- Email: [email protected]
Sepiapterin reductase deficiency: Report of 5 new cases
Accepted Manuscript Sepiapterin reductase deficiency: Report of 5 new cases Sarah AlSubhi, Saad AlShahwan, Mohamed AlMuhaizae, Hamed AlZaidan, Brahim Tabarki PII:
S1090-3798(17)30070-3
DOI:
10.1016/j.ejpn.2017.01.010
Reference:
YEJPN 2180
To appear in:
European Journal of Paediatric Neurology
Received Date: 29 July 2016 Revised Date:
5 January 2017
Accepted Date: 16 January 2017
Please cite this article as: AlSubhi S, AlShahwan S, AlMuhaizae M, AlZaidan H, Tabarki B, Sepiapterin reductase deficiency: Report of 5 new cases, European Journal of Paediatric Neurology (2017), doi: 10.1016/j.ejpn.2017.01.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Video is part of the ms
RI PT
Sepiapterin reductase deficiency: Report of 5 new cases
Sarah AlSubhia, Saad AlShahwana, Mohamed AlMuhaizaeb, Hamed AlZaidanc, Brahim
a
SC
Tabarkia,*
Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City,
M AN U
Riyadh b
Department of Neurosciences, King Faisal Specialist Hospital and Research Center,
Riyadh c
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh,
EP
TE D
Saudi Arabia.
Address Correspondence to: Dr Brahim Tabarki, Division of Neurology, Department of
AC C
Pediatrics, Prince Sultan Military Medical City, PO Box 7889, 11159 Riyadh, Saudi Arabia
Tel. +96614777714
Email. [email protected]
Number of videos: 2 Running title: Sepiapterin reductase deficiency
ACCEPTED MANUSCRIPT 2
RI PT
Abstract
Sepiapterin reductase deficiency is a rare, under-recognized, autosomal recessively inherited disorder of neurotransmitter metabolism. Five new patients from 3 unrelated
SC
Saudi consanguineous families are reported. Symptoms began at 6 months, with delay to diagnosis averaging 8 years. All 5 patients presented with severe symptoms including
M AN U
axial hypotonia, dystonia, and cognitive impairment, associated with hyper-reflexia (4 patients), spasticity (4 patients), bulbar dysfunction (4 patients), and oculogyric crisis (2 patients) with diurnal fluctuation and sleep benefit. Cerebrospinal fluid neurotransmitters analysis showed a typical pattern with increased sepiapterin and increased 7,8-
TE D
dihydrobiopterin. Analysis of the SPR gene identified 3 novel mutations: c.1A>G, c.370T>C, and c.527C>T. Patient one, with early diagnosis, is currently developing within the normal range. The 4 other patients showed significant improvement in their
EP
motor function, but only mild improvement in their cognitive dysfunction. Our cases illustrate the difficulties in the diagnosis of sepiapterin reductase deficiency in infancy,
AC C
and the importance of early recognition and management.
Key words: Sepiapterin reductase deficiency, hypotonia, oculogyric crisis, CSF neurotransmitters
ACCEPTED MANUSCRIPT
1. Introduction
Sepiapterin
reductase
deficiency (SRD) is
RI PT
3
a rare, inherited
dopa sensitive
SC
neurotransmitter disorder, caused by autosomal recessive mutations in the sepiapterin reductase (SPR) gene. The sepiapterin reductase enzyme is the last step in the
M AN U
tetrahydrobiopterin cofactor biosynthesis pathway, and this tetrahydrobiopterin cofactor is required, among others, for catecholamine and serotonin biosynthesis.1 In the early stages, the triad of paroxysmal stiffening, oculogyric crises and hypotonia are highly suggestive in some patients.2,3 In other patients features are nonspecific, and usually remain under-recognized and misdiagnosed as cerebral palsy with hypotonia or dystonia.1
TE D
In reporting the following 5 new cases identified from Saudi Arabia, we stress the importance of early diagnosis of this condition to provide timely and proper treatment.
EP
2. Case reports
AC C
Illustrative case report (case 1)
We present a 24-month-old boy, the second child born to consanguineous Saudi parents. His 4-year-old sister, was diagnosed with hypotonic cerebral palsy with dystonia and received rehabilitation treatment. The parents described the boy’s abnormal movements at 3 months of age as sudden stiffening of the whole body, extension of all extremities, and upward gaze lasting for several minutes often after meals, which we also observed
ACCEPTED MANUSCRIPT 4
during his hospital stay (video 1). These abnormal movements were, initially, mistaken for seizures. The pregnancy and delivery were uneventful. The birth weight was 3 kg, the length 49 cm, and head circumference 35 cm. He was seen for the first time at the age of
RI PT
10 months. The growth parameters were normal, but there was significant developmental delay; mainly motor. He could not hold his neck, could not sit even with support, and was not reaching for objects. He had severe axial hypotonia, with normal deep tendon
SC
reflexes. He had a social smile, and could fix and follow. There was no babbling. The systemic examination was unremarkable, no dysmorphism, no organomegaly, or skin
M AN U
stigmata. Several episodes were recorded in the 24h video-EEG, but no epileptiform discharges or any EEG correlate could be identified. The brain MRI was unremarkable, as was as tandem mass spectrometry, urine organic acid, ammonia, and lactic acid.
The cerebrospinal fluid (CSF) neurotransmitter pattern was abnormal with elevated levels
TE D
of sepiapterin, 14 nmol/L (normal range: not detectable), and 7,8-Dihydrobiopterin 138 nmol/l (0 – 18 nmol/l), and low levels of 5-hydroxyindolacetic acid (5-HIAA), 57 nmol/l
EP
(170 – 412 nmol/l), homovanillic acid (HVA), 69 nmol/l (403 – 919 nmol/l), and a ratio of HVA to 5-HIAA, 1.2 (1.8 – 3.0).
AC C
Mutation analysis revealed a novel homozygous mutation in the SPR gene: c.527C>T (p.A176V), in exon 2, probably causing a nonfunctional enzyme. Both parents were confirmed carriers for the same mutation. His sister was tested, and found to have the same mutation (case 2).
He was started on Sinemet (L-dopa/carbidopa) at 1.5 mg/kg/day, gradually increased over 5 months until reaching 13 mg/kg/day. He showed significant improvement over
ACCEPTED MANUSCRIPT 5
one week; with complete cessation of the oculogyric crisis. Over the next month, he started to sit unsupported, communicate well by cooing, laughing, turning his head to voices, and recognizing his parents (video 2). Currently, he is 24 months old. His motor,
RI PT
language, and cognitive development are within the normal range. The medication was well, tolerated with no side effects observed; and he was recently started on 5-
SC
hydroxytriptophan.
Summary of the 5 cases
M AN U
The main clinical, and genetic findings of our cohort of 5 patients from 3 unrelated Saudi consanguineous families, are summarized in Table 1. Symptoms began at 6 months (range: 3 to 12 months), with a delay to diagnosis averaging 8 years. All 5 patients presented with severe symptoms including axial hypotonia, dystonia, and cognitive
TE D
impairment (only patient 1 had mild cognitive impairment), associated with hyperreflexia in 4 patients, spasticity in 4 patients, bulbar dysfunction in 4 patients (drooling, dysphagia, dysarthria), and oculogyric crisis in 2 patients with diurnal fluctuation and
EP
sleep benefit. One patient showed microcephaly. The brain MRI and EEG findings were normal in all patients. Analysis of the SPR gene identified 3 novel mutations: c.1A>G,
AC C
c.370T>C, and c.527C>T.
All 5 patients were treated with L-dopa/carbidopa (dose ranging from 1 mg/kg/d to 13 mg/kg/d) and 2 patients received a combination of L-dopa and 5-hydroxytriptophan. Patient 1 who had an early diagnosis is currently developing within the normal range, including the motor, language, and cognitive milestones. The 4 other patients had shown a significant improvement in their motor function, starting to walk, improvement of
ACCEPTED MANUSCRIPT 6
dystonia and spasticity, improvement of their sleep, but only mild improvement in their
RI PT
cognitive dysfunction.
3. Discussion
SC
These 5 new patients share with the other approximately 50 cases of SRD reported in the literature4 the core features of dopa-responsive, diurnally fluctuating movement disorder,
M AN U
and motor and cognitive delay (Table 1). Interestingly, oculogyric crises, in contrast with most previous cases, were absent in 3 patients.
The clinical presentation of SRD seems to be age specific. The triad of paroxysmal stiffening, oculogyric crises, and hypotonia, as observed in patient 1, tends to occur early in infancy, and should be defined as early clinical hallmarks of SRD.1-4 Oculogyric crises,
TE D
when present, are a good distinguishing sign. Over time, there is development of limb hypertonia, hyper-reflexia, dystonia, and more apparent diurnal fluctuation and sleep
EP
disturbance. Patients with SRD may pose a diagnostic challenge especially early and in those with milder phenotypes, or normal intelligence, or both. As pointed out by
AC C
Friedman et al, SRD is commonly misdiagnosed as cerebral palsy.1 The developmental delay and hypotonia may be the only initial symptoms without prominent movement disorder adding to difficulties in early recognition. The diagnosis of SRD relies on CSF analysis of neurotransmitters and SPR gene analysis. Typically CSF analysis of neurotransmitters shows very low levels of neurotransmitter metabolites HVA, 5-HIAA and increased sepiapterin and increased 7,8-dihydrobiopterin
ACCEPTED MANUSCRIPT 7
and total biopterin. It was recently showen that urine sepiapterin excretion can be used as diagnostic marker for SRD.6
RI PT
Twenty pathogenic variants have been reported in SPR (including our 3 mutations).4 Known pathogenic variants are missense, nonsense, and frame-shift. Pathogenic variants have been found in all 3 exons, the 5’ untranslated region, and the intronic region in the
SC
splicing acceptor consensus sequence preceding exon 3. Homozygosity for the intronic variant c.596-2A>G was the most common genotype found in a cohort of affected
M AN U
individuals from Malta, suggesting a possible founder effect.7
SRD is a treatable neurometabolic condition, especially if diagnosed and treated early. Most patients seem to respond to a combination therapy with L-dopa and 5hydroxytryptophan.1 As some patients may easily develop side effects, a very low
TE D
starting dosage of about 0.5 to 2 mg/kg/day is recommended. Because of the short halflife period of L-dopa, the ideal dosing frequency would be at least 3 times daily. Treatment with L-dopa alone or with 5-hydroxytryptophan seems, also, to improve the
EP
cognitive performance, as reported in 13 over 38 patients (34%) by Friedman et al.7 The main contributor to neurologic dysfunction (at least motor) in SRD, is the
AC C
neurotransmitter deficit as this may be reversed by precursor supplementation. the residual deficits not responsive to precursor supplementation may be due to underlying fixed brain abnormalities. These fixed abnormalities may be related to elevated dihydrobiopterin and sepiapterin in CSF.
ACCEPTED MANUSCRIPT 8
In conclusion, increased awareness of SRD, will improve the early recognition and treatment of this under-recognized treatable condition. Sepiapterin reductase deficiency should be considered in all childhood, motor/cognitive disorders, especially if axial
RI PT
hypotonia, dystonia, or oculogyric crises are present. Children with developmental delay and normal MRI have to be meticulously evaluated for the presence of subtle movement
AC C
EP
TE D
M AN U
SC
or motor fluctuations as another valuable clue to the diagnosis of SRD.
ACCEPTED MANUSCRIPT
No funding was secured for this study. Financial disclosure
SC
Funding source
RI PT
9
M AN U
The authors have no financial relationships relevant to this article to disclose. Conflict of interest
The authors have no conflicts of interest to disclose. Informed consent
TE D
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from the
EP
patients for being included in the study. No animals were used in this study. A copy of
AC C
the written consent is available for review by the Editor-in-Chief of this journal.
Authors contributions
Sarah AlSubhi, Saad AlShahwan, Mohamed AlMuhaizae, Hamed AlZaidan, and Brahim Tabarki participated in the design, writing, and review of this article.
ACCEPTED MANUSCRIPT
RI PT
10
SC
ACKNOWLEDGEMENT
AC C
EP
TE D
neurotransmitters analysis.
M AN U
We thank Dr Thomas Opladen, University hospital Heidelberg, for performing CSF
ACCEPTED MANUSCRIPT
RI PT
11
SC
References
1. Friedman J, Roze E, Abdenur JE, et al. Sepiapterin reductase deficiency: a
M AN U
treatable mimic of cerebral palsy. Ann Neurol. 2012;71:520-530.
2. Dill P, Wagner M, Somerville A, Thöny B, Blau N, Weber P. Child neurology: paroxysmal stiffening, upward gaze, and hypotonia: hallmarks of sepiapterin reductase deficiency. Neurology. 2012;78:e29-32.
3. Leuzzi V, Carducci C, Tolve M, Giannini MT, Angeloni A, Carducci C. Very
TE D
early pattern of movement disorders in sepiapterin reductase deficiency. Neurology. 2013;81:2141-2.
EP
4. Friedman J. Sepiapterin Reductase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford
AC C
HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington,Seattle;1993-2016.2015 Jul 1.
5. Arrabal L, Teresa L, Sánchez-Alcudia R, et al. Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. Neurogenetics. 2011;12:183-191.
ACCEPTED MANUSCRIPT 12
6. Carducci C, Santagata S, Friedman J, et al. Urine sepiapterin excretion as a new diagnostic marker for sepiapterin reductase deficiency. Mol Genet Metab. 2015;115:157-160.
RI PT
7. Neville BG, Parascandalo R, Farrugia R, Felice A. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain.
SC
2005;128(Pt 10):2291-2296.
M AN U
Video Legend
Patient 1 at 10 months of age: video 1 shows frequent oculogyric crisis and stiffness.
AC C
EP
TE D
Video 2 shows the remarkable improvement after starting treatment.
4 female 6 months
5 male 12 months
6 years
9 years
Severe moderate
severe mild
-
-
+ -
+ -
SC
ACCEPTED MANUSCRIPT Patient Gender Age at first symptom
1 male 3 months
2 female 3 months
Age at diagnosis
15 months
7
Motor delay Cognitive delay
Severe severe
severe moderate
severe moderate
Diurnal variation
+
+
-
Dystonia Oculogyric crisis
+ +
+ +
+ -
Speech delay Sleep benefit Axial hypotonia
+ + +
+ + +
+ + +
+ + +
+ + +
Limb hypertonia
-
episodic
permanent
permanent
episodic
SPR mutation
c.527C>T (p.Ala176Val)
c.527C>T (p.Ala176Val)
c.1A>G (p.Met1Val)
c.1A>G (p.Met1Val)
c.370 T>C (p.Trp124Arg)
Treatment outcome
Started to sit unsupported , communicates up to his age , recognize parents
Dystonia cessation,started to stand and walk with support , speech improvement
Started to use wheel chair , speech and communication improvement, dystonia cessation
Started to walk, dystonia cessation
Mainly motor, dystonia cessation
TE D
EP
16
1/2
years
RI PT
years
M AN U
1/2
3 male 6 months
AC C
Table 1. Summary of the main clinical and genetic findings
ACCEPTED MANUSCRIPT
Highlights
RI PT
Sepiapterin reducatse deficiency should be considered in patients with motor/cognitive delay, dystonia, or oculogyric crisis
It contributes to better recognition of the clinical pattern of sepiapterin reductase deficiency, a
SC
treatable neurometabolic condition
AC C
EP
TE D
M AN U
It emphasizes the importance of early diagnosis and treatment of sepiapterin reductase deficiency
S1090-3798(17)30070-3
DOI:
10.1016/j.ejpn.2017.01.010
Reference:
YEJPN 2180
To appear in:
European Journal of Paediatric Neurology
Received Date: 29 July 2016 Revised Date:
5 January 2017
Accepted Date: 16 January 2017
Please cite this article as: AlSubhi S, AlShahwan S, AlMuhaizae M, AlZaidan H, Tabarki B, Sepiapterin reductase deficiency: Report of 5 new cases, European Journal of Paediatric Neurology (2017), doi: 10.1016/j.ejpn.2017.01.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Video is part of the ms
RI PT
Sepiapterin reductase deficiency: Report of 5 new cases
Sarah AlSubhia, Saad AlShahwana, Mohamed AlMuhaizaeb, Hamed AlZaidanc, Brahim
a
SC
Tabarkia,*
Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City,
M AN U
Riyadh b
Department of Neurosciences, King Faisal Specialist Hospital and Research Center,
Riyadh c
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh,
EP
TE D
Saudi Arabia.
Address Correspondence to: Dr Brahim Tabarki, Division of Neurology, Department of
AC C
Pediatrics, Prince Sultan Military Medical City, PO Box 7889, 11159 Riyadh, Saudi Arabia
Tel. +96614777714
Email. [email protected]
Number of videos: 2 Running title: Sepiapterin reductase deficiency
ACCEPTED MANUSCRIPT 2
RI PT
Abstract
Sepiapterin reductase deficiency is a rare, under-recognized, autosomal recessively inherited disorder of neurotransmitter metabolism. Five new patients from 3 unrelated
SC
Saudi consanguineous families are reported. Symptoms began at 6 months, with delay to diagnosis averaging 8 years. All 5 patients presented with severe symptoms including
M AN U
axial hypotonia, dystonia, and cognitive impairment, associated with hyper-reflexia (4 patients), spasticity (4 patients), bulbar dysfunction (4 patients), and oculogyric crisis (2 patients) with diurnal fluctuation and sleep benefit. Cerebrospinal fluid neurotransmitters analysis showed a typical pattern with increased sepiapterin and increased 7,8-
TE D
dihydrobiopterin. Analysis of the SPR gene identified 3 novel mutations: c.1A>G, c.370T>C, and c.527C>T. Patient one, with early diagnosis, is currently developing within the normal range. The 4 other patients showed significant improvement in their
EP
motor function, but only mild improvement in their cognitive dysfunction. Our cases illustrate the difficulties in the diagnosis of sepiapterin reductase deficiency in infancy,
AC C
and the importance of early recognition and management.
Key words: Sepiapterin reductase deficiency, hypotonia, oculogyric crisis, CSF neurotransmitters
ACCEPTED MANUSCRIPT
1. Introduction
Sepiapterin
reductase
deficiency (SRD) is
RI PT
3
a rare, inherited
dopa sensitive
SC
neurotransmitter disorder, caused by autosomal recessive mutations in the sepiapterin reductase (SPR) gene. The sepiapterin reductase enzyme is the last step in the
M AN U
tetrahydrobiopterin cofactor biosynthesis pathway, and this tetrahydrobiopterin cofactor is required, among others, for catecholamine and serotonin biosynthesis.1 In the early stages, the triad of paroxysmal stiffening, oculogyric crises and hypotonia are highly suggestive in some patients.2,3 In other patients features are nonspecific, and usually remain under-recognized and misdiagnosed as cerebral palsy with hypotonia or dystonia.1
TE D
In reporting the following 5 new cases identified from Saudi Arabia, we stress the importance of early diagnosis of this condition to provide timely and proper treatment.
EP
2. Case reports
AC C
Illustrative case report (case 1)
We present a 24-month-old boy, the second child born to consanguineous Saudi parents. His 4-year-old sister, was diagnosed with hypotonic cerebral palsy with dystonia and received rehabilitation treatment. The parents described the boy’s abnormal movements at 3 months of age as sudden stiffening of the whole body, extension of all extremities, and upward gaze lasting for several minutes often after meals, which we also observed
ACCEPTED MANUSCRIPT 4
during his hospital stay (video 1). These abnormal movements were, initially, mistaken for seizures. The pregnancy and delivery were uneventful. The birth weight was 3 kg, the length 49 cm, and head circumference 35 cm. He was seen for the first time at the age of
RI PT
10 months. The growth parameters were normal, but there was significant developmental delay; mainly motor. He could not hold his neck, could not sit even with support, and was not reaching for objects. He had severe axial hypotonia, with normal deep tendon
SC
reflexes. He had a social smile, and could fix and follow. There was no babbling. The systemic examination was unremarkable, no dysmorphism, no organomegaly, or skin
M AN U
stigmata. Several episodes were recorded in the 24h video-EEG, but no epileptiform discharges or any EEG correlate could be identified. The brain MRI was unremarkable, as was as tandem mass spectrometry, urine organic acid, ammonia, and lactic acid.
The cerebrospinal fluid (CSF) neurotransmitter pattern was abnormal with elevated levels
TE D
of sepiapterin, 14 nmol/L (normal range: not detectable), and 7,8-Dihydrobiopterin 138 nmol/l (0 – 18 nmol/l), and low levels of 5-hydroxyindolacetic acid (5-HIAA), 57 nmol/l
EP
(170 – 412 nmol/l), homovanillic acid (HVA), 69 nmol/l (403 – 919 nmol/l), and a ratio of HVA to 5-HIAA, 1.2 (1.8 – 3.0).
AC C
Mutation analysis revealed a novel homozygous mutation in the SPR gene: c.527C>T (p.A176V), in exon 2, probably causing a nonfunctional enzyme. Both parents were confirmed carriers for the same mutation. His sister was tested, and found to have the same mutation (case 2).
He was started on Sinemet (L-dopa/carbidopa) at 1.5 mg/kg/day, gradually increased over 5 months until reaching 13 mg/kg/day. He showed significant improvement over
ACCEPTED MANUSCRIPT 5
one week; with complete cessation of the oculogyric crisis. Over the next month, he started to sit unsupported, communicate well by cooing, laughing, turning his head to voices, and recognizing his parents (video 2). Currently, he is 24 months old. His motor,
RI PT
language, and cognitive development are within the normal range. The medication was well, tolerated with no side effects observed; and he was recently started on 5-
SC
hydroxytriptophan.
Summary of the 5 cases
M AN U
The main clinical, and genetic findings of our cohort of 5 patients from 3 unrelated Saudi consanguineous families, are summarized in Table 1. Symptoms began at 6 months (range: 3 to 12 months), with a delay to diagnosis averaging 8 years. All 5 patients presented with severe symptoms including axial hypotonia, dystonia, and cognitive
TE D
impairment (only patient 1 had mild cognitive impairment), associated with hyperreflexia in 4 patients, spasticity in 4 patients, bulbar dysfunction in 4 patients (drooling, dysphagia, dysarthria), and oculogyric crisis in 2 patients with diurnal fluctuation and
EP
sleep benefit. One patient showed microcephaly. The brain MRI and EEG findings were normal in all patients. Analysis of the SPR gene identified 3 novel mutations: c.1A>G,
AC C
c.370T>C, and c.527C>T.
All 5 patients were treated with L-dopa/carbidopa (dose ranging from 1 mg/kg/d to 13 mg/kg/d) and 2 patients received a combination of L-dopa and 5-hydroxytriptophan. Patient 1 who had an early diagnosis is currently developing within the normal range, including the motor, language, and cognitive milestones. The 4 other patients had shown a significant improvement in their motor function, starting to walk, improvement of
ACCEPTED MANUSCRIPT 6
dystonia and spasticity, improvement of their sleep, but only mild improvement in their
RI PT
cognitive dysfunction.
3. Discussion
SC
These 5 new patients share with the other approximately 50 cases of SRD reported in the literature4 the core features of dopa-responsive, diurnally fluctuating movement disorder,
M AN U
and motor and cognitive delay (Table 1). Interestingly, oculogyric crises, in contrast with most previous cases, were absent in 3 patients.
The clinical presentation of SRD seems to be age specific. The triad of paroxysmal stiffening, oculogyric crises, and hypotonia, as observed in patient 1, tends to occur early in infancy, and should be defined as early clinical hallmarks of SRD.1-4 Oculogyric crises,
TE D
when present, are a good distinguishing sign. Over time, there is development of limb hypertonia, hyper-reflexia, dystonia, and more apparent diurnal fluctuation and sleep
EP
disturbance. Patients with SRD may pose a diagnostic challenge especially early and in those with milder phenotypes, or normal intelligence, or both. As pointed out by
AC C
Friedman et al, SRD is commonly misdiagnosed as cerebral palsy.1 The developmental delay and hypotonia may be the only initial symptoms without prominent movement disorder adding to difficulties in early recognition. The diagnosis of SRD relies on CSF analysis of neurotransmitters and SPR gene analysis. Typically CSF analysis of neurotransmitters shows very low levels of neurotransmitter metabolites HVA, 5-HIAA and increased sepiapterin and increased 7,8-dihydrobiopterin
ACCEPTED MANUSCRIPT 7
and total biopterin. It was recently showen that urine sepiapterin excretion can be used as diagnostic marker for SRD.6
RI PT
Twenty pathogenic variants have been reported in SPR (including our 3 mutations).4 Known pathogenic variants are missense, nonsense, and frame-shift. Pathogenic variants have been found in all 3 exons, the 5’ untranslated region, and the intronic region in the
SC
splicing acceptor consensus sequence preceding exon 3. Homozygosity for the intronic variant c.596-2A>G was the most common genotype found in a cohort of affected
M AN U
individuals from Malta, suggesting a possible founder effect.7
SRD is a treatable neurometabolic condition, especially if diagnosed and treated early. Most patients seem to respond to a combination therapy with L-dopa and 5hydroxytryptophan.1 As some patients may easily develop side effects, a very low
TE D
starting dosage of about 0.5 to 2 mg/kg/day is recommended. Because of the short halflife period of L-dopa, the ideal dosing frequency would be at least 3 times daily. Treatment with L-dopa alone or with 5-hydroxytryptophan seems, also, to improve the
EP
cognitive performance, as reported in 13 over 38 patients (34%) by Friedman et al.7 The main contributor to neurologic dysfunction (at least motor) in SRD, is the
AC C
neurotransmitter deficit as this may be reversed by precursor supplementation. the residual deficits not responsive to precursor supplementation may be due to underlying fixed brain abnormalities. These fixed abnormalities may be related to elevated dihydrobiopterin and sepiapterin in CSF.
ACCEPTED MANUSCRIPT 8
In conclusion, increased awareness of SRD, will improve the early recognition and treatment of this under-recognized treatable condition. Sepiapterin reductase deficiency should be considered in all childhood, motor/cognitive disorders, especially if axial
RI PT
hypotonia, dystonia, or oculogyric crises are present. Children with developmental delay and normal MRI have to be meticulously evaluated for the presence of subtle movement
AC C
EP
TE D
M AN U
SC
or motor fluctuations as another valuable clue to the diagnosis of SRD.
ACCEPTED MANUSCRIPT
No funding was secured for this study. Financial disclosure
SC
Funding source
RI PT
9
M AN U
The authors have no financial relationships relevant to this article to disclose. Conflict of interest
The authors have no conflicts of interest to disclose. Informed consent
TE D
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from the
EP
patients for being included in the study. No animals were used in this study. A copy of
AC C
the written consent is available for review by the Editor-in-Chief of this journal.
Authors contributions
Sarah AlSubhi, Saad AlShahwan, Mohamed AlMuhaizae, Hamed AlZaidan, and Brahim Tabarki participated in the design, writing, and review of this article.
ACCEPTED MANUSCRIPT
RI PT
10
SC
ACKNOWLEDGEMENT
AC C
EP
TE D
neurotransmitters analysis.
M AN U
We thank Dr Thomas Opladen, University hospital Heidelberg, for performing CSF
ACCEPTED MANUSCRIPT
RI PT
11
SC
References
1. Friedman J, Roze E, Abdenur JE, et al. Sepiapterin reductase deficiency: a
M AN U
treatable mimic of cerebral palsy. Ann Neurol. 2012;71:520-530.
2. Dill P, Wagner M, Somerville A, Thöny B, Blau N, Weber P. Child neurology: paroxysmal stiffening, upward gaze, and hypotonia: hallmarks of sepiapterin reductase deficiency. Neurology. 2012;78:e29-32.
3. Leuzzi V, Carducci C, Tolve M, Giannini MT, Angeloni A, Carducci C. Very
TE D
early pattern of movement disorders in sepiapterin reductase deficiency. Neurology. 2013;81:2141-2.
EP
4. Friedman J. Sepiapterin Reductase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford
AC C
HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington,Seattle;1993-2016.2015 Jul 1.
5. Arrabal L, Teresa L, Sánchez-Alcudia R, et al. Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. Neurogenetics. 2011;12:183-191.
ACCEPTED MANUSCRIPT 12
6. Carducci C, Santagata S, Friedman J, et al. Urine sepiapterin excretion as a new diagnostic marker for sepiapterin reductase deficiency. Mol Genet Metab. 2015;115:157-160.
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7. Neville BG, Parascandalo R, Farrugia R, Felice A. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain.
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2005;128(Pt 10):2291-2296.
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Video Legend
Patient 1 at 10 months of age: video 1 shows frequent oculogyric crisis and stiffness.
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EP
TE D
Video 2 shows the remarkable improvement after starting treatment.
4 female 6 months
5 male 12 months
6 years
9 years
Severe moderate
severe mild
-
-
+ -
+ -
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ACCEPTED MANUSCRIPT Patient Gender Age at first symptom
1 male 3 months
2 female 3 months
Age at diagnosis
15 months
7
Motor delay Cognitive delay
Severe severe
severe moderate
severe moderate
Diurnal variation
+
+
-
Dystonia Oculogyric crisis
+ +
+ +
+ -
Speech delay Sleep benefit Axial hypotonia
+ + +
+ + +
+ + +
+ + +
+ + +
Limb hypertonia
-
episodic
permanent
permanent
episodic
SPR mutation
c.527C>T (p.Ala176Val)
c.527C>T (p.Ala176Val)
c.1A>G (p.Met1Val)
c.1A>G (p.Met1Val)
c.370 T>C (p.Trp124Arg)
Treatment outcome
Started to sit unsupported , communicates up to his age , recognize parents
Dystonia cessation,started to stand and walk with support , speech improvement
Started to use wheel chair , speech and communication improvement, dystonia cessation
Started to walk, dystonia cessation
Mainly motor, dystonia cessation
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16
1/2
years
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years
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1/2
3 male 6 months
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Table 1. Summary of the main clinical and genetic findings
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Highlights
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Sepiapterin reducatse deficiency should be considered in patients with motor/cognitive delay, dystonia, or oculogyric crisis
It contributes to better recognition of the clinical pattern of sepiapterin reductase deficiency, a
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treatable neurometabolic condition
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TE D
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It emphasizes the importance of early diagnosis and treatment of sepiapterin reductase deficiency