Altered dopamine metabolism and response to treatment with levodopa/carbidopa in MCT8 deficiency 

---

In this report, we investigated the underlying mechanisms of movement disorders in Allan-Herndon-Dudley syndrome (AHDS) and evaluated the therapeutic efficacy of levodopa/carbidopa. Also known as monocarboxylate transporter 8 (MCT8) deficiency, AHDS is an ultra-rare X-linked encephalopathy caused by pathogenic variants in the SLC16A2 gene. Variants in this gene impair the transport of thyroid hormones (THs) across the blood-brain barrier beginning in early gestation. This results in markedly low THs levels within the central nervous system and, consequently, altered brain development across multiple cellular populations. 

Clinically, besides the endocrinological manifestations, notably a picture of peripheral thyrotoxicosis that can lead to severe metabolic and cardiac complications, this syndrome manifests with severe neurological impairment. This includes profound developmental delay and intellectual disability, axial hypotonia, spasticity, frequent epilepsy, and extrapyramidal signs that closely fit the definition of developmental parkinsonism. 

Because thyroid hormones are essential for both the fetal development of the basal ganglia and the postnatal synthesis and trafficking of dopamine, we hypothesized that the movement disorders seen in AHDS stem from dopaminergic circuitry impairment. 

To test this hypothesis, we evaluated a cohort of ten male patients presenting with hypokinetic movement disorders. The study measured biogenic amines in the patients' cerebrospinal fluid (CSF) and prospectively and/or retrospectively monitored their clinical response to a levodopa/carbidopa trial through clinical examination, standardized functional neuromotor scales, and videotaping before and after the trial. 

The CSF analysis confirmed dopaminergic pathway involvement. Levels of homovanillic acid (HVA), a primary dopamine metabolite, were pathologically low in three patients, while seven out of ten patients exhibited HVA levels in the lowest quartile of their respective age reference ranges. 

Subsequently, nine of the patients underwent a levodopa/carbidopa trial, titrating up to a target dose of 10 mg/kg/day. The clinical response was notably positive. At doses exceeding 7 to 8 mg/kg/day, seven out of the nine patients demonstrated clear improvements in their parkinsonian features. In fact, patients exhibited decreased hypokinesia and bradykinesia, as well as an improvement in hypomimia, allowing for more evident facial expressions such as smiling. Furthermore, patients showed enhanced attention, social interaction, and reactivity to environmental stimuli. While the increased spontaneous motor activity triggered slightly more prominent action dystonia in some patients, the majority of responders saw overall improvements in their gross motor function scores (GMFM-88). 

In conclusion, this study provides clinical and biochemical evidence that dopaminergic circuitry impairment is a component of AHDS complex pathophysiology. The findings highlight that levodopa/carbidopa is an effective treatment strategy for alleviating extrapyramidal symptoms and improving environmental reactivity in patients suffering from MCT8 deficiency. 

Read the paper