Two Greek siblings with sepiapterin reductase deficiency.
BACKGROUND
Sepiapterin reductase (SR) deficiency is a rare inherited disorder of neurotransmitter metabolism; less than 25 cases have been described in the literature so far.


METHODS
We describe the clinical history and extensive cerebrospinal fluid (CSF) and urine examination of two Greek siblings with the diagnosis of SR deficiency. The diagnosis was confirmed by enzyme activity measurement in cultured fibroblasts and by mutation analysis.


RESULTS
Both patients suffered from a progressive and complex L-dopa responsive movement disorder. Very low concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in CSF. CSF neopterin and biopterin concentrations were abnormal in one case only, whereas in both cases sepiapterin concentrations were abnormally high and 5-hydroxytryptophan was undetectable. Urine concentrations of HVA, 5-HIAA and vanillyl mandelic acid (VMA) were decreased in both cases. Both patients had no detectable SR enzyme activity in primary dermal fibroblasts, and upon analysis of genomic DNA revealed the same homozygous point mutation introducing a premature stop codon into the reading frame of the SPR gene (mutant allele K251X).


CONCLUSIONS
Our cases illustrate that, apart from HVA and 5-HIAA analysis, the specific quantification of sepiapterin in CSF, rather than neopterin and biopterin alone, is crucial to the final diagnosis of SR deficiency. In addition, urinary concentrations of neurotransmitter metabolites may be abnormal in SR deficiency and may provide an initial indication of SR deficiency before CSF analysis is performed. The known, impressive beneficial response of SR deficient patients to treatment with L-dopa, is illustrated again in our cases.
Verbeek
Marcel M
MM
Department of Neurology, Laboratory of Pediatrics and Neurology, 830 LKN, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Willemsen
Michel A A P
MAAP
Department of Pediatric Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Wevers
Ron A
RA
Department of Neurology, Laboratory of Pediatrics and Neurology, 830 LKN, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Lagerwerf
Aart J
AJ
Department of Neurology, Laboratory of Pediatrics and Neurology, 830 LKN, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Abeling
Nico G G M
NGGM
Academic Medical Center, Laboratory Genetic Metabolic Diseases, University of Amsterdam, The Netherlands.
Blau
Nenad
N
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zürich, Switzerland.
Thöny
Beat
B
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zürich, Switzerland.
Vargiami
Euthymia
E
1st Department of Pediatrics, Aristotle University of Thessaloniki, Greece.
Zafeiriou
Dimitrios I
DI
1st Department of Pediatrics, Aristotle University of Thessaloniki, Greece.
D000429:Alcohol Oxidoreductases / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D053898:Biosynthetic Pathways; D002648:Child; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006115:Greece; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid / Q000652:urine; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid / Q000652:urine; D008661:Metabolism, Inborn Errors / Q000134:cerebrospinal fluid / Q000201:enzymology* / Q000235:genetics / Q000652:urine; D009154:Mutation; D018377:Neurotransmitter Agents / Q000134:cerebrospinal fluid / Q000652:urine; D011622:Pterins / Q000134:cerebrospinal fluid / Q000652:urine; D035781:Siblings
D018377:Neurotransmitter Agents; D011622:Pterins; D006897:Hydroxyindoleacetic Acid; C016727:sepiapterin; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D006719:Homovanillic Acid