Adult Presentations of Inherited Metabolic Disorders Flashcards
1
Q
What are types of disorders in metabolic medicine?
A
Inherited metabolic disorders
- Genetically determined alteration of metabolic pathway
Acquired metabolic disorders
- Nutrition: Deficiency of cofactor for metabolic pathways e.g. Thiamine
- Toxins: Damage to enzyme/cofactor in pathway e.g. Alcohol, Drugs, metal
2
Q
What are problems faced by rare diseased patients?
A
- Lack of access to correct diagnosis
- Delay in diagnosis
- Lack of quality information on the disease
- Lack of scientific knowledge of the disease
- Heavy social consequences for patients
- Lack of appropriate quality healthcare
- Inequities and difficulties in access to treatment and care
3
Q
How can we improve lives of patients with rare disease?
A
- By implementing a comprehensive approach to rare diseases
- By developing appropriate public health policies
- By increasing international cooperation in scientific research
- By gaining and sharing scientific knowledge about all rare diseases, not only the most “frequent” ones
- By developing new diagnostic and therapeutic procedures
- By raising public awareness
- By facilitating the network of patient groups to share their experience and best practices
- By supporting the most isolated patients and their parents to create new patient communities or patient groups
- By providing comprehensive quality information to the rare disease community
4
Q
What are features of inherited metabolic disorders?
A
Most commonly autosomal recessive
- Can usually have functional biochemical pathways with >10-15% residual enzyme activity
- NB Familial hypercholesterolaemia - autosomal dominant
Some disorders are X-linked
- Females may be variably manifest due to random x-inactivation or ‘Lyonization’ effect
Mitochondrial DNA
- Maternally transmitted but mitochondrial disorders may manifest any form of inheritance because mitochondrial function is dependent on products of autosomal DNA as well
5
Q
What are examples of Inherited Metabolic Disorders?
A
- Disorders of carbohydrate metabolism: Glycogen storage diseases, galactosaemia
- Disorders of mitochondrial energy metabolism: MELAS, Fatty acid oxidation disorders e.g. LCHAD
- Disorders of amino acid metabolism & transport: Phenylketonuria (PKU), Urea cycle disorders, Organic Acidurias e.g. Maple Syrup Urine Disease, Methyl Malonic Acidaemia
- Vitamin-responsive disorders (overlap other categories): Homocystinuria, hyperhomocysteinemia
- Neurotransmitters & small peptide disorders: Monoamine oxidase deficiencies
- Disorders of lipid & bile acid metabolism: Familial Hypercholesterolaemia, Lipoprotein lipase deficiency, Smith-Lemli-Opitz Syndrome
- Disorders of nucleic acid and haem metabolism: Hereditary porphyrias
- Disorders of metal transport: Haemochromatosis, Wilson’s disease
- Organelle-related disorders: Lysosomal storage disorders eg Fabry’s Disease, Gaucher’s Disease, Mucopolysaccharidoses
6
Q
What are examples of X-linked Inherited Metabolic Disorders?
A
- Fabry disease: a lysosomal disorder of sphingolipid metabolism
- X-linked adrenoleucodystrophy: A peroxisomal disorder of fatty acid ß oxidation
- Ornithine transcarbamylase deficiency: A mitochondrial disorder (of urea generation). The commonest inherited cause of hyperammonaemia
7
Q
What are classifications of Inherited Metabolic Disorders?
A
- INTOXICATION
- ENERGETIC DISORDERS
- COMPLEX MOLECULES
8
Q
What are Intoxication disorders?
A
- Aminoacidopathies (Homocystinurias,OAT,PKU)
- Organic acidurias
- Urea cycle defects (OTC)
- Sugar intolerances (polyols)
- Metals, Porphyrias
- Neurotransmitters (catabolism, synthesis)
9
Q
What are energetic disorders?
A
- Congenital lactic acidemias (PC,PDH,Krebs)
- Respiratory chain disorders
- FAO and ketone bodies disorders
- Gluco / Glyconeogenesis, Glycolysis defects
- Cerebral creatine disorders
- Pentose phosphate pathway
10
Q
What are complex molecule disorders?
A
- Lysosomes
- Peroxisomes
- CDG (ER and Golgi)
- Cholesterol
11
Q
What are clinical presentations of IMD?
A
- Any organs or systems, any scenarios, any age, any modes of inheritance. (sporadic)
- Nervous system very often implicated but isolated mental retardation is very rare
- High significance of associated signs: neurologic and extraneurologic
- Most often progressive disorders
- Acute attacks of decompensations (« crisis ») (triggered by diet, infection, catabolism)
- PERSISTENCE, AGGRAVATION, MYSTERY
12
Q
What are the diagnostic circumstances of IMD?
A
- Antenatal symptoms (echo, NMR)
- Neonatal screening (at risk screening)
- Neonatal symptoms
- Late onset acute (intermittent signs)
- Specific symptoms (eye, skin, liver, heart, kidney, hematologic system ,etc…)
- Chronic/progressive general symptoms: Progressive neuro, mental, cognitive, or behavioral deterioration, epilepsy.
- Failure to thrive.
- Emergencies: Treatable disorders, Urgent protocol
13
Q
What are clinical circumstances of Adult IMD diagnosis?
A
IMD diagnosed in the paediatric age and reaching adulthood:
- treated / untreated natural history
- late onset complications
- fertility / pregnancy
- psycho-social aspects
IMD striking in adulthood:
- unknown presentations
- methods of investigations adapted to adults
IMD diagnosed in adulthood but starting at the paediatric age
14
Q
What are basic principles of diagnostic approach to IMD?
A
- Consider IMD in parallel with other more common conditions in the actual clinical context.
- Be aware of symptoms that persist and remain unexplained after the initial treatment.
- Don’t confuse a syndrome with aetiology.
- IMD can present at any age.
- Most IMD appear sporadic
- Consider first IMD amenable to treatment.
- Take care first of the patient, then of the family
15
Q
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