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An X-linked intellectual disability syndrome with neuromuscular involvement characterized by infantile hypotonia, muscular hypoplasia, spastic paraparesis with dystonic/athetoic movements, and severe cognitive deficiency.
ORPHA:59Classification level: Disorder
At least 132 families with 320 affected individuals have been reported in the literature to date. Although the prevalence is unknown, one study identified AHDS in 1.4% of males with intellectual disability of unknown etiology. Only males are affected.
The disease manifests as congenital hypotonia (appearing at birth or in the first weeks/months of life) that progresses to spasticity (contractures, Babinski sign, and clonus), and is usually detectable early in life. Hyperreflexia appears later in life. Affected males also present, in infancy and early childhood, with 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) and autonomy is never reached. The face has distinctive features that evolve over time: 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, thin everted feet are also typical. Ocular manifestations (i.e. rotary nystagmus and disconjugate eye movements) are rare. Seizures and poor weight gain are reported in some patients. 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), which encodes for monocarboxylate transporter 8 (MCT8), a specific transporter for thyroid hormone T3. Identified mutations include truncations, in-frame deletions, nonsense and missense mutations. Neurological problems may be due to an inability to transport thyroid hormone T3 into some neuronal cells.
Diagnosis is based on clinical findings and on the presence of altered thyroid- hormone serum levels: males have abnormally high 3,3',5'-triiodothyronine (T3), low to normal free tetraiodothyronine (T4) levels, and normal to slightly elevated thyroid stimulating hormone (TSH) levels. Molecular genetic testing revealing mutations in the SLC16A2 gene confirms the diagnosis.
Differential diagnoses include X-linked intellectual disability conditions associated with ataxia, spastic paraplegia or muscle hypoplasia such as X-linked intellectual disability-spastic paraplegia with iron deposits syndrome, X-linked progressive cerebellar ataxia, and spastic paraplegia type 2. Pelizaeus-Merzbacher disease and Snyder-Robinson syndrome should also be considered.
Antenatal diagnosis of a male with AHDS is possible if the mother is a carrier of a specific SLC16A2 mutation.
Transmission is X-linked recessive. 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.
Management and treatment
At present, no treatment is available for AHDS and management consists of supportive measures. Physical, occupational, and speech therapy may be beneficial. Dystonia may be treated with certain medications, including anticholinergics, L-DOPA, carbamazepine, or lioresol. Seizures, when present, can be controlled with standard antiepileptic drugs. Treatment for hypothyroidism does not appear to be beneficial.
Although several patients have survived into their 60s, overall life expectancy is compromised and quality of life is severely affected as most patients are unable to sit, stand or walk independently.