Allan-Herndon-Dudley syndrome (AHDS; OMIM#300523) is a X-linked genetic disorder caused by mutation in the solute carrier family 16 member 2 (SLC16A2; OMIM#300095) gene on chromosome Xq13, resulting in monocarboxylate transporter 8 (MCT8) deficiency. AHDS is characterized by global or axial hypotonia, a variety of movement disorders, severe intellectual disability, quadriplegia or spastic diplegia, growth failure, and seizures [1-3]. In severe cases, patients are unable to walk or talk [4,5]. MCT8 is a transmembrane transporter of the active form of the thyroid hormone triiodothyronine (T3). MCT8 is crucial to the action of thyroid hormones in the brain and facilitates their effective passage through the blood-brain barrier [6,7]. Mutations in SLC16A2 alter thyroid hormone concentrations in the blood and lead to profound neurological impairment and intellectual deficit [2,4,8,9]. Seizures are reported in approximately 20% to 30% of patients; however, the clinical course of AHDS patients with epilepsy has rarely been described. This study was approved by the Institutional Review Board of Soonchunhyang University Bucheon Hospital (SCHBC 2024-02-025) and was exempted from informed consent. We received the patient’s consent form about publishing all photographic materials.

Herein, we report a case of a patient with AHDS who was diagnosed during adolescence with late-onset drug-resistant seizures, congenital hypotonia, global developmental delay, and abnormal thyroid function results.

A 10-year-old boy visited the pediatric neurology department of our hospital with the chief complaint of new-onset generalized tonic seizures with vocalization. Seizures had started two months prior and had increased in frequency to daily. He had been born at 39 weeks of gestation with a weight of 3.6 kg and no perinatal complications. There was no family history of known intellectual disability, cerebral palsy, or thyroid disorders. According to his medical history, he showed early infantile hypotonia and frequent respiratory infections. He had been evaluated for hypotonia at six months of age, when brain magnetic resonance imaging (MRI) showed no structural abnormalities and chromosomal study showed normal 46, XY. The genetic findings including dystrophia myotonia protein kinase (DMPK) gene polymerase chain reaction (PCR) and methylation test for Prader-Willi syndrome were negative.

The patient received rehabilitation therapy until 10 years of age due to the impression of cerebral palsy but remained non-ambulatory with incomplete head control and no verbal ability at the first visit. The patient showed severe growth failure. His height and weight were 125 cm (−2.5 standard deviation score [SDS]) and 16 kg (−4.54 SDS), respectively, with microcephaly (head circumference, 48 cm, −3.80 SDS). He had an elongated face with bifrontal narrowing, narrow and sideways eyes, tented upper lip, and upturned large earlobes with abnormal foldings of the ears (Figs. 1A and B). He showed generalized hypotonia with scoliosis, pectus excavatum, and spasticity on extremities and contractures of joints (Fig. 1C). Ankle clonus and hyperreflexia were detected. His language skill was comparable to that of a 10-month-old, with only simple vowel sounds. Before the onset of epileptic seizures, occasional startle reactions occurred in response to external stimuli. At the time of initial presentation of his generalized tonic seizures, he showed cyanosis and loss of consciousness for 1 to 3 minutes. His electroencephalogram (EEG) revealed diffuse slow wave background rhythms with frequent multifocal spikes and generalized slow spike and waves (Fig. 2). His daily generalized tonic seizures were not well controlled during the initial 3 to 4 months. Drooling and myoclonus/startles were aggravated after seizure onset. With adjustment of more than two anti-seizure medications (ASMs), seizures gradually decreased with valproic acid and zonisamide combination therapy. His seizures ceased and the EEG showed only occasional spikes within the first year of treatment. At 11 years of age, his thyroid function was evaluated as part of regular screening of ASM maintenance and nutritional state. His thyroid function test showed high T3 (2.95 ng/mL; reference range, 0.6-1.81 ng/mL), low free thyroxine (fT4, 0.43 ng/dL; reference range, 0.8-2.0 ng/dL), and normal thyroid-stimulating hormone (TSH, 2.95 µIU/mL; reference range, 0.39-5.44 µIU/mL). He was referred to the pediatric endocrinology department and started on levothyroxine (L-T4) treatment. After the treatment, his thyroid function test showed T3 2.36 ng/mL, fT4 0.64 ng/dL and TSH 1.33 µIU/mL.

To identify causes underlying the disease, whole exome sequencing was performed after obtaining informed consent. Genomic DNA was extracted from the patient’s buccal swab sample. Exome capture was performed using xGen Exome Research Panel v2 (Integrated DNA Technologies) and sequencing was performed using the NovaSeq platform (Illumina) as 150 bp paired-end reads. Sequencing data were aligned to the GRCh37/hg19 human reference genome using BWA-MEM and processed for variant calling with GATK v.3 [10,11]. Variants were annotated using Ensembl Variant Effect Predictor and filtered and classified with EVIDENCE [12] following the American College of Medical Genetics and Genomics guidelines [13]. Medical geneticists and physicians manually reviewed the filtered and classified variant list. The most likely variants that could explain the patient’s phenotype were selected for reporting. The hemizygous c.940C>T (p.Arg314Ter) variant in SLC16A2 (NM_006517.5) was identified and confirmed by Sanger sequencing (Fig. 3). The variant was a stop gain type that is predicted to result in protein truncation and is absent in the general population (https://gnomad.broadinstitute.org/). Thus, this variant was classified as likely pathogenic.

At 14 years of age, the patient showed rare brief startling/myoclonus, with no tonic seizures reported over the two years of poly-ASM therapy. Currently, he is 15 years of age and had been taking L-T4 (50-100 µg/day) for three years; he remains non-ambulatory and non-verbal with persisting poor weight gain. However, he maintains oral feeding and does not require respiratory support despite recurrent respiratory infections and muscle weakness.

Herein, we report a case of late-onset intractable epilepsy with early general hypotonia finally diagnosed during adolescence as AHDS caused by a hemizygous c.940C>T (p.Arg314Ter) variant in the MCT8 allele of the SLC16A2 (OMIM#300095) gene on chromosome Xq13. MCT8 protein is a specific transporter of thyroid hormones into neurons. The central nervous system requires the biologically active form of T3, the intracellular concentration of which depends on MCT8 to selectively regulate thyroid hormone uptake or efflux [14]. MCT8 deficiency causes diverse neurological symptoms, abnormal thyroid function, and other medical complications including recurrent pulmonary infections as well as gastrointestinal and orthopedic disorders.

Seizures reportedly occur in approximately 14.8% to 29.1% of AHDS patients and usually begin during infancy or early childhood [3,15]. The semiology of seizures is variable without a typical electrophysiological pattern [1-3,8,9,14]. Treatment options include many different ASMs, but none have shown specific effectiveness. Our patient developed epileptic seizures in adolescence and experienced generalized tonic seizures several times per day. Late-onset seizures can develop in AHDS, and pharmaco-resistance has been reported in some cases [3,9]. The most frequently used ASM reported in previous AHDS studies was valproic acid, which was also effective in our patient [3].

On physical examination, a narrow/elongated myopathic face, microcephaly, pectus excavatum, scoliosis, flat feet with valgus, and cryptorchidism can be observed. Axial hypotonia, spasticity, hyperreflexia, nystagmus, poor weight gain, and short stature are frequently reported. Our patient showed most of the features compatible with typical AHDS.

The heterogeneous manifestations of AHDS hinder diagnosis based only on clinical presentation. Some X-linked or autosomal recessive diseases with overlapping features such as hypotonia, spasticity, intellectual disability, and seizures are differential diagnoses [16]. The characteristic thyroid hormone function test results consisting of high fT3, low-to-normal fT4, and normal TSH should be considered in male patients with severe intellectual disability and hypotonia. Whole exome sequencing can identify the genetic mutation in such patients with overlapping clinical presentations.

In conclusion, male patients with early axial hypotonia, microcephaly, poor weight gain, scoliosis, severe intellectual disability, and seizures should be considered for AHDS. Thyroid function test results including T3 level should be considered in conjunction with the broad clinical spectrum associated with mutations in SLC162, which encodes MCT8, a thyroid hormone transporter. To the best of our knowledge, our patient was the oldest among AHDS cases in Korea and presented EEG findings of AHDS, successful ASM (valproic acid, zonisamide) response, and clinical characteristics of AHDS at a late age.

We extend our gratitude to the patient and his parents for their valuable contribution to this study. This work was supported by the Soonchunhyang University Research Fund.

No fundings to declare.

Conceptualization: YHH. Formal analysis: SP. Investigation: YLS, GHS. Drafting the article: SP. Critical revision of the article: YHH.