Prevalence of inherited neurotransmitter disorders in patients with movement disorders and epilepsy: a retrospective cohort study

Our retrospective cohort study reports 4% prevalence of inherited neurotransmitter disorders in patients with GDD, neonatal hypotonia, neonatal seizures, epilepsy and movement disorders, who underwent measurements of CSF catecholamine and serotonin metabolites for diagnostic work-up in a single center. Autosomal dominant GTPCH deficiency, TH deficiency, PTPS deficiency, DHPR deficiency, PDE-ALDH7A1 and PNPO deficiency combining inherited monoamine and pyridoxine metabolism disorders were identified in our study cohort. The prevalence of inherited monoamine metabolism disorders (autosomal dominant GTPCH, TH, DHPR and PTPS deficiencies) was 1.3% (4 out of 150 patients), which is similar compared to a previous study reporting 1.5% prevalence [26]. In a retrospective study of 62 patients who underwent CSF metabolic investigations for neurometabolic disorders, 16 patients (25.8%) were biochemically diagnosed with inherited neurotransmitter disorders [13]. None of these diagnoses were confirmed by molecular genetic investigations and the study included serine biosynthesis defects and cerebral folate deficiency, which are not classified as inherited neurotransmitter disorders [1]. For these reasons, this high prevalence of 25.8% is not a true prevalence study [13]. In our retrospective cohort study, 9.3% (14 out of 150) of the patients with normal or non-diagnostic CSF catecholamine and serotonin metabolite measurements had an identifiable genetic cause other than inherited neurotransmitter disorders (Figure 1). Approximately 5.3% (8 out of 150) of the patients had one of the treatable inherited neurotransmitter disorder or inherited metabolic disorder with favorable short-term neurodevelopmental outcomes, highlighting the importance of an early and specific diagnosis. This is a retrospective cohort study and does not include all patients who underwent lumbar puncture during the study period in our hospital. It might be likely that other neurotransmitter disorders, such as glycine encephalopathy and GABA metabolism disorders, are not captured, which might be diagnosed during this retrospective cohort study period.

The estimated incidence of inherited monoamine metabolism disorders with hyperphenylalaninemia is 1-2% of all patients with a positive screen for PKU in the newborn screening programs [7]. In our province, about 150,000 newborns per year are screened and our hospital is the reference center for about 50% of newborns. In our study, the estimated incidence of PTPS or DHPR deficiencies was about 1:320,000 newborns for each PTPS and DHPR deficiencies. In a recent large international registry of patients with tetrahydrobiopterin metabolism defects (BIODEF; http://​www.​biopku.​org), PTPS deficiency was the most common disorder (56.7%) and DHPR deficiency was the second most common disorder (34.7%) [7]. There are no detailed long-term treatment outcome studies reporting whether DHPR deficiency results in normal neurocognitive outcome. In our small study cohort, there were 5 patients with DHPR deficiency and long-term treatment outcome was available in four patients. One of the patients with strict phenylalanine-restricted diet and l-dopa/carbidopa and 5-hydroxytryptophan treatment had normal neurocognitive outcome at the age of 13 years, whereas, 3 patients with treatment compliance problems had various degrees of neurocognitive dysfunction. Detailed retrospective treatment outcome studies of patients with DHPR deficiency would be necessary to increase our understanding for this treatable disease. Studies are underway to determine, if sapropterin would be helpful to control phenylalanine levels instead of protein restricted diet to decrease further burden to the families as well as to decrease contribution of additional high phenylalanine neurotoxicity.

Autosomal dominant GTPCH deficiency is one of the rare and treatable inherited monoamine metabolism disorders [27]. Patients usually present with dystonia in childhood. Atypical presentations with Parkinsonian features e.g. tremor, have also been reported. In a review article, all patients had low CSF HVA, neopterin, and biopterin levels, and some patients had low to low-normal CSF 5-HIAA levels [27-29]. Our patient presented with tremors at the age of ten years, leading to measurements of CSF neurotransmitter metabolites and the diagnosis of autosomal dominant GTPCH deficiency. Less than 80 patients have been reported since the first description of TH deficiency. According to the recent phenotypic classification [30], our patient had very severe phenotype and was on high dose of L-dopa/carbidopa treatment. The only benefit of this treatment is improvements in choreoathetosis, which is in line with the patients reported in the literature for very severe phenotype of TH deficiency.

Low HVA levels secondary to various neurological disorders have been reported between 6-20% of patients [26,31]. In those studies, between 20-37% of the patients were diagnosed with one of the non-neurotransmitter genetic disorders [26,31]. In our cohort, 8 out of the 150 patients (5.3%) had low HVA and 5 (62.5%) of these patients had an underlying inherited neurotransmitter or non-neurotransmitter disorder with a confirmed underlying genetic diagnosis. In our retrospective cohort study, abnormal CSF neurotransmitter metabolite levels were present in 10 out of 130 (7.7%) patients with no identifiable genetic cause and 6 patients (60%) presented with a movement disorder including ataxia, tremor or dystonia. Interestingly, one of the patients was diagnosed with pyridoxal-phosphate responsive epilepsy based on the low HVA, 5-HIAA and pyridoxal-5-phosphate levels in CSF and responded to pyridoxal-5-phosphate monotherapy with seizure freedom. In this patient PDE-ALDH7A1 and PNPO deficiency have been excluded based on the normal urine alpha-amino adipic semialdehyde, direct sequencing and multiplex ligation dependent probe amplification of the ALDH7A1 and PNPO genes.

Targeted next-generation sequencing for movement disorders utilizing 151-gene panel has been recently reported with a diagnostic yield of 20% compared to targeted single gene Sanger sequencing diagnostic yield of 5% [32]. Targeted next-generation sequencing for epilepsy utilizing 35- 265-gene panels has been previously reported with diagnostic yields ranging between 10–48.5% [33-37]. The clinical targeted next generation epilepsy panels include PDE-ALDH7A1, PNPO and GLUT1 deficiencies and dystonia panels include TH, GTPCH, GLUT1, SR and dopamine transporter deficiencies. Expanding the genes in the targeted next generation dystonia panels including SLC18A2 (VMAT2 deficiency), AADC gene (AADC deficiency), QDPR (DHPR deficiency) and PTS (PTPS deficiency) would preempt the necessity of CSF neurotransmitter metabolite measurements. Targeted next generation sequencing panels for dystonia and epilepsy would be the most suitable investigation to apply as first line testing in patients with movement disorders and epilepsy rather than using CSF neurotransmitter measurements. In patients with high clinical suspicion of inherited neurotransmitter disorders who have a negative molecular genetic investigation, CSF neurotransmitter measurements could be helpful to guide symptomatic treatment.