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DOI: 10.1055/s-0038-1675559
Failing Transmission[*]
Publication History
Publication Date:
29 October 2018 (online)
In this issue of the journal, the Heidelberg group reviews our current understanding of metabolic disorders of neurotransmission, with a focus on the dopaminergic system.[1] For the readership of Neuropediatrics, knowledge of this field of neurometabolism is important because many of the related disorders show a good clinical response if treated appropriately![2]
Even as a group, inherited disorders of neurotransmitters are rare.[1] [2] This fact will undoubtedly be an important contributing factor to the limited awareness of clinicians with neurotransmitter deficiencies and thus to doctors' delay when it comes to appropriate diagnosis and treatment. A second obstacle to an early diagnosis of these disorders is that they are generally difficult to recognize since they have no pathognomonic clinical features, lack specific imaging and neurophysiologic characteristics, and don't show laboratory abnormalities during routine work-up. Third, even when considered in the differential diagnosis, the complex diagnostic work-up of (suspected) disorders of neurotransmitters, as extensively discussed by the authors, hampers a swift diagnosis. Altogether, the diagnostic and therapeutic delay encountered in many patients with neurotransmitter deficiencies unfortunately is many years, even up to decades.
As systematically described by Brennenstuhl and colleagues,[1] the cornerstone of the diagnostic process in these disorders is the measurement of neurotransmitter metabolites in cerebrospinal fluid (CSF). Obviously, in the new era of next generation sequencing, genetic work-up isn't that difficult anymore in those parts of the world where modern DNA techniques are available and a genetic diagnosis will often precede metabolic investigation of CSF. Nevertheless, (false) negative results of genetic analysis and the finding of so-called variants of unknown significance may still necessitate a lumbar puncture for metabolic work-up.
I don't agree with the authors' statement that “… any other differential diagnoses in a patient with suspicious muscular hypotonia or movement disorder should be considered before performing a lumbar puncture.” From my point of view, a lumbar puncture should simply (it is neither a difficult nor a dangerous diagnostic procedure) be performed if there is a good indication to study CSF, and the search for a treatable disorder is such a good indication! Fear of a lumbar puncture, encountered in parents but sometimes also in colleagues, should not impede the chance to diagnose a treatable neurometabolic disorder. I also think that clinicians who take care of children with serious neurological signs and symptoms, should either be aware of these neurotransmitters defects (as a group) or work in a network in which they can rely on colleagues who do so. Finally, even if no diagnostic possibilities are available, like in many resource poor countries, patients can at least have a relatively simple therapeutic trial with levodopa once “a neurotransmitter defect” is considered in the differential diagnosis.[3] Every pediatric neurologist, in every part of the world, can in this way contribute to early identification of treatable neurotransmitter deficiencies, with or without the possibility to perform sophisticated CSF or DNA analysis.
The paper by Brennenstuhl and colleagues[1] will increase awareness of clinicians and offers a helpful guide through the complex biochemical and genetic work-up of (suspected) neurotransmitter disorders. It also highlights that a group of clinical and laboratory experts has united in the international working group on neurotransmitter related disorders (iNTD), providing information via the internet and aiming to contribute scientifically to the intriguing field of cerebral neurotransmitter metabolism. It won't be difficult to find one of them for help, in case of diagnostic or therapeutic dilemmas. Ultimately, all different forms of low-threshold and optimal transmission of knowledge and experience between colleagues will be of great benefit for patients in whom transmission fails.
* This article is an editorial comment on “Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment” by Brennenstuhl et al (Neuropediatrics 2019; doi: 10.1055/s-0038-1673630).