Disorders of amino acid metabolism

http://plantandsoil.unl.edu/croptechnology2005/UserFiles/Image/siteImages/AminoAcidLG.gif

General comments on AA metabolis Urea cycle disorders Disorders of aromatic AA metabolism Disorders of branched chain AA metabolism Disorders of sulfur metabolism Other disorders of AA metabolism

~ 400 g

http://uk.geocities.com/[email protected]/images/proteinoverview.png

Energy stores Energy store

amount tissue (g)

Glycogen

liver

Glycogen

muscle

Glucose

blood

Triacylglycerols

fat

Proteins

muscle

energy (kj)

(kcal)

70

1176

280

120

2016

480

20

336

80

15 000

567 000

135 000

6000

100 800

24 000

http://www.studentconsult.com/content/default.cfm?ISBN=9780323053716

http://www.mmi.mcgill.ca/mmimediasampler2002/images/Cianflone-60no5.gif

http://www.natuurlijkerwijs.com/english/b5e55bf0.gif

Protein requirements

Protein intake

https://astrobiology.nasa.gov/media/medialibrary/2014/03/iGen3_06-01_FigureLsmc.jpg

Aminoacidopathies-most common mechanisms Accumulation of AA  Ammonia accumulation  Carbon skeleton accumulationsorganic acids  Product deficiency 

http://www.si.mahidol.ac.th/department/Biochemistry/home/md/images/Aa%20met%201.jpg

http://www.ucl.ac.uk/~ucbcdab/urea/images/deamination.png

Urea cycle disorders

https://astrobiology.nasa.gov/media/medialibrary/2014/03/iGen3_06-01_FigureLsmc.jpg

Ammonia    

amonnia cationt normal level 50-70 µmol/l somnolence above cca 150 µmol/l coma above 300-400 µmol/l

Hyperammonemia is medical emergency

Urinary nitrogen excretion Metabolite

g 24 h*

% total

Urea

30

86

Ammonia ion

0.7

2.8

Creatinine

1.0-1.8

4-5

Uric acid

0.5-1.0

2-3

http://www.studentconsult.com/content/default.cfm?ISBN=9780323053716

UCD- frequency

OTC-clinical variability

Scylla and Charibda

http://images.rxlist.com/images/rxlist/ammonul2.gif

https://astrobiology.nasa.gov/media/medialibrary/2014/03/iGen3_06-01_FigureLsmc.jpg

Disturbances of carbon skeleton catabolism

https://astrobiology.nasa.gov/media/medialibrary/2014/03/iGen3_06-01_FigureLsmc.jpg

Organic acidurias    

 

Several dozens of small molecule disorders Common feature: increased excretion of carboxylic acids in urine Origin of OA: usually degradation of AA carbon moieties Usually acute manifestation, intoxication type of manifestation Intermittent course frequent Typically metabolic acidosis (and hyperamonemia)

Disorders of aromatic amino acid metabolism

PAH

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

PAH

Phenylketonuria

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

Untreated HPA/PKU 



  



CZ 1:6,500, Turkey 1:3,000, very rare Finland, N Europe 1:15,000 1-2% HPA secondary due to primary pterine defectsl 30% patients BH4 sensitive newborn screening untreated HPA- mental retardation, typical mouse odour, light complexions, eczema, epilepsy maternal HPA-VCC, microcephaly a PMR

http://www.dshs.state.tx.us/newborn/images/PKU_untreated.jpg

Classical dietary treatment of PKU

Prof.Horst Bickel

http://www.pkux.co.uk/wp-content/uploads/2009/05/horst-bickel-pku-diet.jpg http://www.milupa-metabolics.com/produkte.php?sourceId=162&sysId=139

Dyfsunkce enzymu při nedostatku kofaktoru

Těžké mutace PAH

Lehké mutace PAH

Deficit BH4

zátěžový test s BH4

http://www.rxlist.com/kuvan-drug/clinical-pharmacology.htm

PKU- 3rd d

PKU- 12the mo http://www.pahdb.mcgill.ca/images/pku.gif&imgrefurl

PAH

Tyrosinemia 2

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

Tyrosine

http://meded.ucsd.edu/isp/1994/im-quiz/images/tyrosine.jpg http://minimalpotential.files.wordpress.com/2007/11/730px-l-tyrosine-skeletal.png

Tyrosinemia type 2

hyperkeratossi

herpetiformic keratitis

http://www.ijo.in/articles/2007/55/1/images/IndianJOphthalmol_2007_55_1_57_29497_2.jpg http://208.96.47.3/images/community/dermatlas/Tyrosinemia_type_2_2_041213.png

Tyrosinemia type 2   





very rare herpetiformic keratitis palmoplantar hyperkeratoses with ulcers PMR, growth retardation dietary tretament

PAH

Alkaptonuria

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif



Harwa, 1500 př.n.l. http://bjo.bmj.com/content/vol83/issue6/images/large/98532.f1.jpeg http://www.scielo.br/img/revistas/rbr/v46n5/a14fig02.jpg http://www.mja.com.au/public/issues/184_12_190606/sha20286_fm-1b.jpg

Coxarthrosis Valvular involvement Urolithiasis

Alkaptonuria treatment-artifical block above the enzyme block nitison (NTBC)

? what are the possible therapy complications? http://www.natuurlijkerwijs.com/english/b4f4ca00.gif

PAH

Tyrosinemia 1

http://www.chemie.fu-berlin.de/chemistry/bio/aminoacid/gif/phe.gif

Tyrosinemia type I   

  

Fumarylacetoacetase deficiency Acute manifestation in infancy Hepatorenal involvement with acute hepatic dysfunction and Fanconi syndrome porfyric crises-abdominal cramps Chronic- ci heatis and ca in cirhosim Diet, nitisone, liver transplant

Tyrosinemia type I

Alkaptonuria a tyrosinemia 1 treatment nitison (NTBC)

http://www.natuurlijkerwijs.com/english/b4f4ca00.gif

Disorders of branched chain amino acids

BCAA

http://www.agron.iastate.edu/courses/Agron317/Images/Branched_chain_aa.jpg

How To Achieve A Positive Nitrogen Balance And Why You Care By Fitness Atlantic Writer: Mike Westerdal

http://www.fitnessatlantic.com/how_achieve_nitrogen_balance.htm

MSUD 

   

http://losyoruguas.com/archivos/0686.gif

Peracute presentation in newborns, intermittent variants Coma, dystoniaboxing, cycling maple syrup odour acute crisis prevention and management long term treatmentdiet

Psychomotor development-MSUD

Isovaleric aciduria

http://images.google.com/imgres?imgurl=http://www.ivasupport.org/images/

Isovaleric aciduria     



IVA-CoA DH deficiency Peracute/intermittent course Coma with acidosis/ketonuria, sweaty feet odour Acute crisis-elimination Long term-diet, karnitine, glycine Newborn screening

http://www.arxmanstyle.com/wp-content/uploads/2009/01/sweaty-feet.jpg

http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi

Propionic acidemia 

 



http://www.uchsc.edu/cbs/images/fig2.JPG

newborn variant: episodes of ketoacidosis/hyperammonemia, coma, pancytopenia milder froms-repeated encefalopathic crises,FTT chronic problems: FTT, infections, variable CNS involvement therapy: IMTV restriction, gut sterilization, biotin in some patients, aggresive treatment of crises, gastrostomy,liver transplant

http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi

Methylmalonic acidemia 

 



newborn variant: acute crisis with ketoacidosis, hyperammonemia and coma milder forms-repeated encephalopatic episodes chronic problems: nephropathy progressing in renal failure, variable CNS involvement (pacin picture partially deaf and mute), infections Candida sp. treatment: IMTV restriction, gut sterilization, in some pateints B12, aggresivní treatment of acute episodes

http://images.google.com/imgres?imgurl=http://www.toby-churchill.com/files/images/lynn5.jpg

Vitamin B12 •complicated synthesis •exogenous intake needed •implied in only 2 reactions •nutritional or endogenous deficiency is common •pregnancy and lactation •advanced age •GIT disorders •long latent course •anemia •demyelinization •psychiatric manifestation •treatment efficient and cheap

http://www.health-spy.com/hydroxob12.png

Resorpce kobalaminu

Metylmalonic and propionic aciduria 1: 50 000

Manoli et Venditti, 2010

Disorders of sulfur amino acid metabolism

Methionine cycle Ser

Gly

Methionine THF DMG S-AdoMet

MG

Methylene-THF Betaine S-AdoHcy Methyl-THF

Homocysteine Cystathionine

H2S

Cysteine

L-gamma-glutamylcysteine

Cysteinesulfinate Glutathione Hypotaurine Taurine

2SO3

SO24

CysGly

Remethylation Ser

Gly

Methionine THF DMG S-AdoMet

MG

Methylene-THF Betaine S-AdoHcy Methyl-THF

Homocysteine Cystathionine

H2S

Cysteine

L-gamma-glutamylcysteine

Cysteinesulfinate Glutathione Hypotaurine Taurine

2SO3

SO24

CysGly

Transsulfuration Ser

Gly

Methionine THF DMG S-AdoMet

MG

Methylene-THF Betaine S-AdoHcy Methyl-THF

Homocysteine Cystathionine

H2S

Cysteine

L-gamma-glutamylcysteine

Cysteinesulfinate Glutathione Hypotaurine Taurine

2SO3

SO24

CysGly

Vitamins and Hcy metabolism Ser

Gly

Methionine THF DMG S-AdoMet

MG

Methylene-THF Betaine S-AdoHcy Methyl-THF

Homocysteine Cystathionine

H2S

Folates B12

Cysteine

L-gamma-glutamylcysteine

Cysteinesulfinate Glutathione

B2

Hypotaurine

B6

Taurine

2SO3

SO24

CysGly

CBS deficiency • frequency 1:6.000-1:900.000 • classical and mild forms • clinical triade •Connective tissue: marfanoid features, kyfoskoliosis, osteoporosis, lens luxation •hemokoagulation: thromboses •CNS: cognitive impairment, seizures

16 y-oral contraceptives Headache, thrombosis of sagital sinus

tHcy 256 mol/l (50 small molecule diseases  Mechanisms: varying toxicity of metabolites 

Subgroup organic acidurias  Subgroup haperammonemias 

Variable clinical symptoms/signs  Diagnosis-special biochemical tests  Therapy generallly possible and efficient  Prenatal testing possible 