A Novel Monocarboxylate Transporter 8 Gene Mutation as a Cause of Severe Neonatal Hypotonia and Developmental Delay

Papadimitriou, Anastasios; Dumitrescu, A; Papavasiliou, Antigone; Fretzayas, Andrew; Nicolaidou, Polyxeni; Refetoff, Samuel

doi:10.1542/peds.2007-1247

Cited by 49 publications

(43 citation statements)

References 16 publications

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“…This study's cohort has the same non‐specific perinatal characteristics as the 146 patients with AHDS reported in the literature Though we also found a 20% occurrence of neonatal jaundice, which was not previously reported, a symptom favoured by dysthyroidism.…”

Section: Discussionsupporting

confidence: 82%

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

Remerand

Boespflug‐Tanguy

Tonduti

et al. 2019

Develop Med Child Neuro

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The aim of the study was to redefine the phenotype of Allan–Herndon–Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty‐four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro‐orthopaedic, pulmonary, and epileptic complications. What this paper adds Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.

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Section: Discussionsupporting

confidence: 82%

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

Remerand

Boespflug‐Tanguy

Tonduti

et al. 2019

Develop Med Child Neuro

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“…1A). LT 4 treatment was previously reported in three other AHDS patients with a single-nucleotide substitution or deletion (15)(16)(17), compared to an almost complete deletion of the MCT8 gene in our patient. Yet, in spite of the distinct genetic differences, all four patients presented with a similar suppression of TSH and no change in cardiovascular indices or neurological functions in response to LT 4 administration.…”

Section: Discussionsupporting

confidence: 58%

“…Subsequently, MCT8 mutations result in a diminished intracellular T 3 concentration (8,9). Patients with MCT8 gene mutations present with severe psychomotor retardation, generalized dystonia combined with spasticity, lack of verbal communication, and poor head control and coordination (1,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). These neurological characteristics were attributed to impaired MCT8 transporter activity into the neurons of the CNS (8,18).…”

Section: Introductionmentioning

confidence: 99%

A child with a deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects of thyroid hormone treatment

Zung

Visser²,

Uitterlinden³

et al. 2011

European Journal of Endocrinology

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Objective: The monocarboxylate transporter 8 (MCT8; SLC16A2) has a pivotal role in neuronal triiodothyronine (T 3 ) uptake. Mutations of this transporter determine a distinct X-linked psychomotor retardation syndrome (Allan-Herndon-Dudley syndrome (AHDS)) that is attributed to disturbed thyroid hormone levels, especially elevated T 3 levels. We describe the genetic analysis of the MCT8 gene in a patient suspected for AHDS and the clinical and endocrine effects of L-thyroxine (LT 4 ) or liothyronine (LT 3 ) treatment intending to overcome the T 3 uptake resistance through alternative transporters. Methods: The six exons of the MCT8 gene were amplified individually by PCR. As multiple exons were missing, the length of the X-chromosomal deletion was determined by a dense SNP array, followed by PCR-based fine mapping to define the exact borders of the deleted segment. The clinical and endocrine data of the patient during 6.5 years of LT 4 treatment and two periods (3 months each) of low-and high-dose LT 3 were evaluated. Results: A partial deletion of the MCT8 gene (comprising five of six exons) was detected, confirming the suspected AHDS. MCT8 dysfunction was associated with partial resistance to T 3 at the hypothalamus and pituitary level, with normal responsiveness at the peripheral organs (liver and cardiovascular system). Thyroid hormone administration had no beneficial effect on the neurological status of the patient. Conclusion: We identified a 70 kb deletion encompassing exons 2-6 of the MCT8 gene in our AHDS patient. Both LT 4 and LT 3 administration had no therapeutic effect. Alternatively, treatment of AHDS patients with thyroid hormone analogs should be considered.

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“…Mutations have 100% penetrance in males who manifest both neuropsychomotor and characteristic thyroid tests abnormalities Carrier females may show only mild thyroid test abnormalities [6, 89, 90]. A single female manifesting the typical features of MCT8 -specific THCMTD had a de novo translocation disrupting the MCT8 gene and unfavorable nonrandom X-inactivation [88].…”

Section: Thyroid Hormone Cell Membrane Transporter Defect (Thcmtd)mentioning

confidence: 99%

The syndromes of reduced sensitivity to thyroid hormone

Dumitrescu

Refetoff

2013

Biochimica et Biophysica Acta (BBA) - General Subjects

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218

161

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Background Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified. Scope of Review The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45 years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3,000 individuals belonging to approximately 1,000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. Major Conclusions Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH. General Significance Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology.

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A Novel Monocarboxylate Transporter 8 Gene Mutation as a Cause of Severe Neonatal Hypotonia and Developmental Delay

Cited by 49 publications

References 16 publications

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

A child with a deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects of thyroid hormone treatment

The syndromes of reduced sensitivity to thyroid hormone

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