattention and worsening school performance
- Deterioration in vision + hearing
- Mild hyperpigmentation
- Ataxia
- Strabismus
Investigations
- Adrenal insufficiency (due to build up of VLCFA in the adrenal cortex)
- > 85% will have adrenal insufficiency
- Elevated ACTH
- High VLCFA levels
- MRI: characteristic white matter lesions involving the posterior white matter, including the corpus callosum
Which statement regarding genetic disorders of metabolism is NOT true?
- In severe disorders, the affected infant may be sick at the time of birth
- Most genetic metabolic diseases are treatable
- The majority of genetic metabolic disease have autosomal recessive inheritance
- Early diagnosis is crucial to good prognosis for most disorders
- Tandem mass spectrometry may identify a large number of disorders with just a few drops of blood
In severe disorders, the affected infant may be sick at the time of birth
In genetic disorders of metabolism, the affected infant is normal at birth and becomes symptomatic later in life. This differentiates these infants from those who appear sick at birth due to birth trauma, intrauterine insults, chromosomal abnormalities, or other genetic diseases. Severe forms of genetic disorders usually become clinically apparent in the newborn period, sometimes as early as hours after birth. The majority of conditions are inherited as autosomal recessive traits. Most of the genetic metabolic conditions can be controlled successfully by some form of therapy, and a few can be potentially cured by the use of bone marrow or liver transplants. This underlines the importance of early diagnosis, which can be achieved through screening of all newborn infants. Tandem mass spectrometry (MS/MS) requires a few drops of blood to be placed on a filter paper and mailed to a central laboratory for assay. A large number of genetic conditions can be identified by this method.
Phenotypes- early neonatal sepsis ‘like’
- Urea cycle disorders
- Galactosemia
- Mitochondrial
- Urea cycle disorders
- Elevated ammonia
- Galactosemia
- Unable to metabolise galactose due to uridyl transferase deficiency
- Vomiting, jaundice, hepatomegaly, hypoglycaemia, irritability, ascites, cirrhosis, cataracts, splenomegaly
- Mitochondrial
- Congenital lactic acidosis
Well for many months than coma-dead or profound hypoglycaemia
- Fatty acid oxidation disorders
- Glycogen storage disorders
- Mitochondrial disorders
Claw hand
MPSI
Gaucher disease features
- Pancytopenia; can present like acute leukaemia
- Hepatosplenomegaly
- Osteopenia
- Bone pain
- Most have NO neurological disease
- Can be treated with enzyme therapy
- Increased frequency of Parkinsons (x10 increased risk)
Non ketotic hyperglycaemia characteristic features
- Abnormal movements in utero with hiccups ++
- Low APGARS
- Seizures as a neonate
What should your CSF sugar level be?
It should be 0.6 or above you BSL
GLUT 1 transporter deficiency
Seizures
Ketogenic diet improves symptoms
Low CSF BSL
