Dopa-responsive dystonia due to sepiapterin reductase deficiency (OMIM#612716) is caused by recessive mutations in the gene encoding sepiapterin reductase (SPR), which plays an important role in the biosynthesis of tetrahydrobiopterin (BH4). One Jordanian patient to first cousin parents is reported in this study. The parents of the proband have recognized the symptoms of their daughter at six months old with motor developmental delay. The symptoms were progressed after-then to include speech delay, seizure, ataxia, oculomotor apraxia, dysarthia and choreoathetosis. Despite of these symptoms, the clinicians in Jordan were unable to diagnose the case. In August 2018, the proband (8 years old) was presented to the department of biotechnology and genetic engineering at Philadelphia University in Jordan for the purposes of performing whole exome sequencing (WES). Analysis of WES data has revealed novel homozygous frameshift variant in the gene SPR (NM_003124.4:c.40delG,p.Ala15Profs*100). The variant is heterozygous in the parents and in the healthy male siblings. Therefore, the studied case was diagnosed with sepiapterin reductase deficiency. Because this disease is likely to be treated recommendations were given to the family immediately to start treatments trials. The case in this study illustrates the difficulties of diagnosing sepiapterin reductase deficiency based on clinical symptoms only and thus renders the possibilities of early management. Also, this study reinforces the importance of running WES to undiagnosed neurodevelopmental cases.

Classic L-dopa-responsive dystonia is characterized by the triad of dystonia, diurnal fluctuation of signs, and dramatic response of signs to low-dose L-dopa therapy. Dopa-responsive dystonia succinctly summarizes the relevant clinical features. However, literal application of this label or consideration of dopa-responsive dystonia as a diagnostic end without molecular and/or biochemical definition may contribute to misdiagnosis and incomplete treatment in dopa-responsive conditions that impair synthesis of monoamine neurotransmitters besides dopamine. We describe and provide video for twin patients with a rare form of dopa-responsive dystonia due to sepiapterin reductase deficiency. As is typical in dopa-responsive dystonia, these patients displayed dramatic improvement with L-dopa/carbidopa therapy. However, treatment was suboptimal until 5-hydroxytryptophan was added to address their serotonergic deficit. Our report highlights the limitations of the dopa-responsive dystonia label and increases awareness of sepiapterin reductase deficiency and other conditions that may present as dopa-responsive dystonia. We provide a diagnostic and therapeutic approach to guide the clinician in evaluating and treating individuals with dopa-responsive dystonia.