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CREDIT SEMINAR
THERAPEUTIC FAILURE OF PHENYLKETONURIA
Name:Simranjit kaur
Regd.no. : CUPB/Msc./SELST/GDMM/2014-15/01
Course : Msc. Genetic Diseases and Molecular Medicines
WHAT IS PHENYLKETONURIA(PKU)?
Autosomal recessive disorder
 High level of Phenylalaine
 Defect in PAH gene
 Deficiency of PAH enzyme
 Deficiency of co-factor BH4

(Source: National institute of child health and human
development).
TYPES
On basis of level of Phenylalanine in blood:
Hyperphenylalanemia
Mild
PKU
Moderate
Svere
or variant PKU
or classic PKU
MECHANISM
Source: mrjvilla.pbworks.com
HISTORY
Discovered by Dr.Asbjorn
Folling(1888-1973) in 1934.
 Named it “Imbecillitas
phenylpyruvica”
Later “PHENYLKETONURIA”.
Got 1st Joseph P Kennedy
International Award (1962).
PKU is first genetic disorder known to
cause mental retardation.

sylviasynyu.blogspot.com
WHERE IS PAH GENE PRESENT?
Present at chromosome no. 12.
 Gene cytogenetic band 12q22-q23.2.
 Size is : 121,256 bp.

Figure showing PAH gene location
Source;https://www.google.co.in/search?q=PAH+gene+image&es_sm=93&source=lnms&tbm=isch&sa=X&ei=UZY5VPf
6DNCAuwTMrIHgCw&ved=0CAgQ_AUoAQ
CHARACTERISTICS
PHENOTYPIC
Blackening
of urine
Intellectual disability or mental retardation
Small head size called microcephaly
Musty odour in urine, breath and skin
Fair skin and blue eyes (albinism)
Seizures, shaking in arms and legs
Slow and stunned growth
Skin rashes
PHENYLALANINE GENETICS
PKU is genetic disorder inherited form parents by off springs
Mother
Father
P
p
Mother
Father
P
p
P
PP
Pp
p
Pp
pp
p
Pp
pp
p
Pp
pp
Cross b/w both affected parents
Mother
Father
p
p
P
Pp
Pp
P
Pp
Pp
Cross b/w affected and unaffected
parents
en.wikipedia.org
Cross b/w affected and carrier parents
Mother
Father
P
p
P
PP
Pp
P
PP
Pp
Cross b/w carrier and unaffected
parents
TREATMENT OF PKU
Various therapies:
 Nutrition or Diet restricted therapy
 BH4 therapy
 Enzyme substitution therapy
 Glycomacropeptide
 New born screeing
 PAH deficiency treatment in pregnancy
 Genetic counselling
NUTRITION OT DIET RESTRICTED THERAPY
Used to normalise blood phe level.
 Low phe diet (120-360 umol/L).
should be started as soon as.
 Diet should include nutrition and other
essential aminoacids for development
 Medical formula should be used (LOFENALAC 1st
FDA approved).
CONT..
It also involves
Diet management of:
 Infants
 Children
 Adults
Limitations
 Deficiency of essential aminoacids and other
nutrients.
 Deficiency of Ca and vitamin B12.
 Neuropsychological problems arises.
MEDICAL FORMULA
Source: http://www.google.com/patents/EP0675689A4?cl=en
BH4 (TETRAHYDROBIOPTERIN) THERAPY
 Vitamin
like susbtance acts as co-factor for PAH
enzyme (1999).
Mechanism :
Phenylalaninehydrolase (PAH)
Phenylalanine
Tetrahydrobiopterin
Tyrosine
Dihydrobiopterin
BH4 SYNTHESIS
Guanosine triphosphate
GTP cyclohydrolase
Dihydroneopterin
triphosphate
6-Pyruvoyl tetrahydropterin
Pyruvoyl
tetrahydropterin (PTP)
Sepiapterin reductase
PTP reductase
Sepiapterin
Lactoyltetrahydropterin
Tetrahydrobiopterin
(BH4)
CONT..
Symptoms
 Siezures
 Mental ratardation
Necessity
 For the functioning of PAH enzyme.
Advantages
 Effective than nutrition therapy
 Useful for mild PKU
Limitation
 Very costly
ENZYME SUBSTITUTION THERAPY
Began in 2009 with biomartin clinical trials.
Involves replacement with:
 PAH enzyme.
 PAL enzyme.
Mechanism of PAH enzyme
Source:http://www.nature.com/mt/journal/v10/n2/fig_tab/mt20041219f1.html#figure-title

Mechanism of PAL enzyme
Source:http://www.nature.com/mt/journal/v10/n2/fig_tab/mt20041219f1.html#figure-title
Difficulties :
Orally taken get degraded .
If injected increases immunogenecity.

TO OVER COME DIFFICULTIES
Polyethylene glycol derivatization(PEGylation)
technique is used
 It prevents degradation by enzymes.
 Also from increased immunogenecity.
CONT..
Advantages
 No need for co-factor
 More stable
 More effective and economically good.
Disadvantages
 Clinical trials under investigation.
NEW BORN SCREENING: A THERAPY
Began by Dr.Robert Guthrie (1990).
 Guthrie test is required for blood testing.






Advantages
Prevents mental retardation in children.
Control over mild and hyperalanimia PKU.
Limitations
Effective but requirement of permanent cure.
PAH DEFICIENCY TREATMENT IN PREGNANCY
Woman having PKU disorder must consult doctor
before conception. She must check her blood
PHE level before conception.
If not cared causes
 CHD diseases.
 Microcephaly
 Mental retardation.
 Intrauterine and postal growth retardation
in infants.
GENETIC COUNSELLING
Becomes easy to treat PKU in family .
 Molecular genetic testing of PAH gene is
possible now.
 After birth treatment is also necessary.

CURRENT THERAPIES UNDER INVESTIGATION
Gene therapy
 Somatic gene therapy
 Induced pluripotent stem cells

GENETIC COUNSELLING
 Molecular
genetic testing.
 Determination of genetic risk.
 Clarification of carrier status.
 Prenatal testing before pregnancy.
PREGNANT WOMEN TREATMENT
Women with PAH deficiency should start a pherestricted diet before conception.
 During pregnancy proper nutrition guidance is
must .

DRUGS FOR PKU
KUVAN:
Also called sapropterin, a synthetic form of BH4.
First FDA approved drug for PKU.
Mechanism

Tyrosine
Phenylalanine
PAH enzyme + BH4
Kuvan
CONT...
LNAA transporters:
 Used as drus as blood brain barrier.
Limitations
 Proves effective for individual alreay having
long term PKU
 Still need clinical trails.
Source: www.pku.com
LATEST UPDATE
CONCLUSION





Therapies are available for PKU but still needs more
investigation.
New born screening and pregnancy treatment proves effective
for children.
Drugs also available but still has major side effects.
Current therapies under investigation holds promise for future
betterment in curation of PKU.
Genetic counselling proves very effective for families having
PKU disorder.
FUTURE PERSPECTIVE
Need of multiple treatment options.
 Individualized treatment.
 Gene therapy and pluripotent stem cell therapy
may prove better in future and studies are
under investigation for them.

MY HYPOTHESIS
REFRENCES
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Arnaud, C.H. (2014). Aptamers recognize small –molecule
targets. Biological SCENE (in press).
Eisensmith, R.C., Woo, S.L.C. (1994). Gene therapy for
phenylketonuria. Acta. Paediatr. Suppl. 407: 124-9.
Eisensmith, R.C., Woo, S.L.C. (1996).Somatic gene therapy for
phenylketonuria and other hepatic deficiencies.Journal of
Inherited Metabolic Disease 19: 412-423.
Giovannini, M., Verduci, E., Salvatici, E., Paci, S., Riva, E.
(2012). Phenylketonuria: nutritional advances and challenges.
Nutrition and Metabolism9(7): 1743-7075.
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Hou, P., Li, Y., Zhang, X., Liu, C., Guan, J., Li, H., Zhao, T., Ye, J.,
Yang, W., Liu, K., Ge, J., Xu, J., Zhang, Q., Zhao, Y., Deng, H.
(2013). Pluripotent stem cells induced from mouse somatic
cells by small molecule compounds.Science341 (6146): 651654.
Kim, W., Erlandsen, H., Surendran, S., Stevans, R.C., Gamez, A.,
Michols-Matalon, K., Tyring, K.S., Matalon, R. (2004).Trends in
enzyme therapy for phenylketonuria.Molecular Therapy 10:
220-224.
Lang chu, W. (2004). New gene therapy techniques cures PKU.
Outsourcing-pharma.com (news).
Mitchell, J.J., Trakadis, Y.J., Scriver, C.R. (2011). Phenylalanine
hydroxylase deficiency.Journal in Medicine 13: 697-707.
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Schuett, V. (2006).National PKU News (in press).
Schuett, V. (2003). Will Tetrahydrobiopterin have a role in PKU
treatment ?National PKU News (in press).
Schuett. V. (2009). National PKU News (in press).
Van Spronsen, F.J., Groot, M.J., Hoeksma, M., Reijngoud, D.J.,
Van Rifn, M. (2010). Large neutral amino acids in the treatment
of PKU: From theory to practice. Journal ofInherited Metabolic
Disease 33(6): 671-676.
Williams, R.A., Mamotte, C.D.S., Burnet J.R. (2008).
Phenylketonuria: An Inborn Error of Phenylalanine Metabolism.
Clinical Biochemistry Review 29(1): 31–41.
THANK YOU