ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia

• Published in: American journal of medical genetics. Part A Vol. 155A; no. 1; pp. 98 - 105
• Main Authors: Cossée, Mireille, Faivre, Laurence, Philippe, Christophe, Hichri, Heifa, de Saint-Martin, Anne, Laugel, Vincent, Bahi-Buisson, Nadia, Lemaitre, Jean-François, Leheup, Bruno, Delobel, Bruno, Demeer, Bénédicte, Poirier, Karine, Biancalana, Valérie, Pinoit, Jean-Michel, Julia, Sophie, Chelly, Jamel, Devys, Didier, Mandel, Jean-Louis
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-01-2011; Wiley-Liss
• Subjects: Adolescent; Adult; Adult and adolescent clinical studies; ARX; Base Sequence; Biological and medical sciences; Child; Child, Preschool; Chromosome Mapping; DNA Repeat Expansion - genetics; dystonia; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Homeodomain Proteins - genetics; Humans; infantile epilepsy; Intellectual deficiency; Intellectual Disability - genetics; Intellectual Disability - pathology; Male; Medical genetics; Medical sciences; Microsatellite Repeats - genetics; Molecular Sequence Data; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Pedigree; Peptides - genetics; Phenotype; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Sequence Analysis, DNA; Syndrome; Transcription Factors - genetics; XLMR; Human; Nervous system diseases; Family study; Epilepsy; ARX; Developmental disorder; Mental retardation; Hand; Involuntary movement; Cerebral disorder; Case study; XLMR; Striated muscle disease; Central nervous system disease; Intellectual deficiency; Dystonia; Neurological disorder; Complex syndrome; infantile epilepsy; Child; Expansion; Extrapyramidal syndrome
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.33785

Mutations in the ARX gene cause both nonsyndromic and several forms of syndromic mental retardation (MR). Two polyalanine (polyA) expansions of ARX are recurrent mutations. The most common one, the c.428_451dup, is associated with a wide spectrum of phenotypes, ranging from the most severe West syndrome to Partington syndrome (MR and hand dystonia), and even nonsyndromic X‐linked mental retardation (NS‐XLMR). Studies of patients not selected for specific clinical signs showed that the c.428_451dup is relatively frequent in families harboring X‐linked MR (7.5%), but less common in familial cases compatible with X‐linked NR (1%), and very rare in sporadic cases (0.1%). The c.333_334ins(GCG)7 expansion is less frequent and mainly associated with West syndrome. We screened for both ARX polyA expansions in 98 unrelated patients selected for the presence of NR associated with different types of epilepsy and/or with hand dystonia. We also studied two families with an initial diagnosis of NS‐XLMR, one of which was identified as showing linkage to the ARX locus. The c.428_451dup was identified in three patients and the c.333_334ins(GCG)7 in one; all of the patients were from families with two affected brothers. We also found the c.428_451dup in the family linked to ARX, and clinical re‐evaluation showed subtle, previously undetected signs. Our study illustrates that ARX polyA expansions are primarily associated with syndromic MR and shows a higher yield (18% in our cohort) when these mutations are screened in familial cases of MR with epilepsy and/or dystonia. © 2010 Wiley‐Liss, Inc.