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

Abstract

BackgroundInherited neurotransmitter disorders are primary defects of neurotransmitter metabolism. The main purpose of this retrospective cohort study was to identify prevalence of inherited neurotransmitter disorders.MethodsThis retrospective cohort study does not have inclusion criteria; rather included all patients who underwent cerebrospinal fluid (CSF) homovanillic and 5-hydroxyindol acetic acid measurements. Patients with CSF neurotransmitter investigations suggestive of an inherited neurotransmitter disorder and patients with normal or non-diagnostic CSF neurotransmitter investigations underwent direct sequencing of single gene disorders.ResultsThere were 154 patients between October 2004 and July 2013. Four patients were excluded due to their diagnosis prior to this study dates. Two major clinical feature categories of patients who underwent lumbar puncture were movement disorders or epilepsy in our institution. Twenty out of the 150 patients (13.3%) were diagnosed with a genetic disorder including inherited neurotransmitter disorders (6 patients) (dihydropteridine reductase, 6-pyruvoyl-tetrahydropterin synthase, guanosine triphosphate cyclohydrolase I, tyrosine hydroxylase, pyridoxine dependent epilepsy due to mutations in the ALDH7A1 gene and pyridoxamine-5-phosphate oxidase deficiencies) and non-neurotransmitter disorders (14 patients).ConclusionPrevalence of inherited neurotransmitter disorders was 4% in our retrospective cohort study. Eight out of the 150 patients (5.3%) had one of the treatable inherited metabolic disorders with favorable short-term neurodevelopmental outcomes, highlighting the importance of an early and specific diagnosis. Whole exome or genome sequencing might shed light to unravel underlying genetic defects of new inherited neurotransmitter disorders in near future.

Movement Disorders and Neurometabolic Diseases

“…Although abnormal movements in young children often alert the clinician to the possibility of an underlying neurotransmitter deficiency disorder, there is significant variability in patient presentation and severity within these disorders. 67,68 PNDs are typically diagnosed based on biochemical abnormalities. While serum and urine testing should be completed first, CSF collection and analysis is necessary for definitive diagnosis.…”

“…Movement disorders are predominant features in the following neurotransmitter deficiency diseases: 6-pyrvuvoyl-tetrahydropterin (PTPS) deficiency caused by pathogenic variants in the PTS gene; dihydropteridine reductase (DHPR) deficiency caused by pathogenic variants in the QDPR gene; autosomal recessive guanosine triphosphate cyclohydrolase 1 (GTPCH1) deficiency caused by pathogenic variants in the GCH1 gene; autosomal dominant GTPCH1 deficiency (dopa-responsive dystonia or Segawa syndrome) also caused by pathogenic variants in the GCH1 gene; aromatic L-amino acid decarboxylase (AADC) deficiency caused by pathogenic variants in the DDC gene; sepiapterin reductase (SR) deficiency caused by pathogenic variants in the SPR gene; and tyrosine hydroxylase (TH) deficiency caused by pathogenic variants in the TH gene. [68][69][70][71][72][73][74] It is important to recognize and quickly diagnose these conditions as several have specific treatments that can alter the disease course. PTPS deficiency responds well to treatment if initiated prior to six months of age.…”

Screening Inherited Metabolic Disorder in Children with Intellectual Disability and Epilepsy

“…Seizures may be a part of a more complex neurologic presentation or sometimes only feature as IMDs. Mercimek-Mahmutoglu et al (9) evaluated 150 patients who underwent lumbar puncture due to epilepsy and movement disorder. IMDs were diagnosed in 6 (4%) of 150 patients.…”

Secondary Abnormal CSF Neurotransmitter Metabolite Profiles in a Pediatric Tertiary Care Centre

“…4 They may be present in acquired central nervous system injuries, some genetic syndromes and inborn errors of metabolism other than congenital neurotransmitter disorders, epilepsy, and epileptic encephalopathy. [5][6][7][8] The mechanisms and approach to treatment of these secondary disorders of neurotransmission have only recently begun to be explored. 3,24 Epilepsy affects 1% of the population, 9 and it has been described to be associated with altered levels of monoamine neurotransmitters.…”