Metabolics Flashcards
List 5 clinical features that are suspicious for IEM in a severely ill neonate
Well at birth Lethargy Poor feeding Seizure Vomiting Hypotonia Liver dysfunction AG-acidosis Hypoketotic hypoglycemia Unusual odor
List 4 clinical presentations of IEM in an older child
Developmental regression Seizures Encephalopathy Myopathy Recurrent vomiting Cardiomyopathy Unusual odor (especially during illness)
What initial labs do you order in suspected IEM
First tier: CBC, diff VBG Lytes Glucose Ammonium Lactate Urine ketones Urine reducing substances
Second tier: Urine OA Plasma AA Plasma acylcarnitine Plasma free carnitine CSF AA, NT, lactate
As a rule of thumb, hyperammonemia with no acidosis is suggestive of which IEM?
Urea cycle defect
As a rule of thumb, hyperammonemia, AG acidosis, ketosis, hypoglycemia is suggestive of which IEM?
Organic acidemias (e.g. propionic acidemia)
As a rule of thumb, AG-acidosis and elevated lactate is suggestive of which IEMs?
- Disorders of glycogenolysis (e.g. GSD I)
- Disorders of pyruvate metabolism (e.g. pyruvate dehydrogenase deficiency)
- Disorders of gluconeogenesis (e.g. fructose 1, 6 bisphosphatase, pyruvate carboxlase deficiency, PEPCK)
- Mitochondrial disorders
What IEMs are associated with cytpenias?
GSD Type I-neutropenia
Propionic acidemia-neutropenia, thrombocytopenia
MMA
Describe the pathophysiology of glycogen storage diseases
Defects in glycogen metabolism cause:
i) Hypoglycemia
ii) Ketosis (because fat is being broken down instead of glucose)
iii) Accumulation of glycogen in tissues
List the most common glycogen storage diseases that primarily affect the liver
Type Ia/Ib (Von GIerke Dz): Glucose-6-phosphatase deficiency
Type III: Debrancher deficiency (involves liver and muscle)
Type IX: Liver phosphorylase kinase deficiency
List the most common glycogen storage diseases that primarily affect the muscle
o Type II (Pompe): Lysosomal acid α-glucosidase deficiency
Type V: Myophosphorylase deficiency (McArdle disease)
How do liver glycogen storage diseases typically present?
Fasting hypoglycemia
Ketosis
Hepatomegaly
Hypotonia
How do muscle glycogen storage diseases typically present?
Symptoms with exercise
Muscle pain, cramps
Myoglobinuria
How does GSD Ia/b (von Gierke) present?
Early infancy Hepatomegaly Hypoglycemia Lactic acidosis Hypotonia Mild DD FTT Recurrent infections (Neutropenia) Bleeding diathesis (platelet dysfn) Renal-large kidneys, FSGS, HTN
List laboratory features consistent with GSD Ia/b
Hypoglycemia Lactic acidosis Ketoacidosis Hyperlipidemia Neutropenia Hyperuricemia
How do you diagnose GSD Ia/b?
Molecular DNA testing
If negative, muscle/liver biopsy
Treatment of GSD Ia/b
- Keep blood glucose normal:
- Frequent administration of uncooked cornstarch
- Add maltodextrin to breastmilk - GCSF for neutropenia
- Allopurinol for hyperuricemia
- Liver transplant
List 3 clinical features of Pompe disease (GSD II)
Cardiomyopathy
Severe hypotonia
Macroglossia
Hepatomegaly (d/t heart failure)
How do you diagnose Pompe disease?
↓ acid maltase activity in leukocytes or fibroblasts can
Muscle biopsy not required
What are the characteristic ECG findings in Pompe disease?
Short PR BV hypertrophy (high voltage QRS in all leads)
Treatment for Pompe disease
Enzyme replacement therapy
High protein, low carbohydrate diet
OT/PT
What enzyme is deficient in classic galactosemia?
GALT (galactose-1-phosphate uridyl transferase)
Describe the pathophysiology of galactosemia
Accumulation of galactose because of GALT deficiency
Galactose converted to galactitol=TOXIC
Injury to kidney, liver and brain
How and when does classic galactosemia typically present?
First few days of life after receiving BF/formula containing lactose
Conjugated hyperbilirubinemia Vomiting Hypoglycemia Cataracts Hepatomegaly-->Liver failure Mental retardation
What infection are neonates with galactosemia at increased risk of?
E. Coli sepsis
If patient has similar symptoms to classic galactosemia, but presents later, what diagnosis do you think of?
Partial transferase deficiency
How do you diagnose galactosemia?
Screen-urine reducing substances
Diagnostic test-RBC-GALT enzyme activity (false negative if pRBC in past 3 months)
Treatment of galactosemia
Elimination of lactose from diet
E.g. soy formula!
What complications of galactosemia are reversed with elimination diet?
Reversed-liver disease, renal disease, cataracts, growth failure
List 2 diseases that cause positive urine reducing subtances
- Galactosemia
2. Congenital fructose intolerance
List 2 long term complications of galactosemia in treated patients (past question)
Premature ovarian failure
Osteopenia
DD
LD
What diagnosis should you think of in a patient with seizures and regression who temporarily responds to glucose load?
GLUT1 transporter defect
- GLUT1 necessary for transport of glucose into CSF
- Low CSF glucose
- Treat with ketogenic diet
What test do you use to diagnose urea cycle defects?
Quantitative serum amino acids
What is deficient in PKU and what substrate accumulates?
Deficiency in either:
Enzyme-Phenylalanine hydroxylase
OR
Cofactor-tetrahydrobiopterin (BH4)
Substrate-Phenylalaline
List clinical manifestations of PKU
Profound mental retardation Seizures Microcephaly Hyperactivity Autistic behaviours Growth retardation Lighter complexion Enamel hypoplasia Visual impairment
How should a positive NBS for PKU be confirmed?
Quantitative measurement of plasma phenylalanine
Treatment of PKU
Phenylalanine-restricted diet for life
Frequent monitoring of phenylalalnine levels
List 3 possible findings in a neonate born to mother with PKU NOT on phenylalanine-restricted diet
Mental retardation
Microcephaly
Growth retardation
Congenital heart disease
Which 3 amino acids accumulate in maple syrup urine disease?
Branched chain amino acids
- Leucine
- Isoleucine
- Valine
How does MSUD typically present?
Present within 1st week of life Vomiting Lethargy Hypertonicity Opisthotonus Seizures Hypoglcemia Metabolic acidosis
What is the most serious complication of MSUD?
Cerebral edema
How is MSUD diagnosed?
Quantiative serum amino acids (elevated levels of leucine (highest), isoleucine, valine)
Treatment of MSUD
Acute:
- Hydration (not usually sufficient)
- Dialysis
Long-term:
- Lifelong diet low in branched-chain amino acids
- Liver transplant
What are the clinical features of homocystinuria?
Same as Marfans with 3 differences:
- Progressive developmental delay
- Prothrombotic
- Lens is typically dislocated downward rather than upward
How do you diagnose homocystinuria?
Urinary cyanide nitroprusside
Quantiative serum amino acids (high homocystine, methionine, low cystine)
How do you treat homocystinuria?
High dose vitamin B6 +/- folate
What is cystinosis?
Systemic disease caused by a defect in the metabolism of cystine
Results in accumulation of cystine crystals in most of the major organs of the body
What are renal manifestations of cystinosis?
- Most common complication
- Fanconi syndrome (proximal RTA)
- Tubulointerstitial fibrosis
- Progression to ESRD
What are the extrarenal manifestations of cystinosis?
1) Liver
- Hepatomegaly
- Portal HTN
2) Eye
- Cystine deposits in the cornea and the conjunctiva
- Retinopathy
3) Brain
- Mild cognitive impariment
- Progressive CNS involvement after age 20
4) Growth retardation
5) Endocrine
- Hypothyroidism
- Hypogonadism
List 2 long term complications in cystinosis
CNS abnormalities
Muscle weakness
Swallowing dysfunction
Pancreatic insufficiency
What are the 3 main organ systems affected in tyrosinemia?
1) Liver
- Acutely hepatitis+hepatomegaly
- Eventually develop cirrhosis
2) Nerves
- Episodes of acute peripheral neuropathy triggered by infection
- Can be painful
3) Renal
- Fanconi like syndrome
How do you diagnose tyrosinemia?
Serum AA, urine OA
Elevated levels of succinylacetone in serum and urine
How do you treat tyrosinemia?
Nitisinone (NTBC) → inhibits tyrosine degradation at 4-HPPD
Liver transplant
What organic acidemia should be considered in the differential for vitamin B12 deficiency?
Methylmalonic aciduria
Vitamin B12 is a cofactor for the enzyme that metabolizes MMA (adenosylcobalamin-dependent enzyme methylmalonyl-CoA mutase)
Management priorities in patient with organic acidemia and metabolic crisis
- 1.5 x fluids with D10W
- NPO
- IV lipids
- Treat hyperammonemia, acidosis, electrolyte abnormalities
- L-carnitine
Laboratory abnormalities common to most organic acidopathies during metabolic crisis
- AG acidosis
- Ketosis
- Hyperammonemia
- Hypoglycemia
- Cytopenias (in PA and MMA)
Which organic acidemia can cause subdural hematomas and be confused with non-accidental injury?
Glutaric Acidemia Type 1
List 3 things that are unique about glutaric acidemia, compared to other organic acidurias
- Rarely presents in newborn period
- Can develop irreversible dystonic movement disorder
- Subdural hemorrhages
What is the most common IEM?
Fatty acid oxidation defects
Describe the pathophysiology of fatty acid oxidation disorders
Problem=Free fatty acids cannot undergo beta oxidation, and thus ketones are not produced
This results in 2 problems:
1) Hypoglycemia
- During prolonged fasting when switch from carbohydrate metabolism to fat metabolism
2) Toxic effects of fatty acid metabolites on liver, muscle, and heart
- Liver failure
- Cardiomyopathy
- Myopathy, rhabdomyolysis
How does MCAD typically present?
Hypoglycemia with prolonged fasting (12-16 hours) or illness Hepatomegaly Reyes-like syndrome Coma SIDS
What tests do you order to diagnose fatty acid oxidation defect?
Plasma acylcarnitine
Urine OA-low in ketones, high in dicarboxylic acids
Total and free carnitine (often get secondary carnitine deficiency)
Treatment of MCAD
Acute: D10WNS to prevent hypoglycemia, suppress lipolysis
Long-term: Avoid fasting > 10-12 hours
What is the presentation of VLCAD?
- More severe than MCAD
- Presents in infancy
- Chronic problems with muscle weakness, myalgia, rhabdo
- Hypertrophic or dilated CM during acute attack
What are the two types of osteopetrosis?
1) Severe autosomal recessive
2) Mild autosomal dominant
Clinical features of osteopetrosis
Macrocephaly Hepatosplenomegaly Deafness Blineness Severe anemia Psychomotor delay Pathologic fractures
What is the xray finding in osteopetrosis?
Diffuse bone sclerosis
Bone within bone appearance
Treatment of osteopetrosis
Gamma interferon
Vitamin D
Restrict Ca intake
EPO for anemia
Defects in the following enzymes result in what type of IEM: carbamyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase
?
Urea cycle defects!
List 3 IEMs that cause hyperammonemia
- Urea cycle defects
- e.g. OTC deficiency - Organic Acidemias
- e.g. Propionic academia, MCAD - Lysinuric protein intolerance
- Hyperammonemia-hyperornithinemia-homocitrullinemia syndrome
- Transient hyperammonemia of the newborn
- Congenital hyperinsulinism with hyperammonemia
List clinical signs of hyperammonemia in a neonate
Lethargy Seizures Coma Tachypnea (resp alkalosis) Bulging fontanelle (raised ICP)
List 3 management steps for hyperammonemia in UCDs
- IV fluids D10W/NS at 1.5 x maintenance
- IV Lipids
- Stop all protein feeds
- Treat hyperammonemia (sodium benzoate, sodium phenylacetate, arginine)
- Dialysis if above treatment fails to lower plasma ammonia
How is OTC deficiency inherited?
X-linked partially dominant
What is transient hyperammonemia of the newborn?
Transiently elevated NH3 seen in neonates with no signficant neurologic sequale
Normal NH3 levels:
Healthy full-term infants <100 μmol/L
Prems <150 μmol/L
Describe the pathophysiology of lysosomal storage disorders
Due to deficiency of lysosomal enzyme
Leads to accumulation of substrate in lysosomes
Accumulation in CNS leads to neurodegeneration, and in organs can lead to organomegaly, skeletal abnormalities, pulmonary infiltration
What kind of IEM is Tay Sachs
Lysosomal storage disorder
GM2 Gangliosidoses
Clinical features of Tay Sachs
GM2Gangliosidoses
- Usually develop normally until 4-5 months, then regress
- Decreased eye contact
- Increased startle reaction
- Loss of motor skills
- Macular pallor and retinal cherry red spots ***
- Macrocephaly
- At 2 y.o. →seizures which may be refractory to AEDs
- Death occurring by age 4-5
What is Sandoff disease?
Similar to Tay Sachs , but also cardiac involvement, HSM, and bony abnormalities
How do you diagnose Tay Sachs and Sandoff disease?
Measuring β-hexosaminidase A and B activities in peripheral leukocytes
What is the most common lysosomal storage disease?
Gaucher disease
What lysosomal storage disorder should be suspected in patients with unexplained organomegaly, easy bruising, and bone pain?
Gaucher disease
List the clinical features of Gaucher (type I, adult form)
- Can present at various ages, with most presenting by adolescence
- Bruising from thrombocytopenia
- Chronic fatigue secondary to anemia
- Hepatomegaly +/- elevated LFTs
- Splenomegaly
- Bone symptoms → pain, pseudo-osteomyelitis pattern, pathologic fractures, lytic lesions, osteosclerosis, bone crises with swelling,erlenmeyer flask deformity of the distal femur
- Pulmonary involvement
- Development and intelligence are normal
How do you treat Gaucher disease?
Enzyme replacement with recombinant beta-glucosidase
Consider BMT
What is the pathophysiology of Niemann Pick A/B?
Types A and B are due to deficient activity of acid sphingomyelinase→ leads to accumulation of sphingomyelin in the monocyte-macrophage system and CNS
What is the pathophysiology of Niemann Pick C?
Due to defective cholesterol transport
How does Niemann Pick A present?
Fatal disorder of infancy characterized by FTT, HSM, and rapidly progressive neurodegenerative course that leads to death by 2-3 y.o.
How does Niemann Pick B present?
Hepatosplenomegaly Pancytopenia (from splenic sequestration) Pulmonulary nodules Liver cirrhosis, portal HTN, ascites Normal IQ
How does Niemann Pick C present?
Prolonged neonatal jaundice
Progressive neurodegenerative course after 1-2 years
What is the enzyme deficient in Fabry disease?
α-galactosidase A
List 3 clinical features of Fabry disease
- Fabry crises***: severe neuropathic or limb pain, which may be precipitated by stress, extremes of heat or cold, and physical exertion
- Telangiectasias and angiokeratomas
- Renal: proteinuria, renal insufficiency
- Hypohydrosis
- In older patients, cardiac involvement and strokes
Describe the pathophysiology of mucopolysaccharidoses
Mutations in lysosomal enzymes needed to degrade glycosaminoglycans →leads to intralysosomal accumulation of GAG fragments
List clinical features of MPS I (Hurler disease)
-Infants appear normal at birth, but inguinal hernias are often present
- Diagnose between 6 and 24 months of age
- HSM
- Coarse facial features
- Corneal clouding
- Large tongue
- Prominent forehead
- Joint stiffness
- Short stature
- Skeletal dysplasia
- Progressive ventriculomegaly
- Valvular heart disease
What is the characteristic X-ray finding in MPS I and II
Xrays show a characteristic skeletal dysplasia known as dysostosis multiplex
What are the clinical features of MPS II?
Similar to Hurler disease except:
- Lack of corneal clouding
- Slower progression
Other features:
- Coarse facial features
- Short stature
- Dysostosis multiplex
- Joint stiffness
- Mental retardation manifest between 2-4 y.o.
How do you diagnose MPS?
Xrays-are useful to detect early signs of dysostosis
Screen=Semiquantitative spot tests for increased urinary GAG excretion
Definitive test=Enzyme assay
Treatment of MPS
- Early BMT (improvement of somatic symptoms and halts neurcognitive degeneration)
- Enzyme replacement therapy
In general, how do mitochondrial disorders classically present?
Affects tissues with most mitochondria-brain, muscle, heart
- Progressive CNS dysfunction
- Myopathy, movement disorders
- Cardiomyopathy
- Lactic acidosis
- Multifocal, relapsing/remitting course (often associated with intercurrent illness)
What are the general principles behind treatment of mitochondrial disorders?
1. Medications to support mitochondrial function: Coenzyme Q10 Riboflavin Thiamine Creatine Levocarnitine
- Avoid medications that inhibit respiratory chain
- e.g. phenobarbitol, valproic acid
List the clinical features of MELAS
- Motor, cognitive regression
- Recurrent stroke like episodes
- Lactic acidosis
- Generalized seizures
- Recurrent HA/migraine, vomiting
- Myopathy
- Ophthalmoplegia
- Pigmentary retinopathy
- Exercise intolerance
- Cardiomyopathy
- Cardiac conduction defects
- Deafness
- Diabetes
- Proximal renal tubular dysfunction.
What is the characteristic finding on muscle biopsy in MELAS?
Ragged red fibres
How do you diagnose MELAS?
MRI/MRS-lactate peak
Muscle biopsy
Molecular testing for MELAS mutations
What is the pathophysiology of Leighs disease?
Mitochondrial disorder
Deficiency in enzymes involved in electron transport chain
What symptom is characteristic of Leighs disease?
Intermittent respirations with associated sighing or sobbing-suggests brainstem dysfunction
Other symptoms:
- Seizures
- Weakness
- Hypotonia
- Ataxia
- Nystagmus
- Opthalmoplegia
- HOCM
- Renal tubular dysfunction
List 3 characteristic features of peroxisomal disorders
Multisystem disease!
- Defect in neuronal migration
- Micronodular cirrhosis of the liver
- Renal cysts
- Eye problems (corneal clouding, cataracts)
- CHD
- Dysmorphic features
What laboratory test is suggestive of peroxisomal disorders?
Elevated VLCFA
How can you distinguish X-linked adrenoleukodsytrophy from ADHD?
X-ALD can mimic ADHD
- Hyperactivity
- Poor school performances
But few differences:
- Visual impairment
- Impaired auditory discrimination
- Ataxia
- Poor handwriting
- Seizures
- Progressive spasticity
- Hearing loss
- Adrenal insufficiency
How do you diagnose X-ALD?
High VLCFA
ACTH stimulation
Molecular testing
MRI has characteristic patter-periventricular white matter lesions in posterior parietal and occipital lobes
Child with respiratory alkalosis, encephalopathic, showing subtle signs of increased ICP, what is the most likely IEM?
UCD
-Hyperammonemia leads to encephalopathy, respiratory alkalosis and raised ICP
List the clinical features of abetalipoproteinemia
Inability to absorb fat soluble vitamins
Clinically indistinguishable from vitamin E deficiency
Progressive ataxia
Retinitis pigmentosa (vit A)
Acanthocytosis (spiculated RBCs on smear)
List 3 IEMs NOT inherited in autosomal recessive manner (previous MCQ)
Fabry disease (X-linked) Hunter disease (X-linked) OTC deficiency (X-linked) X-linked adrenoleukodystrophy
What is the inheritance pattern of MELAS and recurrence risk?
Maternally inherited (mitochondrial DNA)
Difficult to predict recurrence risk because of heteroplasmy (all kids will get mom’s mitochondrial DNA but varying proportions of mutated DNA)
List 3 metabolic disorders that can present with acute encephalopathy (past MCQ)
Organic acidemia UCD GSD MSUD Fatty acid oxidation disorders
What is the presentation of GM1 gangliosidosis?
Presents early infancy Dysmorphism (Low-set ears, frontal bossing, depressed nasal bridge, long philtrum) Progresive developmental delay Progressive psychomotor retardation GTC seizures HSM Skeletal abnormalities Macular cherry red spot (50%)
