Metabolics, Rehab Flashcards
1
Q
Metabolic disorders - general epidemiology, classification, sx
A
- Epidemiology
a. Individually rare
b. Collectively 1/5000
c. 60% AR, 20% AD, 15% X linked, 5% mitochondrial
i. X-linked = Hunter, Fabry, OTC deficiency - Classification
a. According to intracellular site
i. Mitochondrial
ii. Peroxisomal
iii. Lysosomal storage disorders
b. According to biochemical pathway
i. Disorders of intermediary metabolism
ii. Neurotransmitter disorders
iii. Disorders of purines/ pyrimidines - Clinical manifestations
a. Neurological and gastrointestinal manifestations most common
b. Presenting features may be acute or chronic
c. By system
i. Neurological = encephalopathy, movement disorder, diurnal pattern, ataxia, abnormal tone
ii. Hepatic = jaundice, liver failure, hypogylcaemia
iii. Cardiac = cardiomyopathy, rhythm disturbance
iv. Respiratory = OSA, recurrent chest infections
v. Renal = tubular dysfunction, renal stones
vi. Eye = cataract, optic atrophy, retinal abnormalities
vii. Dermatological = alopecia, rash, kinky hair
viii. GIT = chronic diarrhoea
ix. Growth = FTT
x. Dysmorphism - Disorders of cholesterol synthesis – SLO
- Peroxisomal disorders
- Mitochondrial disorders
- Lysosomal disorders (MPS)
- Congenital disorders of glycosylation
- Glutaric aciduria type II
Developmental delay - 1-5% due to IEM
2
Q
NST - things that are missed
A
Tyrosinaemia (type 1) Citrullaemia OTC deficiency (some) Glycine encephalopathy Cobalamin C deficiency Galactosaemia (not screened in Vic)
3
Q
NST - things that are detected (metabolic)
A
Amino acidopathies: PKU, homocystinuria, tyrosinaemia, citrullaemia
Organic acidopathies: methylmalonic acidaemias, isovaleric acidaemia, propionic acidaemia
Fatty acid oxidation defects
Carnitine transport defects
4
Q
Metabolic acidosis - metabolic causes
A
Amino acid disorder
Organic acidaemia
Carbohydrate metabolism abnormalities
5
Q
Lactic acidosis - metabolic causes
A
Mitochondrial disorder
Pyruvate metabolism
6
Q
Respiratory alkalosis - metabolic causes
A
Urea cycle defects
7
Q
Hepatomegaly/splenomegaly - metabolic causes
A
Glycogen storage disorder
Lysosomal storage disease
Galactosemia
Peroxisomal disorders
8
Q
Isolated hepatomegaly - metabolic causes
A
Glycogen storage disorder
Mitochondrial disease
9
Q
Odours - metabolic causes
A
Maple syrup - maple syrup urine disease Sweaty socks - isovaleric acidaemia Fruity - MMA, propionic acidaemia Mouse urine/musty - PKU Fish - trimethylaminuria, carnitine excess
10
Q
Metabolic differentials - neonatal ‘sepsis’ like
A
Organic acidopathies – MMA, PA, HCS Aminoacidopathies – MSUD Urea cycle disorders Galactosaemia Mitochondrial
11
Q
Metabolic differentials - well for months-years then coma and hypoglycaemia
A
FAOD
Glycogen storage disease
12
Q
Metabolic differentials - developmental regression
A
Lysosomal storage disease Mitochondria Peroxisomal – ALD Urea cycle disorders MSUD, organic acidaemia, PKU Other genetic – CDG, Retts, Alexander, VWM etc
13
Q
Metabolic differentials - hepatomegaly/hepatitis
A
Tyrosinaemia Galactosaemia GSD Lysosomal Neimann-Pick C Mitochondrial Bile acid synthesis
14
Q
Metabolic differentials - dysmorphic at birth
A
Peroxisomal
Mitochondrial
Lysosomal
15
Q
Metabolic differentials - seizures, microcephaly
A
Non-ketotic hyperglycinaemia Pyridoxine responsive seizures GLUT-1 transporter Creatinine synthesis/ transporter Sulphite oxidase Menkes Folate disorders
16
Q
Metabolic differentials - movement disorder
A
Glutaric aciduria
Atypical NKH
Neurotransmitter disorder
Lesch-Nyhan
17
Q
Neurodegenerative metabolic disorders - overview
A
- Hallmark of neurodegenerative disease is regression and progressive deterioration of neurological function
- Outcome of neurodegenerative disease is fatal – BMT and other novel therapies may be used
• Common features o Loss of speech, vision and hearing o Loss of locomotion o Feeding difficulties o Seizures o Impairment of intellect
• Classification
o White matter = UMN signs, progressive spasticity, cerebellar signs
o Gray matter = convulsions, encephalopathy, intellectual and visual impairment,
o Mixed grey and white/ Multiorgan/ multisystem
• Aetiology o Inherited o Infective – SSPE, syphilis, HIV o Hypothyroidism o Hydrocephalus o Intoxication
• Investigations o Urine metabolic screen o Plasma amino acids o Urine amino acids and organic acids o CSF amino acids, neurotransmitters, lactate and pyruvate o CSF blood and glucose o Very long chain fatty acids – often abnormal in peroxisomal disorders o Lysosomal enzymes o Biopsies less common o Ophthalmology consult o Metabolic consult o Sequencing - gene panel, whole exome/whole genome/ trios
18
Q
Leukoencephalopathy - classification, red flags
A
• Disorders of white matter can be sub classified further o Demyelinating (broken down) = ALD (?adrenoleukodystrophy) o Dysmyelinating = Krabbe disease, MLD (?metachromatic leukodystrophy) o Hypomyelinating (never formed) = Pelizaeus Merzbacher, Alexander’s disease, vWD o Spongioform (cystic degeneration) Canavan’s disease
• Red flags for white matter disease:
o Motor stagnation or regression
o Episodic deterioration with an intercurrent illness or head injury
o Mixed UMN and cerebellar signs
o Mixed central and peripheral motor signs
o Acquired macrocephaly
o Deterioration in school performance, change in personality or new onset hyperactivity in an adolescent male
Particularly adrenoleukodystrophy
19
Q
Disorders of intermediary metabolism - overview
A
- Includes
a. Defects in protein metabolism
i. Amino acidopathies (MSUD)
ii. Organic acidurias (MMA, PA, IVA, GAI)
iii. Urea cycle defects
b. Defects in fatty acid + ketone metabolism
i. Fatty acid oxidation defects
c. Defects in Carbohydrate metabolism
i. Galactosaemia
ii. GSD
iii. HFI
d. Defects in energy metabolism
i. PDH deficiency
ii. Mitochondrial chain disorders - Clinical presentation
a. Variable age of onset + severity
b. Neurological - encephalopathy
c. Myopathy/ rhabdomyolysis
d. Liver disease/ dysfunction
e. Precipitating factors
i. Feeding/ fasting
1. Dietary overload (eg. protein)
2. Dietary deficiency (eg. vitamin B6, B12, carnitine)
ii. Intercurrent infection/ fever
iii. Surgery
iv. Exercise
v. Specific toxins (eg. valproic acid)
- Usual history
a. Normal pregnancy and delivery
b. Initial symptom free interval
c. Non-specific signs and symptoms
d. Rapid deterioration with no clear cause
20
Q
Amino acidopathies - general/bg
A
- Key points
a. Any defect in breakdown of amino acids, leading to accumulation of amino acids in plasma/ urine
b. Of the 20 amino acids 11 can be synthesized in vivo and 9 cannot (essential amino acids)
c. Amino acid disorders (amino acidopathies) caused by a defect in the metabolic pathway of amino acids
d. Amino acidaemia = abnormal accumulation of amino acids in plasma
e. Amino aciduria = abnormal accumulation of amino acids in urine - Common features
a. Usually well in the newborn period, deteriorating after a period of protein feeding
b. May progress to encephalopathy, coma or death
c. In older children – developmental delay, regression
d. Scents
i. PKU - musty
ii. MSUD – maple syrup
iii. Glutaric acidemia – sweaty feet
iv. Trimethylaminuria -rotting fish
v. Tyrosinemia – boiled cabbage
vi. Isovaleric acidemia – sweaty feet - Investigations
a. Highly variable investigations
b. Many do NOT cause routine chemical disturbances (glucose, pH etc)
c. Amino acids toxic to certain organ
d. Variable (according to up to date):
i. Metabolic acidosis with high anion gap (except for maple syrup urine disease)
ii. Hyperammonemia
iii. Hypoglycaemia with appropriate ↑ ketosis
iv. Deranged LFTS
v. Reducing substrates in urine - Conditions
a. Phenylketonuria
b. Homocystinuria
c. Maple syrup urine disease
d. Citrullinemia
e. Arginosuccinic acidaemia
f. Tyrosinaemia
21
Q
Phenylketonuria - general
A
- Phenylalanine is an essential amino acid
- Dietary phenylalanine not utilized for protein synthesis is degraded
- Deficiency of the enzyme phenylalanine hydroxylase (PAH) or cofactor tetrahydrobiopterin (BH4) accumulation of phenylalanine
- Classification
a. Classic PKU
b. Mild hyperphenylalaninemia - Clinical manifestations
a. Normal at birth
b. Profound intellectual disability if untreated
c. Cognitive delay may be not be evident for first few months
d. Infants
i. Vomiting – early symptom
ii. Lighter in complexion compared with siblings
iii. Seborrheic or eczematoid rash – mild and disappears as child grows older
e. Older untreated children
i. Hyperactive with autistic behaviours, purposeless hand movements, rhythmic rocking, athetosis
ii. 50-70% will have IQ <35
iii. Odour of phenylacetic acid – musty/ mousey
iv. Neurological signs - Seizures – 25%
- Spasticity
- Hyperreflexia
- Tremors
v. Microcephaly
vi. Prominent maxillae with widely spaced teeth, enamel hypoplasia, growth retardation - Diagnosis
a. Now included in NST
b. Quantitative serum phenylalanine level
c. Biopterin deficiency needs to be excluded - Treatment
a. Low phenylalanine diet
b. Administration of large neutral amino acids (LNAAs) - compete with phenylalanine for transporter across intestine and BBB
c. Oral administration of BH4 may be useful
22
Q
Hereditary tyrosinaemia - general
A
= type 1 tyrosinaemia
• Tyrosine is derived from ingested proteins OR synthesized from phenylalanine (NON-essential)
• Precursor of dopamine, noradrenalin, adrenalin, melanin and thyroxine
• Excess tyrosine is metabolized to carbon dioxide and water
- Key points
a. NOT detected by newborn screening - Genetics
a. AR
b. Mutation in fumarylacetoacetate hydrolase (FAH) gene (final step in metabolic pathway of tyrosine) -> shunts to ↑ Succinylacetone which results in alkylation - Clinical manifestations
a. Timing of presentation
i. Affected infants appear normal at birth
ii. Acute (0-6 months) = most common
iii. Sub-acute = first year of life
iv. Chronic = >1 year of age
b. Multisystem disorder
i. Hepatic - Hepatic crisis heralds onset of disease - precipitated by an intercurrent illness
- Fever, irritability, vomiting, haemorrhage
- Hepatomegaly, jaundice, elevated levels of transaminases
- Hypoglycaemia
- Boiled cabbage odour
ii. Neurological = peripheral neuropathy - Resembles acute porphyria
- Weakness + hypertension
- Crisis triggered by minor infection – characterised by severe pain, extensor hypertonia of the neck and trunk, vomiting, paralytic ileus
iii. Renal involvement = Fanconi syndrome - Investigations
a. ↑ Succinylacetone in serum and urine - Treatment
a. Treat with low phenylalanine and tyrosine diet
b. Treatment = nitisinone (blocks an earlier step in the metabolic pathway, avoiding excess succinylacetone)
c. Need to monitor for HCC
23
Q
Homocystinuria - general
A
- Methionine is an essential amino acid - metabolized to S-adenosylmethionine and cysteine
- By product of metabolism is homocysteine, which is recycled to reform methionine in the presence of a folate product + B12 derived cofactor
- Key points
a. Heterogenous disease – variable involvement or each organ system
b. Most common inborn error of methionine metabolism
c. Classification
i. B6 repsonsive – milder form 60%
ii. B6 non-responsive 40%
d. Thrombo-embolism major cause of death and morbidity - Genetics
a. Mutation in CBS – gene encoing cystathione beta-synthase - Clinical manifestations
a. Normal at birth
b. Infancy – non-specific features
c. Diagnosis usually made >3 years – when ectopia lentis occurs
i. Eye - Ectopia lentis and/or severe myopia
ii. Skeletal system - Excessive height, long limbs, scoliosis, pectus excavatum
- Resembles Marfans
iii. Vascular system - Thromboembolism – involve large and small vessels, particularly those of brain
iv. CNS - Devleopmental delay
- Intellectual disabiltiy (may be progressive)
- Investigations
a. ↑ plasma total homocystine and methionine
b. ↑ urine homocystine
c. Low or absent cystine in plasma
d. Genetic testing = mutation in CBS - Treatment
a. High dose vitamin B6 – dramatic improvement in those who are responsive (B6 is a cofactor for CBS)
b. May require folic acid supplementation
c. Restriction of methionine intake in conjunction with cystine supplementation – for patients who are unresponsive to vitamin B6
24
Q
Cysteine disorders - general
A
• Cysteine = nonessential amino acid, synthesized from methionine
Cystinuria
• Rare AR disease
• Abnormal reabsorption of cysteine from proximal tubules predisposes to renal stones due to cysteine crystallization
• Treatment = with regular fluids, alkalinisation of urine with potassium citrate, penicillamine (binds with cysteine to increase reabsorption)
Cystinosis • Accumulation of cysteine in different organs due to abnormal metabolism of cysteine cysteine • AR mutations, can cause in infantile (nephropathic), juvenile and adult forms • Clinical manifestations o Renal tubular acidosis + ESRF o Growth retardation o Eye deposits + visual impairment o Hepatomegaly o Pancreatic disease o Muscular disease o Impaired cognition • Treatment o No effective treatment o Supportive therapies and cysteamine: enters the cell and reacts with cysteine to form cysteine complexes (does not prevent tubular dysfunction and has to be given frequently when topical)
25
Q
Maple syrup urine disease - general
A
= branched chain ketoaciduria
- Genetics + pathogenesis
a. Caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) – the second enzyme of the metabolic pathway of the three branched-chain amino acids (leucine, isoleucine and valine)
b. Defect in the enzyme system involved in decarboxylation of leucine, isoleucine and valine (BCKAD)
c. AR mutation, 1/200,000 - Clinical features
a. Classic MSUD
i. Most common form
ii. Mutations in genes for E1alpha, E1beta and E2 <3% residual enzyme activity
iii. Newborns develop ketonuria within 48 hours of birth – irritability, poor feeding, vomiting, lethargy and dystonia
iv. Neurological abnormalities develop by day 4 - Alternating lethargy and irritability
- Dystonia, rigidity and opisthotonos
- Apnoea
- Seizures
- Unusual odour (maple syrup, urine and ears)
v. Metabolic intoxication - Exacerbation of previously controlled disease
- Triggered by increased catabolism of endogenous protein (intercurrent illness, exercise, injury, surgery, fasting)
- Clinical manifestations – epigastric pain, vomiting, anorexia, and muscle fatigue
- Neurological signs – hyperactivity, sleep disturbance, stupor, decreased cognitive function, dystonia, ataxia
- Death can occur if not treated
c. Intermittent MSUD
i. Second most common type
ii. Affected patients have normal growth and development
iii. Present with ketoacidosis during episodes of catabolic stress – intercurrent illness or protein intake
iv. Signs of neurotoxicity develop – ataxia, lethargy, seizures, coma
v. Death may occur
- Investigations
a. NORMAL glucose, NORMAL ammonia, pH normal
b. Strongly positive urinary dipstick test for ketones
c. DNPH test – add reagent to urine and precipitates
d. Plasma branched chain amino acids = ↑ leucine, isoleucine and valine
e. ↑ urinary alpha-hydroxyacids and alpha-ketoacids - Treatment
a. Diet low in branched chain amino acids
i. Reduce natural protein
ii. BCAA free formula
b. Dialysis to remove toxic metabolites
c. Liver transplantation
26
Q
Organic acidaemias - general/overview
A
- Key points
a. The early steps in the degradation of the branched chain amino acids (valine, leucine, and isoleucine) are similar
b. Intermediate metabolites are all organic acids [non-amino organic acids]
i. Examples = lactate, pyruvate, beta-hydroxy butyrate, methylmalonic acid
c. Deficiency in any causes organic acids proximal to the enzymatic block to accumulate collect in body fluids excreted in the urine
d. Elevated organic acids blocks the urea cycle resulting in hyperammonaemia - Clinical manifestations
a. Most acidaemias become apparent in newborn period or early infancy
b. Present first 1-2 weeks of life – poor feeding, vomiting, floppiness, hypotonia, increased lethargy which progresses to coma
c. After an initial period of being well children develop a life-threatening episode of metabolic acidosis characterised by a widened anion gap
d. Presenting episode may be mistaken for sepsis
e. Children susceptible to metabolic decompensation during episodes of catabolism (eg. illness, trauma, prolonged fasting) - Investigations
a. Metabolic acidosis with widened anion gap (>25 mmol/L)
b. Mild-moderate hyperammonemia
c. Elevated ketones
d. Hypoglycaemia
e. Bone marrow suppression common – results in pancytopaenia
f. Urine = elevated organic acids
g. Acylcarnitine = all organic acids are esterified to carnitine forming acylcarnitine - Common conditions
a. Methylmalonic acidaemia (MMA)
b. Propionic acidaemia (PA)
c. Isovaleric acidaemia (IVA)
d. 3-methylcrotonylglycinuria (3-MCG)
e. GA-1 - Treatment principles
a. Decrease substrate – low protein diet
b. Enhance enzyme activity – biotin, B12 (MMA)
c. Disposal of toxic metabolites – carnitine (propionic acidaemia)
i. Carnitine binds to organic acids then can be excreted in the urine
27
Q
Urea cycle defects - general
A
- Key points
a. Urea cycle = pathway by which nitrogen (produced from amino acid catabolism) is converted to urea for excretion
b. 5 enzymes involved in urea cycle
i. All can have mutations
ii. OTC most common – characterised by low citrulline + orotic acid - Clinical manifestations
a. Vomiting
b. Lethargy
c. Encephalopathy/ coma - Investigations
a. Hyperammonemia
b. Respiratory alkalosis (elevated ammonia stimulates central respiratory drive -> hyperventilation)
c. Ketosis
d. Liver dysfunction
28
Q
Ornithine transcarbamylase deficiency - general
A
- Key points
a. Most common inborn error of urea synthesis - Genetics + Pathogenesis
a. X linked deficiency of OTC enzyme – located in mitochondrial matrix, coded for by Xp21.1
b. Expressed in liver + intestine
c. Hyperammonemia
i. Ammonium binds with glutamate to form glutamine, which has osmotic effect causing cerebral oedema - Clinical manifestations
a. Usually lethal in neonatal period
i. Severe in affected males – history of deaths in male siblings
ii. May manifest in carrier females
b. Protein aversion
c. Recurrent vomiting, decreased GCS, lethargy and coma
d. Acute / chronic encephalopathy - Investigations
a. Hyperammonaemia (> 1000 mmo/L)
b. Additional metabolic markers
i. Low citrulline
ii. Elevated orotic acid
c. No metabolic acidosis (may have respiratory alkalosis as ammonia drives tachypnoea)
d. No urinary ketones
e. Deranged LFTS/ coagulopathy - Treatment
a. Decrease substrate availability = low protein diet
b. Promote anabolism = increase calories by protein free formula
c. Replace deficient metabolites = arginine or citrulline
d. Increase disposal of toxic metabolites = sodium benzoate (binds glycine which contains nitrogen)
e. Rapid removal of toxic metabolites = haemofiltration
f. Liver transplantation
29
Q
Fatty acid oxidation defects - general/overview
A
- Key points
a. Beta oxidation of fatty acids is used to produce energy in periods of starvation/illness, completely oxidized to CO2 and H2O, producing ketone bodies B-hydroxybutyrate and acetoacetate
b. Most identified on newborn screening – otherwise dx on urine organic acids, acetyl carnitine profile - Common features (liver, muscle, heart)
a. Hepatic
b. Cardiac
i. Acute or chronic hypertrophic or dilated cardiomyopathy
ii. Pericardial effusion often accompanies the hypertrophic cardiomyopathy and is often responsible for death
c. Muscle
i. Moderate to severe hypotonia or recurrent rhabdomyolysis
ii. Gross myoglobinuria not observed until CK >30,000 IU/L - Investigations
a. Hypoglycaemia with LOW ketones
b. LFTS may be deranged
c. May have hyperammonemia and a metabolic acidosis
d. Secondary carnitine deficiency may occur – acylcarnitine profile (Guthrie card) - Management
a. Give sugar when sick (oral or IV)
b. Low long chain fat diet + MCT supplement
c. Avoid fasting - Common conditions
a. VLAD
b. SCAD
c. MCAD
d. Carnitine uptake defects
