Two Greek siblings with sepiapterin reductase deficiency

Verbeek, Marcel M.; Willemsen, M.A.A.P.; Wevers, Ron A.; Lagerwerf, A.J.; Abeling, N. G. G. M.; Blau, Nenad; Thöny, Beat; Vargiami, Euthymia; Zafeiriou, Dimitrios I.

doi:10.1016/j.ymgme.2008.04.003

Cited by 23 publications

(21 citation statements)

References 20 publications

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“…4 Clinically the therapy provides a significant and rapid improvement (within hours) of the motor deficits, in some cases enabling immediate sitting, walking, and talking in patients who were not able to stand independently and speak more than a single word before treatment. 3,7,8 Fourteen of 20 cases showed partial improvement of motor symptoms, whereas 6/20 cases could achieve a normalization of motor skills. Unfortunately, there are dosagedependent side effects such as facial and limb dyskinesias which were observed in 5/20 cases and chorea in one case, especially when the dosage of L-dopa was elevated too fast.…”

Section: Discussion and Review Diagnostic Workupmentioning

confidence: 96%

“…[2][3][4][5][6][7][8][9][10] The cognitive impairment ranges were defined as mild to severe, with an IQ ranging between 36 and 60 in 4 tested cases. 4,8,10 There are only 2 patients who received treatment under 1 year of age.…”

Section: Discussion and Review Diagnostic Workupmentioning

confidence: 99%

“…10 Three of 21 cases, 2 Greek siblings 3 and 1 Dutch patient, 9 had minor cognitive delay prior to treatment with L-dopa and were able to attend normal school in later course upon treatment. 3 SRD shows specific clinical findings which may present in infancy as the triad of paroxysmal stiffening, upward gaze, and hypotonia. Later, childhood and adulthood dystonia with hypersomnia and ataxia may be striking.…”

Section: Discussion and Review Diagnostic Workupmentioning

confidence: 99%

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Child Neurology: Paroxysmal stiffening, upward gaze, and hypotonia

Dill¹,

Wagner²,

Somerville³

et al. 2012

Neurology

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Sepiapterin reductase deficiency (SRD) is a dopasensitive neurotransmitter disorder, caused by mutation of the SPR gene located on chromosome 2p14-p12. 1 To date, 31 patients with 14 mutations have been diagnosed (BIODEF database, update November 2010, www.biopku.org).While classic tetrahydrobiopterin deficiencies present with hyperphenylalaninemia and deficiency of monoamine neurotransmitters, SRD is typically associated with normal phenylalanine levels in blood and pterins in urine 2 and not detectable by neonatal screening for phenylketonuria. This implies how important it is to diagnose this condition clinically, in order to provide timely and proper treatment. A summary of the pathophysiology and biochemical pathway is provided by Bonafé et al. 2 With the following case report and review of 21 published cases, 2-10 we elucidate the clinical features of SRD as well as the diagnostic strategy and therapeutic approach.CASE REPORT We present a 5-month-old girl, the first and only child born to consanguineous Turkish parents. The parents described the girl's abnormal movements at 3 months of age as sudden stiffening of the whole body, extension of the extremities, upward gaze, and chewing movements lasting for several minutes often after meals, which we also could observe during her hospital stay. Pregnancy and delivery were uneventful. Birthweight, length, and head circumference were within normal ranges. During EEG, a few episodes with chewing movements could be recorded, but no epileptic discharges were evident. The brain MRI was unremarkable. We suspected gastroesophageal reflux and started therapy with omeprazole. The parents reported that the episodes diminished.At 8 months of age, the patient was readmitted because the crises recurred with an increased frequency and duration of up to 25 minutes. During the episodes, the patient revealed circling movements of the hands and rhythmic tremor of the tongue in addition to the previously mentioned symptoms. Remarkably, the symptoms could be interrupted by voluntary movements. For example, the patient could promptly focus and precisely grab an interesting toy. Yet the abnormal movements resumed immediately when the object was taken away. During these episodes the patient stayed fully conscious, but seemed to be mildly disturbed. Interestingly, the episodes became more severe and lasted longer when the child had an infection or was under emotional stress.Extensive diagnostic workup revealed an abnormal CSF neurotransmitter pattern with elevated levels of sepiapterin, 15.1 nmol/L (normal range: not detectable), and total biopterin 74 nmol/L (10 -50 nmol/L), and low levels of 5-hydroxyindolacetic acid, 10.3 nmol/L (114 -336 nmol/L), and homovanillic acid, 84 nmol/L (295-932 nmol/L), indicating a SRD. This could be confirmed by functional enzymatic fibroblast analysis in which the activity of sepiapterin reductase was not detectable (Ͻ0.1, normal range 99 -185 U/mg protein). Mutation analysis revealed a novel homozygous mutation in the SPR gene allele p.R219X in...

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Section: Discussion and Review Diagnostic Workupmentioning

confidence: 96%

Section: Discussion and Review Diagnostic Workupmentioning

confidence: 99%

Section: Discussion and Review Diagnostic Workupmentioning

confidence: 99%

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Child Neurology: Paroxysmal stiffening, upward gaze, and hypotonia

Dill¹,

Wagner²,

Somerville³

et al. 2012

Neurology

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“…Prolactin levels can also help in monitoring the medication (2,8,12,(15)(16)(17)(18)(19)(20)(21)(22)(23)25).…”

Section: Discussionmentioning

confidence: 99%

“…This disorder is classified as a neurotransmitter disorder (3,4,13,14). The clinical hallmarks of this rare, but probably underdiagnosed disorder are disease onset most often before 1 year of age with paroxysmal stiffening, upward gaze, and hypotonia (2,8,12,(15)(16)(17)(18)(19)(20)(21)(22)(23). Cognitive symptoms, speech disturbances, motoric delay, and dystonic movements with diurnal fluctuations are frequently seen, but normally occur later in the disease course.…”

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confidence: 99%

Clinical and genetic studies in a family with a novel mutation in the sepiapterin reductase gene

et al. 2014

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Objectives -Sepiapterin reductase deficiency is a rare, but treatable inherited disorder of tetrahydrobiopterin and neurotransmitter metabolism. This disorder is most probably underdiagnosed. To date, only 44 cases have been described in the literature. We present the clinical and genetic investigations in a family with a complex movement disorder. Materials and methods -We examined two affected sisters and three healthy family members. The cerebrospinal fluid was analyzed for neurotransmitter and pterins, and the sepiapterin reductase gene (SPR) was sequenced. Results -The sisters had a complex movement disorders with dystonia and diurnal fluctuations. Both had oculogyric crises, and the older sister also hypersomnia. Both sisters had raised prolactin levels twice above the reference level. One sister had a dramatic response to levodopa, the other responded, but developed dyskinesia despite low doses. Both patients improved dramatically over time with levodopa (2.3 and 1.5 mg/kg/day). Very low levels of homovanillic acid and 5-hydroxyindoleacetic acid and increased levels of sepiapterin and dihydrobiopterin were measured in the cerebrospinal fluid before treatment. DNA analyses revealed a novel homozygous mutation in exon 2 in the SPR gene, c.364A >G/p.(Tyr123Cys), located in a highly conserved region in the gene. Both parents and the healthy sister were carriers for the same mutation. Conclusions -A new homozygous mutation in the SPR gene was found in two sisters with dopa-responsive dystonia. This important and treatable neurotransmitter disorder must be considered in patients with a complex movement disorder with diurnal fluctuations with or without intellectual impairment. Patients with these symptoms should undergo levodopa trial, cerebrospinal fluid investigations, and genetic analyses.

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Sepiapterin reductase deficiency: A Treatable Mimic of Cerebral Palsy

Friedman

Roze

Abdenur

et al. 2012

Annals of Neurology

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134

138

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Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction.

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Two Greek siblings with sepiapterin reductase deficiency

Cited by 23 publications

References 20 publications

Child Neurology: Paroxysmal stiffening, upward gaze, and hypotonia

Child Neurology: Paroxysmal stiffening, upward gaze, and hypotonia

Clinical and genetic studies in a family with a novel mutation in the sepiapterin reductase gene

Sepiapterin reductase deficiency: A Treatable Mimic of Cerebral Palsy

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