Neonatal hyperphenilalaninemia

Dr. Mahtab Ordooei

Nonessential AA: AlanineArgininineAsparagineAsparticacidCitrullineCystineGlutamineOrnithineProlineSerineTyrosine

Amino acids

Essential: Histidine Isoleucine Leucine Lysine Methionine Phenylalanin Threonine Tryptophan Valine

PhenylalaninPhenylalanin hydroxilase

+BH4Thyrosine

Thyroid Hormon

Melanin

Catecol Amin

CO2 + H2O

HYPERPHENYLALANINEMIA FROM DEFICIENCY OF THE COFACTOR BH4

BH4 is synthesized from guanosine triphosphate through several enzymatic reactions Four enzyme deficiencies leading to defective BH4 formation have been described. More than half of the reported patients have had a deficiency of 6-pyruvoyltetrahydropterin synthase (PTPS).

Couse of the hyperphenylalaninemia

Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor tetrahydrobiopterin causes accumulation of phenylalanine in body fluids and the central nervous system (CNS).

severity of hyperphenylalaninemia

The severity of hyperphenylalaninemia depends on the degree of enzyme deficiency and may vary from very high plasma concentrations (>20 mg/dL or >1,200 μmole/L, classic phenylketonuria [PKU]) to mildly elevated levels (2–6 mg/dL or 120–360 μmole/L). In affected infants with plasma concentrations >20 mg/dL, excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenylacetate)that are excreted in the urine, giving rise to the term phenylketonuria (PKU)

TRANSIENT HYPERPHENYLALANINEMIA OF THE NEWBORN

In a small number of newborns, plasma tyrosine may rise to as high as 60 mg/dL (3,300 μmole/L) during the 1st 2 wk of life. Most affected infants are premature and are receiving high-protein diets. The condition is presumably due to delayed maturation of 4-HPPD enzyme Lethargy, poor feeding, and decreased motor activity are noted in some patients; most are asymptomatic and come to medical attention because of a high blood phenylalanine level, rendering the screening test for PKU positive. Laboratory findings include marked elevation of plasma tyrosine with a moderate increase in plasma phenylalanine.

Clinical Manifestations

Infants appear normal at birth. severe vomiting ) misdiagnosed

as HPS( Irritability, an eczematoid rash

and an unusual odor may be observed in first few months.

Dermatitis, intractable itching, scleroderma-like changes even in viscera They are fair haired, fair skinned ,

blue eyed in 90% of cases

About a third of patients may have spastic CP.

Another one-third have mild signs. Another third have no neurological signs but

MR Hyperactivity is common. Seizures in 25% , EEG abnormal in 80% Purposeless movements, rythmic rocking ,

tremor and athetosis may be seen. The most important manifestation

is MR and in absence of treatment they lose 50 IQ points in the first

year.

Diagnosis

♦Newborn screening is the best method for early detection of PKU.

♦ BH4 load with 20 mg/Kg and plasma PA and tyrosine at 0,4,8 and 24h, fall in PA shows BH4 is deficient.

♦ Plasma biopterin measurement♦ Neopterin and biopterin in urine♦ Measurement of DHPR enzyme

BH4 loading test

Treatment with BH4 and normal serum phenylalanin BH4 dificient hyperphenylalaninemia.

Treatment with BH4 and decrease serum phenylalanin (no normal level)

responsive to BH4

Neonatal hyperphenilalaninemia in Fars Province, South of Iran

In a period of one year from Nov 2007 to Nov 2008 blood samples were withdrawn from all newborns born in Fars province for measurement of serum phenylalanine. The samples with a serum level of 2 mg/dl were referred to pediatric endocrine clinic for confirmation and determination of the type of hyperphenylalaninemia by quantitive serum phenylalanine measurements by using High-Pressure liquid chromatography (HPLC) method.

Result

Nine cases out of 76996 newborns had a serum phenylalanine level >= 2mg/dl, of which 8 cases were confirmed by HPLC.

Results of BH4 loading test Patients’ no.Ph. A. level at

diagnosis (mg/dl)

Ph. A. level before

BH4 test (mg/dl)

Ph. A. level 4 hours

after BH4 test

(mg/dl)

Ph. A. level 8 hours

after BH4 test

(mg/dl)

Ph. A. 24 hours after BH4

test(mg/dl)

12117.4192019.8

24017.620.517.619

33020202324

41577610

511.4172111.413

61513121112

7153.91.40.91.4

81616.31.50.80.5