Metabolic disorders

A metabolic disorder is a medical disorder which affects the production of energy within individual human (or animal) cells.

Most metabolic disorders are genetic, though a few are "acquired" as a result of diet, toxins, infections, etc. Genetic metabolic disorders are also known as inborn errors of metabolism.

The largest classes of metabolic disorders are:

- Disorders of carbohydrate metabolism - Disorders of amino acid metabolism

- Disorders of fatty acid oxidation and mitochondrial metabolism - Disorders of porphyrin metabolism

- Disorders of purine or pyrimidine metabolism - Disorders of steroid metabolism

- Disorders of mitochondrial function - Disorders of peroxisomal function

- Lysosomal storage disorders

Disorders of carbohydrate metabolism

Pyruvate metabolism and gluconeogenesis

-Glucose-P-isomerase deficiencyAnaemia, neurologic symptoms (musc. spasticity)

-Pyruvate kinase deficiencyhemolytic anaemia

-Pyruvate Dehydrogenase Deficiency (PDHA)It affects a gene which codes for a critical enzyme complex, the Pyruvate dehydrogenase complex (PDC)PDHA causes Lactic acidosis; large amounts of lactic acid in the blood but with a normal pyruvate/lactate ratio. Symptoms are varied, and include developmental defects (especially of the brain and nervous system), muscular spasticity and early death.

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system.Type A: Characteristic features include developmental delay and a buildup of lactic acid in the blood (lactic acidosis). Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. Children with pyruvate carboxylase deficiency type A typically survive only into early childhood.

Type B Pyruvate carboxylase deficiency type B has life-threatening signs and symptoms that become apparent shortly after birth. This form of the condition has been reported mostly in Europe, particularly France. Affected infants have severe lactic acidosis, a buildup of ammonia in the blood (hyperammonemia), and liver failure. They experience neurological problems including weak muscle tone (hypotonia), abnormal movements, seizures, and coma. Infants with this form of the condition usually survive for less than 3 months after birth.

Drug induced hemolytic anemia

Glucose 6-phosphatedehydrogenase deficiency

-inherited disease characterized by hemolytic anemia due to inability to detoxify oxidizing agents-most common disease-producing enzyme abnormality in humans (>200 million people worldwide, ~7%; ~2% of U.S. population)-X-linked deficiency caused by >300 different mutations in the G6PD gene-only some mutations cause clinical disease -life span of individuals with G6PD deficiency shortened somewhat due to complications of chronic hemolysis-G6PD deficiency has been maintained in the human gene pool by the evolutionary advantage of increased resistance to falciparum malaria in female carriers of the mutations in the tropics-geographic distribution (highest in tropical Africa, Asia, Middle East, Mediterranean and Papua New Guinea) follows sickle cell trait (also confers relative resistance to malaria)

Formation of HeinzBodies in Red Blood Cells- RBCs generate superoxide and other ROS during non-enzymatic oxidation of hemoglobin (Hb) to metHb by spontaneous transfer of an electron from the Fe2+ in Hb to bound O2- RBCs depend on G6PD for generatingNADPH to re-reduce glutathione toprotect against this oxidative stress- G6PD deficiency results in disulfide linked aggregates of Hb forming onthe red cell membrane- mechanical stress from lack ofdeformability in small capillaries andROS peroxidation of membrane lipids

Precipitating factors for G6PDdeficiency disease

Oxidant Drugs (A3):AAA= Antibiotics (e.g. sulfamethoxazole) , Antimalarials (e.g. primaquine), Antipyretics (acetanilid, not aspirin or acetominophen)Favism: Mediterranean variant is susceptible to hemolytic affects of ingesting fava bean purine glycosides (vicine and isouramil) which react with reduced glutathione, decreasing GSH levels

Infection: inflammatory response to infection results in the generation of free radicals (ROS) by macrophages and neutrophils; ROS can diffuse into RBCs and induce oxidative damage

Neonatal jaundice: results from impaired hepatic catabolism or increased production of bilirubin (heme degradation product from hemoglobin, myoglobin, cytochromes)

Classification of Glucose-6-phosphate

dehydrogenase deficiency

Common Hexoses

O

CH2OH

HH

OHOH

H

H

OH

H

OH

O

CH2OH

HOH

HOH

H

H

OH

H

OH

O

CH2OH

HH

OHOH

H

OH

H

H

OH

O

OH

CH2OH

HH

OH H

CH2OH

OH

a-D-Glucose a-D-Galactose a-D-Mannose

a-D-Fructose

• Sucrose (table sugar): glucose + fructose and• Lactose: (dairy products) glucose + galactose

Sucrose(Table Sugar)

OO

CH2OH

HHO

H

HOOH

H

H

OH

H HOCH2

H

OH H

H

CH2OHO

α-D-glucopyranosyl-(1→2)-β-D-fructofuranoside

Cleavage of Sucrose(α-glucosidase or invertase)

OO

CH2OH

HHO

H

HOOH

H

H

OH

H HOCH2

H

OH H

H

CH2OHO

H2O

OCH2OH

HH

HOOH

H

H

OH

H

OH

O

HO

HOCH2

H

OH H

H

CH2OHH

Glucose Fructose

Muscle Metabolism of Fructose(Anaerobic Glycolysis)

Muscle Hexokinase can accept fructose as a substrate

O

HO

HOCH2

H

OH H

CH2OH

OHH

ATP ADP

O

HO

POCH2

H

OH H

CH2OH

OHHHexokinase

-D-Fructose

Glycolysis

Fructose-6-P

Liver Metabolism of Fructose IGlucokinase, the liver isoform of hexokinase cannot

transform fructose

O

HO

HOCH2

H

OH H

CH2OH

OHH

ATP ADPO

HO

HOCH2

H

OH H

CH2OP

OHHFructokinase

-D-Fructose

(Committed Step)

Fructose-1-P

Liver Metabolism of Fructose II

CH2OPCCCCCH2OH

OHHOOHH

H OH

Glycolysis

CHOCHOHCH2OH

Glyceraldehyde

O

HO

HOCH2

H

OH H

CH2OP

OHH

DHAP

CH2OPCCH2OH

O

Fructose-1-P

Fructose-1-P Aldolase

Fructose Intolerance• Too Much Fructose

– Fructose-1-P Aldolase ( Aldolase B) is rate-limiting

– Depletion of Pi

– Reduction in [ATP]– Increase in glycolysis– Accumulation of lactate (acid) in blood

• Fructose-1-P Aldolase Deficiency (Genetic Disease)

+ Liver damage

Galactose Metabolism

Lactose Metabolism(Dairy Products)

Glycolysis

O

O

CH2OH

HHO

HOH

H

H

OH

H

O

CH2OH

H

OH

H

H

OH

H

OH

O

CH2OH

HHO

HOH

H

H

OH

OH

H

Lactose

Glucose

-D-Galactose

-Galactosidase

Glycolytic Enzymes are specific and do not recognize galactose!

Need Epimerization

OCH2OH

HHO

HOH

H

H

OH

H

OH

OCH2OH

HH

HOOH

H

H

OH

H

OH

GlucoseGalactose

Epimerization

Phosphorylation of Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

OH

ATP ADPO

CH2OH

HOH

HOH

H

H

OH

H

OPO3=Galactokinase

Galactose Galactose-1-P

Activation of Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

OPO3=

O

CH2OH

HH

OHOH

H

H

OH

H

O P O

O

O–

P O

O–

O

Uridine

O

CH2OH

HOH

HOH

H

H

OH

H

O P O

O

O–

P O

O–

O

Uridine

UMP

Galactose-1-P

Galactose-1-PUridylyl Transferase

UDP-Glucose

Glucose-1-P

UDP-Galactose

Glucose-6-P

Phosphoglucomutase

Glycolysis

Epimerization of UDP-Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

O P UMP

O

O–

[NAD+]O

CH2OH

HH

OHOH

H

H

OH

H

O P UMP

O

O–

UDP-Galactose-4-Epimerase

UDP-GlucoseUDP-Galactose

Lactose intolerance (or hypolactasia) is the term used to describe a decline in the level of lactase, an enzyme needed for proper metabolization of lactose (a sugar that is a constituent of milk and other dairy products), in human beings.Lactose intolerance in varying degrees is physiologically normal in adult mammals, including many human beings. However, certain ethnic groups - particularly those of European descent - continue to produce lactase throughout their lives.

Without lactase, the lactose in milk and dairy remains uncleaved and unabsorbed. Lactose cannot pass easily through the intestinal wall into the bloodstream, so it remains in the intestines. Soon, enteral bacteria adapt to the relative abundance of lactose (relative to other usable sugars like glucose) and their operons quickly switch over to lactose metabolism. Along the way they produce copious amounts of gas by fermentation.The gas causes a range of unpleasant abdominal symptoms, including stomach cramps, bloating, flatulence and diarrhea. Like other unabsorbed sugars, e.g. mannitol, the lactose raises the osmotic pressure of the colon contents, preventing the colon from reabsorbing water and hence causing a laxative effect to add to the excessive gas production.

Galactosemia(Mental Retardation and Death)

Treatment

Galactose-free diet

(reversal of all symptoms except mental retardation)

Cataracts

C

C

C

OHH

OH

HHO

C HHO

C OHH

CH2OH

CH2OH

C

C

OHH

HHO

C HHO

C OHH

CH2OH

NAD(P)H NAD(P)+

Galactose Galactitol

Glycogen storage disease (synonyms: glycogenosis, dextrinosis) is any one of several inborn errors of metabolism that result from enzyme defects that affect the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types.TypesThere are nine diseases that are commonly considered to be glycogen storage diseases. (Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs as type 0 because it is another defect of glycogen storage and can cause similar problems.)

Type 0

Type I

Type II

Glycogen Storage Diseases

Type IV

Type VII

Glycogen Storage 1: von Gierke disease

Accumulation of glycogen in liver and kidney => hepatomegaly

HypoglycemiaEnzyme deficiency: Glucose 6 phosphataseAccumulation: Glycogen

Pompe Disease

Infantile onset < 12 months Late onset > 12 months

Head lag

Enlarged tongue

Respiratoryinsufficiency

Delayed motordevelopment

Muscle weakness

Organomegaly

Cardiomegaly/cardiomyopathy

Morning headacheDaytime somnolence

Shortness of breath/sleep apnea

Scapular winging

Scoliosis

Low back pain

Muscle weakness

Signs &SymptomsSigns &

Symptoms

Hirschhorn R, Reuser AJJ. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3389-3420.

Respiratoryinsufficiency

Gait abnormality

Glycogen storage 2: Pompe disease

cardiomegaly

Death before age 3 of cardiorespiratory failure

Muscle hypotonia

Splenomegaly

Intractable Hypoglycemia

Enzyme deficiency: alpha-1,4 glucosidaseAccumulation: Glycogen

Pompe Disease

CardiomegalyEnlarged tongue/ lax facial features

Hypotonia/head lag/ floppy baby

Signs &SymptomsSigns &

Symptoms

Courtesy of R. R. Howell, MD.Data on file, Genzyme Corporation.

Pompe Disease Signs &SymptomsSigns &

Symptoms

Weak pelvic girdle muscles

Lordosis / Scoliosis

Pompe Disease is autosomal recessive:

FatherCarrier

MotherCarrier

AffectedIndividual

(25%)

UnaffectedCarriers(50%)

UnaffectedNoncarrier

(25%)

1 2 3 4

Inheritance

Unaffected(75%)

Glycogen Storage 3: Cori Disease

Stunted growth

Glycogen in liver -> Hepatomegaly

hypoglycemia

Glycogen accum in heart

Glycogen in skeletal muscle

Enzyme deficiency: Amylo-1,6-glucosidaseAccumulation: Glycogen

Case Description

A female baby was delivered normally after an uncomplicated pregnancy. At the time of the infant’s second immunization, she became fussy and was seen by a pediatrician, where examination revealed an enlarged liver. The baby was referred to a gastroenterologist and later diagnosed to have Glycogen Storage Disease Type IIIB

Glycogen Storage DiseaseType IIIb

• Deficiency of debranching enzyme in the liver needed to completely break down glycogen to glucose

• Hepatomegaly and hepatic symptoms

– Usually subside with age

• Hypoglycemia, hyperlipidemia, and elevated liver transaminases occur in children

Glycogen Storage 4: McArdle Syndrome

Muscle cramps and weakness after exercise

Enzyme deficiency: Muscle phosphorylaseAccumulation: Glycogen

Disorders of amino acid metabolism

Phenylketonuria (PKU)

Phenylalanin hydroxylase (PAH) defected

12. chromosome, >400 diff. mutations

(autosomal recessive disorder)

Symptoms: Without treatment severe mental retardation (very low IQ)

epilepsy

hypopoigmentation: blond, blue eyes

Eczema

Types of PKU 1./ Classical PKU : Phe level in the blood > 10mg%- life-long

treatment

2./ Non PKU hyperfenylalaninaemia: Blood Phe 2-10mg %: not so strict diet

3./ Atypical PKU, PAH-cofactor tetrahydrobiopterin, (BH4) def: retardation during pregnancy, early symptoms, fever, spasticity, mental and developmental retardation. Th: BH4 , diet not enough, serotonin, dopamin supplementation

Without phenylalanine hydroxylase PHE→Tyr not occur Tyr deficiency may lead to hypopigmentationHigh Phe can cause neurologic damage

Newborn screening

Important- early diagnosis and treatment of affected infants resuling in normal growth and development! Since 1965!

At 5. day or after feeding

Method: GUTHRIE test: Bacillus Subtilis grows only Phe containing broth.

Guthrie test

Urine test (Ferri III-chloride)

Diet in PKU Protein: 60 – 80 % - low protein content - fruits, vegetables Phe level: 4 – 8 mg %. NO: milk – diary products, meat, fish, egg, bean, chocolate starch (potato, kukorica)Vitamins, nyomelemChalories: ~ 35 % fat, ~ 15 % tápszer0 50 %

CHO Anyatej: csak lefejve, 100-300 ml/nap, ellenőrizve

phenylalanin szintetSzoptatás= ellenőrizetlen mennyiség bevitel

PKU gyermek, diétán egészséges

Fenilalanin szegény étrend időtartama: korábban 10-12 éves korig, ma tudjuk, egész életre szólóan ajánlott

KÖTELEZŐ: PKU-s felnőtt egykori gondozott a várandósság Teljes ideje alatt: az esetleg egészséges magzatot is károsítja az anyai magasabb fenilalanin!!

Albinism

Albinism

Formation of little or no skin pigment

Classical defect is tyrosinase (tyrosine hydroxylase)

Autosomal recessive

1: 20000

Albinism

Light hair and skin

UV light (esp. 280-320 nm)

Increased light sensitivity

Increased risk for skin cancer

Normal growth and development

Alkaptonuria•Autosomal recessive

•Lack of homogentisate oxidase

•Increased homogentisic acid

Alcaptonuria

Symptoms:• Homogentisate appears in the urine deposited in cartilage-

inflammation in arth• Black dots on cornea• Kidney

• Polymerized homogentisate on the skin=Ochronosis

Ocular ochronosis in alkaptonuric patient

Polymerized homogentisate in ear cartilage

Typical alkaptonuric position

MAPLE SYRUP URINE DISEASE

Most common BCAA disorder (1/185,000)

Defective branched-chain ketoacid dehydrogenase

Similar to PDH with 3 enzyme activities

Thiamine deficiency can produce same result

Keto acids that accumulate smell like burn maple syrup

BCAA also accumulate

Mental retardation

Untreated leads to death

Lipid anyagcsere betegségekLipid/Lizoszómális tárolási betegségek

Definicíó:

öröklött anyagcsere betegség, amelyben a lipidek bizonyos szövetekben, sejtekben kóros mértékben felszaporodnak. A betegeknek vagy nincs egy bizonyos enzimből elegendő mennyiség, vagy olyan enzimet termelnek, ami nem működik megfelelően. Hosszú idő alatt a nagy mennyiségben tárolt lipidek károsodásokat okoznak, főleg az agyban, perifériás ideg rendszerben, májban, lépben, csontvelőben.

Lipidek:

Zsírszerű anyagok, amelyek fontosak a sejtmembránok felépítésében és a myelint burkolják, így védik az idegeket. A sejtek lizoszómákban tárolják őket, és ha szükséges energia forrásként használjuk őket. Ezért lizoszómális tárolási betegségnek is nevezzük őket. A lipid tárolási zavarokon kívül léteznek még mucolipoidosisok (nagy mennyiségű cukor és lipid halmozódik fel), valamint mucopolysaccharidosisok (cukor halmozódik fel).

Lipid tárolási betegségek II.

Tipusai:

•Szfingolipid tárolási bet./Gangliozidozisok: -GM1 gangliozidozis

-GM2 gangliozidozis:

-Tay-Sachs

-Sandhoff

•Gaucher

•Niemann-Pick

•Fabry•Farber•Krabbé

Szfingolipid

GM1 gangliozidozis

β-galaktozidáz hiánya: β-galaktozidból→ monoszacharid

A perifériás, de főleg a központi idegrendszer sejtjei abnormális mennyiségben raktároznaklipideket. Szubsztrátjai közé tartozik: GM1 gangliozid, laktóz, különböző glikoproteinek.

Megjelenési formái és tünetei:

Korai infantilis: süketség, vakság, tüdőgyulladásKésői infantilis: dementia, beszéd zavarFelnőttkori: dystonia

GM2 gangliozidozis:Tay-Sachs, Sandhoff

Tay-Sachs:

Β-hexózaminidáz-A hiány: gangliozidokat bont, a lizoszómákban (főleg neuronok) található

A GM2 gangliozid lebontásához 3 fehérje kell, ebből 2 a hexóaminidáz alegységea 3. kofaktora az enzimnek: GM2 aktivátor protein (glikolipid transzport fehérje).Ha a 3 fehérjéből valamelyik nem működik vagy nincs elegendő mennyiségben→tárolási betegség.Tay-Sachs: ált. az enzim foldingja nem megfelelő, így nincs intracelluláris transzport Megjelenési formák és tünetek:

Infantilis: süketség, vakság, nyelési képtelenség, atrófia

Serdülőkori: dysarthria, dysphagia, spasticitás, ataxia

Felnőttkori: schizofrénia, pszichózis, bénulás

Szűrés vérből!

GM2 gangliozidozis II.

Sandhoff-betegség:

β-Hexózaminidáz-B hiány: agy és gerincvelői neuronokat progresszíven pusztítja

Tünetek:

Mentális retardáció, bénulás, cseresznye piros folt a retinán, (organomegalia)

Gaucher-betegség I.

A lizoszómális glucocerebrosidase(=β-glucosidáz) hiánya

Glukocerebrozid(=glucosylceramide) lebontása zavart (vörös és fehérvérsejtekmembránjának alkotója)

A macrophagok nem tudják ezeket a sejteket teljesen lebontani→glucocerebrozid felhalmozódik→Gaucher-sejt: fénymikroszkóp alatt „felgyűrt-papír”-ra emlékeztetnek

Az idegrendszerben szintén felhalmozódik a glucocerebrozid a lipidekkel együtt

Parkinson-kór, non-Hodgkin-lymphoma,Melanoma, pancreas tumor gyakoribb

Glucocerebrosidase

Gaucher-betegség II.

Tipusai:I. Tipus (=non-neuropathias): Askhenazi zsidók, késői gyerekkor vagy korai felnőttkor, élettartamot kissé csökkenti

II. Tipus: Neurológiai problémák már csecsemőkorban

III. Tipus: Svédország egyik régiójában gyakori

Tünetek:

Hepatomegalia, splenomegalia: -ott destrukciója a vvt, fvst, vérlemezkék →infekció, vérzés hajlam, anaemiaSCsontléziók (fájdalmas), osteoporosis, femur defomációja, nyirokcsomó duzzanat, sárgás-barnás árnyalata a bőrnek, sárga pigmentició a szemben

Neurológiai: II. tipus: görcsök, mentális retardáció, hypertonia III. tipus: görcsök, dementia, szemozgató izmok bénulása

Niemann-Pick-betegség I.

• Condition involving the breakdown and use of fats and cholesterol in the body

• Harmful amounts of lipids accumulate in the spleen, liver, lungs, bone marrow, and brain

• Autosomal recessive pattern of inheritance (two copies of the gene must be present)

• Four variants: A, B, C1, and C2• Clinical feature include: severe liver disease, breathing

difficulties, developmental delay, seizures, increased muscle tone, lack of coordination, problems feeding, and inability to move eyes vertically.

• No treatment

Variants• Types A and B: mutated SMPD1 gene

– SMPD gene carries instructions for cells to produce, sphingomyelinase, which processes lipids.

– Mutations lead to deficiency of sphingomyelinase and accumulations of cholesterol and lipids.

• Types C1 and C2: mutated NCP1 or NCP2 gene– NCP1 gene produces a protein involved in the

movement of cholesterol and lipids within a cell.– May be a cholesterol pump, which is why its mutation

leads to the buildup of lipids and cholesterol in the cell membrane.

– Plays a critical role in regulation of intracellular cholesterol trafficking

– NCP2 gene produces protein that binds and transports cholesterol (not fully understood).

1990. Az akkor 4 éves Ashanti DeSilva, aki génhiba miatt Súlyos Kombinált Immunhiányos Szindrómában (SCID) szenvedett.A hibátlan gént vírus segítségével juttatták a szervezetébe, és azóta tünetmentes.

Az USA-ban jelenleg 200 génterápiás kezelést folytatnak klinikai kipróbálás céljából

A génterápia diadala

1998 September 17 Jesse Gelsinger.

és kudarca (egyben géndopping veszélye)

18.-ként meghalt vírus allergia következtében, előtte 17-en meggyógyultak