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

Dev Med Child Neurol. 2019 Dec;61(12):1439-1447. doi: 10.1111/dmcn.14332. Epub 2019 Aug 13.


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.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cohort Studies
  • Developmental Disabilities / blood
  • Developmental Disabilities / etiology
  • Developmental Disabilities / genetics
  • Developmental Disabilities / physiopathology
  • Humans
  • Infant
  • Intellectual Disability* / blood
  • Intellectual Disability* / etiology
  • Intellectual Disability* / genetics
  • Intellectual Disability* / physiopathology
  • Language Development Disorders
  • Magnetic Resonance Imaging
  • Male
  • Mental Retardation, X-Linked* / blood
  • Mental Retardation, X-Linked* / complications
  • Mental Retardation, X-Linked* / genetics
  • Mental Retardation, X-Linked* / physiopathology
  • Monocarboxylic Acid Transporters / genetics*
  • Muscle Hypotonia* / blood
  • Muscle Hypotonia* / complications
  • Muscle Hypotonia* / etiology
  • Muscle Hypotonia* / genetics
  • Muscle Hypotonia* / physiopathology
  • Muscular Atrophy* / blood
  • Muscular Atrophy* / complications
  • Muscular Atrophy* / genetics
  • Muscular Atrophy* / physiopathology
  • Phenotype
  • Symporters / genetics*
  • Thyroid Hormones / blood*
  • Young Adult


  • Monocarboxylic Acid Transporters
  • SLC16A2 protein, human
  • Symporters
  • Thyroid Hormones

Supplementary concepts

  • Allan-Herndon-Dudley syndrome