Metabolics

Question 1

Carnitine Palmitoyltransferase II Deficiency

Answer 1

Type: Disorder of long-chain fatty acid oxidation

Genetics: Autosomal recessive

3 forms: lethal neonatal, infantile hepatocardiomuscular or myopathic form

Clinical Features: Hypoketotic hypoglycemia, liver failure, cardiomyopathy, seizures, peripheral neuropathy

Myopathic: exercise-induced muscle pain and weakness, myoglobinuria

Investigations:

• Molecular gene testing of CPT2
• Reduced CPT enzyme in muscle
• High CK
• High C12-C18 on acylcarnitine profile

Management:

• High carb, low fat diet
• Carnitine
• Glucose infusions during illnesses
• Stay hydrated
• Avoid triggers and VPA, general anesthesia, ibuprofen and diazepam

Question 2

A child with blonde hair much lighter than her family members is noted to have crystals on her optometry examination.

Answer 2

CYSTINOSIS

Genetics: CTNS gene

Inheritance: Autosomal Recessive

Lysosomal storage disorder leading to cysteine accumulation in all cells

Clinical Features: Normal at birth → failure to thrive, Fanconi syndrome (proximal tubule dysfunction → normal AG metabolic acidosis, volume depletion from polyuria, electrolyte imbalances, hypophosphatemic rickets) by 6-12 months; often fair complexion, photophobia (leads to blindness)

If untreated, ESRD by 10yo.

Investigations:

• Urine: ↑glucose, ↑phosphate, ↑amino acids, ↑organic acids, ↑protein, ↑potassium, ↑bicarbonate
• Serum: ↓phosphate, ↓hypokalemia, non-anion gap metabolic acidosis
• Genetic testing or leukocyte cysteine levels

Management:

• Oral cysteamine - delays onset of complications
• Eyedrops
• Water, sodium, phosphate and potassium supplementation
• Vitamin D
• Bicarbonate supplementation
• Referrals to Nephrology, Metabolics, Ophthalmology, Endocrinology​

Question 3

A hypotonic infant with sweet smelling cerumen

Answer 3

MAPLE SYRUP URINE DISEASE

Presentation: Poor feeding, hyper- or hypotonia, lethargy or encephalopathy

Distinct Features: Maple syrup smelling urine/cerumen

Screening labs: ↑ketones, normal or ↑ ammonia

Acute management:

• IV dextrose
• Branched-chain amino acid-free TPN
• Dialysis PRN

Chronic management:

• Branched-chain amino acid restriction
• Valine and isoleucine supplementation
• Trial of thiamine (rare forms are responsive)
• liver transplantation

Question 4

A developmentally normal child presents with a hypoglycemic seizure during an episode of gastroenteritis. No ketones are noted on workup.

Answer 4

MCAD DEFICIENCY

Presentation: Identified on Newborn Screen.

Neonatal Form: Hypoglycemia, arrhythmia, cardiac arrest

Management:

• Supplement breast milk with formula and/or expressed breast milk after feeds until supply is clearly established
• With illness: Treat with D10W during acute illness (correct hypoglycemia and suppress lipolysis).
• Avoid fasting (<10-12h)

Question 5

Tests positive on a Newborn Screen and is associated with ADHD

Answer 5

PHENYLKETONURIA (PKU)

Inheritance: Autosomal Recessive

If untreated, leads to profound intellectual disability.

Maternal PKU is associated with cardiac defects, microcephaly, ID

Clinical Features:

• Hyperactivity with autistic behaviours, including purposeless hand movements, rhythmic rocking and athetosis
• Lighter skin complexion than unaffected siblings
• Seborrheic or eczematoid rash
• Seizures, spasticity, hyperreflexia, tremors (>50% have EEG abnormalities)
• Microcephaly, enamel hypoplasia, growth retardation
• Low bone mineral density, osteopenia

Investigations: once diagnosed, order BH4 studies to rule out deficiency as cause

Management:

• Formula free of phenylalanine
• Ensure tyrosine intake is adequate
• Screen for ADHD - executive dysfunction seen in early-treated children
• Pegvalase (PEG phenylalanine ammonia lyase)
• Liver transplant

Question 6

Name 5 metabolic disorders that present with an acute presentation?

Answer 6

SMALL MOLECULES

Amino acid disorders: Urea cycle Defects, Maple Syrup Urine Disease

Organic acidemias: Propionic acidemia, MMA

Fatty acid oxidation defects: LCHAD, TFP

Carbohydrate disorders: Galactosemia, GSD

Energy Defects: Lactic acidosis

Vitamins: Biotinidase, pyridoxine dependent seizures

Metals: Menke’s

Question 7

Name 5 metabolic disorders that present with a chronic presentation?

Answer 7

ORGANELLES (MACROMOLECULES)

Lysosomes:

• CNS: Tay Sachs, Krabbe, Batten’s
• Coarse facial features: MPS, Oligosaccharides (Hurler, Sialidosis)
• Organs: Gaucher, Niemann Pick

Peroxisomes: Zellweger, Adrenoleukodystrophy

Mitochondria: MELAS, MERRF, NARP, LHON

Golgi/ER: Congenital disorders of glycosylation

Membranes: Transporters/Trafficking

Macromolecule synthesis/degradation: Lipidomics, protein translation

Question 8

List 5 components of an initial metabolic work-up.

Answer 8

Blood:

Blood gas

Electrolytes (with anion gap calculation)

Glucose

Ammonia

Lactic acid

Plasma/Serum Amino Acids

Acylcarnitine

Total/free carnitine

Urine:

Urinalysis - for ketones

Urine Organic Acids

Question 9

List 2 causes of Nonketotic Hypoglycemia

What is the best test to define the diagnosis?

What is the immediate treatment?

Answer 9

↓insulin, ↑FFA:

• Fatty acid oxidation defect, ketogenic defect

↑insulin, ↓FFA:

• Hyperinsulinism

Plasma Acylcarnitine

Immediate treatment: glucose infusion

Question 10

List 2 causes of Ketotic Hypoglycemia

What is the immediate treatment?

Answer 10

NO Hepatomegaly:

Organic aciduria, Ketolytic defect

YES Hepatomegaly:

Glycogen storage disease, Gluconeogenesis defect

Immediate treatment: glucose infusion

Question 11

Name 2 causes of hyperammonemia

Describe the immediate treatment.

Answer 11

• Organic aciduria (metabolic acidosis, big AG)
• Fatty acid oxidation defect (hyperchloremic acidosis, little/no AG +/- hypoglycemia)
• Urea Cycle Defect (respiratory alkalosis, little/no AG)
• Citrullinemia
• Arginase deficiency
• OTC deficiency

Treatment

• Protein restriction
• Ammonia removal (sodium benzoate and sodium phenylbutyrate, dialysis)
• Arginine to drive urea cycle (except in arginase deficiency)

Question 12

Name 1 metabolic disorder that causes an elevated lactate level.

Answer 12

Organic acidopathies

Fatty acid oxidation defects (acylcarnitine profile)

Glycogen storage disease (GSD I)

Question 13

What metabolic disorder tends to present with the following lab abnormalities in a 4 day old male?

ABG: 7.5/25/20

Na 140, Cl 104, Glucose 4, AG 16

What additional investigation would help narrow your differential?

What additional investigation would confirm your diagnosis?

Answer 13

Urea Cycle Disorder

Ammonia level (ammonia 800µmol/L)

Plasma Amino Acids

Question 14

List 3 options for the management of a Urea Cycle Disorder

Answer 14

Protein restriction

IV glucose infusion (stop catabolism)

Replace arginine (may be playing a role in encephalopathy)

Remove ammonia (sodium benzoate, sodium phenylacetate)

Dialysis - if required

Question 15

What metabolic disorder tends to present with the following lab abnormalities in a 4 day old male?

ABG: 7.0/25/5

Na 140, Cl 103, Glucose 4, AG 32, ammonia 800µmol/L

What test would confirm your diagnosis?

Answer 15

Organic acidemia (metabolic acidosis with big AG)

Urine Organic Acids

Question 16

What metabolic disorder tends to present with the following lab abnormalities in a 4 day old male?

ABG: 7.2/25/14

Na 140, Cl 114, Glucose 2, AG 12, ammonia 800µmol/L

What test would confirm your diagnosis?

Answer 16

Fatty Acid Oxidation Defect (hyperchloremic acidosis, little/no AG, hypoglycemia)

Acylcarnitines

Question 17

Answer 17

HOMOCYSTINURIA due to CβS-deficient Homocystinuria

Clinical Features: ectopia lentis, myopia, osteoporosis, kyphoscoliosis, skeletal dysplasia, high palate, long fingers (Marfanoid), developmental delay, psychiatric issues, thrombosis (arterial and venous), fair, thin skin, myopathy, peripheral neuropathy

Management:

• Pyridoxine (250-500mgs/day)
• Protein restriction
• Betaine
• ASA, Heparin subcutaneously
• Pregnancy management

Question 18

Answer 18

X-LINKED ADRENOLEUKODYSTROPHY

Metabolic disorder: Peroxisomal

Genetics: ABCD1 gene

Inheritance: X-linked recessive

Clinical Features: Onset 4-12yo, developmental regression (classically starting with handwriting, accompanied by behavioural deterioration [hyperactivity, ADHD]), neurologic deterioration with ataxia, seizures and paraplegia, adrenal insufficiency, impaired auditory discrimination

Investigations: Elevated VLCFAs, MRI Brain (occipital demyelination with leading edge enhancement after gadolinium administration), molecular genetic testing

Management:

• Adrenal steroid hormone supplementation
• Bone marrow transplantation
• Lorenzo’s Oil - previously a treatment - has fallen out of favour

Question 19

Answer 19

ZELLWEGER SYNDROME

Metabolic disorder: Peroxisomal

Genetics: several genes involved

Inheritance: Autosomal Recessive

Clinical Features: Facial features (high forehead, upslanting palpebral fissures, hypoplastic supraorbital ridges, epicanthal folds), severe weakness and hypotonia, neonatal seizures, eye abnormalities, jaundice

Investigations: Elevated VLCFAs = screening test; AUS for hepatomegaly, renal cysts; molecular genetic testing for known genes involved

Management: Supportive

Question 20

A metabolic disorder associated with stroke-like episodes before 40-years-old.

Answer 20

MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)

Metabolic disorder: Mitochondrial

Genetics: several involved (including MT-TL1)

Inheritance: Mitochondrial

Clinical Features: normal initial development, symptoms start in childhood with stroke-like episodes, muscle weakness, headaches, vision impairment, vomiting, WPW, conduction abnormalities, LVH, single endocrine disorders (T1DM

Question 21

What metabolic disorder is associated with hypertrophic cardiomyopathy and peripheral neuropathy?

Answer 21

LEIGH SYNDROME

Metabolic disorder: Mitochondrial

Genetics: several involved (including MT-TL1)

Inheritance: Autosomal Recessive

Clinical Features: lactic acidosis, FTT, hypotonia, peripheral neuropathy and hypertrophic cardiomyopathy , seizures

Investigations: mtDNA molecular genetic testing, ↑blood/↑CSF lactate levels, gas - metabolic acidosis, muscle biopsy, respriatory chain enzyme studies; MRI brain - bilateral symmetric hypodensitites in the basal ganglia

Management:

• Suppportive management
• Routine surveillance of new symptoms
• Sodium bicarbonate to treat acidosis
• Antiepileptic drugs to treat seizures (avoid VPA)
• Multidisciplinary team management is encouraged

Question 22

Answer 22

GM2 GANGLIOSIDOSIS - TAY-SACHS DISEASE

Metabolic disorder: Lysosomal lipid storage disorder

Genetics: HEXA gene

Inheritance: Autosomal Recessive

Most prevalent in Ashkenazi Jewish population

Clinical Features: Hyperacusis, no HSM.

• Onset 4-6m. Previously normal development with marked startle reaction, then developmental delay followed by regression.
• By 1yo, lose ability to stand, sit and vocalize + macrocephaly becomes apparent (d/t ↑GM2 ganglioside deposition in brain)
• Hypotonia → spasticity → convulsions, blindness, deafness and bilateral cherry-red spots

Investigations: serum or leukocyte β-hexosaminidase A deficiency

Prognosis: few live beyond 3-4yo; death usually due to aspiration or pneumonia

Question 23

Answer 23

POMPE DISEASE

Metabolic disorder: Glycogen Storage Disease

Genetics: GAA gene

Inheritance: Autosomal Recessive

Clinical Features: Hypertrophic cardiomyopathy, FTT, severe hypotonia, short PR interval, macroglossia

Investigations: muscle biopsy (glycogen-containing vacuoles), ECG (shortened PR, large QRS), enzyme studies, gene studies, urine hex4 (tetrasaccharide) - level correlates with severity

Management: Enzyme replacement therapy

Question 24

Answer 24

HURLER SYNDROME (MUCOPOLYSACCHARIDOSES [MPS1])

Metabolic disorder: Lysosomal Disorder

Genetics: IDUA 4p16.3

Inheritance: Autosomal recessive

MPSI is a spectrum from Hurler (severe) to Scheie syndromes (least severe)

If untreated, Hurler is fatal in 5-10y

Clinical features: ID, coarse facial features, corneal clouding, visceromegaly, short stature, joint contractures, dysostosis multiplex, leucocyte inclusions, mucopolysacchariduria

Investigations: Gene testing, enzyme assays, urine glucosaminoglycans

Management:

• BMT can help disease (if done before CNS symptoms) - usually <1yo
• Enzyme supplementation for non-CNS disease (skeletal penetrance is poor)

Question 25

A jaundiced baby presents with feeding intolerance and is noted to have cataracts, sepsis and evidence of liver failure.

Answer 25

**GALACTOSEMIA** Metabolic disorder: Carbohydrate Disorder Genetics: GALT gene Inheritance: Autosomal Recessive Clinical Features: Vomiting/feeding intolerance, especially lactose-containing foods, **cataracts**, liver failure, jaundice starting unconjugated → conjugated, RTA, **E coli sepsis,** poor growth, expressive language delay, premature ovarian insufficiency Investigations: ↑Total galactose+galatose-1-phosphate, ↑urine galactitol, gene testing, enzyme assays Management: Galactose-free diet, monitor and support ID, growth delay and ovarian failure with treatment

Question 26

**Match the Vitamin Therapy with the Disorder** ## Footnote Biotin Methylmalonic acidemia Pyridoxine Fatty acid oxidation defects Thiamine Vitamin B6 dependency Hydroxycobalamin Mitochondrial disease Carnitine Proprionic acidemia Riboflavin Organic acidemia CoenzymeQ/B vitamins Maple Syrup Urine Disease

Answer 26

Biotin Proprionic acidemia Pyridoxine Vitamin B6 dependency Thiamine Maple Syrup Urine Disease Hydroxycobalamin Methylmalonic acidemia Carnitine Organic acidemia Riboflavin Fatty acid oxidation defects CoenzymeQ/B vitamins Mitochondrial disease

Question 27

Teenager with burning pain and paresthesias of the feet and lower legs causing difficulty walking, often precipitated by fever or physical activity.

Answer 27

**FABRY DISEASE** Metabolic disorder: Carbohydrate Disorder Genetics: GLA gene Inheritance: X-linked recessive Clinical Features: * Presents in late childhood/adolescence * Recurrent episodes of burning pain/paresthesias to feet and lower legs so severe they are unable to walk, often precipitated by fever or physical activity. * No sensory/motor deficits. Reflexes preserved. * Autonomic involvement (arrhythmias, cutaneous mottling, GI persitaltic abnormalities, LVH, CAD, valvular infiltrative myopathy) * Characteristic skin lesions that are in perineal, scrotum, buttocks or periumbilical zone as flat or raised red-black telangiectasias (angiokeratoma corporis diffusum) * Cataracts * Necrosis of femoral heads Investigations: EMG - normal to mildly slow conduction velocities, ECG, echocardiogram, coronary artery assessment PRN, proteinuria present early in course, **Calcifications in pulvinar of thalamus** caused by cerebral hyperperfusion, **zebra bodies** on electron microscopy from skin or sural nerve biopsy, enzyme assays Management: * Supportive with enzyme replacement (agalsidase alfa, beta, migelestat) * Monitor for hypertension and renal disease.