Mental Retardation, X-Linked, Syndromic, Nascimento Type

A number sign (#) is used with this entry because the Nascimento form of syndromic X-linked mental retardation (MRXSN) is caused by mutation in the UBE2A gene (312180) on chromosome Xq24.

Description

The Nascimento type of X-linked syndromic mental retardation is characterized by dysmorphic features, including large head, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, large ears, wide mouth, myxedematous appearance, hirsutism, abnormal hair whorls, micropenis, and onychodystrophy. Female carriers have normal cognition, but may show subtle facial features (summary by Budny et al., 2010).

Clinical Features

Nascimento et al. (2006) reported a family with 3 mentally retarded males in 2 generations, related through their clinically normal mothers. The patients were 46, 19, and 5 years of age, respectively. Dysmorphic features included synophrys, upslanted palpebral fissures, large mouth with downturned corners and thin lips, short, broad neck, low posterior hairline, and hair whorls; 2 had midface hypoplasia and a wide face. The 2 older men had a large head circumference. All were heavy-set with marked generalized hirsutism and a myxedematous appearance. Other features included widely spaced nipples, small penis, small, flat feet, dry skin, and onychodystrophy. All had seizures, 2 had absent speech, and imaging of 2 patients showed white matter hypodensities. The oldest patient developed acute myeloid leukemia at age 46 years.

Budny et al. (2010) reported a 5-generation family in which 5 males had a syndromic form of X-linked mental retardation. The patients had similar physical features, with a large head, prominent supraorbital ridges, synophrys, deep-set, almond-shaped eyes, large ears, wide mouth, widely spaced nipples, and large great toes. Two had hypopigmented skin spots and 2 had onychodystrophy. Two males from another family had a similar disorder. Other common features in these patients included hirsutism, abnormal hair whorls, low posterior hairline, short neck, and micropenis. All were mentally retarded with very poor speech, and most had seizures, aggressive behavior, and echolalia. The phenotype was remarkably similar to that described by Nascimento et al. (2006).

Molecular Genetics

In 3 males with X-linked syndromic mental retardation, Nascimento et al. (2006) identified a nonsense mutation in the UBE2A gene (Q128X; 312180.0001). The mutation was found after screening of candidate genes within a shared region on chromosome Xq23-q25 identified by genotyping of 36 markers spaced approximately 5 cM apart. The presumptive obligate carriers had completely skewed X inactivation in leukocytes. The sister of 1 of the affected males, with a rather random X-inactivation, did not carry this mutation. No mutations in UBE2A were found in 19 idiopathic XLMR-affected families mapped to intervals encompassing UBE2A.

In affected members of 2 unrelated families with syndromic XLMR, Budny et al. (2010) identified 2 different missense mutations in the UBE2A gene (312180.0002 and 312180.0003, respectively).

Cytogenetics

De Leeuw et al. (2010) reported 3 unrelated boys with mental retardation, severely impaired speech, hypotonia, and similar dysmorphic facial features, including synophrys, hypertelorism, and depressed nasal bridge. Two had congenital cataracts and 2 had a short neck. All had ventricular septal defects, which closed spontaneously in 2 patients. Two had a small penis, 2 had cryptorchidism, 2 had hypospadias, and 1 had duplicated kidneys. All had seizures, 1 had white matter lesions on brain MRI, and 1 had cerebellar hypoplasia. Genomewide array analysis identified deletions of Xq24 ranging from 240 to 360 kb, which were different in each patient. All deletions were inherited from an unaffected mother, and each mother showed skewed X inactivation. The deletions encompassed at least 5 genes, including UBE2A and SLC25A5 (300150). Since the clinical features resembled those in patients with point mutations in the UBE2A gene, de Leeuw et al. (2010) concluded that loss of UBE2A is sufficient to account for most of the features in these patients, but also suggested that the cardiac septal defects may be due to loss of SLC25A5.