Metabolics Flashcards
What maternal condition causes a false positive NBST due to low carnitine?
B12 deficiency
Metabolic acidosis - metabolic DDx?
Amino acid disorders
Organic acidemias
Carbohydrate metabolism abnormalities
Lactic acidosis - metabolic DDx?
Mitochondrial disorders
Pyruvate metabolism
Respiratory alkalosis - metabolic DDx?
Urea cycle defects
Hepatomegaly/splenomegaly - metabolic DDx?
GSD
Lysosomal storage disease
Galactosemia
Peroxisomal disorders
Abnormal odours - metabolic DDx?
Maple syrup urine disease
Sweaty socks - isovaleric acidemia, glutaric acidaemia
Fruity - MMA, propionic acidemia
Mouse urine/musty - PKU
Fishy - trimethylaminuria, carnitine excess
Isolated hepatomegaly - metabolic DDx?
GSD
Mitochondrial disease
Early neonatal ‘sepsis’ like presentation - metabolic DDx?
Organic acidopathies - MMA, PA, HCS
Aminoacidopathies - MSUD
Urea cycle disorders
Galactosaemia
Mitochondrial
Well for months/years, then present with coma/hypoglycaemia - metabolic DDx?
FAOD
Glycogen storage disease
Developmental regression - metabolic DDx?
Lysosomal storage disease
Mitochondria
Peroxisomal - ALD
Urea cycle disorders
MSUD, organic acidaemia, PKU
Other genetic - CDG, Retts, Alexander, VWM etc
Hepatomegaly/hepatitis - metabolic DDx?
Tyrosinaemia
Galactosaemia
GSD
Lysosomal
Neimann-Pick C
Mitochondrial
Bile acid synthesis
Dysmorphic at birth - metabolic DDx?
Peroxisomal
Mitochondrial
Lysosomal
Seizures, microcephaly - metabolic DDx?
Non-ketotic hyperglycaemia
Pyridoxine responsive seizures
GLUT-1 transporter
Creatinine synthesis/transporter
Sulphite oxidase
Menkes
Folate disorders
Movement disorder - metabolic DDx?
Glutamic acuduria
Atypical NKH
Neurotransmitter disorder
Lesch-Nyhan
Urea cycle disorders overview
Defect in breakdown of nitrogen -> ammonia
e.g. OTC
Urea cycle disorders basic Ix
Resp alkalosis/normal VBG
Very high ammonia, normal glucose, normal ketones, normal lactate
Amino acid disorders overview
Defect in breakdown of amino acids
e.g. PKU, MSUD, homocystinuria
Amino acid disorders basic Ix
Metabolic acidosis (high anion gap)
High/normal ammonia, low glucose, high ketones, normal lactate
Organic acid disorders overview
Accumulation of organic acids
e.g. pripionic, MMA
Organic acid disorders basic Ix
Metabolic acidosis ++ (high anion gap)
High ammonia, low glucose, high ketones, high lactate
Lysosomal storage disorders overview
Accumulation of proteins/lipids
e.g. MPS, Pompe, Gaucher, Niemann-Pick
Lysosomal storage disorders basic Ix
Normal gas
Normal ammonia, normal glucose, normal ketones, normal lactate
Glycogen storage disorders overview
Defect in glycogen synthesis
e.g. GSD types I-IX
Glycogen storage disorders basic Ix
Metabolic acidosis
Normal ammonia, low glucose, high ketones, high lactate
FAO disorders (?fatty acid oxidation) overview
Unable to break down fatty acids -> ketones
e.g. MCAD deficiency, LCAD deficiency, VLCAD deficiency
FAO disorders (?fatty acid oxidation) basic Ix
Metabolic acidosis
Normal ammonia, low glucose, low ketones, normal lactate
Mitochondrial disorders overview
Insufficient acetyl CoA for Krebs cycle: low ATP
e.g. MELAS
Mitochondrial disorders basic Ix
Metabolic acidosis
Normal ammonia, normal/high glucose, normal ketones, very high lactate
Peroxisomal disorders overview
Reduced metabolism of very long chain fatty acids, reduced bile synthesis
e.g. XL ADL, Refsum, Zellweger
Peroxisomal disorders basic Ix
Normal gas
Normal ammonia, normal glucose, normal ketones, normal lactate
Maple syrup urine disease basic Ix
Low/normal glucose
Normal lactate
Sometimes metabolic acidosis
Normal ammonia
May have elevated anion gap
Strongly positive urine ketones
Examples of amino acidopathies
Phenylketonuria
Homocystinuria
Maple syrup urine disease
Citrullinemia
Arginosuccinic acidaemia
Tyrosinaemia
Overview of phenylketonuria (PKU)
Accumulation of phenylalanine (essential AA)
Occurs due to deficiency of phenylalanine hydroxylate (PAH) or cofactor tetrahydrobiopterin (BH4)
Clinical features of phenylketonuria (PKU) in infants
Normal at birth
Vomiting, light complexion c/w siblings, seborrheic/eczematoid rash
Clinical features of phenylketonuria (PKU) in older untreated children
Hyperactive with autistic behaviours, purposeless hand movements, rhythmic rocking, athetosis
50-70% have IQ<35
Musty odour
Neurological signs (seizures 25%, spasticity, hyperreflexia, tremors)
Microcephaly
Prominent maxillae with widely spaced teeth, enamel hypoplasia, growth retardation
Diagnosis of PKU?
Now in NST
Quantitative serum phenylalanine level
Biopterin deficiency needs to be excluded
Treatment of PKU?
Low phenylalanine diet
Administration of large neutral AAs (to compete with phenylalanine for transport)
Oral BH4 may be useful
How is tyrosine obtained by the body?
Tyrosine is derived from ingested proteins OR synthesised from phenylalanine (NON-essential)
What is tyrosine a precursor of?
Dopamine, noradrenaline, adrenaline, melanin and thyroxine
What is excess tyrosine metabolised to?
Carbon dioxide and water
Genetics of hereditary tyrosinaemia (tyrosinemia type 1)
AR
Mutation in fumarylacetoacetate hydrolase (FAH gene)
Increased succinylacetone which results in alkylation
Most common age to present with hereditary tyrosinemia (type 1)?
0-6 months (most affected babies appear normal at birth)
Earlier presentation associated with poorer prognosis
Features of hereditary tyrosinemia (type 1) when presenting in the first year of life (subacute)?
Progressive liver disease
Failure to thrive
Rickets
HSM
Features of hereditary tyrosinemia (type 1) when presenting >1 year of age (chronic)?
Present with liver failure (cirrhosis) or liver disease
Overview of hereditary tyrosinemia clinical features
Hepatic - fever, irritability, vomiting, haemorrhage, hepatomegaly, jaundice, raised transaminases, hypoglycaemia, boiled cabbage odour
Neurological = peripheral neuropathy
- resembles acute porphyria: weakness and hypertension, crisis triggered by minor infection (severe pain, extensor hypertonia of neck/trunk, vomiting, paralytic ileus)
Renal - Fanconi syndrome
Investigations for hereditary tyrosinemia
Increased succinylacetone in serum and urine
NOT detected on NBST
Treatment of hereditary tyrosinemia (type 1)
Low phenylalanine and tyrosine diet
Treatment = nitisinone
Need to monitor for HCC
Metabolism of methionine
Methionine is an essential AA, metabolised to S-adenosylmethionine and cysteine
Byproduct of this is homocysteine which is recycled to reform methionine in the presence of a folate product and B12 derived cofactor
Overview of homocystinuria
Most common inborn error of methionine metabolism
Two forms: B6 responsive milder form (60%) and B6 non-responsive (40%)
Thrombo-embolism major cause of death and mortality
Genetic inheritance of homocystinuria?
Mutation in CBS - gene encoding cystathione beta-synthase
When is the diagnosis of homocystinuria usually made?
> 3 years, when ectopic lentis occurs
Normal at birth, non-specific features in infancy (FTT, developmental delay)
Ocular features of homocystinuria
Ectopia lentis and/or severe myopia
Glaucoma, astigmatisme, staphylcoma, cataracts, retinal detachment, optic atrophy (later in life)
Skeletal features of homocystinuria
Tall, long limbs, scoliosis, pectus excavatum
Genu valgum
High arched palate
Crowding of teeth
Resembles Marfans!
Vascular features of homocystinuria
Thromboembolism (large and small vessels, particularly in the brain)
Severe consequences including optic atrophy, paralysis, cor pulmonale, severe HTN from renal infarcts
CNS features of homocystinuria
Developmental delay
ID (may be progressive), range of IQ 10-135, higher IQ noted in B6 responsive patients
Psychiatric and behavioural disorders
Seizures
Other manifestations of homocystinuria
Extrapyramidal signs (e.g. dystonia)
Blue eyes, hypopigmentation of skin and hair, molar flush, livedo reticularis
Pancreatitis
Investigations in homocystinuria
High plasma total homocystine and methionine
High urine homocystine
Low or absent cystine in plasma
Genetic testing: mutation in CBS
Treatment for homocystinuria
High dose vitamin B6 - dramatic improvement in those who are responsive
May require folic acid supplementation
Restriction of methionine intake in conjunction with cystine supplementation (for those unresponsive to vitamin B6)
How is cysteine synthesised?
Cysteine = non-essential AA, synthesised from methionine
Overview of cystinuria
Rare AR disease (1/7000)
Abnormal reabsorption of cysteine from proximal tubules predisposes to renal stones due to cysteine crystallisation
Urine MCS shows hexagonal crystals
Treatment = regular fluids, alkalisation of urine with potassium citrate, penicillamine (binds with cysteine to increase reabsorption)
Overview of cystinosis
Accumulation of cysteine in organs due to abnormal metabolism of cysteine
AR mutations causing infantile, juvenile or adult forms
Clinical features of cystinosis
Renal tubular acidosis and ESRF
Growth restriction
Eye deposits and visual impairment
Hepatomegaly
Pancreatic disease
Muscular disease
Impaired cognition
Treatment of cystinosis
No effective treatment
Supportive therapies and cysteamine - reacts with cysteine to form complexes but does not prevent tubular dysfunction
Genetics of MSUD?
Caused by a deficiency of branched-chain alpha ketoacid dehydrogenase complex (BCKDC), part of the pathway of the three branched-chain AAs
Defect in the enzyme system involved in decarboxylation of leucine, isoleucine and valine (BCKAD)
AR mutation, 1 in 200,000
Overview of classic MSUD?
Classic is most common form
Mutations in genes for E1alpha, E1beta and E2 (<3% residual enzyme activity)
Newborns develop ketonuria within 48 hours of birth - irritability, poor feeding, vomiting, lethargy and dystonia
Neurological features of classic MSUD?
Develop by day 4 of life (essentially encephalopathy):
Alternating lethargy and irritability
Dystonia, rigidity and opisthotonos
Apnoea
Seizures
Signs of cerebral oedema
Unusual odour (urine and ears)
Metabolic intoxication in classic MSUD?
Triggered by increased catabolism of endogenous protein (e.g. illness, exercise, injury, surgery, fasting)
Clinical signs - epigastric pain, vomiting, anorexia, muscle fatigue
Neurological signs - hyperactivity, sleep disturbance, stupor, decreased cognitive function, dystonia, ataxia
Can be fatal if not treated
Overview of intermediate MUSD
Rare mutation in E1alpha (3-30% residual enzyme activity)
Symptomatic at any age
Acute neurological symptoms (irritability, dystonia) and developmental delay
Seizures in some patients
Metabolic decompensation is rare
Overview of intermittent MSUD
Second most common form of MSUD
Normal growth and development
Present with ketoacidosis during periods of catabolic stress (intercurrent illness, protein intake)
Signs of neurotoxicity develop - ataxia, lethargy, seizures, coma
Death can occur
Investigations in MSUD
Normal glucose, normal ammonia, normal pH
Strongly positive urinary dipstick for ketones
DNPH test - add reagent to urine and precipitates
Plasma branched chain AAs (high leucine, isoleucine and valine)
High urinary alpha-hydroxyacids and alpha-ketoacids
Treatment of MSUD
Diet low in branched chain amino acids (reduce natural protein, BCAA free formula)
Dialysis to remove toxic metabolites
Liver transplantation
Which are the branched chain amino acids?
Valine
Leucine
Isoleucine
Overview of organic acidaemias
Deficiency in enzymes involved in degradation of branched chain amino acids, resulting in accumulation of organic acids proximal to this point in the pathway
These collect in body fluids -> excreted in urine
Mechanism of hyperammonaemia in organic acidaemias?
Elevated organic acids blocks the urea cycle resulting in hyperammonaemia
Presentation of organic acidaemias
Typically present in first 1-2 weeks of life, with initial period of being well then rapid deterioration
Poor feeding, vomiting, hypotonia, lethargy which progresses to coma
Children are susceptible to metabolic decompensation during episodes of catabolism
Typical VBG findings in organic acidaemias
Life threatening metabolic acidosis characterised by a widened anion gap
Classification of organic acidaemias
Branched chain organic acidaemias
Multiple carboxylase deficiencies
Glutaric acidaemia (or acuduria) type 1 (GA1)
Investigations in organic acidaemias
Metabolic acidosis with widened anion gap (>25mmol/L)
Mild-moderately raised ammonia
Elevated ketones
Hypoglycaemia
Bone marrow suppression commonly (pancytopenia)
Urine = elevated organic acids
Acylcarnitine: all organic acids are esterified to carnitine forming acylcarnitine
Common organic acidaemias
Methylmalonic acidaemia (MMA)
Propionic acidaemia (PA)
Isovaleric acidaemia (IVA)
3-methylcrotonylglycinuria (3-MCG)
Glutaric acidaemia (GA1)
Principles of treatment for organic acidaemias
Decrease substrate (low protein diet)
Enhance enzyme activity (biotin, B12)
Disposal of toxic metabolites (carnitine: binds to organic acids then can be excreted in the urine)
Treatment of hyperammoniaemia secondary to urea cycle disorders?
Sodium benzoate - reduces ammonia content by conjugating with glycine to form hippuric acid, which is rapidly secreted by the kidneys
Manifestations of galactosemia?
Liver dysfunction - conjugated/unconjugated hyperbilirubinaemia, elevated transaminases and synthetic dysfunction with coagulopathy
Renal tubular dysfunction with metabolic acidosis
Mucopolysaccharidosis overview?
A group of disorders
Caused by absence/malfunctioning of lysosomal enzymes required for glycosaminoglycans breakdown (therefore accumulate in cells)
Result in permanent and progressive cellular damage
Overview of MPS type 1?
= Hurler syndrome
Mutations of IUA gene encoding alpha L-iduronidase
Severe and progressive, death by 10 years
Normal at birth, may have inguinal hernias
Diagnosed at 6-24 months with: hepatosplenomegaly, coarse facial features, large tongue, prominent forehead, joint stiffness, short stature
Most common lysosomal storage disease?
Gaucher disease
Features of Gaucher disease?
Haematologic problems, organomegaly, skeletal involvement (bone pain, pathological fractures)
Due to progressive deposition of accumulated glycolipid substrates in cells of the reticuloendothelial systems
Type 2 has earliest onset (within 3-6 months) and is fatal
Cause of maple syrup urine disease?
Deficiency of branched chain alpha-ketoacid dehydrogenase enzyme - involved in metabolic pathway of branched chain amino acids
Build up of BCAAs (leucine, isoleucine and valine) which results in encephalopathy, poor feeding and vomiting
In MSUD, build up of which BCAAs occurs?
Leucine
Isoleucine
Valine
Impact of physiological stress in MSUD?
Stress such as infection/fever, leads to risk of protein catabolism resulting in worsening build up of BCAAs
The goal is to reduce toxic metabolites by restricting protein intake acutely (whilst providing additional calories)
Biochemical findings in hyperinsulinaemia hypoglycaemia?
No acidaemia
Low free fatty acids
Low ketones
High lactate, acidaemia and hypoglycaemia?
May be organic acidaemia or disorders of gluconeogenesis (such as glycogen storage disease type 1, fructose-1,6-biphosphatase deficiency and pyruvate carboxylase deficiency)
A child with hoarse voice, swollen and painful joints, lipogranulomas under the skin?
= Farber disease
Overview of Farber disease
AR condition caused by abnormal lipid metabolism
Lipids accumulate abnormally, esp around joints
Can present with neuropathic/limb pain with telangiectasias and angiokeratomas
A child with melanocytes naevi on the background of known mucopolysaccharidosis?
= Hurler syndrome
A child who is poorly compliant with dietary treatment and presents with developmental delay, hypopigmentation and eczema
= Phenylketonuria
Risk of what condition when children with phenylketonuria are non-compliant with phenylalanine reduced diet?
Eczema
High ammonia, hypoglycaemia, mildly raised lactate without acidosis, elevated anion gap, and ketonuria?
Maple syrup urine disease
(can also have metabolic acidosis)
Normal physiological response of urine to metabolic acidosis?
Kidneys will increase urinary acid excretion, with the urine pH therefore usually falling below 5
Overview of methylmalonic acidaemia?
Organic acidaemia due to defect in methylmalonyl-CoA mutase which affects cobalamin/B12 formation
Lactate and ketones accumulate leading to a high anion gap metabolic acidosis
Present with ketoacidosis, failure to thrive, vomiting and hyperammonaemia
Physiological response to severe diarrhoea?
Normal anion gap metabolic acidosis with bicarbonate loss from the gut
Urine pH can be >5.5 due to volume contraction and resulting decreased Na reabsorption in the collecting duct, leading to lessened negative intratubular electrochemical potential and therefore rate of proton secretion
Physiological response to toxic ingestion of ethylene glycol?
High anion gap metabolic acidosis
Osmolal gap can help determine whether there are unmeasured osmotically active substances circulating which lead to acidosis
Elevated osmolal gap >10 may be seen in isopropyl alcohol, ethanol, methanol and acetone ingestions
Acylcarnitine profile is used in screening of which metabolic conditions?
Used to screen for disorders of fatty acid oxidation and organic acidaemia, due to these disorders resulting in accumulation of c2-c18 acyl-CoA species
Defects in LIPIN 1 mutation predispose to which metabolic process?
Rhabdomyolysis
LIPIN-1 is an important enzyme in the pathway of triglyceride and phospholipid biosynthesis
Disorders leading to hypoglycaemia?
Fatty acid oxidation disorders
Glycogen storage diseases
Gluconeogenic disorders
Hereditary fructose intolerance
Amino acid disorders
Organic acidaemias
Mitochondrial disorders
Genetic disorders leading to metabolic acidosis?
Organic acidaemias
Glycogen storage diseases
Fatty acid oxidation defects
Defects of pyruvate metabolism
Disorders of fructose metabolism
Mitochondrial disorders
Features of LIPIN-1 deficiency?
Episodic myalgia and myoglobinuria in the setting of intercurrent illness, febrile illness, prolonged fasting and exercise
Baby with encephalopathy and dehydration, hepatomegaly with a nappy odour resembling sweaty feet?
= Isovaleric acidaemia
Organic acidaemia, present in newborn period with encephalopathy and malodorous urine resembling sweaty feet
Baby with irritability, poor feeding, vomiting, lethargy, ketonuria?
= Maple syrup urine disease
Well at birth, present in the first week with encephalopathy, may have hypoglycaemia and ketonuria (which is unique in babies)
Baby with poor feeding, jaundice, hepatomegaly, has had E. coli sepsis and coagulopathy with significant transaminitis?
= Galactosaemia
Tend to present in the first week of life after starting feeds containing galactose (e.g. breast milk), hepatomegaly is a common finding, classically also associated with E. coli sepsis
Initial symptoms of Batten disease?
Progressive visual loss and retinal pigmentary changes often result in an initial diagnosis of retinitis pigmentosa
- Batten disease is the most common form of neuronal ceroid lipofuscinosis
Overview of Leigh disease
Is a mitochondrial encephalomyopathy
Prominent features include:
1. Signs of brain and muscle dysfunction - seizures, weakness, ptosis, external ophthalmoplegia, psychomotor regression, hearing loss, movement disorders and ataxia
2. Lactic acidosis
Progressive and degenerative disorder, usually presenting during infancy with feeding/swallowing issues
May also have developmental delay
Intermittent respirations are classic and suggest brainstem dysfunction
CT/MRI shows bilaterally symmetric areas of low attenuation in the basal ganglia and brainstem as well as elevated lactic acid on MR spectroscopy
Overview of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)
DD, weakness, headache, focal signs suggesting stroke
Brain imaging does not fit with typical vascular territories
Children with MELAS may be normal initially but gradually display motor/cognitive delays and short stature.
Clinical syndrome and investigations seen in MELAS?
Recurrent episodes of hemiparesis or other focal neurological signs, lactic acidosis, ragged red fibres plus at least two of: focal/generalised seizures, dementia, recurrent migraine headaches and vomiting
CSF protein is often increased
Neuropathology can show cortical atrophy with infarct-like lesions in cortical/subcortical structures, basal ganglia calcifications and ventricular dilatation
Clinical manifestations of metachromatic leukodystrophy (MLD)?
Late infantile form (most common): presents at 12-18 months with irritability, inability to walk, and hyperextension of the knee causing gene recurvatum
Deep tendon reflexes are diminished/absent
Gradual muscle wasting, weakness and hypotonia become evident, then progress to develop nystagmus, myoclonic seizures, optic atrophy, and quadriparesis with death within the first decade of life
Overview of glycogen storage disorder V (GSDV)?
Also known as McArdle disease, AR disorder
Mutations in PGYM lead to myophosphorylase deficiency
Present with muscle pain, tiredness, stiffness and cramp associated with exercise, commonly experience a “second wind” after 10 minutes of exercise
Dietary advice for baby diagnosed with phenylketonuria?
Can breastfeed, but 75% of feeds should be phenylalanine-free formula, and should have support by a metabolic dietician
Cause of phenylketonuria?
Most are PAH deficiency, AR disorder caused by multiple mutations in the gene for PAH
Small amount (2%) are BH4 deficiency
Which genetic syndrome is associated with a higher risk of ketotic hypoglycaemia beyond the neonatal period?
Russel Silver syndrome
Myoclonic seizures since 3/12 (burst suppression during sleep), developmental delay, progression of seizures to absence and GTCS not responding to AEDs, during fasting becomes confused and dystonic
= SLC2A1 mutation: results in glucose transport protein type 1 (GLUT1) deficiency, resulting in mutation in GLUT1 transporter protein responsible for moving glucose from blood into the CSF
Features of GLUT1 deficiency?
Low CSF: plasma glucose ratio (<0.4)
Myoclonic, atonic or tonic-clonic seizures, confusion or paroxysmal dyskinesias/dystonic movements ESPECIALLY with fasting/with exertion
Which metabolic conditions respond to treatment of seizures with pyridoxine?
Antiquitin deficiency (more common)
Pyridoxine 5/phosphate oxidase (PNPO) deficiency
Overview of glutamic acidaemia (GA1)?
Ketoacisosis, hyperammonaemia, hypoglycaemia and encephalopathy
Can also result in bilateral subdural haemorrhages (about 25% of these will present with dystonia rather than decompensation)
Untreated children can develop oro-facial dyskinesia
Microencephalic macrocephaly is typical (often earliest sign)
Can develop normally if treated with L-carnitine and low-protein diet
Presentation of carnitine palmitoyltransferase II deficiency (CPT)?
Long chain fatty acid oxidation defect, AR
Neonatal onset: hypotonia, cardiomyopathy, renal cysts, arrhythmias
Late onset: ‘myopathic’ type - reduced exercise tolerance, episodes of rhabdo, and elevated CK
Presentation of Pompe disease?
= glycogen storage disease type 2
Acid alpha glucosidase deficiency (lysosomal enzyme)
Infantile onset: severe generalised muscular hypotonia, cardiomyopathy, cardiomegaly, hepatomegaly, FTT, elevated CK
Presentation of McArdle disease?
= Glycogen storage disease type 5
Most common glycogen storage disease, myophosphorylase deficiency
Adolescents: exercise intolerance, fatigue, weakness and myalgias, elevated CK and frequent episodes of rhabdomyolysis
Presentation of Zellweger syndrome?
Hypotonia, encephalopathy, craniofacial dysmorphism, hepatomegaly, skeletal abnormalities (calcific stippling and shortened proximal limbs)
NO elevated CK
Which antiepileptic can trigger metabolic decompensation in urea cycle defects?
Sodium valproate - can lead to hyperammonaemia by inhibition of caramoyl phosphate synthetase 1 (necessary for ammonia elimination via urea cycle)
- can also occur with phenobarb, phenytoin or carbamazepine
High ammonia and glutamine with orotic acid peak in the urine, low serum citrulline?
Suggestive of OTC deficiency
Most common inherited disorder of the urea cycle?
OTC deficiency - X linked
Phenotype can vary from asymptomatic to severe neonatal hyperammonaemia
Later onset forms can be triggered by metabolic stressors (infection, protein consumption, medications)
Presentation of glutaric acidaemia?
= multiple acyl-CoA dehydrogenase deficiency
Neonatal (severe): metabolic crisis with acidosis, high ammonia, hepatomegaly, hypotonia and odour of ‘sweaty feet’
NON-KETOTIC hypoglycaemia!!! (as with other fatty acid oxidation disorders)
Congenital abnormalities: progressive cardiomyopathy, polycystic kidneys, hypospadias, dysmorphism
Presentation of isovaleric acidaemia?
Organic acidaemia caused by deficiency of isovaleryl-CoA dehydrogenase that is involved in leucine breakdown
Vomiting, lethargy, ‘sweaty feet’ odour
Metabolic acidosis with KETOTIC hypoglycaemia
Presentation of Hurler syndrome?
= Mucopolysaccharidoses type 1 (lysosomal storage disorder caused by deficiency in alpha-L-iduronidase)
Dysostosis multiplex, hepatosplenomegaly, ID, coarse facial features, macrocephaly and cardiac abnormalities (hypertrophic cardiomyopathy), hydrocephalus, corneal clouding, hernias
No metabolic derangement
Presentation of GLUT1 deficiency?
Low CSF glucose compared to paired serum glucose
Seizures (early onset absences), epilepsy, developmental delay and paroxysmal exertion dyskinesias
Can be treated with ketogenic diet
Cause of GLUT1 deficiency?
SLC2A1 mutation
GLUT1 = glucose transporter, moves glucose across the blood brain barrier
What metabolic condition should be suspected if mum is a vegetarian?
OTC deficiency = affected female carriers often cannot tolerate the high protein load in meat
Most helpful investigation for suspected urea cycle defects?
Ammonia
Presentation of medium-chain acyl-CoA dehydrogenase deficiency (MCADD)?
Usually 18 months-3 years during a period of stress (usually a viral infection)
Children younger than this usually feed frequently therefore symptoms are masked
The treatment is to avoid prolonged periods of fasting
By what mechanism does MCADD result in hypoglycaemia?
Impaired gluconeogenesis
- hypoketotic hypoglycaemia
What size are the fatty acids which are metabolised by short chain acyl-CoA dehydrogenase?
C4 carbon chain
What size are the fatty acids which are metabolised by medium chain acyl-CoA dehydrogenase?
C6-8 carbon chain
(plasma acylcarnitine profile may show elevated C6, C8 and C10)
What size are the fatty acids which are metabolised by long chain acyl-CoA dehydrogenase?
C8-12 carbon chain
(plasma acylcarnitine profile may show elevated C16:1-OH, C18:1-OH
What size are the fatty acids which are metabolised by very long chain acyl-CoA dehydrogenase?
> 22 carbon chain
(plasma acylcarnitine profile may show elevated C14:1, C14, C16:1, C16
Buzzword symptoms for Leigh disease?
Intermittent respirations with sighing or sobbing (brainstem dysfunction)
Associated with failure to thrive, ataxia, seizures, developmental delay, lactic acidosis
Features of Hunter syndrome?
MPSII, X linked, deficiency in iduronate 2-sulfatase
No corneal clouding
Pearly papules over scapulae/arms/thighs
CNS involvement - sleep disturbance, aggressive behaviours
Features of Sanfiippo syndrome?
MPSIII, AR
Progressive CNS degeneration with developmental delay, behavioural problems, hyperactivity, aggression and sleep disorders
Physical findings are milder than type 1 (can lead to delay in diagnosis)
Features of Morquio syndrome?
MPS IV, AR, due to abnormal keratan sulphate and chondroitin-6-sulfate
Skeletal involvement including short trunk dwarfism, pacts carinatum, kyphoscoliosis, gene valgum, odontoid dysplasia, vertebral platysponylisis and abnormal gait
NORMAL INTELLIGENCE, no CNS involvement
Baby with poor feeding, abnormal posturing, vomiting and a seizure (encephalopathy), marked hyperammonemia, respiratory distress, and respiratory alkalosis on VBG
Urea cycle disorders
- typically present after feeding has started
- encephalopathy and high ammonia cause central hyperventilation -> respiratory alkalosis
Infant with dysmorphism, FTT, hypotonia, abnormal pattern of serum transferrin isoform?
Congenital disorders of glycosylation
- screened by testing for transferrin isoforms
- features include hypotonia, big ears, abnormal fat pads, developmental delay, failure to thrive, protein losing enteropathy
Baby with vomiting, drowsiness, encephalopathic, no previous NGST, poor feeding, hypoglycaemic with no ketones
Fatty acid oxidation disorder
- hypoglycaemia with no ketones
How many calories in fats and carbs?
1g of fat = 9kcal
1g of carbohydrate/protein = 4kcal
e.g. 10kg boy receiving 10% dextrose at maintenance rate plus 3g/kg of SMOF over 24 hours
Maintenance is 1000ml in 24 hours
10% dextrose = 10% carb = 100g carbohydrate
100g carb = 400kcal
30g of lipids = 30g of fat = 30x9 = 270kcal
400 + 270 = 670kcal
Mechanism of porphyria?
Accumulation of one or more heme synthesis pathway intermediates which can present either in hepatic or erythropoietic form, depending on whether the intermediates first accumulate in the liver or bone marrow
Most common porphyria in children?
Erythropoietic protoporphyria (EPP)
Overview of erythropoietic protoporphyria (EPP)?
Caused by ferrochelatase deficiency and characterised by immediate photosensitivity within minutes of sunlight exposure - acute pain followed by erythema and swelling of the face, hands and feet (may last several days)
Total erythrocyte protoporphyrin is elevated
Overview of acute intermittent porphyria?
Acute neurovisceral attacks, with neuropathic abdominal pain, autonomic changes and photosensitivity
Urine porphobilinogen is elevated
(more common in adults)
Which metabolic conditions can lead to hypertrophic cardiomyopathy?
Disorders associated with glycogen storage or lysosomal substrates
Which metabolic conditions can lead to dilated cardiomyopathy?
Diseases associated with excessive acidic metabolites (organic acidaemias, amino acidopathies and systemic carnitine deficiency)
Why should steroids be avoided in patients with urea cycle disorders?
Corticosteroids increase protein catabolism - increased risk of hyperammonaemia which in UCDs leads to metabolic decompensation
Raised 3-methylglutaconic acid in urine is suggestive of?
3-MGA type 2 (Barth syndrome)
- can also have failure to thrive, cardiomyopathy
1 year old with developmental delay, jaundice as a baby, cataracts on examination?
Galactosaemia
- usually detected on NBST (think in refugees)
Child with progressive weakness since 4 months, regression, macrocephalic and hyperreflexis, cherry red macula on fundoscopy?
Tay Sachs disease
- lysosomal storage disorder presenting after 3 months, with regression of motor skills
- macrocephaly common due to accumulation of GM2 ganglioside
Difference between Tay Sachs and Niemann Pick disease type A?
Both have developmental regression and a cherry red macula
Tay Sachs is associated with macrocephaly and hyperreflexia, NPD type A has absent/reduced reflexes and no macrocephaly
6 month old with developmental delay, recurrent sinopulmonary infections, hepatosplenomegaly, corneal clouding?
Hurlers syndrome (mucopolysaccharidoses)
- typical to have recurrent infections and developmental delay before facial features develop
- Hunters does NOT have corneal clouding (hunters need good eyesight!)
- Morquio has predominantly skeletal features but can also have corneal clouding
Features of hereditary fructose intolerance?
Profuse vomiting
Hypoglycaemia
Lactic acidosis
Liver and renal failure if continued intake
Which cofactor defect is associated with phenylketonuria?
Tetrahydrobiopterin (BH4)
- essential cofactor for phenylalanine hydroxylase
- defects in BH4 metabolism can account for around 2% of patients presenting with elevated phenylalanine levels
- presentation similar to PKU
What are neopterins?
Products of guanosine triphosphate (GTP) catabolism, result from cellular immune activation by pro-inflammatory cytokines
Most sensitive metabolic marker of neuroinflammation in the CSF
