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Phenylketonuria

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Phenylketonuria
   Classifications and external resources

   Phenylalanine
     ICD- 10   E 70.0
     ICD- 9    270.1
      OMIM     261600
   DiseasesDB  9987
   MedlinePlus 001166
    eMedicine  ped/1787  derm/712
   MeSH        C10.228.140.163.100.687

   Phenylketonuria (PKU; IPA: UK /ˌfiːnʌɪlˌkiːtɘˈnjʊɘrɪɘ/ or
   /ˌfɛnʌɪlˌkiːtɘˈnjʊɘrɪɘ/, US /ˌfɛnɘlˌkitnˈjʊrɪɘ/ or /ˌfinɘlˌkitnˈjʊrɪɘ/)
   is a human genetic disorder, in which the body lacks phenylalanine
   hydroxylase, the enzyme necessary to metabolize phenylalanine to
   tyrosine. Left untreated, the disorder can cause brain damage and
   progressive mental retardation as a result of the accumulation of
   phenylalanine and its breakdown products. The incidence of occurrence
   of PKU is about 1 in 15,000 births, but the incidence varies widely in
   different human populations from 1 in 4,500 births among the population
   of Ireland to fewer than one in 100,000 births among the population of
   Finland. Phenylketonuria can also exist in mice, which have been
   extensively used in experiments into the correct treatment of PKU.

History

   Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn
   Følling in 1934 when he noticed that hyperphenylalaninemia (HPA) was
   associated with mental retardation. In Norway, this disorder is known
   as Følling's disease, named after its discoverer. Dr. Følling was one
   of the first physicians to apply detailed chemical analysis to the
   study of disease. His careful analysis of the urine of two retarded
   siblings led him to request many physicians near Oslo to test the urine
   of other retarded patients. This led to the discovery of the same
   substance that he had found in eight other patients. The substance
   found was subjected to much more basic and rudimentary chemical
   analysis than is available today. He conducted tests and found
   reactions that gave rise to benzaldehyde and benzoic acid, which led
   him to conclude the compound contained a benzene ring. Further testing
   showed the melting point to be the same as phenylpyruvic acid, which
   indicated that the substance was in the urine. His careful science
   inspired many to pursue similar meticulous and painstaking research
   with other disorders.

Defects

   Classical PKU is caused by a defective gene for the enzyme
   phenylalanine hydroxylase (PAH). A rarer form of the disease occurs
   when PAH is normal but there is a defect in the biosynthesis or
   recycling of the cofactor tetrahydrobiopterin (BH[4]) by the patient.

   This enzyme normally converts the amino acid phenylalanine to tyrosine.
   If, due to a faulty or missing enzyme, this reaction does not take
   place, levels of phenylalanine in the body can be far higher than
   normal, and levels of tyrosine lower than normal.
   Simplified pathway for phenylalanine metabolism
   Enlarge
   Simplified pathway for phenylalanine metabolism

Large neutral amino acid transporter

   Large neutral amino acids (LNAAs), , compete for transport across the
   blood brain barrier (BBB). Excessive phenylalanine in the blood
   saturates the large neutral amino acid transporter (LNAAT), which
   carries LNAAs across the BBB. Thus, excessive levels of phenylalanine
   significantly decrease the levels of other LNAAs in the brain. These
   amino acids are required for protein and neurotransmitter synthesis.
   Reduced protein and neurotransmitter synthesis disrupts brain
   development in children, leading to mental retardation.
   Biosynthesis of neurotransmitters from tyrosine
   Enlarge
   Biosynthesis of neurotransmitters from tyrosine
   Biosynthesis of the neurotransmitter serotonin
   Enlarge
   Biosynthesis of the neurotransmitter serotonin

   Low levels of tyrosine also leads to lowered production of the pigment
   melanin, so children with this condition tend to have fairer hair and
   greener eyes than other members of their family. The excess
   phenylalanine is converted instead into the phenylketones which are
   excreted in the urine - hence the name for this condition. The
   phenylketones produced in phenylketonuria are phenylacetate,
   phenyllactate, phenylpyruvate, and phenylethylamine. The sweat and
   urine of an affected child not on the low-protein diet has a musty
   odour due to the phenylacetate.

Clinical Features

   Untreated children with classic phenylketonuria are normal at birth,
   but fail to attain early developmental milestones, develop
   microcephaly, and demonstrate progressive impairment of cerebral
   function. Hyperactivity, seizures, and severe mental retardation are
   major clinical problems later in life. Electroencephalographic
   abnormalities; “mousy” odour of skin, hair, and urine (due to
   phenylacetate accumulation);and a tendency to hypopigmentation and
   eczema complete the devastating clinical picture. In contrast, affected
   children who are detected and treated at birth are less likely to
   develop neurological problems and have seizures and mental retardation,
   though there is a chance that it can happen.

Diagnosis

   The problem is readily detectable within days of birth from a small
   blood sample -- the Guthrie heel prick test, so screening for
   phenylketonuria is done routinely in most industrialized countries,
   usually combined with testing thyroid function and other genetic
   disorders of metabolism.

   In some areas, a repeat test is performed at the age of two weeks, but,
   if a child has been tested shortly after birth (once feeding has
   commenced), there is no evidence that this second test is really
   necessary.

Therapy

   If the condition is diagnosed early enough, an affected newborn can
   grow up with normal brain development, but only by eating a special
   diet low in phenylalanine for the rest of their life. This requires
   severely restricting or eliminating foods high in phenylalanine, such
   as breast milk, meat, chicken, fish, nuts, cheese and other dairy
   products. Starchy foods such as potatoes, bread, pasta, and corn must
   also be avoided. Many diet foods and diet soft drinks that contain the
   sweetener aspartame must also be avoided, as aspartame is metabolized
   into several constituent chemicals, including phenylalanine.
   Supplementary formulae are used in these patients to provide the other
   amino acids and other necessary nutrients that would otherwise be
   lacking in a protein free diet. In those patients with a deficit in
   BH[4] production or PAH has a low affinity for BH[4], treatment
   consists of giving this cofactor as a supplement; this is referred to
   as BH[4] responsive PKU. There are a number of potential other
   therapies currently under investigation, including gene therapy, and an
   injectable form of PAH. However, it is likely that it will be many
   years before these are available for use in affected individuals.

Maternal phenylketonuria

   Phenylketonuria is inherited in an autosomal recessive fashion
   Enlarge
   Phenylketonuria is inherited in an autosomal recessive fashion

   For women with PKU it is essential for the health of their child to
   maintain low phenylalanine levels before and during pregnancy. Though
   the developing fetus may only be a carrier of the PKU gene, the
   intrauterine environment can have very high levels of phenylalanine,
   which can cross the placenta. The result is the child may develop
   congenital heart disease, growth retardation, microcephaly and mental
   retardation. PKU women themselves are not at risk from additional
   complications during pregnancy directly as a result of their disorder.
   In most countries, women with PKU who wish to have children are advised
   to lower their blood phenylalanine levels before they become pregnant
   and carefully control their phenylalanine levels throughout the
   pregnancy. This is achieved by performing regular blood tests and
   adhering very strictly to a diet, generally monitored on day-to-day
   basis by a specialist metabolic dietitian. When low phenylalanine
   levels are maintained for the duration of pregnancy there are no
   elevated levels of risk of birth defects compared with a baby born to a
   non-PKU mother.

Inheritance

   As PKU is an autosomal recessive genetic disorder each parent must have
   at least one defective allele of the gene for PAH, and the child must
   inherit a defective allele from each parent. As such, it is possible
   for a parent with a PKU phenotype to have a child without PKU if the
   other parent posseses at least one functional allele of the gene for
   PAH. A child of two parents with the PKU phenotype will always receive
   two defective alleles so will always have PKU. The gene for PAH is
   located on chromosome 12, at location 12q22-q24.2.

   Retrieved from " http://en.wikipedia.org/wiki/Phenylketonuria"
   This reference article is mainly selected from the English Wikipedia
   with only minor checks and changes (see www.wikipedia.org for details
   of authors and sources) and is available under the GNU Free
   Documentation License. See also our Disclaimer.
