Enzymopathy – Inherited

Metabolic Disorders

RNDr. Hana Zoubková, PhD

Energy -228

Mutation in nuclear DNA

Mutation in mitochondrial DNA

Dysfunctional enzyme, protein

substrate

product

Multi-organ failure

• 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 characteristics

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 consequences

• 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

General characteristics

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

Inherited metabolic disorders

acid oxidase

Tyrosinemia, new type

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

acid oxidase

Tyrosinemia, new type

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 1,2-

dioxygenase, 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

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.

Tyrosinemia type I

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 diseaseGM2–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)

Caused by enzymes deficiencies operating in the

synthesis of heme. Defects of enzyme in the early

stage cause accumulation of substrate: acid 5-

aminolevulinic acid and porfobilinogen

Defects in the later stages lead to the accumulation of

porfyrinogens - accumulation of substrate and by-

products

Skin, liver damage

congenital erytropoetic porfyria

Porfyria

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

Nuclear and mitochondrial heredity

Maternal mitochondrial heredity

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

LHONTissue with a high level of requirement of ATP (the brain, muscle,

liver, heart, kidney . . .) are affected.

Mitochondrial diseases

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

Mutations in mtDNA

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 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.

Mutations in mtDNA

Thanks for attention

Literature

Thompson and Thompson: Clinical Genetics, 6. edition, 2004

Adkinson J R, Brown M.D.: Elsevier‘s Integrated Genetics, 2007