(2) inborn errors of metabolism · 2015-03-22 3 metabolic diseases - definition any of the diseases...

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2015-03-22 1 Metabolic diseases dr hab. n. med. Sylwia Kołtan Metabolism all biochemical processes and pathways in the body enzymes play a key role in many of these processes; changes in their function, as a result, of genetic mutation can lead to problems in metabolism important role coenzymes and cofactors

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Page 1: (2) Inborn errors of metabolism · 2015-03-22 3 Metabolic diseases - definition any of the diseases or disorders that disrupt normal metabolism etiology: can be inherited, in which

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Metabolic diseases

dr hab. n. med. Sylwia Kołtan

Metabolism

� all biochemical processes and pathways in the body � enzymes play a key role in many of these processes; changes in

their function, as a result, of genetic mutation can lead to problems in metabolism

� important role – coenzymes and cofactors

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Coenzymes

� coenzymes are organic molecules that are required by certain enzymes to carry out catalysis

� they bind to the active site of the enzyme and participate in catalysis but are not considered substrates of the reaction

� coenzymes often function as intermediate carriers of electrons, specific atoms or functional groups that are transfered in the overall reaction

Cofactors

� inorganic substances that are required for, or increase the rate of, catalysis

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Metabolic diseases - definition

� any of the diseases or disorders that disrupt normal metabolism

� etiology: can be inherited, in which case they are also known as inborn errors of metabolism, or they may be acquired during lifetime

� affect many systems of the body, some of them will only dietary restrictions, other - significantly reduce psychomotor performance, and even lead to death

Inborn metabolic diseases

� individual inborn or congenital errors are very rare � but: 9 more than 1400 inherited metabolic diseases have been

described 9 many of these disorders are potentially treatable via diet

and/or drug therapy 9 it is essentiale – a rapid accurate diagnosis and adequate

treatment

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Inborn metabolic diseases – pathophysiological diagnostics group

� Disorders that disrupt the synthseis or catabolism of complex molecules with symptomes that are permanent, progressive, independent of intercurrent events and not related to food intake; these include lysosomal disorders, peroxisomal disorders and disorders of intracellular transprt and processing

� Disorders that lead to an acute or progressive accumulation of toxic compounds as a result of metabolic block; these include disorders of amino acid metabolism (phenylketonuria, homocystynuria, maple syrup urine disease), organic acidurias, congenital urea cycle defects and sugar intolerances (galactosemia)

� Disorders with symptomes due to a deficiency of energy production or utilisation within the liver, myocardium, muscle or brain; these include congenital lactic acidemias, fatty acid oxydation defects, gluconeogenesis defects and mitochondrial respiratory chain disorders

Inborn metabolic diseases (IMD) – incidence and prevalance

� the majority of IMD are inherited by autosomal recessive genetics

9 the individual incidence of metabolic disorders can vary depending on the ethnic origin of the local population

9 especially high risk of incidence in „closed population” � overall incidence of individual IMD can range as follows:: 9 very rare (e.g. maple syrup urine disease 1: 250 000,

homocystinuria 1: 250 000) 9 extremely rare (1: 1 000 000) 9 relatively more common but still rare (e.g. phenlketonuria 1

: 10 000 – 20 000, galaktozemia 1 : 60 000) � however, if there are more than 1000 IMD overall, each

occurring at the rate of one in a milion, this means that one in 1000 people will be affected and one in 500 will be a carrier!

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IMD – the importance of family history

� diagnosis of metabolic disease in the family - the risk of repetition, especially in siblings!

� unexplained deaths of children in the family - an alarm for many congenital diseases, including metabolic!

IMD – signs and symptomes

� acute neonatal symptomes – non-specific symptoms in apparently healthy baby:

9 respiratory distress without signs of respiratory disease 9 hypotonia 9 poor sucking reflex 9 vomiting 9 diarrhoea 9 dehydration 9 lethargy 9 seizures These can easily be attributed to other causes, such as infection

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� failure to thrive � CNS symptoms: 9 developmental delay, movement or psychiatric disorder 9 cerebral palsy � sudden infant death syndrome (SIDS)

IMD – signs and symptoms

SUID - Sudden Unexpected Infant Death

IMD – signs and symptoms

� episodic illness - anorexia, vomiting, lethargy, coma � cardiomyopathy � muscular – hypotonic, weakness, cramps � gastrointestinal: 9 anorexia 9 vomiting 9 diarrhoea 9 malabsorption

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� liver disease, cholestasis

� ophtalmic abnormalities � Reye’s syndrome – like illness � dysmorphic features � metabolic: 9 acidosis 9 hypoglycaemia

IMD – signs and symptoms

� a Reye-like syndrome is attributed to inborn errors of metabolism

� in Reye-like syndrome hypoglycemia, hypoketonemia, elevated ammonia, and organic aciduria are often evident

� it is well-known that fatty-acid oxidation defects can present as Reye-like syndrome

� the most commonly diagnosed metabolic disorder in association with Reye syndrome has been medium-chain acyl coenzyme A dehydrogenase deficiency

� the present consensus seems to be that Reye syndrome is very rare, and that any child suspected of manifesting this disorder should undergo investigations for inborn errors of metabolism

IMD – signs and symptoms

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� acute symptoms in neonatal period (as above) � babies with metabolic disorders of accumulation show

deterioration after a normal initial period of hours to weeks � late-onset acute and recurrent symptomes 9 occurs in one third of patients with IMD of toxic accumulation

or energy production 9 fhe symptom free period is often over one year and may extend

into late childhood, adolescence or even adulthood 9 symptoms may be precipitated by minor viral infection, fever or

severe diarrhea witch result in the body reverting to the breakdown of stored protein within the cells and tissue – this is known as decompensation

9 children may improve spontaneously without intervention or require intensive care; they may appear normal between attacks

IMD – clinical cathegories

� chronic and progressive general symptoms; many apparently delayed onset presentations of metabolic disorders may be preceded by insidious symptoms such as gastrointestinal, neurological and muscular complaints

� specific and permanent symptoms may reveal or accompany metabolic disorders

some symptoms are distinctive but rare (lens discolouration and thromboembolic events in homocystynuria), other are non- specific and common (hepatomegaly, seizures, mental retardation)

IMD – clinical cathegories

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IMD – diagnosis

� easy, if the disease is detected through screening tests (eg. phenylketonuria) or actively diagnosed disease in families with a positive family history

� screening tests for suspected metabolic disease, suspected based on the clinical picture (GCMS, tandem mass spectrometry - TANDEM)

� specialized blood tests, tissue (eg. liver biopsy), fibroblasts in the detection of various metabolic errors

� genetic studies, confirming the diagnosis of congenital metabolic error at some

IMD – diagnosis

TANDEM is used in some countries for neonatal screening for IMD.

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IMD – diagnosis

IMD – the main aim of managing

� induce activity, as in the vitamin-responsive disorders

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IMD – the main aim of managing

� counteract the biochemical disturbance and prevent acute intercurrent decompensation

� prevent chronic and progressive deterioration by diet and/or drug therapy

� approximately 12% of inborn errors of metabolism can be

significantly controlled by therapy � in a further 55%, treatment is beneficial � but… in the remaining 33%, treatment has little efect

IMD – emergency treatment

� suspicion of metabolic disease in an infant with acute symptoms - fast diagnosis, symptomatic treatment, and in case of suspicion of the disease, in which it is possible to eliminate the intolerant substance - diet, f.e. in galactosemia

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IMD – suppoprtive care in acute decompensation

� ventilatory and circulatory support � correction of electrolyte imbalance � rehydration and maintenance hydration to counter poor

feeding, increased renal fluid loss and to ensure efficient diuresis of toxic metabolites

� correction of acidosis, although mild acidosis can be protective against hyperammonemia in urea cycle defects

� adequate nutricion � exogenus toxin removal – peritoneal dialysis, haemofiltration

or hemodialysis can be effective in removing toxic metabolites, such as ammonemia in urea cycle defects

� vitamins – mega-doses of specific vitamins can act as cofactors to induce metabolism in various metabolic disorders

Question to the students

� Which of the following situations may suggest a inborn metabolic disease in a child?

1. newborn to 3 weeks of age, in the opinion of the parents -

previously healthy; admitted to the ward because of a lack of appetite from the day before, vomiting, muscle flaccidity, pathological sleepiness - the child did not respond even to very strong pain stimuli; in additional studies - hypoglycemia, metabolic acidosis

2. newborn to 3 weeks of age, previously healthy; from two days more anxious, rhinitis, sporadic cough. On admission to the ward poor apetite, quickly gets tired during breastfeeding; tachypnea, tachycardia; in additional studies, decreased oxygen saturation (89%), compensated respiratory acidosis

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Selected IMD

Congenital hypothyroidism

� definition: thyroid deficiency present at birth � the most common congenital human endocrinopathy – from

1: 2000 to 1: 4000 births � the most common preventable causes of mental retardation � clinical manifestations are often subtle or not present at birth

due to: 9 trans-placental passage of some maternal thyroid hormone

and/or 9 many infants have some thyroid production of their own

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� in iodine sufficient countries – 85% of CH is due to thyroid dysgenesis (thyroid ectopy, athyreosis and thyroid hypoplasia)

� 10-15% of cases can be attributed to the inborn errors of thyroid hormone synthesis – dyshormonogenesis

� permanent CH requires life-long treatment

Permanent CH

� a temporary deficiency of thyroid hormones at birth, but then recovering to normal thyroid hormone production

� recovery to euthyroidism typically occurs in the first few months or years of life

� most commonly occurs in preterm infants born in areas of endemic iodine deficiency

Transient CH

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Clinical manifestations of CH

� depend on the degree of thyroid hormones deficiency and its duration

� in the neonatal period can be very discreet � the only way of the early diagnosis can be newborn thyroid

screening test

CH

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CH

� common symptoms at birth: 9 decreased activity 9 feeding difficulty 9 constipation 9 prolonged jaundice

� common signs in newborns and infants: 9 myxedematous facies 9 large fontanelles 9 macroglossia 9 a distandet abdomen with umbilical hernia 9 hypotonia

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Signs and symptoms of CH in untreated older children and adults

� mild to severe impairment of both physical and mental growth and development

� poor length growth is apparent as early as the first year of life; adult stature without treatment ranges from 1 to 1.6 metres, depending on severity, sex and other genetic factors

� bone maturation and puberty are severely delayed; ovulation is impeded and infertility is common

� neurological impairment may be mild, with reduced muscle tone and coordination, or so severe that the person cannot stand or walk

� cognitive impairment may also range from mild to so severe that the person is nonverbal and dependent on others for basic care

� thought and reflexes are slower � other signs may include thickened skin, enlarged tongue, or a

protruding abdomen

Signs and symptoms of CH in untreated older children and adults

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Signs and symptoms of CH in untreated older children and adults

October 08, 2009By Sandra E. Kurtin, RN, MS

CH lack of diagnosis and treatment from neonatal period - irreversible

developmental disorders, especially the central nervous system

Early treatment – excellent recovery!!!

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CH – newborn thyroid screening tests

� very important to early diagnosis but… � of the worlwide birth population of 127 million, it is estimated that

25% undergo screening for congenital hypothyroidism � various algorithms using measurement of T4, TSH, or both

CH – diagnostic algorithm

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CH – diagnostic algorithm

CH – other evaluation

� X-ray of the long bones – retarded bone age � ECG - ST-segment changes � EEG - low voltage, excess slow activities, delay of bioelectric

maturation � CBC - normocytic anemia

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Treatment and prognosis

� Levothyroxine – the treatment of choice � the recommended starting dose is 10-15 mcg/kg/day � the immediate goal of treatment are to rapidly raise the serum T4

above 10 ug/dl and normalize serum TSH levels � frequent laboratory monitoring in infancy is essential to ensure

optimal neurocognitive outcome; serum TSH and T4 should be measured every 1-2 month in the first 6 months of life and every 3-4 months thereafter

� in general, the prognosis of infants detected by screening and started on treatment easly is excellent, with IQs similar to sibling or classmate controls

� a lower neurognitive outcome may occur in those infants started at a later age (>30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more sever hypothyroidism

Introduction to galactosemi…

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Introduction to galactosemia…

� galactose is a monosaccharide sugar � galactose + glucose = lactose (disacharide) � in nature, lactose is found primarily in milk and milk products � galactose metabolism, which converts galactose into glucose, is

carried out by the three principal enzymes in a mechanism known as the Leloir pathway; the enzymes are listed in the order of the metabolic pathway: galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT), and UDP-galactose-4’-epimerase (GALE)

� galactose forms part of glycolipids and glycoproteins, which is found in many tissues

� galactose is a component of the antigens present on blood cells that determine blood type within the ABO blood group system; in O and A antigens, there are two monomers of galactose on the antigens, whereas in the B antigens there are three monomers of glucose

Introduction to galactosemia…

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Galactosemia

� there are three forms of the disease: 9 galactose-1 phosphate uridyl transferase deficiency (classic

galactosemia, the most common and most severe form) 9 deficiency of galactose kinase 9 deficiency of galactose-6-phosphate epimerase

Galactosemia

� an inherited disorder � autosomal recessive disease � occurs in approximately 1 of every 60 000 births among Caucasians;

the rate is different for other groups: from 1 : 30 000 to 40 000 in Europe to 1 : 1 000 000 in Japan

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Biochemical abnormalities

� a high level of: 9 galactose-1-phosphate 9 galctose 9 galactilol

� additionally: 9 hypoglicemia 9 hyperbilirubinemia

Clinical description

� a child with galactosemia is born apparently healthy, although there have been cases intrauterine fetal damage

� symptoms appear several hours or days after the first milk feeding

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Signs and symptoms in neonates

Finding Percent Additional details

Hepatocellular damage 89%

Jaundice (74%) Hepatomegaly (43%)

Abnormal liver function tests (10%) Coagulation disorders (9%)

Ascites (4%)

Food intolerance 76% Vomiting (47%) Diarrhea (12%)

Poor feeding (23%)

Failure to thrive 29%

Lethargy 16%

Seizures 1%

Sepsis 10%

E.Coli (26 cases) Klebsiella (3)

Enterobacter (2) Staphylococcus (1)

Beta-Streptococcus (1) Streptococcus faecalis (1)

From a survey reporting in 270 symptomatic neonates (Waggoner et al. 1990)

Signs and symptoms

� if a lactose-restricted diet is provided during the first 10 days of life, the neonatal signs usually quickly resolve and the complications of liver failure, sepsis and neonatal death are prevented

� despite adequate treatment from an early age, children with classic galactosemia remain at increased risk for: 9 developmental delays 9 speech problems (childhood apraxia of speech and dysarthria) 9 abnormalities of motor function (tremors, cerebellar ataxia,

dystonia) 9 cataract 9 diminished bone density 9 almost all females – premature ovarian insufficiency (POI)

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Organs damage

� high levels of galactose 1-phosphate – cause of brain damage � excessive hydration and environmental hypertonia due to high

concentration of galactilol - cataracts

Signs and symptoms

Galactosemia

� GALT mutations – three variants of disease: 9 classic galactosemia: severe GALT enzyme deficiency with

absent or barely detectable activty in erythrocytes and liver

9 clinical variant galactosemia: 1-10% residual GALT enzyme activity in erythrocytes and liver

9 biochemical variant galactosemia: 15-33% residual GALT enzyme activity in erythrocytes; is associated with specific mutations in GALT (Duarte variant – D2)

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Galactosemia: diagnosis

� classic galactosemia and clinical variant galactosemia may be suspected and confirmed in three clinical scenarios: 9 a newborn who is positive on newborn screening (NBS) 9 a newborn with a previously affected sib and/or high-risk

ethnicity 9 an infant, child, or adult with signs and/or symptoms

suggestive of classic galactosemia or clinical variant galactosemia

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Galactosemia: newborn screening

� newborn screening utilizes a small amount of blood obtained from a heel prick to quantify: 9 total content of erythrocyte galactose-1-phosphate and

blood galactose concentration AND/OR 9 erythrocyte GALT enzyme activity

WRI, within reference interval

Clinical Chemistry 56:3 437–444 (2010)

Galactosemia: other laboratory tests

� concentration of glucose � liver function tests (ALT, AST, GGTP, bilirubin) � coagulogram � albumin level � electrolytes serum levels � CBC � urine analysis

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Differential diagnosis

� infectious diseases but… very important: establishing the diagnosis of sepsis does not exclude

the possibility of galactosemia, as sepsis, particularly E. coli sepsis occurs commonly in infants with classic galactosemia

� hereditary spherocytosis � biliary atresia � other metabolic diseases

Differential diagnosis

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Treatment

� prevention of primary manifestations: standard of care in any newborn who is “screen-positive” for galactosemia or suspected of galactosemia is immediate dietary intervention while diagnostic testing is underway

� if erythrocyte galactose-1-phosphate concentration is >10 mg/dL and erythrocyte GALT enzyme activity is ≤10% of control activity (i.e., the child has classic galactosemia or clinical variant galactosemia), restriction of galactose intake is continued and all milk products are replaced with lactose-free formulas (e.g., Isomil® or Prosobee®) containing non-galactose carbohydrates

� management of the diet becomes less important after infancy and early childhood

Treatment

� treatment of manifestations: 9 in rare instances cataract surgery may be needed in the first

year of life 9 childhood apraxia of speech and dysarthria require expert

speech therapy 9 developmental assessment at age one year by a psychologist

is recommended in order to formulate a treatment plan with the speech therapist and treating physician

9 for school age children, an individual education plan and/or professional help with learning skills and special classrooms as needed

9 hormone replacement therapy as needed for delayed pubertal development and/or primary or secondary amenorrhea.

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Treatment and surveillance

� prevention of secondary complications: recommended calcium and vitamin intake to help prevent decreased bone mineralization

� routine monitoring for: 9 the accumulation of toxic analytes (e.g., erythrocyte

galactose-1-phosphate and urinary galactitol) 9 cataracts 9 speech and development 9 premature ovarian insufficiency (POI) 9 osteoporosis

Avoindance…

� agents/circumstances to avoid: breast milk, proprietary infant formulas containing lactose, cow’s milk, dairy products, and casein or whey-containing foods; medications with lactose and galactose

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Hereditary fructose intolerance - introduction

� fructose, or fruit sugar, is a simple ketonic monosaccharide found in many plants, where it is often bonded to glucose to form the disaccharide sucrose

Hereditary fructose intolerance - introduction

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� other fructose metabolism in liver, muscle and adipose tissue 9 muscle and adipose tissue: fructose phosphorylation by hexokinase → fructose-6-phosphate → entrance to glycolysis

9 liver: fructokinase converts fructose to fructose-1-phosphate → cleavage by fructose-1-phosphate aldolase to glyceraldehyde and dihydroxyacetone phosphate → entrance to glycolysis

Hereditary fructose intolerance - introduction

Abnormalities in fructose metabolism � inborn errors in fructose metabolism: 9 essential fructosuria: the absence of fructokinase →

asymptomatic condition 9 hereditary fructose intolerance: the absence of fructose-1-

phosphate aldolase (aldolase B) → very serious consequences

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� autosomal recessive disorder � the incidence of HFI in Europe is about 1:20.000 � the accumulated fructose-1-phosphate inhibits glycogen breakdown

and glucose synthesis → severe hypoglicaemia following ingestion of fructose

� accumulation of fructose-1-phosphate → hepatic and/or kidney failure and death

Hereditary fructose intolerance (HFI)

� the condition is manifested usually during infancy at weaning, when the child is introduced to fruits and vegetables, or when feeding is transferred from breast milk to artificial nutrients

� usually very serious, occur after the intake of fructose: 9 hypoglycemia 9 severe metabolic acidosis 9 seizures 9 jaundice 9 hepatomegaly 9 coagulation disorders 9 emaciation 9 coma 9 renal Fanconi syndrome 9 vomiting

� affected children soon develop an aversion to all foods and protect themselves by self-imposed fructose and sucrose restriction

Hereditary fructose intolerance – signs and symptoms

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� current diagnostic methods include the measurement of clinical symptoms upon intravenous fructose challenge or the direct assay of aldolase activity in liver biopsy samples

� both of these diagnostic methods are relatively invasive and the clinical analyses of fructose loading tests or aldolase assays are not routinely available

� in addition, diagnosis by a fructose tolerance test leads to the same acute symptoms that can be life threatening

Hereditary fructose intolerance – diagnosis

� the treatment for HFI is the exclusion of fructose, sucrose, and sorbitol (less than 40 mg/kg per day) from the diet and results in complete alleviation of most symptoms and a normal life span

� older HFI subjects who adhere to a self-imposed fructose-restricted diet may continue to live undiagnosed and lead relatively normal lives

� complete exclusion of fructose is often difficult, however, and many HFI patients develop a syndrome of chronic fructose intoxication characterized by retarded growth, chronic liver disease, and hepatomegaly; furthermore, if not treated properly, these patients suffer episodes of hypoglycemia, general ill health, and strained relationships with family members due to their peculiar eating habits

� constant daily risk remains for HFI individuals due to the increasingly widespread use of these sugars as nutrients and sweeteners

Hereditary fructose intolerance – tretment

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Phenylalanine

� an essential amino acid (the human body cannot make it so it is essential to the diet)

� phenylalanine that is ingested is largely transformed (hydroxylated) to form the amino acid tyrosine, which is used in protein synthesis

Metabolic pathways

� the conversion of Phe to Tyr occurs by a hydroxylating system consisting of: 9 phenylalanine hydroxylase (PAH) 9 the unconjugated pterin cofactor, tetrahydrobiopterin (BH4) 9 enzymes which serve to regenerate BH4, namely dihydropteridine

reductase and 4α-carbinolamine dehydratase

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Hyperphenyloalaninemia

� may be classified into: 9 classical phenylketonuria (PKU) 9 mild PKU 9 non-PKU HPA, depending on the level of serum phenylalanine at the time of diagnosis; this level provides an estimate of the residual enzyme activity that partly depends on the mutation in the PAH gene and makes it possible to define the biochemical phenotype

� atypical PKU (variant PKU), results from the deficient biosynthesis or regeneration of the PAH cofactor, tetrahydrobiopterin (BH4)

Phenylketonuria

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� autosomal recessive disorder � prevalence: varies by country ranging from between one in 10,000

and one in 20,000 births in U.S.A. and Europe

Phenylketonuria

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PKU – natural history

� infants appear until normal thay are a few months old � the natural history of the phenylketonuria consists in a progressive

irreversible neurological impairment during infancy and childhood � the most common outcome is severe mental retardation � a “mousy” odor, eczema and reduced hair skin and iris pigmentation

� reduced growth, microcephaly and neurological signs as tremor, epilepsy

� all untreated patients have behavioral problems as hyperactivity, stereotypy and anxiety

� the severity of the clinical phenotype directly correlates with blood phenylalanine levels that reflect the degree of enzymatic deficiency

PKU - diagnosis

� in advanced clinical presentation is easy, confirmed by the high levels of phenylalanine in serum - but there is no possibility of effective treatment

� in most european countries newborn screening is routinely carried out within 72 hours of birth, by taking a small pin prick of blood from the baby’s heel for laboratory analysis

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PKU - treatment

� the foundation of PKU treatment is a low Phe diet which, by reducing or normalising Phe concentrations, prevents the development of the neurological and psychological changes

� since neurological changes have been demonstrated within one month of birth, it is recommended that dietary restriction should be started early and be continued through childhood when neural development is maximal

� clinical neurological abnormalities, affected neuropsychological performance and brain imaging in adults with PKU has led to a consensus opinion that the PKU diet should be followed for life

� an even more stringent regime of Phe restriction is required for women with PKU contemplating starting a family, particularly during pregnancy, as elevated blood Phe concentrations are teratogenic towards the developing foetus

PKU - treatment

but…

� early treated PKU patients have normal intellectual quotients (I.Q.), but can have an I.Q. gap when compared to their non-PKU siblings

� patients with PKU frequently have lower scores for certain neuropsychological functions, with executive function being the most affected area

� the Phe-restricted diet with semi-synthetic supplementation is not without risk

� PKU patients under dietary treatment can have low concentrations of trace elements and cholesterol, and some disturbance to folate metabolism as well as distortion of their fatty acid profile

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Phe in food

New Strategies for the Treatment of Phenylketonuria (PKU)

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