Allan-Herndon-Dudley Syndrome (AHDS)

At a glance

Most affected neonates and infants with this disorder appear to develop normally in the first few months of life; however, the presence of poor muscle tone is most often already present at birth. By the age of 6 months, hypotonia with the inability to hold up the head and severe muscle atrophy become obvious. In addition, severe mental retardation and multiple congenital anomalies are present.

Synonyms

Allan-Herndon Syndrome; X-Linked Mental Retardation with Hypotonia.

History

First described by the American geneticists William Allan and Nash Herndon, and their social worker, Florence Dudley in 1944.

Incidence and genetic inheritance

Approximately 25 families with around 100 male members have been described with this disorder. Inheritance is X-linked recessive. More than 100 different mutations in the MCT8 gene (SLC16A2, Solute carrier family 16 [monocarboxylic acid transporters], member 2) have been associated with AHDS. This gene encodes monocarboxylate transporter 8, a protein that is implicated in the transport of thyroid hormone and has been mapped to chromosome Xq21. MCT8 is present in several organs (eg, brain, liver, kidneys, pituitary, and thyroid gland) and allows, depending on the tissue, for a greater than 10-fold increase in the uptake of triiodothyronine (T₃) into tissues and to a smaller extent of thyroxine (T₄).

Diagnosis

Based on the clinical features and family history.

Clinical aspects

Only males are affected. Except for hypotonia, these boys appear normal at birth. Commonly at approximately 6 months of age, the parents notice that the child is unable to hold up the head. Motor development is so severely impaired that the ability to walk is achieved either very late or never at all. Generalized muscular atrophy, which is associated with myopathic findings on histologic examination, becomes obvious in early infancy. Congenital hypotonia and weakness later in infancy progress to spasticity, dystonic posturing, and joint contractures. Hyperreflexia with clonus, ataxia, athetosis, and dysarthria become increasingly more apparent. These boys often display a phenomenon known as paroxysmal dyskinesias that can either occur spontaneously or being provoked by passive movements of the body or limbs. In infancy, provocative actions can include a simple diaper change or other physical maneuvers. The paroxysmal dyskinesias typically last less than a minute and can manifest as turning of the head with hyperextension in the neck, stretching of the limbs, dystonic posturing of the distal limbs or yawn-like mouth opening. The attacks can usually be terminated by flexion of the neck and trunk. Seizures are present in approximately one quarter of these patients. Scoliosis and pectus excavatum have been described in many of these boys. Mental retardation is generally severe. Prenatal and infantile hypotonia may lead to changes in the facial structures, particularly the lower face (open ...