Chemical pathology VIII - Inherited metabolic disease

Question 1

Define Inborn errors of metabolism (IEM)

Answer 1

heterogeneous group of genetic diseases involving disorders of synthesis, metabolism, transport, and
storage of biochemical compounds

Question 2

Typical inheritance pattern for IEM?

Effect on substrate, metabolites production and consumption?

Answer 2

Autosomal recessive mostly

Mutational impairment of sequential enzyme in metabolic pathways

• Toxic accumulation of substrate proximal to the blocked enzyme
• Excessive synthesis of secondary metabolites
• Inhibited formation of distal products

Question 3

List some common metabolic diseases in HK

• Organic acidemias, Amino acid metabolism, Urea cycle defects, Fatty acid oxidation?

Answer 3

Organic acidemias: Multiple carboxylase deficiency, Glutaric aciduria Type I

Amino acid metabolism: Phenylketonuria, Homocystinuria, Maple syrup urine disease, Nonketotic hyperglycinemia

Urea cycle defects: Citrullinemia, Arginiemia

Fatty acid oxidation: Carnitine transporter/ translocase/ transferase deficiency, different acyl CoA dehydrongenase deficinecies

Question 4

Growth problems associated with IEM

Answer 4

Failure to thrive

Neurological development delay

Hearing and/or visual impairment

Organomegaly

Question 5

Skin changes associated with IEM

Answer 5

Skin rash, abnormal pigmentation, dysmorphism

Question 6

Unexplained Illnesses associated with IEM

Answer 6

Gastrointestinal disturbances, e.g. recurrent vomiting, diarrhea

arrhythmias, unexplained cardiac failure

Endocrine dysfunction

Unexplained episodic illness with “rule-out sepsis” picture

Question 7

Presentation of metabolic decompensation

• Time of onset?
• Symptoms and signs?

Answer 7

Occurs in the neonatal period or in infancy, sometimes not until adulthood

Hypoglycemia, ketoacidosis, primary lactic acidosis, hyperammonemia

Intractable seizures, acute metabolic encephalopathy

Acute liver failure

Question 8

Outline the items in Basic metabolic investigation to Dx IEM

Answer 8

Complete blood count

liver function tests

international normalized ratio (INR) of prothrombin time

CK, creatinine

plasma urea, urate

Question 9

Outline the items in Special metabolic investigation to Dx IEM

Answer 9

Blood gases,

plasma electrolytes,

plasma glucose, plasma lactate, plasma ammonium,

urinary ketones (ketostix),

blood beta-hydroxybutyrate

Question 10

Definitive test for IEM in newborn. **

Answer 10

Dried blood spot metabolic screening of IEM by tandem mass spectrometry

measure multiple analytes in one sample analysis which can cover >20 IEM,

Question 11

Advantage of dried blood spot metabolic screening? (4) ****

Answer 11

Covers a wide spectrum of IEM with good sensitivity and specificity

Simple sample collection, delivery and storage

Rapid TAT (turnaround time) to accommodate urgent request

Low cost

Question 12

Which IEM are associated with newborn cardiac death

Answer 12

Carnitine transporter/ translocase/ transferase deficinecy

Other impaired fatty acid oxidation pathways

Question 13

Explain the MS/MS measuring with 2 scans for IEM investigation?

What are the 2 scans?

Answer 13

Detects mass-to-charge ratio (shared by isomers) – highest sensitivity and selectivity

2 scans (e.g. 89.9 > 43.9):
 MS1 – obtain the mass of molecular ion (89.9) >> then break the molecule into fragments
 MS2 – measures characteristic fragment ion (43.9)

Question 14

Define neonatal DM

2 types?

Answer 14

insulin-requiring hyperglycemia with plasma random glucose >11.1 mmol/L

Onset within the first six months of age

• Transient NDM (resolve in 3 months)
• Permanent NDM (life-long treatment, metabolic complications, neurodevelopment issues)

Question 15

2 mutations that cause transient neonatal DM

Answer 15

Gain-of-function mutations of ABCC8 (cannot release insulin)

ZAC/HYAMI imprinting defect on chromosome 6q

Question 16

4 mutations that cause permanent neonatal DM

Answer 16

Heterozygous gain-of-function mutations in KCNJ11

Heterozygous or homozygous activating mutations in ABCC8

homozygous mutationsin glucokinase GCK

Heterozygous gain-of-function INS

Question 17

Extranpancreatic defects of Neonatal Diabetes Mellitus

Answer 17

 Cerebellar agenesis

 Congenital hypothyroidism and glaucoma

 Pancreatic hypoplasia

 Mitochondrial disorders

 Epiphyseal dysplasia or acute hepatic failure in EIF2AK3 mutations

Question 18

How to use genetic testing to dictate treatment for permanent neonatal DM?

Answer 18

ABCC8 or KCNJ11 mutations:

• Use oral sulfonylurea instead of life-long insulin