inborn errors of metabolism Flashcards
(35 cards)
inborn errors of metabolism are individually — but collectively —- the presentation is at – age neonate into adulthood
- diagnosis:
1- doesnt require extensive knowledge of biochemical pathway or individual metabolic disease
2- understanding of broad clinical manifestation of IEM provides basis of knowing when to consider diagnosis
3- high index of suspension most important in making decisions
- emergancy treatment requires prompt therapy aimed at metabolic stabilisation
- rare
- common
- any age
-genetic disorders of metabolism mostly involve – genes which code for enzymes involved in —- pathway or — proteins
- clinical representation:
1- accumulation of — which interferes w normal function
2- — of — of the metabolic pathway
- single
- metabolic
- transport
- deficiency
- product
( it can cause from: impaired enzyme activity , substate build up)
age of onset of IEM:
- age at clinical presentation varies for individual IEM and variants
1- the timing of presentation depend on:
2- onset and severity can be exctracted by:
1.
- the level of accumulation of toxic metabolites
- deficiency of products
2.
- diet
- intercurrent illness
presentation of IEM:
1- disorders of carbs or metabolism and energy production tend to:
2- fatty acid oxidation, glycogen storage and lysosomal storage disorders tend to:
1.
- present in neonantal periods or early infancy
- to be unrelenting and rapidly progressive
- less severe variant usually present later
2- present in infancy or childhood with subtle neurological
or psychiatric features often undiagnosed until adulthood
the rationale for newborn screening allows for early — before clinical signs or symptoms and allows early diagnosis for early — which leads to better clinical —
it reduces — and premature —-
- the heel pick test at — old
- early detection
- treatment
- outcomes
- reduces morbidity or premature mortality
- 3-5 days
newborn screening in Ireland includes:
1- disorders for carb metabolism as:
2- amino acid disorders as:
3- disorders for fatty acids oxidation as:
4- organic acuduria as:
- galactosaemia
- PKU , maple syrup urine disease , homocystinuria
- MCADD
- glutamic acuduria type 1 ( GA1)
( info: we also screen for cystic fibrosis and congenital hypothyroidism even tho they are not IEM )
the 3 classification of IEMs:
1- disorder causing intoxication as — which leads to progressive accumaltion of toxic compounds
2- disorders of energy metabolism as — which are intermediary metabolism or symptoms due to part of energy deficiency
3- disorders involving complex molecules as ——- which involves cellular organelles including diseases associated w distributed synthesis or catabolism of complex molecules
1- PKU , MSUD , organic aciduris
2- mitochondrial or cytoplasmic defects
3- lysosomal storage disorders , perixomal disorders , intracellular trafficking disorders
1- disorders which give rise to intoxication:
- share clinical similarities as:
1- they don’t interfere w —– development
2- present after a —- interval
3- clinical signs of intocification may include:
- acute as:
- chronic as:
4- most are — with removal of —
- embryo- foetal development
- symptom-free
- vomit , coma , liver failure
- failure to thrive , developmental delay , ectopic lentil ( dislocation of lens )
- treatable
- toxin
disorders which gives rise to intoxification :
1-Amino acidopathies:
* Phenylketonuria, Maple Syrup Urine Disease, Homocystinuria, Tyrosinaemias
2-Organic acidurias:
* Methylmalonic aciduria, Propionic aciduria, Glutaric aciduria Type l
3-Urea cycle disorders
* Ornithine TransCarbamylase (OTC) deficiency, Citrullinaemia
4-Sugar intolerances
* Classical Galactosaemia, Hereditary Fructose Intolerance
5-Metal intoxication
* Wilson’s disease, Menkes disease, Haemochromatosis
6-Porphyrias
PKU: ( hyperphenalylanameia or phenletouria )
1- its a — disorder
2- incidence :
- 97% from — enzyme defect
- 3% due to defective synthesis of —-
3- diagnosis includes:
4- clinical symptoms if not detected ;
5- managemt:
- autosomal recessive
- phenylalanine hydroxylase enzyme defect
- the cofactor tetrahydrobiopterin
- new-born screen ( heel prick ) test or biochemical amino acid analysis
- symptoms include:
1– irritability, vomiting, seizures
2– irreversible brain damage by 4 - 6 months
3– reduced melanin production - pale skin, fair hair, blue eyes
4– frequently generalised eczema - managed by:
– Diet low in Phenylalanine; supplemented with Tyrosine
– Cofactor related form - Neurotransmitter supplementation
( check slide 16 , 17)
— is the deficiency in fumarylacetoacetate hydrolase and the biochemistry is when the accumulation of fumarly acetoacetate and its metabolites in urine particularly succinylcholine-aceton
Tyrosinaemia type I
symptoms include:
* Characteristic cabbage like odor
* Liver failure and renal tubular acidosis
treatment by:
* dietary restriction of Phe and Tyr
* Drug - nitisinone
( check slide 19 , 20 )
Alkaptonuria is characterised by — and the pigmentation phenotype is called — which is the pigment of ears and eyes
- arthritis associated with calcification of —
- dark urine
- ochronosis
- joints
maple syrup urine disease ( branched-chain ketoacid dehydrogenase )
1- the defect in the metabolism of — which is the deficiency in ——
2- biochemistry is —– which is elevated in —–
3- symptoms include:
4- treatment
- metabolism of leucine , isoleucine , and valine which is the deficiency in alpha keto acid dehyrodgenase
- alpha acids and their alpha ketone analogs which is elevated in urine and plasma
-symptoms:
1-normal first few days of life progressive lethargy, weight
loss, episodes of hypertonia & hypotonia.
2-Maple syrup odour to the urine.
Ketosis, coma and death if not treated. - treatment: Dietary restriction of branched chain amino acids
-Homocytinuria is a defect in — which leads to the accumaltion of —-
- methionine and metabolites elevated in —-
- leads to:
- cystathionine synthase
- homocysteine in urine
- in blood
- Cardiovascular disease, deep vein thrombosis, thromboembolism & stroke, brain damage, osteoporosis, dislocation of the lens
-Some IEMs “giving rise to intoxication” can be classified as —-
- which causes accumulation of organic acid in —–
- its a —-
- the organic acids are:
- organic acuduria
- blood and urine
- autosomal recessive
- include carboxylic acids, with or without keto, hydroxyl or other non-amino functional groups
- common features – water soluble, acids and ninhydrin stain negative (No N group)
- Derived from dietary protein, fat and carbohydrate
Glutaric acuduria type 1 ( GA1)
defect in:
biochemistry:
symptoms:
treatment:
1- metabolism of lysine, hydroxylysine & tryptophan (defieciency in glutaryl CoA dehydrogenase)
2- harmful organic acids accumulate
3- Dystonia, dyskinesia, excretion of glutaric and 3 hydroxy glutaric acids in urine, neuronal degeneration, seizures
untreated => brain damage & possibly death
4-Dietary restriction of protein ,
supplementation with carnitine
group 2: disorders involved in energy metabolism
1- diagnosis is often —-
2- common symptoms include:
3- the disorders include:
- difficult
- Hypoglycaemia, lactic acidaemia, hepatomegaly, severe hypotonia, myopathy, cardiomyopathy,
sudden unexpected death (SIDs) - disorders include:
- Mitochondrial defects:
- Congenital lactic acidaemias:
– Pyruvate dehydrogenase deficiency
– Pyruvate carboxylase deficiency
– TCA cycle enzyme deficiencies - Respiratory chain disorders
- Fatty Acid Oxidation and ketone body disorder
- Some mitochondrial disorders may interfere with embryo-foetal development
- Cytoplasmic defects:
- Glycolysis, Gluconeogenesis and Glycogen metabolism
—– is a disorder of fatty acid oxidation due to impaired break down medium-chain fatty acids into acetyl-CoA.
Medium-chain acyl-coenzyme A
dehydrogenase deficiency (MCADD)
1-symptoms of MCADD include:
2- intolerance to:
3- MCAD is responsible for the — step of fatty acids w chain lengths between 6 and 12 as they undergo beta oxidation in the mitochondria. the beta oxidation of long chain fatty acids produces —-
-Symptoms: hypoketotic hypoglycemia, liver dysfunction, SID, lethargy,seizures and coma.
- fasting
- dehydrogenation
- 2 carbon units , acetyl-coA , and the reducing equivelancts NADH and FADH2
- Defect in the acyl-coA dehydrogenase
- prevents FADH2 formation
- Prevents formation of subsequent reactions therefore
- Prevents formation of NADH+ H+
- And Actyl CoA
are all under —- and they leads to huge —- production
- MCADD
- loss of energy
-synthesis of glucose refers to —- and the substrates are —–
- specific enzymes are required to by pass the —– reactions in glycolysis
- glycogenesis
- substrates include:
1* Lactate (from anaerobic glycolysis)
2* Glycerol(from hydrolysis of triacylglycerols
in fasting state)
3* Amino acids - 3 irreversible reactions
disorders of glucogensis are associated w —-
hypoglycaemia
disorders of glucogenesis include:
1-Pyruvate carboxylase deficiency
* Presentation:
* Severe neonatal - seizures, coma, lactic acidosis, mild hypoglycaemia,
* Mild infantile – psychomotor impairment, mild lactic acidosis
* Diagnosis
* ↑ lactate, ketosis
2-Fructose-1,6-bisphosphatase deficiency
* Presentation:
* Acute onset with hepatomegaly,
* Hypoglycaemia, seizures, coma
* Diagnosis
* ↑ lactate, ketosis
3-PEP carboxykinase deficiency
* Extremely rare
—- is a maternal inheritance and only egg contribute mitochondrial to developing embryo so basically only mothers can pass it to offsprings
- if the mom has this condition – offsprings inherit it
- if the father has is – inherit it
- mitochondrial inheritance
- all
- none
