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At a glance

Nonspecific X-linked mental retardation syndrome. Congenital mental retardation with Dandy-Walker malformation of the cerebellum and fourth ventricle. Associated with basal ganglia disease and seizures.

Synonyms

Dandy-Walker Malformation with Mental Retardation; Basal Ganglia Disease and Seizures; X-Linked Mental Retardation Syndromic-5 with Dandy-Walker Malformation.

Incidence

Fewer than 50 affected individuals described.

Genetic inheritance

X-linked recessive transmission with highly variable expression.

Pathophysiology

A mutation in the AP1S2 gene is thought to be responsible. This gene encodes for the sigma-2 subunit of the heterotetrameric adaptor protein 1 (AP1) complex found in the cytosolic side of coated vesicle in the Golgi compartment. AP1 mediates the recruitment of clathrin and the recognition of sorting signals of transmembrane receptors.

Diagnosis

Clinical features (mental retardation, abnormal neurological signs) together with radiological findings of dilatation of the fourth ventricle. Necropsy demonstrates iron accumulation in the basal ganglia with neuroaxonal dystrophy.

Clinical aspects

The major symptom is mental retardation. The phenotypic features are variable and nonspecific. Other key manifestations include early hypotonia with progression to spasticity and contractures, choreoathetosis, seizures, a long, narrow face with coarse features, cystic enlargement of the fourth ventricle with cerebellar hypoplasia (Dandy-Walker Malformation).

Precautions before anesthesia

The patient’s history should be evaluated in relation to seizures and, in particular, current anticonvulsant therapy and complications resulting from the therapy. In patients with raised intracranial pressure, no sedative premedication should be administered.

Anesthetic considerations

Unwillingness or inability to cooperate because of fear, anxiety, and incapacity to communicate in addition to the degree of mental retardation.

Pharmacological implications

Pharmacological triggers that potentiate occurrence of seizures are to be avoided (enflurane with hypocapnia, methohexital, ketamine). Drugs that potentially cause or exacerbate extrapyramidal symptoms (eg, phenothiazines, butyrophenone derivatives including droperidol, and metoclopramide) should be avoided. Ketamine has been shown to be effective as a monotherapy in hypotonic children for minor surgical procedures.

References

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Cacciagli  P, Desvignes  JP, Girard  N,  et al: AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome). Eur J Hum Genet 22:363, 2014.  [PubMed: 23756445]
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Pettigrew  AL, Jackson  LG, Ledbetter  DH: New X-linked mental retardation disorder with Dandy-Walker malformation, basal ganglia disease, and seizures. Am J Med Genet 38(2-3):200, 1991.  [PubMed: 2018058]

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