Metabolics

Question 1

Kearns - Sayre Syndrome

Answer 1

Mitochondrial defect
Onset by age 20

External opthalmaplegia
Heart block
Retinitis pigmentosa
Multiple endocrine abnormalities
Cerebellar syndrome/ataxia
Elevated CSF protein

Question 2

Leigh Disease (Subacute Necrotising Encephalopmyopathy)

Answer 2

Mitochondrial defect
Progressive degenerative disorder presenting in infancy
Developmental delay and regression - strokes in basal ganglia
Decompensation during periods of stress Generalised seizures, weakness, hypotonia, ataxia, tremor, pyramidal signs and nystagmus
Intermittent respiratory with associated sighing or sobbing
External ophthalmoplegia, ptosis, retinitis pigmentosa, optic atrophy, and ↓visual acuity
Hepatic and renal failure
HOCM

Ix: Lactic acidosis, MRI brain: necrotising areas in brainstem

Question 3

MELAS = Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis + Stroke-Like Episodes

Answer 3

Mitochondrial defect
Initially normal –> progressive motor and cognitive deficits due to recurrent stroke like episodes

At least 2 of the following
i. Focal or generalised seizures
ii. Dementia
iii. Recurrent migraine headaches
iv. Vomiting
Other possible features exercise intolerance, myopathy, ophthalmoplegia, cardiac conduction defects, hypertrophic or dilated cardiomyopathy, deafness, diabetes and proximal renal tubular dysfunction

Investigations
a. Lactic acidosis
b. Ragged red fibres (muscle biopsy)

Question 4

Metachromatic leukodystrophy

Answer 4

The clinical manifestations of the late infantile form of MLD, which is most common, usually present between 12 and 18 months of age as irritability, inability to walk, and hyperextension of the knee, causing genu recurvatum. The clinical progression of the disease relates to the pathological involvement of both central and peripheral nervous system, giving a mixture of upper and lower motor neuron and cognitive and psychiatric signs. Deep tendon reflexes are diminished or absent. Gradual muscle wasting, weakness, and hypotonia become evident and lead to a debilitated state. As the disease progresses, nystagmus, myoclonic seizures, optic atrophy, and quadriparesis appear, with death in the first decade of life

Question 5

Smith- Lemi- Opitz

Answer 5

Gene- DHCR7
7-dehydrocholesterol reductase deficiency
Poor growth, microcephaly, intellectual disability, syndactyl/webbing of toes, photosensitivity, ambiguous genitalia (hypospadias + cryptochordism), cardiac defects
Ix: elevated 7-DDHC, low serum cholesterol, sequence gene mutation
Rx: cholesterol supplementaiton

Question 6

Causes normal anion gap metabolic acidosis

Answer 6

Loss of bicarb
Renal losses
Gastro losses - eg diarrhoea

Question 7

Causes high anion gap metabolic acidosis

Answer 7

in metabolics- organic acidurias (addition of acid)

Question 8

Acylcarnitine profile can be used to investigate ..

Answer 8

fatty acid oxidation defects
Organic academies
B12 disorders

Question 9

What does urinary GAGs test for?

Answer 9

Muchopolysaccharidosis

Question 10

Galactoseaemia investigations

Answer 10

urine reducing substances, coagulopathy, low albumin, mildly abn LFTs, may or may not have hypoglycemia
Increased RBC galactose 1 phosphate concentration (not affected by blood transfusion)
Definitive: RBC GALT activity (affected by blood transfusion)

Question 11

Which metabolic conditions are x linked?

Answer 11

X linked aderenoleukodystrophy
Hunter disease
Fabry disease
OTC deficiency

Question 12

what is the treatment for tyrosinemia type 1

Answer 12

Nitisinone
Low protein (esp low tyrosine and phenylalanine ) diet
Liver transplant

Question 13

what causes elevated succinylacetone

Answer 13

tyrosinemia type 1

Question 14

3 manifestations of tyrosinemia type 1

Answer 14

liver failure - (cirrhosis), high risk HCC
Fanconi syndrome —> hypophosphatemic rickets
nephromegaly
Neurological issues - variable

Question 15

which metabolic defect is most likley to not be picked up by newborn screening

Answer 15

lysosomal storage disordrs

Question 16

which enzyme is affected in pompe disease

Answer 16

acid alpha glucosidase

Question 17

Tyrosinemia 1

Answer 17

Disease of liver, kidneys and peripheral nerves
Usually presents 2-6 mo of age with progressive liver disease/acute hepatic crisis - hepatomegaly, transaminitis, cholestasis –> jaundice, ascites, hypoglycemia, coagulation abormalities/GI bleeding
often precipitated by illness
Renal- fanconi syndrome –> hypophosphatemic rickets
Mild to severe neurological dysfunction
Ix: elevated succinulacetone (plasma organic acids)
Rx:low tyrosine + phenylalanine diet
Nitisinone
Liver transplant

Question 18

Chediak Higashi syndrome

Answer 18

• immune disorder, increased risk infection esp sinopulmunary
  Ix: giant granules in granulocytes
  Slightly increased bleeding tendancy
  hypopigmentation

Question 19

Maple syrup urine disease

Answer 19

Aminoacidopathy
Presents within first week of life
Deficiency in BCKDC
Build up of leucine, isoleucine, valine (leucine the one that causes encephalopathy)
Present with irritability, poor feeding, vomiting, hypertonia/dystonia, abdnomal movements, seizures,
Ix: may have hypoglycemia/metabolic acidosis, always have ketones +++ in urine. Elevated urine and plasma amino acids (leucine, isoleucine, valine)
METABOLIC EMERENCY
Rx: dialysis to remove toxic metabolites, then diet low in branched chain amino acids
Liver transplant

Question 20

Organic acidemia

Answer 20

Acute form: present in first 2 weeks of life, lethargy, seizures, vomiting, sweaty feet odor
Chronic: acute episodes of metabolic decompensation during capabolic states eg infection
Ix: metabolic acidosis classically with wide anion gap, +/- hypoglycemia, elevated ketones, mild-mod hyperammonemia
Urine- elevated organic acids, acylcaritine profile
Rx a. Decrease substrate – low protein diet (protein completely withheld during acute illness- 10% dextrose +0.9% n/saline)
b. Enhance enzyme activity – biotin, B12 (for MMA)
c. Disposal of toxic metabolites – L-carnitine (life saving) (especially for proprionic acidemia)
i. Carnitine binds to organic acids then can be excreted in the urine
d. Ammonium scavengers- sodium benzoate or sodium phenylbutyrate
Hemofiltration/dialysis

Question 21

Niemman pick

Answer 21

lysosomal storage disease
A and B: deficinecy in activity of sphingomyelinase –>accumulation of sphingomyelin which accumulates in CNS and non-neural tissue
A: classic form. FTT, HSM, progressive rapid neurodegeneration that leads to death by 2-3 years of age. Psychomotor retardation is evident by 6mo. Absent reflexes. Cherry red spot.
B: non neuronopathic, may present older. HSM. May have pulmunary involveement. Normal IQ
C: neuronopathic, defect in cholesterol transport. May present as prolonged neonatal jauncdice. Appear normal for 1-2 years, then slowly progressive neurodegeneration. HSM less severe than Type A or B. Can have ataxia, delayed motor milestones, galastic cataplexy, vertical supranuclear gaze palsy

Question 22

Galactosemia

Answer 22

GALT deficiency after the onset of galactose-containing feedings (eg, human or cow’s milk)
Presents within first few days of life
Liver- conjugated and unconjugated hyperbilirubinemia, deranged LFTs, coagulopathy, +/-hypoglycemia
E.coli sepsis
Fanconi syndrome (renal tubular acidosis)
Cataracts
Rx: soy formula (avoid galactose containing products)

Question 23

which gene encodes GLUT1

Answer 23

SLC2A1
Mutation leads to GLUT1 deficiency (inability to transport glucose into brain, low glucose in CSF)

Question 24

Netherton syndrome

Answer 24

Mutations in the SPINK5 gene.
Children have “bamboo hair” (trichorrhexis invaginate) and are predisposed to atopy

Question 25

most sensitive metabolic marker of neuroinflammation in CSF

Answer 25

Neopterins are products of guanosine triphosphate (GTP) catabolism that result from cellular immune activation by pro-inflammatory cytokines. They are non-specific with regard to aetiology.

Question 26

what would you see on hypo screen with hyperinsulinemia

Answer 26

no acidemia
low free fatty acids (inhibition of lipolysis)
low ketones (inhibition of fatty acid oxidation)
detectable insulin levels in face of low BSL

Question 27

what length of carbon chain metabolism is affected by MCAD

Answer 27

C6-8

therefore in MCAD plasma acylcarnitine profile may show elevated c6, c8, c10

Question 28

miglustat

Answer 28

competitive inhibitor of glucosylceramide synthase

treatment for neimenn pick type c and gaucher disease

Question 29

treatment cystinosis

Answer 29

mercaptamine (cysteamine) = oral form + eye drops, high water intake, Na + K supps, HCO3 sups, phosphate supps, vit D supps