Metabolic Flashcards
Cherry red macula is seen in?
Tay-Sachs (hyperreflexic, macrocephaly) and Neimann-Pick (hyporeflexic)
Glutaric acidaemia type 1 can present with …?
Bilateral subdural haemorrhages, differential for NAI
Which urea cycle defect is not autosomal recessive?
Ornithine transcarbamyase (OTC) deficiency (X-linked)
Describe Farber’s disease
- Also known as Farber’s lipogranulomatosis
- Hoarse or weak cry, lipogranulomas and swollen, painful joints, hepatomegaly, developmental delay
- Rare autosomal recessive condition caused by abnormal lipid metabolism. Lipids accumulate abnormally throughout the body, especially around the joints
Developmental delay, hypopigmentation (blond hair, blue eyes) and eczema
Phenylketonuria (PKU)
The mucopolysaccharidoses are a group of disorders caused by?
- Absence or malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans
- Glycosaminoglycans accumulates in cells, blood, and tissues
- Results in permanent, progressive cellular damage which affects physical appearance, physical abilities, organ and system functioning and usually development
What is the treatment of acute hyperammonemia?
- Fluid, electrolytes, glucose (5-15%), and lipids IV
- Sodium benzoate or sodium phenlyacetate infusion
- Dialysis if above treatment fails
Unwell 2 day old neonate with hyperammonemia, respiratory alkalosis, normal blood glucose and normal anion gap?
Urea cycle defect e.g.
- OTC deficiency (ornithine transcarbamylase deficiency, high glutamine/ornithin/alanine, low citrulline, high urine orotic acid)
- Or classic citrullinemia (ASA deficiency, high citrulline)
- Argininosuccinic aciduria (ASA lyase deficiency, high argininosuccinic acid)
- Need amino acid profiles to distinguish between types of urea cycle defects
Describe Pompe disease
- Glycogen storage disease type II (GSDII) with defect in lysosomal metabolism
- AR inherited deficiency of the enzyme acid α-glucosidase (GAA), which hydrolyzes glycogen to glucose
- Hypertrophic cardiomyopathy in infants
- Skeletal and respiratory muscle weakness, hypotonia, areflexia
- Raised CK
- Enzyme replacement with recombinant human GAA has improved survival, and cardiac/resp/motor function
2 day olds with jaundice, hepatomegaly, poor feeding and vomiting. Investigation and diagnosis?
- Galactosaemia
- Children present after commencing feeds with jaundice, hepatomegaly and vomiting, E.Coli sepsis
- Cataracts are not present initially. On newborn screening
- Deficiency in GALT enzyme (galactose-1-phosphate uridyltransferase) leads to an increase in galactose and galactose-1-phosphate. Accumulates in liver and eyes causing jaundice + cataracts
- GALT level not useful if RBC transfusion in past 3/12
- Usually positive reducing substances in the urine
- Treatment: elimination of galactose from diet for life
An 18-month-old, gastroenteritis with diarrhoea and vomiting, brought to ED with reduced level of consciousness. Diagnosis?
- Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) typically presents in children aged 18m-3y during a period of stress (usually a virus).
- Children younger than this usually feed so frequently that it masks the disorder.
- The treatment is to avoid prolonged periods of fasting.
- Ix: Acylcarnitine profile
Describe maple syrup urine disease (MSUD)
- Presents day 3-5
- Poor feeding and vomiting during the first week of life
- Seizures, hypertonicity, loss of moro, periods of flaccidity, can be mistaken for sepsis/meningitis
- Death from cerebral oedema without treatment
- Hypoglycaemia, ketosis and ketonuria, unremarkable bloods otherwise; occ metabolic acidosis with increased anion gap
- Branched chain a-ketoacid dehydrogenase deficiency
- Raised leucine, isoleucine, valine, alloisoleucine
- Leucine smells like maple syrup
Describe phenylketonuria
- Picked up on Guthrie, otherwise progressive developmental delay is the most common presentation
- Untreated children in later infancy may have vomiting, seizures, eczema, mousy odour, mental retardation and behavioural disorders.
- The fair skinned colouring is due to tyrosine deficiency.
Describe the process of glycolysis
- Glucose broken down to form 2 x pyruvate molecules ( no organelles or oxygen required)
- This produces energy in the form of 2 x extra ATP + 2 x NADH (these then enter electron transport chain, to make 3 ATP each)
- Pyruvate enters mitochondria (needs oxygen) to enter Krebs cycle = extra 30 x ATPs
- Glucose -> glucose-6-phosphate via addition of phosphate molecule from glucokinase (liver + pancreas) and hexokinase (all cells)
- Insulin increases glycolysis, glucagon decrease glycolysis
What is the role of GLUT?
- Glucose transporters, helps get glucose from the bloodstream into cells
- Insulin acts on GLUT to increase uptake of glucose
Describe the process of gluconeogenesis
- The process of making glucose from amino acids (broken down muscle), lactate, and glycerol (broken down triacylglycerides)
- Mainly occurs in liver, can occur in kidney + intestines
- Essentially the opposite of glycolysis. Use ATP to turn pyruvate (from lactate and amino acids) into glucose
What is glycogenolysis?
- Extra glucose (leftover after glycolysis) is stored in liver and muscle cells in the form of glycogen
- This can be utilised via process of glycogenolysis to produce glucose. This helps for around 12-24 hours of fasting
- Glucagon (from pancreas) stimulates liver cells to break down glycogen. This produces free glucose into bloodstream
- Epinephrine stimulates skeletal muscle cells to break down glycogen. This produces G6P which undergoes glycolysis to make energy
What two processes can the liver use during times of fasting to make glucose?
- Gluconeogenesis and glycogenolysis
- Gluconeogenesis makes glucose from amino acids, lactate, glycerol. Can keep going, main process of making glucose after 12 hours of fasting
- Glycogenolysis converts glycogen into glucose (good for 12-24 hrs fasting)
What is the role of lactate dehydrogenase?
- Converts lactate into pyruvate, so pyruvate can undergo gluconeogenesis to form glucose in times of fasting
- This makes an NADH molecule
What is the major form of glucose storage in the body?
- Glycogen in the liver and skeletal muscle cells.
- Glycogen synthesis is stimulated by insulin.
- Glycogen is utilised during periods of fasting via the process of glycogenolysis which is stimulated by glucagon and epinephrine
How is fructose intolerance diagnosed?
Via hydrogen breath test
Describe Tay Sachs disease
- Lysosomal storage disorder that presents after 3 months with regression of gross motor skills and weakness, exaggerated startle reflex or myoclonic seizures
- Macrocephaly due to accumulation of GM2 ganglioside in the brain. Beta-hexosaminidase A deficiency
- Hypotonia, hyperreflexia (c.f. Niemann Pick Disease is hyporeflexic), seizures, visual disturbance
- Cherry red macula. No visceromegaly
- Inc in Ashkenazi Jew population
- Death by age 4 but can have late-onset forms
Describe glutaric acidaemia (GA1)
- Present like sepsis, may have associated infection and fever
- Metabolic decompensation with ketoacidosis, hyperammonemia, hypoglycaemia, and encephalopathy.
- Can cause bilateral subdural haemorrhages
- 25% present with dystonia (these children are often diagnosed with cerebral palsy)
- Rarely presents in the newborn period
- Can develop oro-facial dyskinesia
- Microencephalic macrocephaly is typical and if present at birth, can be the earliest sign.
- Cam develop normally if they are treated with L-carnitine and a low-protein diet when initially diagnosed through newborn screening.
Raised anion gap metabolic acidosis
- > 20
- Exclude tissue hypoxia = lactic acidosis
- Exclude diabetes = ketones
- Think: organic acidaemia, disorders of gluconeogenesis, mitochondrial/Kreb cycle
- Tests: ammonia, glucose, ketones
(less likely to be low anion gap apart from organic acidemias presenting with renal tubular acidosis and bicarb loss)
Respiratory alkalosis in metabolic disease is consistent with?
Hyperammonemia
Anterior beaking of vertebrae is seen in?
Mucopolysaccharidosis
Pancytopenia, hepatosplenomegaly, hip pain (osteonecrosis of the femoral head)
- Gaucher disease
- Lysosomal storage disorder
- Beta-glucocerebrosidase deficiency
- Anaemia and thrombocytopenia, splenomegaly
- Treatment with enzyme replacement therapy
Encephalopathy, dystonia, macrocephaly. Triggered by fever.
Glutaric aciduria type 1. Treatment: low lysine diet, carnitine, emergency regime
Discuss the acylcarnitine profile
- Fatty acids (from lipids) form complex with coenzyme A = acyclCoA
- Transported by carnitine into mitochondria
- Makes an acylcarnitine and free coenzyme A - enters Kreb cycle and forms ketones
- Chopped up by enzymes (MCAD and LCAD) to make free coenzyme A
What are the tests used in investigating metabolic disease?
- Urine organic acids
- Plasma amino acids
- Acylcarnitine profile
- Urine glycosaminoglycans - diagnosis of MPS only
- Urine tandem metabolic screen (urine AA and OA)
Hypoglycemia, low cortisol, slightly tanned
Adrenal insufficiency (Addison’s)
Discuss glycogen storage diseases
- Hepatomegaly, proximal weakness, short stature/poor growth
- Ketotic hypoglycemia due to abnormal glycogenolysis - increased lactate (due to shunting) and triglycerides
- Avoid catabolism - regular daytime feeds, emergency plan when unwell, may need continuous overnight feeds or cornstarch
- Ix: raised CK, raised cholesterol and triglycerides
- Muscle phenotypes Pompe (II) and McArdle (V)
Mildly ketotic hypoglycemia with severe lactic acidosis indicates?
- Gluconeogenesis disorder, fructose 1-6 bisphosphatase deficiency
- F16BP is a key enzyme in gluconeogenesis from food
- Hypoglycemia develops when glycogen reserves are limited
- Disease begins before 2 years of age
- Can be hypoketotic (as acetylCoA is diverted into Krebs cycle to metabolise pyruvate rather than making ketones)
Hypoketotic hypoglycaemia with normal free fatty acids
- Abnormal fatty acid oxidation
- MCAD deficiency - medium chain acyl CoA dehydrogenase deficiency
- Impaired gluconeogenesis
Hypoglycaemia with low ketones and low free fatty acids
- Due to high insulin which stops catabolism and counter-regulatory hormones
- Hyperinsulinism
- Key clues: glucose requirements to maintain BSL > 3.5 = >10mg/kg/min
How much glucose do children usually need for the brain?
4-6mg/kg/min.
50% of glucose is used by the brain.
Brain can use ketones and lactate, but lack of these and hypoglycaemia = high risk of brain damage
Describe the normal starvation response
- Initially have glucose from food. As this decreases then glycogenolysis begins (breakdown of glycogen for glucose).
- Then gluconeogenesis starts - production of glucose from lactate, alanine, and fructose
- Then get fatty acid oxidation which causes production of acetlyCoA and ketones
Normal pattern of hypoglycaemia
- Low glucose
- Insulin suppressed
- Cortisol and growth hormone normal or elevated
- Fatty acids mobilised and acetlyCoA then ketones are produced
- If inc ketones but no FFA then cannot take up into cell. If inc FFA but no ketones then FA oxidation disorder.
What conditions are associated with impaired fasting tolerance at:
- 0-2 hrs
- 2-6 hrs
- 6-12 hrs
- 12-24 hrs
- 0-2 hrs: hyperinsulinism
- 2-6 hrs: glycogen storage diseases
- 6-12 hrs: disorders of gluconeogenesis
- 12-24 hrs: fatty acid oxidation or GH/cortisol deficiency
Permanent ketosis is pathognomonic for …?
SCOT deficiency = succinyl-coA-3-oxoacid CoA transferase deficiency
= disorder of ketone metabolism
Discuss idiopathic ketotic hypoglycaemia
- Exaggerated starvation response e.g. at 12-13 hours
- Presents between 18m and 7y
- Recurrent episodes of hypoglycaemia and ketonuria often during intercurrent illness
- Seizures may occur, neurological sequelae are rare
- Low BSL, inc ketones and FFA
- Low BSL responds quickly to PO or IV glucose
- Work-up normal
- Improves with age, rarely seen after puberty
What is the pathophysiology of idiopathic ketotic hypoglycaemia?
- Unknown
- Significant decrease in glycogenolysis without a compensatory increase in gluconeogenesis
- Limitation in availability of gluconeogenic amino acid alanine
- Increased dependency on gluconeogenesis when younger as glycogen stores rapidly depleted during fasting
Management of idiopathic ketotic hypoglycaemia?
- Avoidance of prolonged fasting, especially in presence of illness
- May need cornstarch at night if have ketones in morning
- Diagnosis of exclusion of other IEM and endocrine disorders
Causes of hypoglycaemia with and without acidosis?
- No acidaemia
- Low ketones + FFA = hyperinsulinism
- Low ketones, inc FFA = FAO defects
- Acidaemia
- Inc lactate = gluconeogenesis defects
- Inc ketones = ketotic hyperglycaemia, GH or cortisol deficiency, glucogenoses
Metabolic acidosis with raised anion gap, high ammonia, encephalopathy…?
Organic acidaemia:
- Methylmalonic acidaemia
- Propionic acidaemia
- Present in infancy, progress to coma and death if untreated
- Often present prior to Guthrie results
What are the investigations and treatment for organic acidemias?
- Ix: urine organic acids, plasma amino acids (elevated glycine), and acylcarnitine profile
- Tx: stop feeds, IV dextrose 8mg/kg/min CHO, lipid, insulin, L-carnitine (helps to detoxify chemicals and into urine), no protein
- Hydroxocobalamin B12 trial after critical samples taken (co-factor)
Chronic:
- Calories, protein restriction, L-carnitine (binds to and helps excrete organic acids), amino acid supplement formula
- Metronidazole, cycled to reduce intestinal flora (stop propionyl acid formation by gut bacteria)
- Liver +/- kidney transplantation
Discuss holocarboxylase synthase deficiency
- Carboxylase deficiency, unable to use biotin
- Alopecia, rash, immunodef, lethargy, poor feeding, seizures
- Metabolic acidosis, high anion gap, lactic acidosis
- Ix: urine organic acids and acylcarnitine profile
- Tx: stop feeds, IV dextrose 8mg/kg/min CHO, insulin, L-carnitine
- High dose biotin for Samoan variant (much more severe in Samoan population)
- Chronic: biotin, calories, ER, L-carnitine
How do we investigate for and treat urea cycle defects?
- Ix: urine organic acids (orotic acid for OTC) and amino acid profile. High ammonia without acidosis, low urea
- Tx: stop feeds, IV dextrose 8mg/kg/min CHO, lipid, insulin, ammonia scavengers
- Chronic: protein restriction, calories for growth, strict ER, sodium benzoate/phenylbutyrate (mop up nitrogen and excrete it from body, don’t work well in neonates)
- Phenylbutyrate, arginine, citrulline
- Liver transplant
Encephalopathy, normal gas and ammonia, elevated ketones, increased leucine, isoleucine, valine…?
Aminoacidopathy = maple syrup urine disease
What is the investigation and treatment for MSUD?
- Ix: urine organic acids (branch chain ketoacids) and amino acid profile
- Tx: stop feeds, IV dextrose 8mg/kg/min CHO, insulin
- Chronic: MSUD formula (no leucine, isoleucine, valine), protein restriction, calories for growth, liver transplant
What is the treatment for phenylketonuria?
- Phenylalanine hydroxylase (not funded in NZ, cofactor for enzyme, may mean can have normal diet)
- Protein restriction
- PKU formula (has no phenylalanine in it)
- High carb/energy foods
Lumbar kyphosis, hypotonia, developmental delay, recurrent ear infections, snores. Positive urine glycosaminoglycans
- Mucopolysaccharidosis
- T1 = Hurlers, Scheie = AR
- T2 = Hunters = X-linked
What is the treatment for MPS1?
- Hurlers disease
- Enzyme replacement therapy - laronidase
- HSCT - cross correction
- High transplant-related morbidity, outcome greatly improved if <2.5y age
7yo boy with mild developmental delay, new regression in behaviour and lower limb spasticity?
- X-linked adrenoleukodystrophy
- Diagnosed via VLCFA accumulation
- Abnormal MRI - myelin instability
- Hyperpigmentation
- Oxidative stress and damage
- Tx: HSCT - inhibits the advancing demyelination if administered early
What is the role of the peroxisome?
- Makes bile acids and plasmalogens
- Breaks down phytanate, pristanate, and VLCFAs
X-linked adrenoleukodystrophy vs metachromatic leukodystrophy on MRI
Metachromatic also has corpus callosum involvement on MRI, whereas X-linked only posteriorly involved
Hypotonia, large fontanelle, hepatomegaly, mild transaminitis, blindness
Peroxisomal disorders e.g. Zellweger syndrome
What is the role of mitochondria?
- Generation of ATP via oxidative phosphorylation (mitochondrial respiratory chain)
- Generation of reactive oxygen species
- Intracellular calcium homeostasis
- Role in programmed cell death
- “battery of our cells”
Metabolic acidosis, high anion gap, mild-mod ammonia, high urinary ketones…?
Organic acidaemia (propionic acidemia, methylmalonic acidemia, glutaric acidemia)
Metabolic acidosis, normal anion gap, normal ammonia…?
Aminoacidopathy (MSUD, PKU, homocystinuria)
High ammonia, normal anion gap respiratory alkalosis…?
Urea cycle disorder (OTC, citrullinemia, argininosuccinic aciduria)
Propionic acidemia vs methylmalonic acidemia
- Both cause metabolic acidosis
- PA - defect in propionyl CoA carboxylase, elevated 3-OH propionic acid (UOA), elevated C3 acylcarnitine (NBS), elevated glycine (PAA)
- MA - defect in methylmalonyl CoA mutase, elevated methylmalonic acid (UOA), elevated C3 acylcarnitine (NBS), elevated alanine and glycine (PAA)
Discuss Glutaric Acidemia type 1 (GA)
- Organic acidemia that doesn’t present with metabolic acidosis, commonly has normal metabolites
- Defect in enzyme glutaryl CoA dehydrogenase
- “cerebral” organic acidemia
- Microencephalic macrocephaly
- Dystonia and movement disorder with febrile illness (catabolic crisis causing injury to basal ganglia)
- Doesn’t usually present in neonatal period
- Bilateral subdural haematomas, ddx NAI
- High urine glutaric acids
What is the most common inborn error of amino acid metabolism?
PKU - phenylketonuria
What is the cause and presentation of PKU?
- Low phenylalanine hydroxylase enzyme (converts phenylalanine to tyrosine), therefore high phenylalanine and low tyrosine levels
- Elevation of phenylalanine leads to permanent brain injury and dysfunction
- Fair skin and hair, light sensitivity, eczema, hair loss
- If untreated: ID, musty/mousy odour, epilepsy 50%, eye abnormalities
- MRI brain may show demyelination and volume loss
What is the treatment for PKU?
- Start ASAP, lifelong
- Dietary restriction of phenylalanine, supplementation of tyrosine
- Supplements: essential amino acids, vitamins and minerals
- Tetrahydrobiopterin (BH4) supplementation
- Test phenylalanine levels monthly
What effects can maternal PKU have on the fetus?
- IUGR, microcephaly
- Intellectual disability
- Dysmorphism, congenital heart disease
- Pre-conception counselling very important + monitoring phenylalanine levels
Discuss features, diagnosis, and management of homocystinuria
- Aminoacidopathy
- Intellectual disability, Marfan-like, ectopia lentis (down), osteoporosis, not flexible, thrombosis/CVA
- Decrease in cystathionine b-synthetase, leads to elevated homocysteine in plasma and urine
- Elevated methionine on NBS and PAA
- Tx: dietary restriction of methionine, Betaine (helps decreased homocysteine levels), aspirin, B12/folic acid/pyridoxine supplementation
What is the function of the urea cycle?
To dispose of toxic ammonia from the deamination of amino acids, by converting it to non-toxic urea for renal excretion
Discuss Fabry disease
- Lysosomal storage disorder
- X-linked, alpha-galactosidase deficiency
- Neuropathic pain hands and feet, recurrent abdo pain, hypohydrosis, poor exercise tolerance and corneal opacities
- Angiokeratomas and telangiectasia 2nd decade, in groin and periumbilical area
- Symptoms are usually present by 10 years of age but the diagnosis is often delayed
- Can develop proteinuria and ESRF, CVA in adults
Discuss possible presentations of MCAD
- Lethargy, vomiting, low GCS
- Sudden infant death syndrome
- Reye’s syndrome
How can children with long chain fatty acid oxidation disorders present?
- Cardiomyopathy and hypoglycaemia
- Rhabdomyolysis
What is the management of MCAD?
- Impaired gluconeogenesis therefore avoid fasting
- Supplement with carnitine. Dextrose during acute episodes.
- Carbohydrate snacks at bedtime
- 25% of babies die before results of Guthrie
What are possible complications of galactosemia (even if treated early)
- Tremors
- Learning difficulties
- Speech and language issues
- Ovarian failure requiring oestrogen replacement in adolescence
Discuss galactokinase deficiency
- Similar to galactosemia but without systemic complications
- Only develop cataracts
- Treatment with dietary restriction of galactose
Newborn with hypoglycaemia, lactic acidosis, hyperuricemia, hyperlipidaemia, neutropenia, hepatomegaly, doll-like face (fatty cheeks), thin extremities…?
- Von Gierke disease (glycogen storage disease type 1)
- Deficiency in glucose-6-phosphate enzyme, inability to release free glucose from glycogen - accumulation in liver causes hepatomegaly
- Lactic acidosis due to inability of gluconeogenesis
- Ix: glucagon administration produces no hyperglycaemic response, requires genetic testing
- Tx: older children cornstarch keeps BSL stable 4-6h, younger children require continuous NGT feeds to sustain BSL, especially overnight
How does GSDI (Von Gierke disease) present?
Hypoglycaemia, lactic acidosis, hyperuricemia, hyperlipidaemia, neutropenia, hepatomegaly, doll-like face (fatty cheeks), thin extremities
Strenuous exercise leading to muscle cramps, high CK, myoglobinuria?
- McArdle disease (GSDV)
- DDx: exercise-induced rhabdomyolysis
Discuss McArdle disease?
- GSDV
- Develop muscle cramps, raised CK, myoglobinuria post strenuous exercise, “2nd wind”
- Due to myophosphorylase enzyme deficiency
- Treatment: avoid strenuous exercise to avoid rhabdomyolysis, give oral fructose/glucose to improve exercise tolerance
Discuss hereditary fructose deficiency
- Deficiency of fructose 1,6 bisphosphate aldolase
- AR, initially healthy infant who presents age 4-6m when fructose introduced into diet
- Develop jaundice, vomiting, lethargy, seizures, irritability post fructose intake e.g fruit
- Positive urinary reducing substances
- Tx: avoid all sucrose, fructose, sorbitol
Discuss fructokinase deficiency
- Asymptomatic, present with fructosuria
- No treatment necessary
What are mucopolysaccharidosis disorders and their features?
- Hurler syndrome, Hunter syndrome, SanFilippo syndrome
- Progressive conditions due to accumulation of lysosomes (mucopolysaccharides, sphingolipids, oligosaccharides)
- Hepatosplenomegaly, bony deformities, developmental regression, sensory loss (hearing and vision), coarse facial features
Discuss the key differences between Hunter, Hurler, SanFilippo, and Morquio syndromes
- Hurler (MPSI) - AR, alpha-L-iduronidase deficiency, melanocytic naevi, corneal clouding
- Hunter syndrome (MPSII) - X-linked, iduronate 2 deficiency, pearly papules, normal eyesight
- SanFilippo syndrome (MPSIII) - AR, visceral and bony manifestations less prominent
- Morquio syndrome (MPSIV) - skeletal problems, corneal clouding
What are the types of lysosomal storage disorders?
- Mucopolysaccharidosis
- Tay Sachs, Fabry’s disease, Gaucher disease type 1
- Krabbe’s disease, Pompe disease, Wolman syndrome
- Batten disease
Name the different glycogen storage disorders
- GSDI - Von Gierke disease
- GSDII - Pompe disease (also lysosomal storage issue)
- GSDV - McArdle disease
Discuss Wolman syndrome
- Lysosomal acid lipase deficiency (lysosomal storage disorder)
- Poor feeding, FTT
- High lipids and triglycerides
- Bilateral adrenal calcifications on CT scan
Discuss Krabbe’s disease
- Lysosomal storage disorder
- Galactosylceramidase deficiency
- Increasing muscle tone, profound irritability, seizures, vision loss, developmental regression
Discuss Zellweger syndrome
- Peroxisomal disorder, VLCFA oxidation defect
- Involves all organs of the body
- Dysmorphic facies, prominent forehead, seizures, liver disease
- Bone involvement, hypotonia, hearing and vision deficits
- Ix: plasma VLCFAs
- MRI brain: leukodystrophy (abnormal myelination)
- Usually fatal in infancy
What are examples of peroxisomal disorders?
- Zellweger syndrome
- X-linked adrenoleukodystrophy
Discuss adrenoleukodystrophy
- X-linked, peroxisomal disorder
- Due to deficiency in peroxisomal oxidation of VLCFAs
- Developmental regression age 4-11y, new-onset spasticity, behavioural issues, seizures
- Hyperpigmentation gums
- Adrenal failure typically in school-aged boys (low Na and BP)
- MRI: white matter T2 hyperintensity in occipital and parietal regions
- Tx: HSCT - inhibits the advancing demyelination if administered early
Discuss MELAS
- Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
- Present with developmental delay, weakness, headache, stroke-like presentation
- Short-stature, cardiac disease, hearing loss, endocrinopathy, exercise intolerance, neurodegenerative disease
- CSF protein is often increased
- MRI: may show cortical atrophy with infarct-like lesions in both cortical and subcortical structures, basal ganglia calcifications, and ventricular dilatation
Discuss Kearns-Sayre syndrome
- Mitochondrial disorder due to defective phosphorylation
- Cardiac conduction abnormalities
- Cardiomyopathy
- Lactic acidosis
- Progressive external ophthalmoplegia
- Can treat with pacemaker, vitamins, but no cure for disease
Discuss metachromatic leukodystrophy
- AR, white matter disease
- Deficiency of arylsulfatase A (ASA), which is required for the hydrolysis of sulfated glycosphingolipids
- Late infantile form most common: 12-18m of age with irritability, inability to walk, and hyperextension of the knee, causing genu recurvatum
- Involves central and peripheral NS, UMN and LMN signs, cognitive and psychiatric signs
- Deep tendon reflexes are diminished or absent
- Gradual muscle wasting, weakness, and hypotonia
- As the disease progresses develop nystagmus, myoclonic seizures, optic atrophy, and quadriparesis
- Death in the first decade of life
When would you see ragged red fibres?
- MERRF - mitochondrial disease with myoclonic epilepsy and ragged red fibres
- Mutation in mitochondria resulting in lack of ATP
- Muscle weakness, diplopia, fatigue
- Muscle biopsy: ragged red fibres
- High lactate and CK
- Seizures, ataxia
- Tx: mitochondrial supplements
Discuss Leigh disease
- Mitochondrial encephalomyopathy
- Progressive degenerative disorder, become apparent during infancy: feeding + swallowing problems, vomiting, and FTT
- Delayed motor and language milestones, generalised seizures, weakness, hypotonia, ataxia, tremor, pyramidal signs, and nystagmus
- Intermittent respirations with sighing or sobbing - suggest brainstem dysfunction
- External ophthalmoplegia, ptosis, retinitis pigmentosa, optic atrophy, and decreased visual acuity
- MRI: bilateral symmetric areas of low attenuation in basal ganglia and brainstem
- Elevations in serum lactate levels are characteristic
- Hypertrophic cardiomyopathy, hepatic failure and renal tubular dysfunction can occur
Discuss Batten disease
- Most common type of neuronal ceroid lipofuscinoses (NCLs), juvenile
- Inherited lysosomal storage disorder
- Symptoms usually start after age 5 - initially progressive visual loss, retinal pigmentary changes, often results in an initial diagnosis of retinitis pigmentosa
- Subsequent progressive dementia, seizures, motor deterioration, and early death
What are some mitochondrial disorders?
- MELAS
- MERRF (myoclonic epilepsy with ragged red fibres)
- Leigh disease
- Kearns Sayre disease
What conditions can cause a high ammonia?
- Urea cycle disorders (respiratory alkalosis)
- Organic acidemias (metabolic acidosis with high anion gap)
- Falsely elevated: tourniquet, inappropriate sample handling
What is the key finding in hyperinsulinism and fatty acid oxidation disorders?
Lack of ketones - hypoketotic hypoglycaemia
What are the causes of high lactate?
- Ischaemia, poor tissue perfusion
- Hypoxia
- Haemolysis
- MELAS, Kaerns Sayre
- Von Gierke disease (GSDI)
Which conditions are you checking for when you send urine organic acids?
- Organic acidemias (e.g. methylmalonic acidemia, propionic acidemia)
- Aminoacidopathies (e.g. MSUD, PKU, homocystinuria)
- Fatty acid oxidation disorders (e.g. MCAD)
- Most sensitive when patient is in catabolic state e.g. fasting/illness
Elevation of which acylcarnitines are seen in IEOM?
- C3 or C5 in some organic acidemias
- C6 to C10 in MCAD
Cause of isolated large liver?
+ chronic liver disease?
+ large spleen?
+ large spleen + chronic liver disease?
- Large liver = GSD
- Liver + CLD = tyrosinemia type 1, galactosemia, some GSD (III, IV), UCD
- Liver + spleen = Gaucher, Niemann Pick A (neuro), B (lungs), osteopetrosis
- Liver + spleen + CLD = tyrosinemia, Wolman, Niemann Pick C
Glycogen storage type 1 A vs B
A = normal neutrophils B = neutropenia, ulcers, gut disease - GCSF
Discuss GLUT-1 transporter disorder
- Presents with developmental delay, seizures, microcephaly
- Low CSF glucose: serum glucose
- Cannot transport glucose in to brain
- Caused by mutations in the SLC2A1 gene
- Tx: ketogenic diet - provides more fuel for the brain, improves developmental outcome
Discuss tyrosinemia, including treatment
- Aminoacidopathy
- Accumulation of tyrosine leads to liver (hepatitis, jaundice) and kidney disease, Rickets, risk of HCC due to liver cirrhosis
- Type 1 - increased succinylacetone on UOA
- Nitisinone (inhibitor of tyrosine catabolism), special low protein pasta and bread, tyrosine and phenylalanine-free formula daily
Niemann Pick A vs B vs C
- A: early onset disease, hepatosplenomegaly, severe brain disease
- B: lungs
- C: supranuclear gaze palsy
Which IEOM are not detected on Guthrie screening?
Lysosomal storage disorders
Discuss Rett syndrome
- X-linked dominant, affected boys die after birth, MECP2 gene mutation
- First symptoms 6-18m age
- Developmental regression, stereotypical movements, flapping hands, autistic behaviours
- Periods of hyperventilation
- Normal HC at birth, then progressive microcephaly
- Seizures, scoliosis
- Tx: supportive, anticonvulsants
These amino acids are elevated in which conditions?
- Phenylalanine
- Leucine
- Tyrosine
- Homocysteine
- PKU - brain damage, treat with protein restriction
- MSUD - present with coma, bloods usually normal
- Tyrosinaemia - liver disease, jaundice, kidney disease
- Homocysteinuria - Marfan-like, ID, ectopia lentis down, thrombus risk
Where do organic acids come from, and what are some examples?
Breakdown product of amino acids. e.g. lactate, ketones, acetic acid, glutaric acid, malenic acid
How do we test for lysosomal disorders?
White cell enzymes, urine GAGs
What is the role of the lysosome?
Recycling and digestion centre of cell. If errors then the material is not broken down and you develop congestion of cells and organs
What are examples of lysosomal disease groups?
- Mucopolysacharidosis - Hunter, Hurler, SanFillipo
- Sphingolipids - Tay Sachs, Sandhoff
- Leukodystrophy - metachromatic, Krabbe
- Liver/spleen/blood - Gaucher, Neimann Pick
- Fabry
Non ketotic hyperglycinemia can present with?
- “hiccups” in utero = seizures
- Most common metabolic issue in Maori
- Elevated CSF: plasma glycine ratio
Child with developmental delay and Addison’s disease?
Think X-linked adrenoleukodystrophy
Discuss Lesch-Nyhan syndrome
- X-linked recessive
- Build up of uric acid as unable to recycle purines
- Hyperuricaemia
- Inc uric acid secretion in urine - precipitates and crystaises - urate stones
- Urate crystal deposits in kidney (nephropathy), joints (gout), subcutaneously (chalky tophi lumps)
- Leads to low dopamine in brain - behavioural issues, GDD, hypotonia, dystonia, chorea, finger biting and head banging
- Ix: hyperuricaemia, HGPRT gene mutation
Tx: allopurinol, benzos
Discuss Niemann Pick disease
- Build up of sphingomyelin in lysosomes (lipid-laden appearance, foam cells)
- A: early onset, HSM, weak, hyporeflexia, cherry red macula, ILD and resp failure, fatal by age 3
- B: less severe, no neuro, splenomegaly, low plts and WCC, ILD
- C: supranuclear gaze palsy
Congenital disorders glycosylation
Rare, defect in enzymes involved in glycosylation of proteins. CDG1a most common
CDG1a most common
Dysmorphic, developmental delay, inverted nipples, abnormal subcutaneous fat, cerebellar hypoplasia
Diagnosis Transferrin isoelectric focusing
Elevated CSF lactate
Mitochondrial disorder
Often get elevated Alanine with high lactate
Diagnosis molecular studies
Creatine synthesis transporter defect
Elevated urine creatine/creatinine ratio
No creatinine peak on MR spectoscropy
Present ID, ASD, neurological - epilepsy
Whats tested for on newborn screening / Guthrie
The current conditions screened for are:
Amino acid disorders (for example PKU and MSUD)
Fatty acid oxidation disorders (for example MCAD)
Organic academia’s
Galactosaemia
Biotinidase deficiency
Congenital hypothyroidism (CH)
Cystic fibrosis (CF)
Congenital adrenal hyperplasia (CAH)
Severe combined immune deficiency (SCID).
PKU caused by…
Associated with elevated ..
Phyenylalanine hydroxyls or its cofactor tetrahydrobioterin (BH4), causes accumulation phenylalanine
Treatment of Pompe disease
Disease treatable with recombinant human acid d-glucosidase (myozyme)
Glycogen-storage disease type II (GSD II), also known as Pompe disease, is part of a group of metabolic diseases called lysosomal storage disorders (LSDs). GSD II is an autosomal-recessive disorder that results from deficiency of acid alpha-glucosidase (also known as acid maltase), a lysosomal hydrolase.
Enzyme replacement therapy (ERT) for the treatment of glycogen-storage disease type II (GSD II) has been available since 2006.
