​MCT-8 Deficiency:
A Debilitating Condition
MCT-8 deficiency (also known as Monocarboxylate Transporter 8 deficiency) is a rare, X-linked genetic disorder caused by mutations in the SLC16A2 gene, which encodes the MCT-8 protein.
This protein plays a crucial role in the active transport of thyroid hormones, specifically triiodothyronine (T3), across cellular membranes.
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As a result of the defective or absent MCT-8 protein, T3 is unable to effectively enter cells in key tissues, including the brain, muscles, and heart, leading to profound systemic and neurological dysfunction.
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Etiology & Genetic Basis
MCT-8 deficiency is caused by mutations in the SLC16A2 gene located on the X chromosome. This gene encodes the monocarboxylate transporter 8 (MCT-8), a protein responsible for the cellular uptake of thyroid hormones, primarily T3 and to a lesser extent thyroxine (T4). In MCT-8 deficiency, mutations in the SLC16A2 gene lead to an impaired ability to transport T3 into cells, which disrupts the normal thyroid hormone signaling process.
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Inheritance
MCT-8 deficiency follows an X-linked recessive inheritance pattern, meaning that males with the mutated gene on their single X chromosome are most severely affected. Females, having two X chromosomes, can be carriers and often exhibit mild or asymptomatic forms of the disease, though some may show partial clinical manifestations. Male infants with the condition typically present in the neonatal period or early infancy with significant developmental and neurological deficits.
Pathogenesis
Disruption of Thyroid Hormone
Transport and Signaling
Thyroid hormones play a pivotal role in regulating metabolic processes, growth, development, and neurodevelopment. They exert their effects by entering target cells and binding to thyroid hormone receptors within the nucleus, which regulate gene expression involved in critical cellular functions, including metabolism, neurogenesis, and synaptic plasticity.
In MCT-8 deficiency, the defective MCT-8 transporter severely impairs the cellular uptake of T3, particularly in brain cells and other tissues where thyroid hormones are essential for normal function. The key pathophysiological mechanisms include:
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Elevated circulating T3 levels: Despite an overall deficiency in intracellular T3, plasma levels of T3 can be markedly elevated due to the inability of cells to uptake the hormone for intracellular use. This results in thyroid hormone dysregulation, which can affect systemic metabolism and cellular homeostasis.
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Deficient intracellular T3: Critical tissues like the brain, muscles, and heart exhibit deficient T3 levels, as the impaired MCT-8 transport prevents the hormone from entering cells and exerting its biological effects. In the brain, this results in impaired neurodevelopment, neurodegeneration, and a failure to regulate key processes like neuroplasticity, neurogenesis, and synaptic signaling.
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Reduced thyroid hormone signaling in the brain: The brain is especially sensitive to thyroid hormone deficiency, particularly during neurodevelopment. Insufficient T3 transport into neurons disrupts neurogenesis, synaptogenesis, and myelination, leading to severe neurological impairment and developmental delays.
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Altered dopamine and serotonin metabolism: The lack of efficient T3 signaling also affects the dopamine and serotonin pathways, crucial for mood regulation, cognition, and motor control. Deficient T3 leads to disruptions in the dopamine transporter (DAT) and serotonin metabolism, exacerbating motor symptoms and contributing to cognitive and psychiatric manifestations in MCT-8 deficiency.
Clinical Manifestations
The clinical presentation of MCT-8 deficiency is severe and multisystemic, with neurological impairment being the hallmark feature. Key clinical manifestations include:
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Developmental Delays:
Infants with MCT-8 deficiency often experience significant developmental delays, including delayed motor milestones (such as sitting, standing, and walking) and speech delays. Severe cognitive deficits typically manifest in early childhood, ranging from mild to profound intellectual disability.
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Neurological Impairments:
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Dystonia and Spasticity: Affected individuals frequently present with abnormal postures, involuntary muscle contractions, and poor coordination due to disruptions in motor control pathways.
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Ataxia: Impaired motor coordination and difficulty maintaining balance, often leading to falls and difficulty walking.
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Severe Hypotonia: Reduced muscle tone in infancy leads to feeding difficulties and delayed motor development.
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Cognitive Impairment:
Most individuals with MCT-8 deficiency experience severe cognitive disabilities, ranging from learning difficulties to profound intellectual disability. These deficits may affect verbal communication, social interaction, and adaptive behaviors, severely limiting quality of life.
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Speech and Communication Deficits:
The impairment of speech and language development is common. Many children exhibit difficulty with speech acquisition, and some may be nonverbal.
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Thyroid Hormone Dysregulation:
Although circulating T3 levels are elevated, there is a paradoxical deficiency in T3 within key tissues. This leads to altered metabolic regulation and endocrine abnormalities. Notably, elevated T3 levels and low T4 levels in the bloodstream are diagnostic features.
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Cardiovascular Symptoms:
Thyroid hormone dysregulation can also affect the cardiac system, with some individuals developing arrhythmias or other cardiac complications due to the lack of T3 action in the heart.
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Early Mortality:
In the most severe cases, respiratory failure, cardiac complications, or severe neurological degeneration may lead to early mortality in affected individuals.
Diagnostic Evaluation
Diagnosis of MCT-8 deficiency is confirmed through genetic testing to identify mutations in the SLC16A2 gene. Elevated T3 levels, with normal or low T4 levels, may also serve as a diagnostic indicator. Neuroimaging may reveal brain structural abnormalities in some individuals, though clinical findings are generally sufficient for diagnosis.
Current & Future
Therapeutic Approaches
Currently, there is no FDA-approved treatment or cure for MCT-8 deficiency, and management focuses on symptom management and supportive care, such as physical therapy, occupational therapy, and speech therapy.
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Currently, there are Thyroid hormone analogs being developed to bypass the MCT-8 transporter and effectively enter cells and restore normal thyroid hormone function. Unfortunately, these compounds have not been shown to address the neurological symptoms associated with the condition.
We believe that our compound AB-101 can address both the endocrinological AND the neurological symptoms associated with the MCT-8 deficiency to alleviate the symptoms and improve the quality of life for patients affected by MCT-8 deficiency.