Allan-Herndon-Dudley syndrome in a female patient and related mechanisms

Olivati, Caroline; Favilla, Bianca Pereira; Freitas, Erika Lopes; Santos, Bibiana Alves dos; Melaragno, Maria Isabel; Meloni, Vera Ayres; Piazzon, Flávia Balbo

doi:10.1016/j.ymgmr.2022.100879

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…The MCT8 de ciency can lead to severe psychomotor de cits that include hypotonia, muscle hypoplasia, spastic paraplegia, intellectual disability, movement disorders, and microcephaly often with abnormal thyroid function test (TFT) results such as high free T3, low free T4, and normal or slightly elevated TSH concentrations [2,3]. While the vast majority of AHDS patients are male, a few cases have been reported in females due to defects in X-inactivation processes [4,5]. Causative variants of AHDS have typically been identi ed in protein-coding regions or adjacent junctions.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing

Yoon,

Lee,

Park

et al. 2024

Preprint

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Background: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder caused by a pathogenic variant in the SLC16A2gene. Although most reported variants are found in protein-coding regions or adjacent junctions, structural variations (SVs) within non-coding regions have not been previously reported. Methods: To investigate two male siblings with severe neurodevelopmental disorders and spasticity, who had remained undiagnosed for over a decade and were negative from exome sequencing, we utilized long-read HiFi genome sequencing. We analyzed short-tandem repeats (STRs) and SVs to identify the genetic cause in this familial case. Results: While coding variants and STR analyses yielded negative results, SV analysis revealed a novel hemizygous deletion in intron 1 of the SLC16A2 gene (ChrX:74,460,691-74,463,566; 2,876 bp), inherited from their carrier mother and shared by the siblings. Determination of the breakpoints indicates that the deletion probably resulted from Alu/Alu-mediated rearrangements between homologous AluY pairs. The deleted region is predicted to include multiple transcription factor binding sites, such as Stat2, Zic1, Zic2, and FOXD3, which are crucial for the neurodevelopmental process, as well as a regulatory element including an eQTL (rs1263181) that is implicated in the tissue-specific regulation of SLC16A2 expression, notably in skeletal muscle and thyroid tissues. Conclusions: This report, to our knowledge, is the first to describe a non-coding deletion associated with AHDS, demonstrating the potential utility of long-read sequencing for undiagnosed patients. It may expand the genomic spectrum of AHDS and highlight the identified region with a high priority for future investigation and functional studies.

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Section: Introductionmentioning

confidence: 99%

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing

Yoon,

Lee,

Park

et al. 2024

Preprint

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“…However, female patients have been described with a milder phenotype and a skewed X chromosome inactivation profile. 2,4 This study aims to describe a series of 3 Colombian male patients with confirmed genetic diagnosis of AHDS and detail the MD phenomenology, providing a more robust basis to correlate known genotypes associated with the disease, including those reported in our cohort.…”

mentioning

confidence: 99%

“…Its inheritance is X‐linked, so it typically manifests more frequently in males. However, female patients have been described with a milder phenotype and a skewed X chromosome inactivation profile 2,4 …”

mentioning

confidence: 99%

Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan–Herndon–Dudley Syndrome

Ramon‐Gomez,

Cortés‐Rojas,

Polania‐Puentes

et al. 2024

Movement Disord Clin Pract

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BackgroundDeficiencies in the thyroid hormone transporter monocarboxylate 8 (MCT8) due to pathogenic variants in the SLC16A2 gene (OMIM 300095) result in a complex phenotype with main endocrine and neurologic symptoms. This rare disorder, named Allan–Herndon–Dudley syndrome (AHDS) (OMIM 300523), is inherited in an X‐linked trait. One of the prominent features of AHDS is the presence of movement disorders (MD), which are complex and carry a significant burden of the disease.CasesPatient 1: male with hypotonia since birth, developmental delay, dystonic posturing at 4 months and at 15 months, and startle reaction developed with sensory stimuli. Patient 2: male, at 2 months, shows hypotonia and developmental delay, paroxysmal episodes triggered by a stimulus with sudden blush, tonic asymmetric posture, and no epileptiform activity. At 10 months, generalized dystonic posturing. Patient 3: typical neurodevelopmental milestones until 6 months; at 24 months, dystonia, startle reaction, and upper motoneuron signs.ConclusionsWe aim to describe our patients diagnosed with AHDS, focusing on MD phenomenology and strengthening the phenotype–genotype correlations for this rare condition.

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Late diagnosis of the X-linked MCT8 deficiency (Allan–Herndon–Dudley syndrome) in a teenage girl with primary ovarian insufficiency

Sriram,

Shahid,

Mysliwiec D

et al. 2024

Journal of Pediatric Endocrinology and Metabolism

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Objectives To report an unusual case of MCT8 deficiency (Allan–Herndon–Dudley syndrome), an X-linked condition caused by pathogenic variants in the SLC16A2 gene. Defective transport of thyroid hormones (THs) in this condition leads to severe neurodevelopmental impairment in males, while heterozygous females are usually asymptomatic or have mild TH abnormalities. Case presentation A girl with profound developmental delay, epilepsy, primary amenorrhea, elevated T3, low T4 and free T4 levels was diagnosed with MCT8-deficiency at age 17 years, during evaluation for primary ovarian insufficiency (POI). Cytogenetic analysis demonstrated balanced t(X;16)(q13.2;q12.1) translocation with a breakpoint disrupting SLC16A2. X-chromosome inactivation studies revealed a skewed inactivation of the normal X chromosome. Conclusions MCT8-deficiency can manifest clinically and phenotypically in women with SLC16A2 aberrations when nonrandom X inactivation occurs, while lack of X chromosome integrity due to translocation can cause POI.

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Allan-Herndon-Dudley syndrome in a female patient and related mechanisms

Cited by 4 publications

References 19 publications

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing

Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan–Herndon–Dudley Syndrome

Late diagnosis of the X-linked MCT8 deficiency (Allan–Herndon–Dudley syndrome) in a teenage girl with primary ovarian insufficiency

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