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Allan-Herndon-Dudley syndrome

Orpha number ORPHA59
Synonym(s) AHDS
MCT8 deficiency
Monocarboxylate transporter 8 deficiency
X-linked intellectual disability - hypotonia
Prevalence <1 / 1 000 000
Inheritance X-linked recessive
Age of onset Neonatal
ICD-10
  • E03.1
ICD-O -
OMIM
UMLS -
MeSH
  • C537047
MedDRA -

Summary

Allan-Herndon-Dudley syndrome (AHDS) is an X-linked mental retardation syndrome with neuromuscular involvement characterized by hypotonia, muscular hypoplasia and intellectual deficit. At least 25 families with 89 affected individuals have been reported in the literature so far. Although the prevalence is unknown, one study identified AHDS in 1.4% males with mental retardation of unknown etiology. Only males are affected. The disease manifests as congenital hypotonia that progresses to spasticity (hyperreflexia, contractures, Babinski sign, and clonus). Affected males also present muscle hypoplasia and generalized muscle weakness that manifests as difficulty in supporting the head and delayed motor milestones. Hypotonia and severe intellectual deficit are present in 100% of patients. Severe psychomotor delay is present from the outset (delay of motor and language milestones). Autonomy is never reached. The facies has distinctive features: open mouth, tented upper lip, ptosis, abnormal folding of the ears, thickening of the soft tissue of the nose and ears, and upturned earlobes. Long and thin everted feet are also typical. Ocular manifestations are rare. Seizures may occur. Pectus excavatum and scoliosis are sometimes present, perhaps as a result of the hypotonia and muscle hypoplasia. AHDS is caused by mutations in the SLC16A2 gene (Xq13.2), encoding monocarboxylate transporter-8 (MCT8) which is a specific transporter for thyroid hormone T3. Identified mutations include truncations, in-frame deletions, nonsense and missense mutations. Transmission is X-linked recessive. Diagnosis is based on clinical findings and on the presence of disturbances in serum levels of the thyroid hormones: males with abnormally high free T3, but low to normal free T4 levels, and TSH levels in the normal range should be tested for mutations in SLC16A2. Differential diagnoses include X-linked mental retardation conditions associated with ataxia, spastic paraplegia or musclehypoplasia: Apak ataxia-spastic diplegia, Arena syndrome (see this term), Goldblatt spastic paraplegia, and X-linked mental retardation-spastic paraplegia-athetosis. Pelizaeus-Merzbacher disease (see this term) can also be added to this list even though it is not associated with muscle hypoplasia. Snyder-Robinson syndrome (see this term) should also be considered because of the muscle hypoplasia and hypotonia. Affected families should be offered genetic counseling and informed that boys have a 50% risk of being affected if the mother is a carrier of a SLC16A2 mutation and that girls have a 50% risk of inheriting the SLC16A2 mutation if their mother is a SLC16A2 mutation carrier. Antenatal diagnosis of a male with AHDS is possible if the mother is a carrier of a specific SLC16A2 mutation. At present, no treatment is available for AHDS and management consists of supportive measures. Although several patients have survived into their 60s, overall life expectancy is compromised.

Expert reviewer(s)

  • Dr Charles SCHWARTZ

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Detailed information

Review article
  • EN (2011)
Clinical genetics review
  • EN (2013)
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