Metabolics Flashcards
Homocysteinuria
Clinical features
Ix
Tx
Most common inborn error of methionine metabolism
Presentation:
Infancy – non-specific features
i. Failure to thrive
ii. Developmental delay
c. Diagnosis usually made >3 years – when ectopia lentis occurs
Eye
- Downward lens dislocation (ectopia lentis)
- Glaucoma, astigmatism, cataracts, retinal detachment, optic atrophy
Skeletal (resembles marfans)
- Tall stature
- Long limbs
- pacts excavatum
- Osteoporosis (early onset) and flattened vertebrae
- genu valgum
- crowded teeth
Neuro
- Dev delay
- Intellectual disability
- Psych/behavioural difficulties
- Seizures
- Extrapyramidal signs /dystonia
Fair features: hair, skin, blue eyes, malar flush
Risk of vaso-occlusive disease (thromboembolism) - main cause of death
Ix
- Incr total plasma homocysteine and methionine
- incr urine homocysteine
- low or absent cystine in plasma
- Genetics: mutation in CBS
Tx
- High dose vitamin B6 (pyridoxine) - dramatic improvement in those who are responsive
- Folate supplementation
- Dietary methionine restriction
- Cystine supplementation
Spot diagnosis:
Infant with seizures, ataxia, developmental delay, alopecia and brittle hair, angular stomatitis, eczema-like rash, hearing loss
Biotinidase deficiency
- an inherited disorder in which the body is unable to recycle the vitamin biotin
- diagnosed by measuring serum biotinidase activity (will be reduced)
Spot diagnosis:
tall stature, downward lens dislocation, ID vintage
Homocystinuria
Spot diagnosis:
Macula - cherry red spots on fundoscopy
Developmental regression
Lysosomal storage disorder
- Diagnosis with serum white cell (leucocyte) enzymes
Ddx
- Neiman Pick disease - infantile HSMegaly, FTT/poor weight gain, developmental regression after the 1st birthday +/- interstitial lung disease
- Tay Sachs (GM2 gangliosidosis type 1) - Ashkenazi Jews, infant onset with early neurological regression, macrocephaly, hypotonia, seizures
Spot diagnosis:
kinky hair, hypotonia, laxity of joints/ skin, dev delay
What causes this condition?
What other manifestations can it have?
Ix
Tx
Menke disease
- mutation in ATP7A gene which is involved in Cu transport around body
- Also can cause prolonged jaundice and osteoporosis and subdural haematomas
Ix: low levels of serum copper and ceruloplasmin; light microscopy of hair follice can be diagnostic; genetic testing for ATP7a mutation
Tx: injections of Cu
What is the major cause of death and morbidity in homocystinuria?
Thrombo-embolism
What is homocystinuria caused by?
Mutation in CBS – gene encoding cystathione beta-synthase
Dietiary amino acid intake contains methionine (essential aa) -> converted to homocysteine -> requires CBS to convert it to cystine as metabolite
- > accumulation of homocysteine and methionine
- > deficiency in cysteine
Cystinuria
Cause
Presentation
Diagnosis
Tx
• Aminoaciduria; Rare AR disease 1/7000
• Defective aa transportation in prox renal tubules -> reduced reabsorption of cysteine ->
RECURRENT RENAL STONES due to cysteine crystallization
• Excessive cystine in urine
Diagnosis: urine cyanide-nitroprusside (urine turns magenta colour)
Treatment
• Regular fluids (dissolves stones)
• Alkalinisation of urine with potassium citrate (melts stones)
• Chelation (D- Penicillamine or tiopronin bind with cysteine to increase reabsorption)
Sepsis presentation (feeding difficulties, vomiting, dehydration, hypoglycaemia) in neonatal period
With metabolic acidosis (widened anion gap)
And high serum ammonia
Organic acidemia - ddx:
a. Methylmalonic acidaemia (MMA)
b. Propionic acidaemia (PA)
c. Isovaleric acidaemia (IVA)
d. 3-methylcrotonylglycinuria (3-MCG)
e. GA-1
NOT urea cycle defect (also get high ammonia w encephalopathy but respiratory alkalosis and NORMAL glucose)
Ix and Treatment of organic acidaemias
Ix
- blood gas: metabolic acidosis w high anion gap (>20)
- high ketones
- high serum ammonia
- low BSL
- often pancytopenia from bone marrow suppression
- Elevated organic acids in urine
Tx
- Low protein diet (decr aa substrate)
- Enhance enzyme activity (biotin, b12)
- Carnitine supplementation (binds to organic acids to enhance urinary excretion)
Which organic acidaemia RARELY presents in neonatal period and features
microencephalopathic macrocephaly, dystonia,
subdural haemmhorages
Glutaric academia (GA1)
Children typically present with a similar clinical picture to sepsis and may have associated infection and fever. Investigations will reveal metabolic decompensation (in response to infection/surgery/trauma etc) with ketoacidosis, hyperammonaemia, hypoglycaemia, and encephalopathy
What is the role of the urea cycle and what enzymes are involved?
Pathway by which nitrogen (produced from amino acid catabolism) is converted to urea for excretion
Protein -> ammonia (CNS toxic) -> urea cycle -> urea (non-toxic, excreted)
Enzymes
- OTC deficiency (most common) -> decr plasma citrulline, incr urine orotic acid
- Carbamylphosphate synthetase (most severe, presents early in neonatal period and quick progression to seizures, coma, death) -> reduced plasma citrulline and normal urine orotic acid
- Arginosuccinate synthetase deficiency -> incr arginase
- Arginosuccinate lyase deficiency -> incr citrullin
- Arginase deficiency -> incr arginine
Causes of lactate elevation
- Organic acidaemia (metabolic acidosis with high ammonia)
- Glycogen storage disorder (t1, Van Gierke’s)
- Mitochondrial disorders (also have elevated lactate in CSF and elevater serum CK)
What is the most common urea cycle defect?
And what is this, how does it present?
OTC (ornithine transcarbamyase deficiency)
- > x linked deficiency of OTC enzyme which is a mitochondrial enzyme located in liver and intestine
- > causes ammonium to build up, binds with glutamate to form glutamine
Presentation
After onset of BM feeds encepaloapthy with feeding difficulty, vomiting leathargy and progression to seizures and coma.
Glutamine has osmotic effect -> cerebral oedema
Milder form will present older during episode of illness/catabolism with encephalopathy and elevated ammonia
Presentation of urea cycle defect
Key features on ix
Presentation
- presents in neonatal period (males) after starting milk feeds (protein intolerance)
- recurrent vomiting
- decr GCS
- lethargy
- coma
- acute/chronic encephalopathy
Examples
OTC
Classic citrullinaemia (also known as argininosuccinate synthetase deficiency)
Arginase deficiency
Argininosuccinate lyase (ASL) deficiency (also known as argininosuccinic aciduria)
N-acetyl glutamate synthetase (NAGS) deficiency.
Key features:
Often self-limitation of protein intake as a learned behaviour in these patients
a. High ammonia
b. Respiratory alkalosis (elevated ammonia causes respiratory depression)
C. Liver dysfunction
D. Normal BSL! Normal ketones
Zellweger syndrome
Genetics/cause
Presentation
MRI
Bloods
Prognosis
‘cerebro-hepato-renal syndrome’
- AR
- Mutations in multiple PEX genes associated with peroxisome biogenesis
- Unable to import proteins into peroxisomes efficiently
Heterogeneous presentation within first few days of life, essentially progressive deterioration of liver, kidney, brain with death ~6mo after onset
- Dysmorphic
- FTT, feeding difficulties
- neurological (seizures, severe mental retardation, hypotonic, seizures, brain malformations)
- eye abnormalities (corneal opacification, retinal dystrophy)
- Chondrodysplasia punctata: stippled appearance of epiphyses on Xray
MRI - unmyelinated white matter
Bloods: incr VLCFA
Prognosis
- death in infancy
Hallmark feature of peroxisomal conditions (in terms of ix for diagnosis)
Presentation is abnormal FROM BIRTH
Incr VLCFA
What conditions cause high ammonia
Urea cycle disorder (VERY high ammonia; normal ketones/glucose/lactate)
Organic acid disorder (mild-mod lactate elevation; low glucose, high ketones and lactate)
Fabry disease
What is it
What is it caused by?
Features
Treatment
Most prevalent lysosomal storage disorder
Caused by mutation in GLA gene - defective alpha galactosidase A enzyme -> defective metabolism of glycosphingolipid (lipid) causing build up within lysosomes
pneumonic - FABRY C
F-foamy urine
Angiokeratoma around lower abdomen and upper thighs (red spots under skin), anhydrosis, alpha-galactosidase A deficiency
Burning pain in hands and feet with exercise, stress, illness (peripheral neuropathy)
Renal failure
Y chromosome - males (x linked), youth death
Cardiac disease, corneal clouding
If untreated -> cardiac and renal disease/failure
Tx: alpha galactosidase A enzyme replacement
Function of lysosome
- Digestive system of cell - degrades material from outside cell and digests obsolete cellular components
- Contains hydrolytic enzymes
Pancytopaenia and Hepatospenomegaly and recurrent fractures, most recently AVN of femoral head.
Blood Film shown below
What is this condition?
Gaucher disease
2nd Most common lysosomal storage disease (after Fabrys) caused by deficiency in enzyme glucocerebrosidase -> lipid accumulation within lysosomes in macrophages
Pathology - Gaucher cells look like crumbled tissue paper = lipid accumulation in macrophages
Hepatosplenomegaly (lipid fills liver and spleen)
Pancytopaenia (lipid fills BM)
B/L AVN femoral heads (reduced blood supply to bones, osteoporosis, fractures and pain crises)
+/- resp involvement (ILD, pulmonary vasc disease/pulm HTN)
+/- neurological involvement
—> type 1 no CNS involvement adolescent onset Ashkenazi jews
—> type 2 early CNS onset in neonatal period and death
—> type 3 chronic/later insidious onset)
Niemann Pick
What is it?
What is it caused by?
Sx
Lysosomal storage disease resulting in accumulation of cholesterol deposits inside lysosomes
NPC1 or 2 mutation -> impaired intracellular cholesterol transport -> brain, BM, liver, spleen, lung damage
Sx
- A characteristic early finding in children with NPC is impairment of the ability to look upward and downward (vertical supranuclear gaze palsy or VSGP
- hepatosplenomegaly
- prolongued cholestatic neonatal jaundice
- Thrombocytopenia secondary to splenic sequestration -> easy bleeding and bruising
Progressive neurological dysfunction
- Early infantile onset: delayed motor milestones, hypotonia, developmental regression
- Infantile and childhood onset: learning difficulties/ID, progressive cerebellar ataxia, dysarthria, dysphagia, seizures, cataplexia
- Teenage/adult onset: can be psychiatric sx, often misdiagnosed as early onset dementia
- Resp failure common reason for death
No cure
Tx is supportive
What are Mucopolysaccharidoses caused by?
What is the inheritance pattern?
Lysosomal storage disorders caused by a deficiency in enzymes required for breakdown of glycosaminoglycans (GAGs)
Fragments of partially degraded GAGs accumulate in lysosomes resulting in cellular dysfunction and clinical abnormalities
MPS 1-7
Range of clinical severity - Severe = Hurler syndrome, Mild = Scheie disease
All autosomal recessive EXCEPT MPS II which is X linked
Clinical manifestations of MPS 1 (Hurler- Sheie syndrome)
What is it caused by?
Features?
Treatment?
Alpha L iduronidase deficiency (test for this enzyme in leukocytes and test urine for mucopolysaccharides)
- Dysmorphic features: Coarse features – wide nasal bridge, flattened midface, prominent forehead, coarse, thick hair, ‘puffy face, large tongue, prominent gums, large head
- Skeletal -short stature, kyphosis, stiff joints and contractures, Dysostosis multiplex (generalized thickening of most long bones, particularly the ribs)
- Eyes - corneal clouding, can being in 1st year of life and lead to blindness
Other:
Hepatosplenomegaly
Sinus Disease
Cardiovascular - valvular disease
Neuro- developmental delay, seizures, hydrocephalus
Soft tissue storage and skeletal disease with or without brain disease (MPS I, II (later onset), VII)
Soft tissue and skeletal disease (MPS VI)
Primarily skeletal disorders (MPS IV A and B)
Primarily CNS disorders (MPS III A to D)
Treatment
Enzyme replacement
BMT
Medium chain acyl co-A dehydrogenase deficiency
What is it?
Inheritance?
Clinical features
Ix findings
Tx
FA oxidation defect (most common)
AR
Picked up on NST
High mortality rate (20-25%)
Clinical ft
- onset 3mo-5yo
- hypoglycaemic (with LOW ketones) during periods of fasting or illness
- NO acidosis
- lethargy, encephalopathy, liver dysfunction, hepatomegaly
- Ix: incr medium chain fatty acid
- -> secondary carnitine deficency
Treatment
- avoid fasting
- high carb, low fat diet
- may require tx w carnitine, IV hydration, dextrose
what condition features resp alkalosis and why?
urea cycle defects
ft high ammonia -> drives hyperventilation -> decr CO2 -> alkalosis
Phenylketonuria (PKU)
What is it/what causes it
Inheritance
Sx
Diagnosis and tx
Is an aminoacidopathy caused by deficiency or absence of phenylalanine hydroxylase -> accumulation of dietary phenylalanine accumulates; the brain is the main organ affected, possibly because of disturbance of myelination.
Spectrum depending on degree of enzyme deficiency/absence
AR inheritance
Normal at birth
Light skin, hair, eyes
Eczema-like rash
Unpleasant, musty body odor
Intellectual disability and cognitive delay if untreated
Seizures
Microcephaly
Diagnosis
- NST
- Phenylalanine levels
- Tyrosine normal or borderline low
Tx
- lifelong dietary protein restriction
Presentation within the first three months of life with rapidly progressive muscle weakness (‘floppy infants’), diminished muscle tone (hypotonia), respiratory deficiency, and hypertrophic cardiomyopathy and hepatomegaly.
Diagnosis?
Key features and cx if untreated?
Ix and tx?
Pompe disease = Lysosomal Glycogen storage disease type II (AR)
Caused by acid alpha glucosidase deficiency -> glycogen buildup within lysosomes
GIANT HEART (Hypertrophic cardiomyopathy) -> eventual heart failure
HYPOTONIA - Floppy weak
Enlarged tongue and liver
Bulbar/swallowing difficulties
Prognosis: if unrecognised, leads to
- > Respiratory failure
- > Cardioresp failure
- > death by 2yo
Ix: GAA enzyme activity in serum
Tx: enzyme replacement and supportive tx
Leigh disease
What is it?
Presentation /sx
Ix
Prognosis
Subacute necrotising encphalomyopathy
Mitochondrial disorder with progressive neurodegeneration and then death
Affects basal ganglia/corpus callous
Multiple diff mutations and inheritance
Sx
- onset before 2 yo
- Episodic developmental regression during times of metabolic stress (infection, surgery etc)
- feeding, swallowing problems
- vomiting
- FTT
- seizures
- eye stuff
- intermittent hyperventilation (‘sighing’ resps)
- hepatic and renal filaure
- HOCM
Ix
- Elevated serum and CSF lactate
- MRI B - hyperintensity (White) of basal ganglia on t2 (symmetrical basal ganglia and brainstem lesions)
- Muscle bx for enzyme analysis (resp chain enzymes)
Prognosis
- often death early childhood
- most common cause of death is resp failure
What is this condition?
How does it present?
Metachromic leukodystrophy (lysosomal storage disorder)
periventricular dominant white matter abnormality (looks like a X on MRIB)
Is a lysosomal storage disorder
Late infantile, childhood or adult onset forms
Causes central and peripheral demyelination -> peripheral neuropathy, Decr reflexes, hypotonia, ataxia, trouble speaking and eating/swallowing, seizures
What is this condition?
Inheritance/gene
Sx, assoc condition
Ix
Tx
MRI findings of adrenoleukodystrophy
X-linked Adrenoleukodystrophy
Posterior (occipital) white matter changes
- Mutation in ABCD1 gene.
- Peroxisomal disorder, increased serum VLCFA
- Boys present early with ADHD like sx (behavioural difficulties) then developmental regression, loss of vision and hearing and motor and sensory function. End result vegetative state and death within 2-3 years of sx onset.
- Can have assoc Addison’s disease (adrenal insufficiency)
Tx HSCT
What condition features ‘ molar tooth sign’ on MRIB?
Joubert syndrome (Jou - lolly, eating lolly w your molars)
what should your insulin level be when you are hypoglycaemic?
should be 0 - if there is nay insulin, this is ABNORMAL . sign of hyperinsulinaemia.
What metabolic condition gives you hypoglycaemia with high FFA but low ketones?
How would you definitively diagnose this?
Fatty acid oxidation defects (inability to break down stored fats into ketones for energy during periods of fasting/illness/stress etc)
- > require SIGNIFICANT catabolic stress for presentation, thus often presents later in childhood or adulthood c/w glycogen storage disorders
- > ex: MCAD (most common), VLCAD, LCHAD, CPT1
Diagnosis via: Serum acylcarnitine profile
Encephalopathy and neurological changes
Ix
Increased plasma ammonia
Normal blood glucose
Increased urine orotic acid
Whats the diagnosis?
Urea cycle defect
-> OTC deficiency
**Ammonia is acutely poisonous to the brain***
Where is mitochondrial DNA inherited from?
Mother! Not father
IE inheritance for mitochondrial DNA disease is inherited down maternal lineage
What metabolic condition is associated with addison’s disease (hyperpigmentation, hypoglycaemia)
X-linked adrenoleukodystrophy
Corneal clouding - what condition is it associated with?
Lysosonal storage diseases
ddx
- Mucopolysaccharoidosis (type 1 is Hurler disease - coarse facial features, skeletal features, seizures, dev dealy etc)
- Fabry’s disease (foamy urine, angiokeratomas, burning pain to extremities, renal failure)
Hepatomegaly with liver disease ddx metabolic
- Galactosaemia
- Some types of glycogen storage disorder (GSD1 Van Gierke and 2 Pompe and 3 Cori/Forbes = massive; GSD6, GSD 9 mild-mod)
- Tyrosinaemia (aminoacidopathy)
Hepatomegaly with splenomegaly ddx metabolic
Lysosomal storage disease (ex: Gaucher disease)
Hepatomegaly WITHOUT liver disease ddx metabolic disease
Glycogen storage disorders
what is this?
X-linked adrenoleukodystrophy
- occipitocortico distribution involving corpus collosum
Diagnosis?
Infant with metabolic acidosis and ketotic hypoglycaemia
Elevated lactate and FFAs
Hepatomegaly
‘Bright’ liver on ultrasound
Glycogen storage disorder type 1 (Van Gierke disease)
- > large amounts of glycogen stored in liver but are unable to catabolise it/break it down into glucose to be used as fuel
- > during periods of stress/starvation/illness they become hypoglycaemic (instead release fat stores -> incr ketones and FFA)
Infant presenting with encephalopathy and macrocephaly with ketotitc hypoglycaemia and metabolic acidosis
MRI - widened Sylvian fissure and and b/l basal ganglia T2 hyper intensity
What would you expct the ammonia to be?
Diagnosis?
Treatment?
Glutaric aciduria type 2 (could also be type 1)
Expect ammonia to be high
tx: low lysine diet, carnitine, emergency diet
Serum acylcarnitine profile - what is it used to diagnose?
Measures the breakdown products of fat
Carnitine transports fatty acyl CoA into mitochondria -> beta oxidation makes acetyl CoA which enters krebs cycle to form ketones
Measures fats bound to carnitine
Diagnosis of fatty oxidation defects
Chronic encephalopathy
Developmental delay (speech delay >> others) or regression -> stabilisation
Movement disorder
Seizures
New stiffening left arm
Elevated guanidinoacetate and low creatinine on urine metabolic panel
diagnosis?
GAMT deficiency (guanidinoacetate methyltransferase deficiency) -\> leads to cerebral creatinine deficiency
Treatable!
Oral creatinine and ornithine supplements
what diagnosis does urine glycosaminoglycans look for?
GAG:Cr ratio
for diagnosis of mucopolysaccharidoses (the only lysosomal storage disorder you can diagnose this way)
Normal at birth
Progressive ID
Fair hair, skin, blue eyes
Dry skin/eczema rash
Spastic CP
Athetosis
Musty smell
What is the diagnosis?
What ix to confirm?
Tx?
Phenylketonuria - form of aminoacidopathy where deficiency in phenylalanine hydroxylase prevents metabolism of phenylalanine to tyrosine
Ix: high levels serum phenylalanine (picked up on NST usually)
Tx - limit phenylalanine (low protein diet), supplement tyrosine
What ix findings are diagnostic of MSUD?
what is this caused by?
presentation
Amino acidopathy
High serum levels of isoleucine, leucine and valine
Due to decr activity of alpha ketoacid dehydrogenase
Presentation: acute onset encephalopathy either soon after birth or intermittently during periods of stress or illness. sweet/fenugrek smelling urine during periods of metabolic crisis.
elevated lactate and CK = ?
Mitochondrial disorder (ex: Leigh syndrome)
What metabolic condition has tendency to cause bilateral subdural haemorrhages?
Other features of this condition? Earliest sign at birth? tx?
Glutaric aciduria type 1 (type of organic acidaemia)
- Metabolic ketoacidosis, hyperammonaemia, hypoglycaemia, and encephalopathy - decompensation following infection/illness
- Microencephalic macrocephaly is typical and if present at birth, can be the earliest sign.
- Tx - Low protein diet, L-carnitine, B12 + biotin, avoid catabolism
Also Menkes disease (disorder of copper metabolism -> LOW levels)
- Also ft prolonged jaundice, hypothermia, hypotonia, and feeding difficulties, normal hair at first replaced by sparse brittle hair, development of seizures and developmental regression ~2-3months; loose skin, lax joints.
- Diagnosis - Low levels of serum caeruloplasmin and copper + light microscopy of hair follicle +/- genetic testing for ATP7A gene
- Tx - copper injfections
What is this condition?
Child has developmental regression from 18 months and over the next 18 months he regresses further with periods of relative stability and occasional rapid decline associated with viral illnesses. By three years of age, he is unable to walk and has truncal ataxia when sitting.
Elevated serum and CSF lactate
Leigh syndrome
Mitochondrial disorder
which UCD is not AR?
OTC deficiency - is x-linked
MCAD - pathophys and presentation and ix and tx
Medium chain acyl-CoA dehydrogenase deficiency is a rare genetic metabolic disorder characterised by a deficiency of the enzyme ‘medium chain acyl-CoA dehydrogenase’ (MCAD).
- > This enzyme is found to be most active in the liver, leukocytes, and fibroblasts, and is necessary for the oxidation of medium chain fatty acids.
- > Failure to break down these fats can lead to the abnormal accumulation of fatty acids in the LIVER and the BRAIN.
- > Causes decreased ATP production and ketogenesis.
- > The rate of gluconeogenesis is similarly reduced, and the endogenous glucose supply is rapidly exhausted, resulting in HYPOGLYCAEMIA.
- > Patients get HYPOKETOTIC hypoglycemia triggered by fasting or illness, with vomiting, lethargy, hepatomegaly, seizures
- > Cause of sudden death in infancy
Think of it with: HYPOKETOTIC hypoglycemia, HEPATOMEGALY (fatty liver) and elevated FFA
May also be assoc w cardiomegaly and arrhythmia and rhabdomyolysis (heart and skeletal muscle particularly reliant on FA)
Diagnosis: urine organic acids and blood acylcardnitine profile, fibroblast FAOD enzyme studies
Tx: regular oral feeds/intake of carb solution (IV/PO) uring periods of catabolic stress
What is Fabry disease
Sx
Cx
Lysosomal storage disorder.
- Features include neuropathic pain, hypohydrosis, poor exercise tolerance and corneal opacities.
- Angiokeratomas and telangiectasia are usually evident in the second decade of life and are seen in the groin and peri umbilical area.
- Symptoms are usually present by 10 years of age but the diagnosis is often delayed.
- Cardiovascular and renal complications are common in adulthood and can results in a fatal cerebrovascular event or ESRF.
A breast fed 4 day-old presents with poor feeding, vomiting and irritability. The child is jaundiced and has hepatomegaly.
?Most likely diagnosis
?Ix for diagnosis
Other presentations of this condition
Tx
Galactosaemia
- Deficiency in GALT enzyme (galactose 1 phosphate urtidyl transferase)
- Therefore unable to metabolise galactose or lactose (glucose+galactose)
Diagnosis: Red blood cell enzyme assay (low GALT)
Children present after commencing feeds (usually second half of first week of life) with jaundice, hepatomegaly and vomiting.
- Cataracts are not present initially.
- Galactosaemia is included in newborn screening but children may present before screening results are available.
- Red blood cell galactose-1-phosphate activity will be reduced but is not accurate if the child has received a blood transfusion in the preceding three months.
- May also present with E COLI SEPTICAEMIA, renal tubulopathy
- Urine: positive reducing substances but negative for glucosuria
Tx: Lactose/galactose free diet (soy- or casein hydrosylate based formula)
A boy develops progressive weakness from the age of four months. He was previously able to sit without support but has lost this skill. On examination, he is macrocephalic and hyperreflexic. Fundoscopy reveals a cherry red macula.
Diagnosis?
Tay Sachs
- lysosomal storage disorder
- beta herosamidase A deficiency
A child presents at six months with developmental delay and recurrent sinopulmonary infections. On examination, the child has hepatosplenomegaly and corneal clouding.
diagnosis?
ix for diagnosis?
Hurler’s disease
mucopolysaccharidosis type I
Diagnosis: elevated urine GAGs, white cell enzymes (deficiency in alpha-L iduronidase)
Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year.
Developmental regression from 6 months
Low weight
Normal head circumference and length
Hypotonic
Brisk reflexes
Hypersegmented neutrophils with macrocytic red cells
Methylmalonic acid and homocystine increased in the urine
Urine - increases in Methylmalonic acid and homocystine
Diagnosis?
Vitamin B12 deficiency
A one-day-old baby boy is brought to ED because he has been vomiting. On arrival he is floppy and lethargic. His airway is patent. His chest is clear but he is tachypnoeic. He was born at term by NVD. His mother tells you that there were no complications in the pregnancy and that she is vegetarian.
diagnosis?
Urea cycle defect
ammonia level
This scenario describes a child with a urea cycle defect. They present at 24-48 hours of life. The clues in this scenario are the tachypnoea (suggesting hyperventilation) and his mother is a vegetarian (The child is likely to have OTC deficiency, the only X linked urea cycle defect. Affected female carriers often become vegetarian because they cannot tolerate the high protein load in meat.) The most helpful investigation is ammonia - children with urea cycle defects will have extremely high levels of ammonia
An 18-month-old attends a kindergarten where there has been a recent outbreak of viral gastroenteritis. She developed diarrhoea and vomiting yesterday and is brought to ED today with reduced level of consciousness.
diagnosis?
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) typically presents in children aged 18 months to three years during a period of stress (usually a viral infection). Children younger than this usually feed so frequently that it masks the disorder. The treatment is to avoid prolonged periods of fasting.
Diagnosis: Acylcarnitine profile
GSD type 1 Von Gierke’s -
What is it?
Presentation
Bloods /ix
An autosomal recessive disease in which gene expression of glucose-6-phosphatase (which normally catalyze reactions that ultimately convert glycogen compounds to glucose) is absent, resulting in hypoglycemia due to lack of glucose production.
Accumulation of glycogen in liver and kidney leads to organomegaly, particularly massive hepatomegaly.
Increased concentrations of lactic acid and hyperlipidemia appear in the plasma.
Clinical gout often appears in early childhood
Metabolic acidosis
High free fatty acids and beta-hydroxybutyrate (ketones) Very low insulin levels, and high levels of glucagon, cortisol, and growth hormone (adaptation to chronically low BSLs)
Elevated lactate
Diagnosis is conirmed by laboratory and genetic techniques such as liver biopsy with electron microscopy, assay of glucose-6-phosphatase activity in the tissue or specific gene testing.
Diazoxide - indication for use and MOA
Used in perisistent hyperinsuliaemic hypoglycaemia of infancy
Binds to the SUR1 subunit of K-ATP channel, causing opening of the K-ATP channels and inhibition of insulin secretion
Ix supporting diagnosis of hyperinsuliaemic hypoglycaemia of infancy
High levels insulin and c-peptide IRRESPECTIVE OF PLASMA GLUCOSE LEVEL
Low plasma free fatty acids, beta-hydroxybutyrate (ketones), and insulin growth factor binding protein 1 (IGF-BP1) (due to IGF-BP1 gene transcription suppression by insulin).
Increase in plasma glucose in response to glucagon administration during hypoglycaemia (will not get this with glycogen storage disorders)
A glucose infusion rate above 6–8 mg/kg/min to maintain normoglycemia is typical of this condition.
Galactosaemia
- Cause
- Sx
- Ix
- Tx
- This condition can be caused by various defects in metabolism of galactose.
- Galactose is formed (along with glucose) from lactose breakdown during energy utilization.
- The most common defect is galactose-1-phosphate uridyl transferase (GALT) deficiency
- These infants may present with hyperketotic hypoglycemia, which may be post-prandial (post breast or lactose formula feed) due to accumulation of galactose-1-phosphate.
- Other common manifestations include hepatosplenomegaly, transaminitis, jaundice, e coli sepsis, seizures, developmental delay, DIC, cataracts, urinary excretion of glucose and aa (proximal renal tubular defect)
- They also may have growth delays and ovarian failure
- The newborn screening test measures RBC GALT enzyme activity, and differ according to location in which it is performed.
- Treatment includes avoidance of lactose and galactose (soy or casein hydrosylate based formulas).
Hereditary fructose intolerance
- What is it caused by?
- Presentation
- Diagnosis
- Tx
- Cx if untreated
- AR, deficiency of fructose-1-phosphate aldolase isoenzyme b, which inhibits gluconeogenesis through accumulation of fructose-1-phosphate.
= unable to metabolise fructose or sucrose (glucose and fructose) - Present with hypoglycemia (abdo pain, vomiting, diarrhoea) when fructose or sucrose is introduced into the diet (solid diet of fruit and veg).
- Additionally, they may have hepatomegaly (Fruc-1-Ph accumulates in hepatocytes) , failure to thrive, hyperuricemia, and lactic acidosis.
- Diagnosis via liver biopsy: enzyme analysis and genetics
- Tx: avoidance of fructose ingestion
- Untreated fructose intolerance may lead to progressive renal and liver failure +/- growth retardation, seizures, deadness
Aminoacidopathies - which is associated with the following presentations (can be repeated):
- Liver dysfunction/hepatosplenomeaglay +/- coagulopathy?
- Rapidly progressive lethargy -> hypotonia, coma, seizures -> death within hours of birth of untreated?
- Musty odour with acquired microcephaly, ID, fair hair, skin, eyes and tendency towards eczema
- Cabbage odour and renal fanconi, rickets
- Peripheral neuropathy
- hyperketotic hypoglycaemia, lethargy, poor feeding, FTT and seizures in neonatal period with sweet smelling urine
- Ectopia lentís, fair hair, skin, eyes and molar flush. tall, thin habitus.
- Tyrosinaemia (deficiency in FAH enzyme -> incr serum tyrosine and succinylacetonuria)
- Hyperglycinaemia (elevated CSF: plasma glycine ratio. tx sodium benzoate lowers glycine levels)
- PKU (elevated phenylalanine, low tyrosine. deficient phenylalanine hydroxylase)
- Also Tyrosinaemia
- Tyrosinaemia
- MSUD (elevated serum isoleucine, leucine, valine due to dysfunctional alphaketoacid dehydrogenase)
- Homocystinuria. Elevated serum homocysteine and methionine due to deficient cystathione synthase..
Which form of glycogen storage disease is associated with muscle cramps with exercise? what is a consequence of this?
McArdles disease (GSD 5) Cx: rhabdomyolysis -\> incr serum CK, urine myoglobinuria -\> AKI
Which form of glycogen storage disease is associated with weak but enlarged muscles and vacuoles lymphocytes?
Pompe disease (GSD type 2) -> also assoc w infantile cardiomegaly and hepatomegaly, hypotonia
Increased 7-Dehydrocholesterol levels is diagnostic of what condition?
What are the presenting features of this condition?
Smith–Lemli–Opitz syndrome (SLOS)
- > AR condition
- > Deficiency of 7-dehydrocholesterol reductase (DHCR7; primarily catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol).
- > In SLOS, this results in decreased cholesterol and increased 7DHC levels
Presentation :
- 2nd/3rd toe syndactyly is most common
- FTT, Dev delay, ID, autistic features
- Cardiac: ASD, VSD, PDA, HTN
- Hypospadius, cryptorchidism, ambiguous genitalia in males
- Renal anomalies
Infant with FTT, vomiting, abdo distension and hepatosplenomegaly and jaundice
Imaging shows calcification of adrenal glands
Diagnosis = ?
Pathopneumonic for Wolman disease
- lysosomal storage disorder
- AR , LIPA gene mutation
- prognosis : death in infancy
Krabbe disease
- what is it
- what is it caused by/genetics
- presentation and prognosis
Krabbe disease = lysosomal storage disorder and leukodystrophy (myelin sheath/white matter degeneration)
- AR GALC gene mutation -> Galactosyltransferase deficiency
- Build-up of unmetabolised lipids -> myelin sheath degeneration
- Presents in infancy (3-4months) with feeding difficulty, painful spasticity, stiffness, seizures, vision loss
- Progressive neuroloical deterioration and death by 2 yrs of age
