Dataset Information

Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature.

ABSTRACT:

Background

Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients with this condition have been identified, and clinical and biochemical details remain incomplete.

Results

The present work reports a patient suffering from severe, recurrent episodes of metabolic acidosis and psychomotor delay, showing a pathogenic loss-of-function variation c.747_750del in homozygosity in SLC16A1 (which codes for MCT1). Persistent ketotic and lactic acidosis was accompanied by an abnormal excretion of organic acids related to redox balance disturbances. Together with an altered bioenergetic profile detected in patient-derived fibroblasts, this suggests possible mitochondrial dysfunction. Brain MRI revealed extensive, diffuse bilateral, symmetric signal alterations for the subcortical white matter and basal ganglia, together with corpus callosum agenesia.

Conclusions

These findings suggest that the clinical spectrum of MCT1 deficiency not only involves recurrent atacks of ketoacidosis, but may also cause lactic acidosis and neuromotor delay with a distinctive neuroimaging pattern including agenesis of corpus callosum and other brain signal alterations.

SUBMITTER: Stanescu S

PROVIDER: S-EPMC9215049 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature.

Stanescu Sinziana S Bravo-Alonso Irene I Belanger-Quintana Amaya A Pérez Belen B Medina-Diaz Montserrat M Ruiz-Sala Pedro P Flores Nathaly Paola NP Buenache Raquel R Arrieta Francisco F Rodríguez-Pombo Pilar P

Orphanet journal of rare diseases 20220621 1

<h4>Background</h4>Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients with this condition have been identified, and clinical and biochemical details remain incomplete.<h4>Results</h4>The present work reports a patient suffering from severe, recurrent episodes of metabolic acidosis and psychomotor delay, showing a pathogenic loss-of-function ...[more]

PMID: 35729663

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Project description:Monocarboxylate transporter 8 (MCT8) deficiency or the Allan-Herndon-Dudley Syndrome (AHDS) is an X-linked psychomotor disability syndrome with around 320 clinical cases described worldwide. SLC16A2 gene mutations, encoding the thyroid hormone (TH) transporter MCT8, result in intellectual disability due to impaired TH uptake in the developing brain. MCT8 deficiency is a multi-organ affecting disease with a predominant neuronal cell-based pathology, with the glial component inadequately investigated. However, deficiency in myelin, a key component of white matter (WM) enabling fast nerve conduction, is a TH-dependent hallmark of the disease. Nevertheless, analysis of the myelin status in AHDS patients has led to conflicting interpretations. The majority of individual case studies reported delayed myelination, that was restored later in life. In contrast, post-mortem studies and high-resolution MRIs detected WM (micro-) abnormalities throughout adolescence, suggesting permanent hypomyelination. Thus, interpretations vary depending on methodology to investigate WM microstructure. Further, it is unknown whether the mutation within the MCT8 is linked to the severity of the myelin deficiency. Consequently, terminology is inconsistent among reports, and AHDS is occasionally misdiagnosed as another WM disorder. The evolutionary conserved TH signaling pathway that promotes the generation of myelinating oligodendrocytes enabled deciphering how the lack of MCT8 might affect myelinogenesis. Linking patient findings on myelination to those obtained from models of MCT8 deficiency revealed underlying pathophysiological mechanisms, but knowledge gaps remain, notably how myelination progresses both spatially and temporally in MCT8 deficiency. This limits predicting how myelin integrity might benefit therapeutically, and when to initiate. A recurrent observation in clinical trials is the absence of neurological improvement. Testing MCT8-independent thyromimetics in models, and evaluating treatments used in other demyelinating diseases, despite different etiologies, is crucial to propose new therapeutic strategies combatting this devastating disease.

Dataset Information

Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature.

Background

Results

Conclusions

Publications

Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature.

Similar Datasets

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