2. • A 1 yr old girl is brought to her pediatrician’s office with
concerns about her development. She had an uncomplicated
birth at term. The mother reports that the baby is not
achieving the normal milestones for a baby of her age. She
also reports an unusual odor to her urine and some areas of
hypopigmentation on her skin and hair. On examination, the
girl is noted to have some muscle hypotonia and
microcephaly. The urine collected is said to have mousy odor.
• What is the most likely diagnosis ?
• PHENYLKETONURIA
3. • Autosomal recessive
• Metabolic genetic disorder
• Incidence of 1 in 10,000 live births ( 1 in 18,300 in India )
• Mutation in the gene coding for phenylalanine hydroxylase
(PAH)
• It is this enzyme that is necessary to convert phenylalanine
into another amino acid called tyrosine
• If this chemical pathway can not occur, phenylalanine builds up
in the bloodstream and brain tissue, causing mental
retardation and central nervous system problems
• Discovered by Norwegian physician Ivar Folling , thus also
called as Folling’s disease
4.
5. Normal serum phenylalanine levels
are 1 to 2 mg%
Increase in phenylalanine levels
Decrease in tyrosine levels
6. Signs & Symptoms
• Untreated children are normal at birth , but fail to attain early
developmental milestones
• Seizures
• Microcephaly
• Progressive impairment of cerebral function
Executive function ( cognitive abilities )
Information processing speed
ADHD ( late manifestation )
Learning disabilities( late manifestation )
basically untreated PKU show symptoms of mental retardation
by the age of 1 yr
• Musty or Mousy odor of skin ,hair ,sweat and urine (due to
phenylacetate accumulation)
• Tendency towards hypopigmentation and eczema
12. Newborns are screened for PKU
• All US babies are screened for PKU by
heel-prick test.
• Performed 2-7 days after birth and repeat
at 2 weeks of age.
• Blood tested for excess phenylalanine.
• Blood placed on agar plate with bacteria
that need phenylalanine to grow.
• Healthy babies’ blood doesn’t have extra
phenylalanine, so bacteria can’t grow
• Babies with PKU have extra
phenylalanine, so bacteria grow
13. Guthrie test for PKU
Bacterial plate with newborn blood samples
Negative controls: no bacterial
growth
Positive blood test results: bacterial
halo = PKU
Negative blood test results: no
bacterial growth = healthy babies
Positive controls : increasing
phenylalanine concentrations give
bacterial halos
http://www.childrenshospital.org/cfapps/research/data_admin/Site2940/mainpageS2940P4sublevel15.html
14.
15. • Infants may still be breastfed to provide the benefits of breast
milk , but quantity should be monitered
• Top fed with special infant formula called Lofenalac ( low in
phenylalanine )
• Kuvan ( sapropterin dihydrochloride , BH4 ,
tetrahydrobiopterin)
• Glycomacropeptide ( protein derived from goat milk , which is
free of Phe , but it is to be substituted with Tyr and Trp )
• Large neutral amino acid therapy ( LNAA )
16. Sickenly sweet Aspartame
• Aspartame = artificial sweetener made from
amino acids phenylalanine and aspartic acid
• Found in “diet”, “light”, and “sugar-free” foods
• Highly toxic to people with PKU
17.
18. Other modalities of treatment
• Enzyme substitution therapy ( PEG-PAL ) : Phenylalanine
ammonia lyase is joined to polyethylene glycol.
PAL breaks down Phe to transcinnamic acid and ammonia
which further break down into non-toxic compounds that can
be easily handled by the body.
• Therapeutic liver cell ( hepatocyte ) repopulation
• Gene therapy
19.
20. Types of hyperphenylalaninemia
• Classical PKU
400 disease causing mutations have been seen on the PAH
gene located on chromosome number 12
• Persistent hyperphenylalaninemia
Decreased PAH enzyme activity , can be managed by
temporary dietary therapy
• Transient mild hyperphenylalaninemia
Maturational delay in PAH enzyme
• Tetrahydrobiopterin-deficient hyperphenylalaninemia
21. Tetrahydrobiopterin-deficient hyperphenylalaninemia
• Rare form of hyperphenylalaninemia when PAH is normal
• Defect in the gene coding for dihydrobiopterine reductase , thus
BH4 cannot be replinished and made available for PAH enzyme for
its activity.
• Additional supplements required
• Differentiate with the help of prolactin levels ( prolactin levels
normal in treated classical PKU )
23. Alkaptonuria
• Also known as Black bone disease or Black urine disease
• Autosomal recessive inheritance
• Metabolic genetic disorder
• Incidence is 2 to 5 per million live births
• Deficiency in homogentisate 1,2-dioxygenase, an enzyme
which converts homogentisic acid (HGA ) to maleylacetoacetic
acid in the tyrosine degradation pathway
• Accumalation of HGA at 2000 times the normal rate
• The gene coding for homogentisate 1,2-dioxygenase is located
on chromosome number 3
• First described by Sir Archibald Garrod in 1901 in London as
one of his tetrad
24.
25. • Alkaptonuria has three major features :
1) HGA accumulates in the blood and appears in the urine, which on
standing is oxidized to a black pigment (alkapton), hence the name
Black urine disease
2) Ochronosis ( bluish-black pigmentation of connective tissue )
Accumulation of HGA and its oxidation product benzoquinone
acetate in the connective tissue
• Brown pigmentation of the sclera is observed midway between
the cornea and the outer and inner canthi at the insertin of the
recti muscles. Pigment deposition may also be seen in the
conjunctiva and cornea. The pigmentation does not affect vision .
• Ear cartilage pigmentation is first seen in the concha and antihelix,
and later in the tragus. The cartilage is slate blue or gray and feels
irregular or thickened. Calcification of the ear cartilage may be
observed on radiographs.
• Pigment also appears in cerumen and in perspiration, causing
discoloration of clothing.
• A deep purple discoloration may be seen on the skin of the hands,
corresponding to the underlying tendons, or in the web between
the thumb and index finger.
3) Arthiritis
26. Natural History
• During childhood , AKU is asymptomatic apart from the urine
turning dark on standing
• AKU does not cause cognitive impairment or developmental
delay
• From the third decade of life signs and symptoms due to
ochronosis begin to manifest ( low back pain may be the
presenting symptom at this age indicating the involvement of
the spine )
• By the fifth decade arthritis manifests in the large joints
• Other organ involvement
Aortic and Mitral Valve calcification
Renal stones and Prostate stones
27. Diagnosis
• Biochemical testing. The diagnosis of alkaptonuria is based on
the detection of a significant amount of HGA in the urine by
gas chromatography-mass spectrometry analysis. The amount
of HGA excreted per day in individuals with alkaptonuria is
usually between one and eight grams .
• A normal 24-hour urine sample contains 20-30 mg of HGA.
• HGD molecular genetic testing to confirm the diagnosis
• Prenatal diagnosis in high-risk families
28. Treatment
• No cure for AKU
• Only treatment offered to patients is palliative, pain management
till joint collapse and joint replacement surgery
• Important to avoid sports and exercise that put too much stress on
joints
• Dietary restriction does not help much , but red meat can be
avoided just to control the Phe and Try levels
• Nitisinone a triketone herbicide an inhibitor of 4-hydroxyphenyl
dioxygenase , the enzyme that produces HGA
Drug approved for the use in tyrosinemia type 1 , clinical trials
going on for its use in AKU
Reduces HGA formation at the expense of elevated Tyr levels ,
which may cause photophobia and rarely corneal crystals
30. Tyrosinemia type I
• Also known as hepato-renal tyrosinemia / Tyrosinosis /
Hereditary infantile Tyrosinemia
• Most severe form of tyrosinemia
• It is inhereted in an autosomal recessive pattern with an
incidence of 1 in 1,00,000 ( incidence is quite common in
Quebec ,Canada of 1 in 16,000 )
• Deficiency of enzyme fumaryl acetoacetate hydrolase
• This leads to build up of fumaryl acetoacetate and succinyl
acetone
• This enzyme is expressed more in the liver and proximal renal
tubular epithelial cells
31.
32. Pathophysiology
• Fumaryl acetoacetate along with its metabolites accumulate
in the hepatocytes and renal tubular cells, causing oxidative
damage and DNA damage along with dysfunctional gene
expression which alters the metabolic processes like protein
synthesis and damages these organs
• The symptoms of Tyrosinemia type 1 are due to accumulation
of tyrosine and its metabolites ( Succinylacetone,
Succinylacetoacetate and fumarylacetone ) in the liver, kidney
and central nervous system
• Succinylacetone inhibits enzyme δ-ALA dehydratase in the
liver and circulating RBC’s
33. Signs and Symptoms
• The so-called acute form is present at birth or during the few first months
of life.
• Infants with the acute form of tyrosinemia type 1 exhibit rapid onset of
symptoms,
• usually beginning with failure to thrive. Additional early symptoms
include:
• • Fever
• • Diarrhea/bloody stools
• • Vomiting
• • Enlarged liver
• • Tendency to bruise easily
• • Jaundice
• • Lethargy
• • Irritability
• • Some infants may have a distinctive cabbage-like odor to the skin and
urine
Untreated acute tyrosinosis progress towards life-threatening liver
failure and succumb to the same by 8 months of age
34. • Chronic form of Tyrosinemia type 1
Characterized by a more gradual onset
and less severe expression of symptoms
Present with hepato-splenomegaly and
failure to thrive
Developmental delay and repeated
acute neurological
episodes like acute polyneuropathy and
altered mental status
Cirrhosis of liver ( increased risk of HCC )
Renal Fanconi syndrome
• Untreated chronic cases survive upto 10
years of age
35. Diagnosis
• Diagnosed as a result of newborn screening
• Suspicion of diagnosis in infants who display failure to thrive
and hepatomegaly in first 3 months of life
• Detection of Succinylacetone in urine and decreased activity
of FAH enzyme in liver tissue or cultured fibroblasts confirms
the diagnosis
• Elevated plasma Tyrosine, Phenylalanine and Methionine
levels
• Increased urinary excretion of δ-ALA
• Markedly elevated AFP
• Prolonged PT and pTT
• Prenatal diagnosis : Succinylacetone levels in amniotic fluid
and FAH enzyme activity in amniotic fluid cells.
36. Treatment
• Prompt indentification and treatment may prevent severe
liver, kidney and neurological problems and child can
experience a normal growth
• 1) Dietary treatment : Low protein diet that contains limited
amounts of Phe and Tyr
• 2) Medical Treatment : Nitisinone, inhibitor of 4-
hydroxyphenylpyruvate dioxygenase.
• 3) Liver transplant : infants with end stage liver failure
37. Tyrosinemia Type II
• Also known as Oculocutaneous Tyrosinemia / Richner Hanhart
Syndrome
• Autosomal recessive inheritance
• Deficiency of enzyme tyrosine aminotransferase due to
mutation in the gene located on chromosome number 16
• Incidence is 1 in 2,50,000
• It affects the eyes , skin and mental development
• Manifestations are due to accumulation of tyrosine and its
metabolites by an unknown mechanism
38.
39. Clinical Manifestation
• Excessive lacrimation, redness, pseudodendritic keratitis,
corneal deposits, corneal ulcers followed by scarring
Usually manifest in the first year of age
• Non-pruritic , hyperkeratotic papules and plaques principally
located on palms and soles ( palmoplantar hyperkeratosis ).
The lesions are painful and progressive and associated with
hyperhidrosis
Usually manifest after 1 year of age
• Central nervous system involvement is variable and usually
manifests as intellectual deficit
40.
41. Diagnosis and Treatment
• Detection of high levels of plasma and urinary tyrosine
• Management :
Dietary limitation of Phe and Tyr.
Oral retinoids for skin lesions.
Oculocutaneous manifestations resolve with dietary
control.
Its unknown wether CNS symptoms resolve with dietary
control.
42. Tyrosinemia type III
• Very rare disorder
• Autosomal recessive inheritance
• Deficiency of enzyme 4-hydroxyphenylpyruvate dioxygenase,
leading to accumulation of 4-hydroxyphenylpyruvate and its
metabolites like 4-hydroxyphenylacetate and 4-
hydroxyphenyllactate along with increased plasma levels of
tyrosine
• Deficiency is due to mutation in the gene coding for the
enzyme , locate don chromosome number 12
• It is characterized by mild mental retardation, seizures and
intermittent ataxia observed during the infancy period
• Not much is studied about the disease
45. Albinism
• It is a group of genetic disorder that is potrayed by the
absence or diminished pigmentation in the skin, eyes and hair
of the organism.
• Albinism at first was considered an innate error of metabolism
in the genetic makeup of organisms in 1908 by scientist Sir
Archibald Garrod
• Two general types :
1) Ocular Albinism
2) Oculocutaneous Albinism
46.
47.
48. Signs and Symptoms
• It affects the pigmentation of skin, hair and eyes
• Visual problems :
1) Photophobia & decreased visual acuity
2) Nystagmus , Astigmatism
3) Strabismus
4) Optic Chiasma abnormalities
The above manifestations are because poor development of
retinal pigment epithelium and foveal hypoplasia
Iris, being pigmented normally controls the amount of light
falling on the retina ( through pupil ).
In albinism the iris is completely trans-illuminated and and
displays the colour of retina itself
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65. • Gene Therapy
▫ Improve visual acuity by implementing healthy OA1 protein into the
RPE cells (Anderson, et. al, 2004).
▫ This enriched visual acuity and improving overall eye sight of those
affected with albinism (Anderson, et. al, 2004).
