Diagnosis and treatment of neurotransmitter disorders

Abstract

The neurotransmitter disorders represent an enigmatic and enlarging group of neurometabolic conditions caused by abnormal neurotransmitter metabolism or transport. A high index of clinical suspicion is important, given the availability of therapeutic strategies. This article covers disorders of monoamine (catecholamine and serotonin) synthesis, glycine catabolism, pyridoxine dependency, and gamma-aminobutyric acid (GABA) metabolism. The technological aspects of appropriate cerebrospinal fluid (CSF) collection, shipment, study, and interpretation merit special consideration. Diagnosis of disorders of monoamines requires analysis of CSF homovanillic acid, 5-hydroxyindoleacetic acid, ortho-methyldopa, BH4, and neopterin. The delineation of new disorders with important therapeutic implications, such as cerebral folate deficiency and PNPO deficiency, serves to highlight the value of measuring CSF neurotransmitter precursors and metabolites. The impressive responsiveness of Segawa fluctuating dystonia to levodopa is a hallmark feature of previously unrecognized neurologic morbidity becoming treatable at any age. Aromatic amino acid decarboxylase and tyrosine hydroxylase deficiency have more severe phenotypes and show variable responsiveness to levodopa. Glycine encephalopathy usually has a poor outcome; benzoate therapy may be helpful in less affected cases. Pyridoxine-dependent seizures are a refractory but treatable group of neonatal and infantile seizures; rare cases require pyridoxal-5-phosphate. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Treatment directed at the metabolic defect with vigabatrin has been disappointing, and multiple therapies are targeted toward specific but protean symptoms. Other disorders of GABA metabolism, as is true of the wide spectrum of neurotransmitter disorders, will require increasing use of CSF analysis for diagnosis, and ultimately, treatment.

Sepiapterin reductase deficiency in a 2‐year‐old girl with incomplete response to treatment during short‐term follow‐up

“…Our patient on treatment, similarly to earlier described patients, has demonstrated transitory worsening mainly during infections: weakness, intensification of oculogyric crises, and dystonic posturing of the limbs (Abeling et al 2006;Echenne et al 2006;Pearl 2006;Pearl et al 2004).…”

Association of cognition with temporal discounting in community based older persons

“…Second, an experienced neuropsychologist, blinded to subject age, sex, and race, reviewed the results of the cognitive testing including impairment ratings, data on education, sensory and motor deficits, and rendered a clinical judgment regarding the presence of cognitive impairment. Third, diagnostic classification was performed according to standard diagnostic criteria by an experienced clinician blinded to all previously collected data after a review of all available data from that year’s clinical evaluation, including the ratings by the neuropsychologist, MMSE scores and the details of the neurological examination [24,25]. …”

Doparesponsive dystonier

“…Sped-og småbarn med dystoni eller andre bevegelsesforstyrrelser, eventuelt ledsaget av andre nevrologiske symptomer som hypotoni, hypersomni og/eller autonom dysfunksjon, bør også utredes for doparesponsiv dystoni. Okulogyre kriser, som er anfall med dystone, konjugerte bevegelser av øynene, bør vekke mistanke om sykdommene (2,3,6,12,23,24).…”

“…På grunn av den gode behandlingsresponsen og det brede kliniske bildet ved doparesponsive dystonier bør pasientene utredes grundig (3,6,24). Mange pasienter gjennomgår først en negativ utredning med magnettomografi av hjernen, elektroencefalogram og rutinemessige spinalvaeskeundersøkelser (celler, protein, glukose, aminosyrekvantitering, laktat) samt metabolsk screening i urin og blod.…”