Metabolic Flashcards
Prenatal diagnosis of Zellweger (cerebrohepatorenal) syndrome can be achieved through?
Assays of peroxisomal enzymes activity (dihydroacetone-phosphate acyltransferase), peroxisomal metabolites, or molecular screening techniques. MRI performed in the third trimester can allow analysis of cerebral gyration and myelination
What does the peroxisome normally do?
Makes bile acids and plasminogen (key for cell wall structure)
Breaks down Phyntane and VLCFA
What does the lysosome do?
Helps recycle and breakdown cell particles within an acidic environment
Upturned nose, toes 2-3 syndactyly, tented upper lip
Smith-lemli-Opitz
How does ammonia cause respiratory encephalopathy?
Raises your respiratory drive and thus low CO2
Beaking of lumbar vertebrae
MPS - type I or II
Ketotic hypoglycaemia with elevated lactate and hepatosplenomegaly….fatty liver on imaging
Glycogen storage disease type I
Encephalopathic child with dystonia, macrocephaly
T2 hyperintensity of basal ganglia
Episode triggered by fever
Glutaric aciduria Type I
Pancytopenia, hepatosplenomegaly, hx of hip pain
Gaucher disease
What is an acylcarnitine profile?
Looks at fatty acid oxidation disorders
Looks at metabolites of beta oxidation
What does urine organic acid look for?
Many many disorder - looks for organic acidaemias, amino acidopathies, peroxismal disorders, disorders of neurotransmission
Addison’s disease is linked to _______
X linked adrenoleukodystrophy
Suspected Glycogen storage disorder with muscle weakness (at 2yo) …?
Glycogen Storage Type III
Glycogen storage disorder with neutropenia?
Glycogen storage Ib
Elevated octanylcarnitine…
MCAD
In ALD you see an accumulation of ______ due to abnormalities in _______
Tissue accumulation of VLCFA caused by deficiency peroxisomal degradation of FA
Acetyl Coa is converted to _____ which enters the electron chain transfer
Citrate
Lab findings in phenylketonuria?
Elevated serum and urine levels of phenylaline and low levels of tyrosine
Phenylketonuria is due a deficiency in which enzyme?
Phenylaline hydroxylase
How do you treat phenylketonuria?
You treat with Phenylaline free diet and tyrosine supplements
What are the risks associated with poorly controlled maternal phenylketonuria?
Risk of microcephaly, CHD, learning difficulties, corpus collosum hypoplasia and growth retardation in infants
This metabolic disorder due to reduced activity in BCKD and results in accumulation of branched amino acids (leucine, isoleucine and valine).
What is the disorder?
Maple syrup urine disease
What age group and common presentation of maple syrup urine disease?
Presents in the first week of life and often with encephalopathy/FTT/vomitting
Most common enzyme deficiency in classic homocysteinuria?
Apart from homocysteine, what else is elevated?
Cystathione synthetase
Elevated levels of Methanione
Homocysteinuria and Marfans syndrome can have similar findings - what are some ways of differentiating?
- Marfans AD mostly, homocystinuria is mostly AR
- both associated with lens dislocation (ectopia lentis) - in homocysteinuria it is down and out (Marfans up and in)
- Mental retardation in homocysteinura
- Homocysteinura are associated with arterial and venous thrombi
- Homocysteinura also stiff joints, rather than lax joints
How do you treat Homocysteinuria?
1) Pyridoxine (works in 50%) and folate: both cofactors for cystathione B synthetase
2) Betaine: decreases homycystiene
3) Rest have horrible methionine restricted and cystiene supplemented diet
Options for treating cysteinuria?
1) Low Na diet, reduces the excretion of AA in urine
2) Low methione diet (cysteine arises from methione metabolism through homocysteine)
3) Alkalise urine
What are the three amino acids that accumulate in maple syrup disease?
leucine, isoleucine and valine
Cystinuria prevents reabsorption of 4 common urine metabolites (AA’s) - what is the pnemonia and what are they?
C.O.A.L.
cystine, ornithine, arginine, lysine
What is the common age and presentation of organic acidaemias?
Newborn in the first 1-2 weeks of life with poor feeding, lethargy, encephalopathy and increased lethargy
Can present older in a child with lethargy, vomitting, FTT -> acute decompensation -> severe metabolic acidosis
This acidaemia is due to a deficiency in propionyl CoA carboxylase and can be associated with pancreatitis and cardiomyopathy… what is it?
Propionic acidaemia
Methylmalonic aciduria is due to a deficiency in which enzyme
Due to a deficiency in methylmalonyl CoA mutase -> leads to accumulation of methylmalonyl
How does methylmalonic aciduria typically present?
Presents with acute encephalopathy in the neonatal period: lethargy, poor feeding, hypotonia, vomitting, apnea, seizure, metabolic acidosis and hypoglycaemia
How do you treat methylmalonic acidaemia?
High doses of B12 - it is a cofactor for methylmalonyl
With B12 deficiency you can get elevation of which two biochemicals?
1) Homocysteine - non-specific
2) Methylmalonic acid (more specific)
In GSD 1 - Von Gierke’s - you are unable to produce glucose from _________ and _________ due to a deficiency in _________
- Unable to produce glucose from glycogeneogenesis or gluconeogenesis
Due to G6P deficiency
Which metabolic disorder?
Present at 3-4 mo of age with hepatomegaly, hypoglycemic seizures.
Affected children often have a doll-like face with fat cheeks, relatively thin extremities, short stature, and a protuberant abdomen that is a consequence of massive hepatomegaly. The kidneys are also enlarged, whereas the spleen and heart are not involved.
hepatosplenomegaly (Secondary fatty acid accumulation and increased FAs from pyruvate) and ketosis with lactic acidosis and sometimes encephalopathy
GSD 1 - Von Geirkes disease
hepatosplenomegaly (Secondary fatty acid accumulation and increased FAs from pyruvate) and ketosis with lactic acidosis and sometimes encephalopathy
GSD 2 - Pompe’s disease is due a deficiency in ______
Acid maltase
Responsible for degradation of glycogen in lysosomes
Which syndrome?
- Clinical: infantile form -> death from cardiomyopathy and muscle weakness pre age 2 years
- Present in first few months of life with hypotonia and generalised muscle weakness aka “floppy infants”
- Cardiac weakness -> short PR and high voltage QRS
Also: big tongue, hepatomegaly
Pompe’s disease (GSD 2)
GSD 5 is due to _________ enzyme deficiency
Glycogen phosphorylase deficiency which is needed for breakdown of glycogen to glucose
What are the four major biochemical anomalies in GSD 1?
hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia
Very significant triglyceride levels - can look milky
This metabolic disorder can present at any age with typical features:
- Muscle cramping and pain with exercise
Rhabdomyolysis and myoglobinuria with exercise
GSD V - McArdle disease
Common/weird lab anomaly seen with fructose intolerance is ?
Hypophosphateaemia
Other lab findings:
lactic acidosis, hyperuricemia, and hypermagnesemia
Fructose intolerance is seen due to a deficiency in which enzyme?
fructose-1,6-bisphosphate aldolase (aldolase-B)
Fructose intolerance is more commonly seen in which autoimmune condition?
Coeliac disease
_______ is due to a deficiency in enzymes fumarylacetoacetate hydrolase (FAH) and leads to elevated levels of succinylacetone
Tyrosinaemia
the treatment of choice for Tyrosinaemia is_____
The treatment of choice is nitisinone
Tyrosinaemia I presents with _____
- Presents in the first year of life
- An acute hepatic crisis typically heralds the onset of the disease and is usually precipitated by an intercurrent illness that produces a catabolic state
- Fanconi syndrome
- Peripheral neuropathy
- HOCM and hyperinsulinism can also be seen
_________ is a rare autosomal recessive disorder caused by deficiency of cytosolic tyrosine aminotransferase and results in palmar and plantar hyperkeratosis, herpetiform corneal ulcers, and intellectual disability
Tyrosinemia type II
Transient tyrosinemia is thought to result from delayed maturation of _________
4-HPPD
What’s the most common enzyme deficiency that leads to Galactosemia?
Galactose 1 phosphate uridyl transferase deficiency (Needed to convert galactose-1-Po4 into glucose-1-PO4)
_____ sepsis is seen commonly in Galactossemia
E. Coli
A Metabolic disorder
Eyes: cataracts
Genital: female gonadal failure
Renal: fanconis, aminoaciduria
sepsis: 25-50% risk E coli sepsis
In particular, this enzyme deficiency can present with cataracts
Galactossemia
Galactose Kinase deficiency can present with cataracts
How do you diagnose Galactossemia?
- urinary reducing substances to screen
- detect levels of galactose-1-phosphate uridyl transferase in erythrocytes
Oxidation of fatty acids occurs in the ______
Mitochondria
Increased acetylcarnitis and acetylglycines in urine are seen with _____
Medium chain AcetylCoa deficiency
Carnitine is normally required for…..
Transporting long chain fatty acids into the mitochondria for beta oxidation
It is theorised that carnitine deficiency is a major cause of _____ (AED) hepatotoxicity
Valproate
Which group of metabolic disorders is not screened on newborn screening tests?
Lysosomal storage disorders
Which metabolic disorder:
- Coarse features, prominent forehead, depressed nasal bridge and macroglossia + Cherry red spot + clear cornea =
GM1 Gangliosidoses
B-galactosidase deficiency
Gangliosides are lipids, part of neuronal and synaptic membranes. Thus GM1 gangliosidoses can present with…
Hepatosplenomeglay, kyphoscoliosis, seizures, GDD, progressive blindness, spastic quadriplegia
Often death in first 2-4 years
GM2 Gangliosidoses is also known as ____
Tay Sachs disease
GM2 Gangliosidoses or Tay Sach’s disease is caused by deficiency of which enzyme?
Hexosaminidase A
Which metabolic disorder?
Initially normal development then hypotonia at 4-6 months; 1-2 years later noted macrocephaly, seizures, spasticity, blindness + CHERRY RED SPOT (100%)
Tay Sach’s disease
Note: Nil hepatosplenomegaly
_________ very similar to Tay Sachs but have doll like facies and hepatosplenomegaly
Sandhoff disease v
Name the metabolic disorder:
A rare AR neurodegenerative disease characterised by severe myelin loss, and presence of globoid bodies in white matter.
Due to a deficiency in lysosomal enzyme galactocerebrosidase
Krabbe disease (Globoid cll leukodystrophy)
Note: This is a disorder of myelin destruction, NOT abnormal myelin formation.
Galactocerebrosidase cannot be metabolised during normal myelin turnover and so it stimulates formation of globoid cells -> these reflect destruction of oligodendroglial cells
Name the syndrome:
- Excessive irritability and crying, unexplained hyperpyrexia, feeding problems
- Generalised seizures apear early
- Opisthotonus and visual inattentiveness (due to optic atrophy)
CT: Symmetric increased densities in caudate nuclei and thalami
KRABBE DISEASE
Globoid Cell Leukodystrophy
Name the syndrome:
- Initially gait abnormalities at 1-2 years
- Over a few months the child can no longer stand, deterioration in intellectual function, deterioration in speech and vision with optic atrophy
- Within one year of onset the child is unable to sit unsupported and develops decorticate postures
- Pseudobulbar palsies -> impaired feeding and swallowing -> NGT and gastrostomy
- Usually die of aspiration or bronchopneumonia by 5-6 years
Late infantile metachromatic leukodystrophy
Foam cells in bone marrow =
Neimann-pick disease
Which is the most common type of Neimann pick disease and how does it classically present?
- Type C (more common):
- Cholestatic jaundice in infancy which resolves is a typical feature
- later: neurodegeneration, cerebellar ataxia, oculomotor apraxia (vertical gaze apraxia is pathognomonic)
Name the syndrome:
Due to deficiency of glucocerebrosidase which results in accumulation of undegraded lipid substrates, (glucosylceramide), in cells of the reticuloendothelial system
Massive splenomegaly > hepatomegaly (may get hypersplenism)
Gaucher disease
In Neimann-Pick disease:
Type C is the most common; but out of type A and B:
- Which is more severe?
- Which presents more commonly in infants
- Type A: more infantile: more severe and present with hepatosplenomegaly and then regression
- Type B: more juvenile, less common, less severe neurologically, more liver issues
Triad of strabismus, trismus/nuchal rigidity and opisthotonus is associated with a progressive spastic and seizure disorder =
Type 2 Gaucher disease = infantile form/acute neuropathic form
Rapid degenerative course with death at 1-2 years
Increased Lactate: Pyruvate ratio is seen with which type of metabolic disorder?
Mitochondrial disease
Which syndrome?
- Commonest MPS
- Predominantly skeletal issues
- Major feature is neurological deterioration with behavioural problems and severe ID
- Mild somatic features
- Heparin sulfate found in urine only
- Death by 20 years
SanFilippo disease (MPS 3)
Myoclonic epilepsy with ragged red fibres =
MERRF
MUCOPOLYSACCHARIDOSES are all autosomal recessive in inheritance except ______ disease
Hunter disease (MPS2) = it is X-linked recessive
Name the syndrome:
- Often appear normal at birth, except for inguinal hernias
- Coarse facies: large skull, large tongue, thick lips
- dystosis multiplex/ skeletal dysplasia
- Corneal opacity
Hurler disease
Often communicating hydrocephalus -> ventriculomegaly and increased ICP
Death before ten years
Which syndrome?
Investigations
- Most important/specific finding: demonstration of abnormally high levels of VLCFA in plasma, RBCs or cultured fibroblasts (seen in all affected boys and 85% heterozygous girls)
CT/MRI: lesions involving the periventricular white matter in posterior parietal and occipital lobes
X-Linked leukodsytrophy
Which syndrome?
- Commonest MPS
- Predominantly skeletal issues
- Major feature is neurological deterioration with behavioural problems and severe ID
- Mild somatic features
- Heparin sulfate found in urine only
- Death by 20 years
SanFilippo disease (MPS 3)
Which syndrome?
- Brushfield spots
- Stippling of patella is characteristic
Death at <1yr
Zelleweger syndrome
Which syndrome:
Due to an enzyme block in B-oxidation of phytanic acid to pristanic acid
- Clinical onset between 4-7 years
o Intermittent motor and sensory neuropathy
Ataxia, progressive neurosensory hearing loss, retinitis pigmentosa and loss of night vision, ichthyosis and liver dysfunction
Refsum disease
Which syndrome?
- Sx between 4 and 8 years
- First symptom is usually hyperactivity
- Auditory discrimination is impaired: may -> difficulty using the phone, or impaired performance in verbally presented intelligence tests
- Other early Sx: disturbance of vision, ataxia, poor handwriting and strabismus
- Seizures in nearly all pts
X-Linked Leukodystrophy
Which syndrome?
Investigations
- Most important/specific finding: demonstration of abnormally high levels of VLCFA in plasma, RBCs or cultured fibroblasts (seen in all affected boys and 85% heterozygous girls)
CT/MRI: lesions involving the periventricular white matter in posterior parietal and occipital lobes
X-Linked leukodsytrophy
How may you be able to differentiate Neimann-Pick disease and Tay Sachs?
Neimann-Pick they often have absent or reduced reflexes.
In Tay Sachs they are hyperreflexic (also have macrocephaly)
Melanocytic naevi are also associated with .. which mucopolysaccharidoses?
Hurlers syndrome
Hunter’s syndrome is associated with Syndrome
Which metabolic disorder can present in the first year of life with subdural haemorrhage and hyperammonia?
Glutaric aciduria
