Download Inherited Metabolic Disorders

Enzymopathy – Inherited
Metabolic Disorders
RNDr. Hana Zoubková, PhD
Energy -228
substrate
Mutation in
nuclear DNA
Dysfunctional
enzyme, protein
product
Multi-organ failure
Mutation in
mitochondrial DNA
General characteristics
• Inherited metabolic disorders caused by enzyme
disorders
• hereditary type recessive – Heterozygotes Aa with 50% residual
activity of enzyme are clinically normal.
• diffused
versus macromolecular substrates –
Macromolecular s. are only in the tissue, where the substrate is accumulated.
• acumulation of substrate (1), deficit of product
(2) of origin of toxic substances, (3) or combination
General consequences
1. the accumulation of molecules proteins, enzyme,
which is not eliminated and excluded in the right
way
2. the absence of the protein molecules, enzyme or
other substances in the organism
3. the formation of by-substances (proteins,
enzymes, or other substances), which do not
belong to the body, and cause acute or slow
poisoning
General characteristics
• A single patient may have a loss of more than one
enzyme.
They share the same cofactor, a common activator, modifying or stabilizing
protein; may be missing a whole group of enzymes or the entire organelle
is abnormal.
• phenotype homology
Diseases are caused by other enzymes, but in the same area of metabolism.
The diseases are different, but arise in the partial or complete defect of one
enzyme.
• It does not concern catalytic RNAs.
General characteristics
• It is currently recognized more than 850 IMD.
Approximately 100 of them are curable or
controllable by diet.
• Low-protein, lactose free, gluten free diet
Every year is born around 1,000 children with IMD
in Czech republic
Inherited metabolic disorders
IMD aminoacids: Hyperphenylalaninemia, Tyrosinemia,
Alkaptonuria, Homocystinuria, Cystinuria, Cystinosis
Leucinosis - Organic aciduria (acidemia)
IMD saccharides: Galactosemia, Galactokinase deficiency,
Fruktose-intolerance, UDP-Galactose-4-epimerase
deficiency, Fructose 1,6-Diphosphatase deficiency,
glykogenosis
IMD purin/pyrmidin - Porfyria, disorders of urea cycle
IMD lysosoms - Tay-Sachs disease
peroxisoms, mitochondria
Tyrosinemia, new type
acid oxidase
Fumarylacetoacetate
hydrolase
block
Tyrosinemia, type I
Hyperphenylalaninemia
Is characterized by mildly or strongly elevated levels of the
aromatic amino acid phenylalanine in the blood.
Are caused by lossing mutations in gene for enzyme
phenylalanine hydroxylase (PAH) or in gene for cofactor.
Enzyme is necessary for metabolism of amino acid
phenylalanine (Phe) to the amino acid tyrosine.
Phenylketonuria - PKU
Variant PKU
Non-PKU
Phenylketonuria PKU
AA phenylalanine accumulates and is converted into
phenylpyruvate (phenylketone), which is detected in
the urine. It is toxic for the body and causes
mental retardation, light pigmentation. Main treatment
for classic PKU patients is a strict PHE-restricted diet.
chromosome 12q24.1, incidence 1:5 000 a 1:15 000
1:6 000 in Cz
Alelic heterogenity
- 400 alleles, 6 mutations in each of the 13 exons
Newborn screening od PKU
is included in the panel of most countries.
Treatment is the diet – it is effective, if it is
launched at birth.
Tyrosine
Tyrosinemia, new type
acid oxidase
Fumarylacetoacetate
hydrolase
block
Tyrosinemia, type I
Albinism classical, type IA.
• lack of product, pigment of
skin and hair, achromatosis
• lack or non-functional
tyrosinase
Tyrozinase negative
• Typ IB – tyrozinse is positive, non-
active
• Type II – frequent, tyrozinase positive
but with gene mutation
Alkaptonuria - AKU
the failure of metabolism of homogentisic acid,
Caused by lack of enzyme homogentisate 1,2dioxygenase, homogentisic acid oxidase (HGD),
Accumulation of substrate
Homogentisic acid is changed to brown-black pigment –
alkapton - excretion to the urine, accumulation in tissues ochronosis
incidence 1 : 250 000
Tyrosinemia type I
is caused by the failure of tyrosine metabolism, of
enzyme fumarylacetoacetate hydrolase (FAH).
Accumulation of tyrosine (substrate) and toxic
secondary metabolites, mainly for the liver and
kidneys
Incidence 1: 100 000-120 000
Tyrosinemia type II and III are rare and the level of toxic metabolite sukcinylaceton
is not so high. Treatment of alkaptonuria and tyrosinemia by diet and nitison.
Methionine
Cysteine
Degradation
of methionine
Homocystinuria
Methionine is metabolized to cysteine ​via
homocysteine.
Is caused by the lack of cystathionine β-synthase (CBS),
which causes the increased value of homocysteine ​and
methionine in the urine.
Accumulation of substrate is harmful for four organ
systems: the eye, skeleton, vascular endothelium
and central nervous system
Ectopia lensis,
excessive
height, length
of limbs,
vascular
abnormalities
Valine
Leucine
Isoleucine
Organic aciduria (acidemia)
The group of specific enzymes disorders in the catabolism of
branched amino acids leucin, valin and isoleucin.
Accumulation of toxic organic acids (by-products)
causes medium acidification of organism, especially
disability of brain.
Every year is born 10 patients with one of the organic aciduria
in Czech Republic
„Maple syrup urine disease - MSUD“
Or
Leucinosis
Is the failure of metabolism of branched-chain α-keto acids.
The failure of certain dehydrogenase in multienzyme
complex
Accumulation of keto-acids in the body, accumulation
of substrate causes food intolerance, failure to thrive,
vomiting, lethargy, and the smell of urine and earwax after
maple syrup.
1: 20 000-50 000, Mennonites – 1: 1000
Galactose
Galactosemia, classical
Is the failure of metabolism of monosaccharide
galactose (component of lactose).
Toxic by-products of metabolism are toxic to liver,
brain, kidneys and eye lens; cause malnutrition, cirrhosis
and mental retardation.
Galactose-1-phosphate uridyltransferase – GALT
(9.chromosome, 160 mutations)
1:18 000 to 1:70 000
Tay-Sachs disease
GM2–gangliosidosis
Is the failure of degradation of sfingolipid GM2 –
gangliosid. It is the hexosaminidase A (HEXA)
deficiency, which causes accumulation of substrate.
Substrate affects mainly the brain and causes degeneration of nerve
system.
Syndrome
- cherry-red spot on retina
increased incidence (1:3600) for ashkenazi Jewish population
(1:360 000, chromosome 15)
Porfyria
Caused by enzymes deficiencies operating in the
synthesis of heme. Defects of enzyme in the early
stage cause accumulation of substrate: acid 5aminolevulinic acid and porfobilinogen
Defects in the later stages lead to the accumulation of
porfyrinogens - accumulation of substrate and byproducts
Skin, liver damage
congenital erytropoetic porfyria
Nuclear and mitochondrial heredity
Mutated gene in nucleus
Mutated gene v mitochondria
Combination of maternal and
Genetic maternal information
paternal genetic information
of prokaryotic type
- chromosomes
Mendel‘s law
Maternal line
Disability throughout the body
Variable expression
Maternal mitochondrial heredity
Mitochondrial diseases
are a heterogeneous group with dysfunctions in
respiratory chain.
They are metabolic disorders and
neurodegenerative or muscle diseases.
Are caused by the lack of product.
Affection is multi-systematic, with exception of
LHON
Tissue with a high level of requirement of ATP (the brain, muscle, liver,
heart, kidney . . .) are affected.
Mutations in mtDNA
Variable expresivity typical for mitochondrial
disease - distribution to daughter cells is random,
distribution of mutated and normal mtDNA is
variable
Homoplasmy = only mutated or only normal
mtDNA in the cell
the mixture of normal and mutant mtDNA =
Heteroplasmy
Defect in mitochondrial respiratory chain
should be considered for patients, which have
any unexplainable combination of neuromuscular
and/or different symptoms,
with proceeding course and affecting seemingly
unrelated organs.
Munnich et al, OMMBD, chapter 99
Mitochondrial
encephalomyopathy
with
lactic
acidosis and stroke-like episodes (MELAS) -
brain
and nervous system (encephalo-) and muscles (myopathy), lactic
acid, muscle spasms, impaired muscle coordination (ataxia)
Leber hereditary optic neuropathy – LHON degeneration of retinal ganglion cells, acute or subacute loss of
central vision
MELAS,
Association with mutaion (A3243G)
mtDNA in gene for tRNA Leu (UUR).
Mutations in mtDNA
Mutations cca 10x more often then in nuclear DNA,
because histons and some reparation mechanisms
are absent.
Approximately 10% of all mitochondrial proteins are
encoded by nucleus. In case of mutations in these
genes - AR heredity
Some mitochondrial proteins are aggregates with
origin in nucleus and in mitochondria.
Thanks for attention
Literature
Thompson and Thompson: Clinical Genetics, 6. edition,
2004
Adkinson J R, Brown M.D.: Elsevier‘s Integrated
Genetics, 2007