Metabolic medicine Flashcards
Features of propionic acidaemia
- Defective propionyl-coenzyme A carboxylase
- Causes accumulation of propionic acid
- Early symptoms: Vomiting, dehydration, hypothonia, lethargy, and seizures
- Later symptoms: Encephalopathy, movement disorders (basal ganglia damage), and low IQ
- Treatment is with a low-protein diet, L-carnitine and biotin supplementation
Features of isolvaleric acidaemia
- Mutation or deficiency in isovaleric acid-CoA dehydrogenase
- Causes build up of isovaleric acid (smells of sweaty feet)
- Symptoms: Lethargy, poor feeding, vomiting, seizures, and encephalopathy
- Treatment is with a protein-restricted diet and L-carnitine
Features of methylmalonic acidaemia
- Defect in the conversion of methylmalonyl-CoA to succinyl-CoA
- Causes accumulation of methylmalonic acid
- Symptoms: Lethargy, vomiting, dehydration, seizures, recurrent infections, progressive encephalopathy, stroke
- Ketoacidosis and hyperammonemia can be seen during infective episodes
- Treatment is with a protein-restricted diet, L-carnitine and cobalamin supplementation
Features of maple syrup urine disease
- Decreased levels of alpha-keto acid dehydrogenase enzyme
- Causes an accumulation of branched chain amino acids (BCAAs), allo-isoleucine, and branched-chain ketoacids
- Symptoms: Hypotonia, poor feeding, vomiting, lethargy, seizures, and encephalopathy
- Treatment is with leucine and branched-chain amino acid (BCAA)-free nutrition and supplementation with isoleucine and valine
What does the smooth endoplasmic reticulum do?
Synthesis of steroids and lipids
What does the peroxisome do?
Catabolism of very long chain fatty acids and amino acids
Results in the formation of hydrogen peroxide
How common is PKU/MCADD in the UK?
Both 1:10,000
How common are MSUD, IVA, GA1, or HCU in the UK?
All 1:100,000
Which metabolic diseases are screened for in the UK?
- Phenylketonuria (PKU)
- Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
- Maple syrup urine disease (MSUD)
- Isovaleric acidaemia (IVA)
- Glutaric aciduria type 1 (GA1)
- Homocystinuria (pyridoxine unresponsive) (HCU)
Features of alkaptonuria
- Autosomal recessive condition characterised by homogentisic acid oxidase deficiency. This leads to an accumulation of homogentisic acid.
- Homogentisic acid is rapidly cleared by the kidney. If the urine is left standing, however, it oxidises to form a pigmented polymer which colours the urine black.
- Over time, a similar process occurs with homogentisic acid in the body and it is deposited in cartilage, causing blue/grey discolouration in young adulthood (a process called ochronosis). These changes can be seen in cartilage, tendons, nail beds, eyelids, axillae, genital areas and buccal mucosa.
- Deposition in the heart can cause cardiac valve problems, particularly aortic stenosis. Nearly all patients develop arthritis and joint pains due to deposition in joints.
- Treatment includes protein restriction and vitamin C supplementation.
- The main differential diagnosis is acute intermittent porphyria.
Features of PKU
musty body odour, eczema, hyperactivity, developmental delay, behaviour problems, convulsions, and low IQ.
Normal at birth
Radiological findings in vitamin D deficiency
- Poor mineralisation
- Delayed development of epiphyses
- Irregularly widened epiphyseal plates
- Increased distance between the end of shaft and the epiphyseal center
- Cortical spurs projecting at right angles to the metaphysis
- Coarse trabeculation (as opposed to the ground-glass pattern seen in scurvy)
- Periosteal reaction
Common features of peroxisomal disorders
- Developmental delay
- Psychomotor retardation
- Skeletal and craniofacial dysmorphism
- Neonatal seizures
- Liver dysfunction
- Progressive sensorineural hearing loss
- Retinopathy and cataracts
Diagnostic features of peroxisomal disorders
- Elevated blood levels of very long chain fatty acids (VLCFA)
- Elevated phytanic acid and pipecolic acid
- Elevated bile acid intermediates
What kind of disorder are the following:
- Zellweger syndrome
- Infantile and classic Refsum’s disease
- Rhizomelic chondrodysplasia punctata
- X-linked adrenoleukodystrophy
Peroxisomal disorders
Causes of normal anion gap acidosis
H - Hyperalimentation/hyperventilation
A - Acetazolamide
R - Renal tubular acidosis
D - Diarrhoea
U - Ureteral diversion
P - Pancreatic fistula/parenteral saline
Features of Hartnup disease
- Reduced absorption and transport of amino acids leading to B3 deficiency
- Clinical features:
- Most children are asymptomatic
- Pellegra like rash (photosensitive)
- Diarrhoea
- Failure to thrive
- Ataxia
- Aminoaciduria
- Low IQ, poor growth, neurologic features, ocular features, and psychiatric features are less common
- Urine chromatography aids diagnosis (increased amino acids in urine) coupled with normal plasma amino acids
- Jejunal biopsy or skin biopsy may be needed
- Exacerbators:
- Sunlight (most common)
- Pyrexia
- Poor nutrition
- Exercise
- Physical or emotional stress
- Medications
Causes of low anion gap acidosis
Haemorrhage
Nephrotic syndrome
Intestinal obstruction
Hormones increased in stress response
- GH
- Cortisol
- Renin
- Adrenocorticotrophic hromone
- Aldosterone
- Prolactin
- ADH
- Glucagon
Hormones decreased in stress response
Insulin, testosterone, oestrogen
Features of hereditary fructose intolerance
- Deficiency of the enzyme (aldolase B) needed to metabolise fructose
- Autosomal recessive metabolic condition
- Even small amounts of fructose cause low blood sugar levels
- Symptoms include vomiting, poor eating, failure to thrive, hypoglycemia, haemorrhage, jaundice, hepatomegaly, hyperuricemia
- If sugars are not excluded, it can lead to liver and renal failure
- Treatment is with life-long exclusion of fructose, sucrose, and sorbitol
- Sugars which patients are able to metablise include glucose and maltose
- Attacks of hypoglycaemia are treated with glucose (oral or IV)
Features of nonketotic hyperglycinaemia
- Also called glycine encephalopathy
- Autosomal recessive
- Type of inborn error or metabolism
- 80% due to mutations in the GLDC gene, and 10-15 % due to mutations in the AMT gene
- Defects in the glycine cleavage system causing high levels of glycine in CSF and the brain where it does most of its damage
- Glycine is both an amino acid and a neurotrasmitter
- Neurological symptoms and signs are most common
- Majority presents in neonates, but can present in first 6 months
- Presents with lethargy, feeding difficulties, myoclonic jerks, hypotonia, seizures, apnoea, and sometimes death
- In surviving infants, difficulty epilepsy, developmental delay, and intellectual disability is common
- Milder forms exist which present later
- Currently no treatment exists, but trials suggest treatment with sodium benzoate and N-methyl D-aspartate (NMDA) receptor site antagonists may be effective
- Other treatments include: antiepileptic drugs, ketogenic diet, gastrostomy tube, treatment for gastroesophageal reflux, and physical therapy
- Sodium valproate is contraindicated as it increases glycine levels
- Overall prognosis is better in males
Causes of ketotic hypoglycaemia
Glycogen storage disease
Adrenal insufficiency
Organic acidurias
Maple syrup urine disease
Causes of non ketotic hypogylcaemia
Hyperinsulinism
Disorders of fructose or galactose metabolism
Fatty acid oxidation
Growth hormone deficiency
