The inborn errors of metabolism and phenyl ketonuria

Dr Anitha MA BHMS,MD(Hom)
Dr.Padiyar Homoeopathic Medical College.Kerala

Inborn errors of metabolism
In the nucleus of every cell lie DNA molecules, which are the storehouses of genetic information. DNA is made up of a double helix of two polynucleotide chains, which are bound together. Each nucleotide is composed of a sugar molecule, a nitrogenous base, and a phosphate radical. The nitrogenous bases in the DNA are the purines and the pyrimidines. Adenine and guanine are the purines and cytosine and thymine are the pyrimidines.

A part of the DNA that codes for a particular protein is called a gene. The primary action of a gene is to synthesize a protein by various combinations of 20 different aminoacids. Genetic information is stored in the DNA molecule in the form of a triplet code such that a sequence of three bases specifies the structure of the aminoacid.

An inherited mutational event can result in an alteration of the structure of a primary protein or even affect the synthesis of the particular protein. The protein, which is affected, can be an enzyme, a receptor, transport vehicle, membrane pump, or a structural element. In the absence of the normal constituent or presence of the abnormal constituent, so many metabolic processes are interfered with, resulting in the various inborn errors of metabolism.

Clinical findings associated with inborn errors of metabolism
Clinical findings are non specific and similar to infants suffering from infections. Symptoms like poor feeding, lethargy, convulsions, and vomiting may develop soon after birth. A history of clinical deterioration in a previously normal infant should raise the suspicion of an inborn error of metabolism. Most of the affected infants loose their lives within the first two years of life.

  • Neurologic abnormalities
  • Metabolic acidosis with ketosis
  • Pernicious vomiting
  • Liver disease
  • Miscellaneous

Miscellaneous : clinical

  • Dislocated lenses
  • Renal stones
  • Thrombosis
  • Deafness
  • Microcephaly
  • Cataracts
  • Hematuria
  • Self mutilation
  • Abnormal urine color / odor
  • Coarse facies
  • Persistent eczema
  • Abnormal hair

Laboratory findings

  • Osteoporosis
  • Rickets
  • Hypoglycemia
  • Unexplained jaundice
  • Bony x-ray changes
  • Increased anion gap
  • Ketoacidosis
  • Abnormal liver function

Clinical approach to a newborn infant with a suspected metabolic disorder
The consequences of important errors in metabolism include:-
1. Absence of an end product Eg. albinism
2. Accumulation of intermediate compounds Eg.The storage diseases
3. Increased use of a minor pathway with detrimental consequences Eg. Phenyl ketonuria
4. Loss of feed back mechanism Eg. Lesch- Nyhan syndrome

I. The absence of an end product – eg. Albinism
In this condition the person lacks the enzyme TYROSINASE, which is involved in converting L-Tyrosine into DihydrOxy PhenylAlanine ( DOPA). Dopa is subsequently converted into quinone and then to melanin. The deficiency of melanin manifests as a hypomelanotic syndrome, which can be classified into the ocular form and the oculocutaneous form, the former is a rare condition and it affects only the eyes, where as the latter is the more common variety which affects both the eyes and the skin.

II. Accumulation of intermediate compounds
the storage diseases
The lysosomes are the normal constituents of the cell. These contain hydrolytic enzymes, which help the hydrolytic division of the various metabolites entering the cell. In the presence of these enzymes the metabolite is converted into various components by utilizing the hydrogen radical and the hydroxyl radical obtained by splitting a water molecule. The hydrogen radical attaches to one end of the molecule and the hydroxyl to the other end of the molecule. This highly unstable compound is split into its constituents like water, carbon dioxide etc.
In the absence of these specific enzymes, or in presence of abnormal, nonfunctioning enzymes, the corresponding metabolite fails to be converted into its components and hence gets collected in the cell interior. Lysosomal storage diseases result from the abnormal accumulation of cytoplasmic materials. Depending upon the organ, which is involved in the metabolic process, the clinical features are produced.

This defect can be because of multiple causes including,

  • Lack of synthesis of a particular enzyme.
  • Synthesis of abnormal enzyme
  • Inability to transport the enzyme to the lysosome
  • Synthesis of enzymes, which are inactive when inside the lysosomes
  • Absence or inactivity of activator enzymes, which activate the precursor of the enzyme.

There are four different types of lysosomal storage diseases:

  • Sphingolipidoses
  • Mucopolysaccharidoses
  • Mucolipidoses
  • Glycogen storage diseases

III. Loss of feed back mechanism   Eg. Lesch-nyhann syndrome
Lesch- Nyhan syndrome is a rare X-linked recessive inborn error of metabolism which is due to the deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase. The syndrome is characterized by gout and severe overproduction of uric acid, associated with choreoathetosis, spasticity, variable degree of mental deficiency and compulsive self mutilation. The prenatal detection can be undertaken using amniotic fluid cells.

IV. Increased use of a minor pathway with detrimental consequences eg. Phenyl ketonuria
All defects causing persistent hyperphenylalanemia are inherited as autosomal recessives. The importance of the study on Phenyl ketonuria lies in the fact that prompt recognition of the condition in the first days of life helps the infant to be grown under strict dietary regulations so that one can prevent early death, or even worse, survival with mental retardation. Another inborn error of metabolism that has a similar prognosis is Galactosemia.

Phenyl alanine is an essential aminoacid. Dietary phenylalanine, which is not used for protein synthesis, is normally degraded by the tyrosine pathway. Deficiency of the enzyme, phenyl alanine hydroxylase, or of its cofactor tetrahydrobiopterin, causes accumulation of phenylalanine in the body fluids. Several clinically and biochemically distinct forms of phenyl alanemia exist.
Classic phenyl ketonuria
PKU due to deficiency of cofactor tetrahydrobiopterin
Persistent hyperphenylalanemia
Transient phenylalanemia

Classic phenyl ketonuria
This condition is characterized by complete or near complete absence of the enzyme phenylalanine hydroxylase. Hence excess phenylalanine is converted into phenyl pyruvic acid or decarboxylated to phenyl ethylamine. These products along with their byproducts and the excess phenylalanine disrupt the normal metabolism and cause brain damage.

Clinical features

  • The affected infant is normal at birth.
  • Mental retardation may develop gradually and need not be detected soon after birth (Untreated infants loose about 50 points in IQ by the end of the first year)
  • Vomiting some times misdiagnosed, as pyloric stenosis may be an early symptom.
  • Older children become hyperactive with purposeless movements, rhythmic movements and athetosis.
  • Clinical findings
  • Infants are blonder than their siblings; they have fair skin and blue eyes.
  • Some have seborrheic or eczemoid rash, which usually disappears when the child becomes older.
  • Children have an unusual odor of phenyl acetic acid, described as musty, mousy or wolf like.
  • Infants are hypotonic, with hyperactive deep tendon reflexes.
  • About one fourth have seizures, and EEG changes.
  • Microcephaly with widely spaced teeth, enamel hypoplasia and growth retardation.


  • Plasma levels of phenyl alanine above 20 mg / dl
  • Normal tyrosine level
  • Increased urinary levels of metabolites of phenylalanine like phenyl pyruvic acid and o-hydroxy phenyl acetic acids.
  • Inability to tolerate an oral challenge of phenylalanine.
  • Normal concentration of cofactor tetrahydrobiopterin.


  • Diet low in phenylalanine
  • The optimum serum level of phenylalanine should be maintained at 2-9 mg /dl
  • Reduced amount of phenylalanine in the blood may cause features like lethargy, anorexia, anemia, rashes, diarrhea, and even death.
  • Pregnant mothers with PKU have a higher risk of spontaneous abortion. Infants born to such mothers are generally mentally retarded and may have microcephaly and/or congenital heart anomaly. In affected mothers care should be taken to maintain the blood value of phenyl alanine at 10 mg/dl.
  • Phenyl ketonuria due to deficiency of cofactor tetrahydrobiopterin -BH4
  • In about 2% of cases presenting with phenylalanemia, the defect lies in one of the enzymes necessary for the production of BH4. There is neurological deterioration in the infant.

Persistent hyperphenylalanemia
Occasionally identified are children whose blood levels of phenylalanine are only slightly elevated. These concentrations are insufficient to result in the excretion of phenyl pyruvic acid. The infants are asymptomatic and may develop normally without special dietary treatment.
Transient hyperphenylalanemia –Moderately elevated levels of phenylalanine occur in transient hyperphenylalanemia


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