Disorder of Biopterin Metabolism

Sarah M. Alfaqaih, MD

Content : Introduction Metabolic derangement Inheritance Clinical presentation Diagnosis workup Treatment Prognosis

Defect in BH4 metabolism account for approximately 2 % of patients with elevated PHA levels .

However , some variants of these defects may present with symptoms of neurotransmitter deficiency without hyperphenylalannemia.(GTPCH)

BH4 is also a cofactor for tyrosine hydroxylase and tryptophan hydroxylase , which are involved in biosynthesis of dopamine and serotonin respectively.

Introduction

Metabolic derangement

4α-carbinolamine tetrahydrobiopterin

BH4 deficency can result from decreased regeneration by dihydropteridine reducrase (DHPR)

Pterin-4-carbinolamine dehydratase Or from impaired synthesis from

guanosine triphosphate cycclohydrolase 1 (GTPCH), 6-pyruvoyl-tetrahydrobiopterin synthase , and sepiapterin

Inheritance Most of disorders of BH4 metabolism are

autosomal recessive . One exception to the autosomal

recessive mode of inheritance is DYT5 without HPA , which is AD caused by a heterozygous mutation in the gene encoding GTPCH.

Clinical manifestation These infant are diagnosed as having PKU ,

but they are deteriorate neurologically despite adequate control of plasma PHA .

Neurologic manifestation :loss of head control , truncal hypotonia ( floppy baby ) , drooling , swallowing difficulties and myoclonic seizures, developing after 3 mo despite adequate dietary therapy.

These progressive neurologic manifestation occur due to decrease production of neurotransmitter : dopamine , serotonin , epinephrine and norepinephrine.

Diagnosis 1) measurment of elevated concentartions of

biopterin or neopterin in blood , urine and CSF.

2) BH4 loading test : An oral dose of BH4 ( 20mg/kg ) normalizes plasma phenylalanine in patients with BH4 deficiency within 4-8 hours The blood PHA should be elevated >400µmole/l to enable interpretation of the result .This may be achieved by discontinuing diet therapy for 2 days before the test or the administration a loading dose of PHA 100mg/kg 3hr before the test.

3) Enzyme assay

Dihydropteridine reductase dry blood spot filter paper

6-pyruvoyltetrahydropterin synthase liver , kidneys and erythrocyte

Carbinolamine dehydratase activity liver and kidneys

GTP cyclohydrolase activity liver and cytokine ( interferon –γ) stimulated mononuclear cells or fibroblasts

4) CSF neurotransmitters: the measurment of HVA and 5-HIAA is an essential part of the diagnostic investigation and is also subsequently required to monitor amine replacement therapy with L-dopa and 5HT.

CSF must be frozen in liquid nitrogen immediately after collection and stored at -70c prior to analysis.

Treatment

In DHPR deficiency treatment with folinic acid is necessary to prevent CNS folate deficiency

Where the reduction of CNS folate can be a consequence of long term treatment with L-dopa , so folinic acid supplement may be required

DHPR deficiency , HPA should be corrected by dietary means and BH4 should not be given

PCD does not usually require treatment , although BH4 may be used initially if the child is symptomatic

CNS amines replacement therapy is given as oral L-dopa ( with carbidopa) and 5HT.

Initially should be started in low dose then increased gradually to the recommended effective doses

Further dose adjusment depends on the results of CSF HVA and 5HIAA levels.

Monitor of treatment CSF amines levels should be monitored 3-

monthly in the first year , 6-monthly in early childhood and yearly thereafter.

CSF folate should be measured Serum prolactin can be used as a method

to monitor treatment , with normal values indicating adequate L-dopa replacement , and it has been suggested that this may be a more sensitive marker than the CSF HVA level deciding on dose adjustment.

Blood PHA must be monitored.(DHPR)

outcomeWithout treatment the natural history of

GTPCH , 6PTPS and DHPR deficiency is poor , with progressive neurological disease and early death.

The outcome with treatment depends upon the age at diagnosis and initiation of therapy and phenotypic severity.

Most patient with GTPCH deficiency have some degree of learning difficulties despite adequate treatment.

Patients with PTPS deficiency may have satisfactory cognitive outcome if detected early.

DHPR deficiency, if started on diet , amines replacement therapy and folinic acid within the first months of life can show normal development and growth.

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