Clinical/Scientific Notes
Vincenzo Leuzzi, MD Claudia Carducci, PhD Manuela Tolve, PhD Maria Teresa Giannini, PT Antonio Angeloni, MD Carla Carducci, PhD
Supplemental data at www.neurology.org
Sepiapterin reductase deficiency (SRD; Online Mendelian Inheritance in Man *182125) is a rare disorder of biogenic amines synthesis caused by mutations of the SPR gene on chromosome 2p14-p12.1 The most common presenting symptoms of SRD are developmental delay and axial hypotonia.2 The few patients observed during the very early stage of the disease suggested a peculiar pattern of neurologic impairment.3,4 With the aim of contributing to this topic, we report on a new case diagnosed and treated since the first months of life.
acid 18 nmol/L (r.v. 189-1,380); 3-methoxy-4hydroxyphenylethyleneglycol 42 nmol/L (r.v. 98-168). Prolactin was only mildly increased (20.8 ng/mL; r.v. 1-17.5). Blood and CSF amino acids were normal. Sequencing of the SPR gene (NM_003124.4) detected 2 previously described pathogenetic mutations: p.Arg150Gly (c.448A . G) in exon 21,5 and p.Lys251* (c.751A . T) in exon 3.2 Study of segregation in the family confirmed the proband was a compound heterozygote. Treatment with increasing doses of levodopa/ carbidopa (1 to 5 mg/0.25 to 1.25 kg/day) plus 5-OH-triptophan (1 to 4 mg/kg/day) was started at the age of 5.5 months and resulted in a prompt improvement of movement disorders (videos 5 and 6).
Case report. This 8-month-old girl was born at term, after normal pregnancy and elective cesarean section due to podalic presentation of the fetus, from healthy nonconsanguineous Italian parents. At birth the Apgar score was 9/10. She was small for gestational age (weight 2.480 kg, length 45 cm, head circumference 32 cm). Since the first days of life, the mother noticed occasional jerks of the upper left limb that in the next few weeks became continuous in the awake state involving the limbs, trunk, and head and were associated, from the age of 3 months (video 1 on the Neurology® Web site at www.neurology.org), with upward gaze deviation and altered tongue movements (video 2). On examination at the age of 5 months, head circumference was under the third percentile (with weight and length within the normal range). The patient exhibited severe motor delay (no head control or intentional grasping), a spasmodic pattern of extensor stiffening of the head and trunk associated with upward gaze deviation that was relieved by sleep, hypokinesia, limb rigidity, and almost continuous oscillatory movements of the limbs, trunk, and head at rest (video 3). Remarkably, this symptom could be interrupted by voluntary movement (video 4) or by being handled by the examiner. Social smile and reactivity were preserved. Brain MRI and EEG were normal. CSF examination revealed the following: neopterin 4.52 mg/L (reference values [r.v.] 2.30-10. 10); biopterin 21.05 mg/L (r.v. 2.40-11.80); sepiapterin 17.5 nmol/L (r.v. , 1); homovanillic acid 77 nmol/L (r.v. 324-1,379); 5-hydroxyindolacetic
Discussion. A recent retrospective study found a mean diagnostic delay of 9.1 years in the diagnosis of SRD,2 which was still compatible with a dramatic improvement of the movement disorders in virtually all the patients under levodopa/carbidopa treatment. Regrettably, a high percentage of subjects experienced a poor neurocognitive outcome.2 In contrast to other defects of tetrahydrobiopterin metabolism, SRD is not associated with hyperphenylalaninemia (even though a subclinical phenylalanine hydroxylase impairment may be revealed by phenylalanine [Phe] loading test1) and therefore cannot be detected by neonatal screening. So the possibility (if any) of preventing mental disability and restoring normal motor development rests on the prompt clinical recognition of this condition. We describe a peculiar constellation of motor symptoms in the very early stage of SRD, which encompasses the following: 1) hypokinetic-rigid syndrome with impairment of the postural reaction development; 2) spasmodic dystonia of the trunk with oculogyric crises; and 3) tremor of the limbs and head at rest that can be inhibited by skin contact and spontaneous movement. This is an unusual feature in infancy, recently reported in another early diagnosed patient with SRD.4 It differs from the repetitive, sometimes compulsory and ballistic, jerks reported in the dopamine transporter defect,6 which seem to be myoclonic rather than oscillatory in nature. Tremor, movement disorders, and dwarfism are described in young SPR2/2 mice and disappeared under tetrahydrobiopterin plus biogenic amine precursor
VERY EARLY PATTERN OF MOVEMENT DISORDERS IN SEPIAPTERIN REDUCTASE DEFICIENCY
Neurology 81
December 10, 2013
2141
ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE
treatment.7 In contrast to the human disease, SPR2/2 mice show extremely high blood levels of Phe, which may affect the clinical phenotype and proved to be responsive to tetrahydrobiopterin.7 The low weight at birth in our patient would suggest a prenatal impairment of dopamine-mediated factors regulating the fetal growth. Growth retardation was detected in one of the 2 index cases.1 We confirm the dramatic efficacy of low dosage of biogenic amine precursors on early-onset movement disorders due to SRD.2 A more protracted follow-up is required in order to evaluate the consequence of early treatment on the child’s neurocognitive development. From the Department of Pediatrics and Child Neurology and Psychiatry (V.L., M.T.G.); Department of Experimental Medicine (Claudia Carducci, M.T., Carla Carducci); and Department of Molecular Medicine (A.A.), Sapienza Università di Roma, Rome, Italy. Author contributions: All authors have made a substantial contribution so as to qualify for authorship. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript. Vincenzo Leuzzi: drafting/ revising the manuscript, analysis and interpretation of clinical and biochemical data, acquisition of data. Claudia Carducci: drafting/ revising the manuscript, biochemical analysis execution and interpretation. Manuela Tolve: drafting/revising the manuscript, molecular analysis execution and interpretation. Maria Teresa Giannini: drafting/revising the manuscript, analysis and interpretation of patient’s neuromotor patterns. Antonio Angeloni: drafting/revising the manuscript, genotype/biochemical phenotype correlation interpretation. Carla Carducci: drafting/revising the manuscript, molecular analysis interpretation. Study funding: University of Rome (Sapienza Università di Roma) 2011–2012. Prog. N. C26A11CEXE.
Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. Received June 5, 2013. Accepted in final form August 12, 2013. Correspondence to Prof. Leuzzi: [email protected] © 2013 American Academy of Neurology 1.
2.
3.
4.
5.
6.
7.
Bonafé L, Th}ony B, Penzien JM, Czarnecki B, Blau N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet 2001;69:269–277. Friedman J, Roze E, Abdenur JE, et al. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol 2012;71:520–530. Neville BGR, Parascandalo R, Farrugia R, Felice A. Sepiapterin reductase deficiency: a congenital doparesponsive motor and cognitive disorder. Brain 2005; 128:2291–2296. Dill P, Wagner M, Somerville A, Thöny B, Blau N. Child Neurology: paroxysmal stiffening, upward gaze, and hypotonia. Hallmarks of sepiapterin reductase deficiency. Neurology 2012;78:e29–e32. Friedman J, Hyland K, Blau N, MacCollin M. Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 2006;67:2032–2035. Kurian MA, Li Y, Zhen J, et al. Clinical and molecular characterization of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol 2011;10:54–62. Yang S, Lee YJ, Kim JM, et al. A murine model for human sepiapterin-reductase deficiency. Am J Hum Genet 2006; 78:575–587.
Save These Dates for AAN CME Opportunities! Mark these dates on your calendar for exciting continuing education opportunities, where you can catch up on the latest neurology information. AAN Annual Meeting
• April 26-May 3, 2014, Philadelphia, Pennsylvania, Pennsylvania Convention Center
You’re Committed to Continually Expanding Your Knowledge NeuroSAE™ is committed to helping you. The Sixth Edition of the AAN’s convenient online selfassessment examination is now available, featuring 150 questions and 8 self-assessment CME credits upon successful completion to help meet ABPN MOC requirements. See all the available NeuroSAE versions and purchase the exam today at AAN.com/view/neuroSAE.
2142
Neurology 81
December 10, 2013
ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE
Very early pattern of movement disorders in sepiapterin reductase deficiency Vincenzo Leuzzi, Claudia Carducci, Manuela Tolve, et al. Neurology 2013;81;2141-2142 Published Online before print November 8, 2013 DOI 10.1212/01.wnl.0000437299.51312.5f This information is current as of November 8, 2013 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/81/24/2141.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2013/11/08/01.wnl.000043729 9.51312.5f.DC1.html
References
This article cites 7 articles, 3 of which you can access for free at: http://www.neurology.org/content/81/24/2141.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Mental retardation http://www.neurology.org//cgi/collection/mental_retardation
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2013 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Vincenzo Leuzzi, MD Claudia Carducci, PhD Manuela Tolve, PhD Maria Teresa Giannini, PT Antonio Angeloni, MD Carla Carducci, PhD
Supplemental data at www.neurology.org
Sepiapterin reductase deficiency (SRD; Online Mendelian Inheritance in Man *182125) is a rare disorder of biogenic amines synthesis caused by mutations of the SPR gene on chromosome 2p14-p12.1 The most common presenting symptoms of SRD are developmental delay and axial hypotonia.2 The few patients observed during the very early stage of the disease suggested a peculiar pattern of neurologic impairment.3,4 With the aim of contributing to this topic, we report on a new case diagnosed and treated since the first months of life.
acid 18 nmol/L (r.v. 189-1,380); 3-methoxy-4hydroxyphenylethyleneglycol 42 nmol/L (r.v. 98-168). Prolactin was only mildly increased (20.8 ng/mL; r.v. 1-17.5). Blood and CSF amino acids were normal. Sequencing of the SPR gene (NM_003124.4) detected 2 previously described pathogenetic mutations: p.Arg150Gly (c.448A . G) in exon 21,5 and p.Lys251* (c.751A . T) in exon 3.2 Study of segregation in the family confirmed the proband was a compound heterozygote. Treatment with increasing doses of levodopa/ carbidopa (1 to 5 mg/0.25 to 1.25 kg/day) plus 5-OH-triptophan (1 to 4 mg/kg/day) was started at the age of 5.5 months and resulted in a prompt improvement of movement disorders (videos 5 and 6).
Case report. This 8-month-old girl was born at term, after normal pregnancy and elective cesarean section due to podalic presentation of the fetus, from healthy nonconsanguineous Italian parents. At birth the Apgar score was 9/10. She was small for gestational age (weight 2.480 kg, length 45 cm, head circumference 32 cm). Since the first days of life, the mother noticed occasional jerks of the upper left limb that in the next few weeks became continuous in the awake state involving the limbs, trunk, and head and were associated, from the age of 3 months (video 1 on the Neurology® Web site at www.neurology.org), with upward gaze deviation and altered tongue movements (video 2). On examination at the age of 5 months, head circumference was under the third percentile (with weight and length within the normal range). The patient exhibited severe motor delay (no head control or intentional grasping), a spasmodic pattern of extensor stiffening of the head and trunk associated with upward gaze deviation that was relieved by sleep, hypokinesia, limb rigidity, and almost continuous oscillatory movements of the limbs, trunk, and head at rest (video 3). Remarkably, this symptom could be interrupted by voluntary movement (video 4) or by being handled by the examiner. Social smile and reactivity were preserved. Brain MRI and EEG were normal. CSF examination revealed the following: neopterin 4.52 mg/L (reference values [r.v.] 2.30-10. 10); biopterin 21.05 mg/L (r.v. 2.40-11.80); sepiapterin 17.5 nmol/L (r.v. , 1); homovanillic acid 77 nmol/L (r.v. 324-1,379); 5-hydroxyindolacetic
Discussion. A recent retrospective study found a mean diagnostic delay of 9.1 years in the diagnosis of SRD,2 which was still compatible with a dramatic improvement of the movement disorders in virtually all the patients under levodopa/carbidopa treatment. Regrettably, a high percentage of subjects experienced a poor neurocognitive outcome.2 In contrast to other defects of tetrahydrobiopterin metabolism, SRD is not associated with hyperphenylalaninemia (even though a subclinical phenylalanine hydroxylase impairment may be revealed by phenylalanine [Phe] loading test1) and therefore cannot be detected by neonatal screening. So the possibility (if any) of preventing mental disability and restoring normal motor development rests on the prompt clinical recognition of this condition. We describe a peculiar constellation of motor symptoms in the very early stage of SRD, which encompasses the following: 1) hypokinetic-rigid syndrome with impairment of the postural reaction development; 2) spasmodic dystonia of the trunk with oculogyric crises; and 3) tremor of the limbs and head at rest that can be inhibited by skin contact and spontaneous movement. This is an unusual feature in infancy, recently reported in another early diagnosed patient with SRD.4 It differs from the repetitive, sometimes compulsory and ballistic, jerks reported in the dopamine transporter defect,6 which seem to be myoclonic rather than oscillatory in nature. Tremor, movement disorders, and dwarfism are described in young SPR2/2 mice and disappeared under tetrahydrobiopterin plus biogenic amine precursor
VERY EARLY PATTERN OF MOVEMENT DISORDERS IN SEPIAPTERIN REDUCTASE DEFICIENCY
Neurology 81
December 10, 2013
2141
ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE
treatment.7 In contrast to the human disease, SPR2/2 mice show extremely high blood levels of Phe, which may affect the clinical phenotype and proved to be responsive to tetrahydrobiopterin.7 The low weight at birth in our patient would suggest a prenatal impairment of dopamine-mediated factors regulating the fetal growth. Growth retardation was detected in one of the 2 index cases.1 We confirm the dramatic efficacy of low dosage of biogenic amine precursors on early-onset movement disorders due to SRD.2 A more protracted follow-up is required in order to evaluate the consequence of early treatment on the child’s neurocognitive development. From the Department of Pediatrics and Child Neurology and Psychiatry (V.L., M.T.G.); Department of Experimental Medicine (Claudia Carducci, M.T., Carla Carducci); and Department of Molecular Medicine (A.A.), Sapienza Università di Roma, Rome, Italy. Author contributions: All authors have made a substantial contribution so as to qualify for authorship. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript. Vincenzo Leuzzi: drafting/ revising the manuscript, analysis and interpretation of clinical and biochemical data, acquisition of data. Claudia Carducci: drafting/ revising the manuscript, biochemical analysis execution and interpretation. Manuela Tolve: drafting/revising the manuscript, molecular analysis execution and interpretation. Maria Teresa Giannini: drafting/revising the manuscript, analysis and interpretation of patient’s neuromotor patterns. Antonio Angeloni: drafting/revising the manuscript, genotype/biochemical phenotype correlation interpretation. Carla Carducci: drafting/revising the manuscript, molecular analysis interpretation. Study funding: University of Rome (Sapienza Università di Roma) 2011–2012. Prog. N. C26A11CEXE.
Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. Received June 5, 2013. Accepted in final form August 12, 2013. Correspondence to Prof. Leuzzi: [email protected] © 2013 American Academy of Neurology 1.
2.
3.
4.
5.
6.
7.
Bonafé L, Th}ony B, Penzien JM, Czarnecki B, Blau N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet 2001;69:269–277. Friedman J, Roze E, Abdenur JE, et al. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol 2012;71:520–530. Neville BGR, Parascandalo R, Farrugia R, Felice A. Sepiapterin reductase deficiency: a congenital doparesponsive motor and cognitive disorder. Brain 2005; 128:2291–2296. Dill P, Wagner M, Somerville A, Thöny B, Blau N. Child Neurology: paroxysmal stiffening, upward gaze, and hypotonia. Hallmarks of sepiapterin reductase deficiency. Neurology 2012;78:e29–e32. Friedman J, Hyland K, Blau N, MacCollin M. Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 2006;67:2032–2035. Kurian MA, Li Y, Zhen J, et al. Clinical and molecular characterization of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol 2011;10:54–62. Yang S, Lee YJ, Kim JM, et al. A murine model for human sepiapterin-reductase deficiency. Am J Hum Genet 2006; 78:575–587.
Save These Dates for AAN CME Opportunities! Mark these dates on your calendar for exciting continuing education opportunities, where you can catch up on the latest neurology information. AAN Annual Meeting
• April 26-May 3, 2014, Philadelphia, Pennsylvania, Pennsylvania Convention Center
You’re Committed to Continually Expanding Your Knowledge NeuroSAE™ is committed to helping you. The Sixth Edition of the AAN’s convenient online selfassessment examination is now available, featuring 150 questions and 8 self-assessment CME credits upon successful completion to help meet ABPN MOC requirements. See all the available NeuroSAE versions and purchase the exam today at AAN.com/view/neuroSAE.
2142
Neurology 81
December 10, 2013
ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE
Very early pattern of movement disorders in sepiapterin reductase deficiency Vincenzo Leuzzi, Claudia Carducci, Manuela Tolve, et al. Neurology 2013;81;2141-2142 Published Online before print November 8, 2013 DOI 10.1212/01.wnl.0000437299.51312.5f This information is current as of November 8, 2013 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/81/24/2141.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2013/11/08/01.wnl.000043729 9.51312.5f.DC1.html
References
This article cites 7 articles, 3 of which you can access for free at: http://www.neurology.org/content/81/24/2141.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Mental retardation http://www.neurology.org//cgi/collection/mental_retardation
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2013 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
