Ron C. Michaelis

Townes-Brocks syndrome

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder with multiple malformations and variable expression. Major findings include external ear anomalies, hearing loss, preaxial polydactyly and triphalangeal thumbs, imperforate anus, and renal malformations. Most patients with Townes-Brocks syndrome have normal intelligence, although mental retardation has been noted in a few.

Absence of MeCP2 mutations in patients from the South Carolina autism project

The methyl‐CpG binding protein 2 (MeCP2) gene has recently been identified as the gene responsible for Rett syndrome (RS), a pervasive developmental disorder considered by many to be one of the autism spectrum disorders. Most female patients with MeCP2 mutations exhibit the classic features of RS, including autistic behaviors. Most male patients with MeCP2 mutations exhibit moderate to severe developmental delay/mental retardation. Ninety nine patients from the South Carolina autism project (SCAP) were screened for MeCP2 mutations, including all 41 female patients from whom DNA samples were available plus the 58 male patients with the lowest scores on standard IQ tests and/or the Vineland Adaptive Behavior Scale. No pathogenic mutations were observed in these patients. One patient had the C582T variant, previously reported in the unaffected father of an RS patient. Two other patients had single nucleotide polymorphisms in the 3′ UTR of the gene, G1470A and C1516G. These variants were seen in 12/82 and 1/178 phenotypically normal male controls, respectively. The findings from this and other studies suggest that mutations in the coding sequence of the MeCP2 gene are not a significant etiological factor in autism.

Diffusion-weighted magnetic resonance imaging in boys with neural cell adhesion molecule L1 mutations and congenital hydrocephalus.

The phenotype of severe congenital hydrocephalus secondary to neural cell adhesion molecule L1 (L1CAM) gene mutations includes the distinct finding of brainstem corticospinal tract hypoplasia. Using diffusion‐weighted imaging (DWI), we failed to demonstrate anisotropy in the corticospinal tracts of the basis pontis in 4 affected boys with L1CAM mutations. The DWI findings correlated with the neuropathological findings in a fifth patient. DWI may be a useful technique to screen for boys with L1CAM mutations. Ann Neurol 2000; 47:113–117

The HOXA1 A218G polymorphism and autism: Lack of association in white and black patients from the South Carolina Autism Project

A recent study has suggested that the A218G polymorphism in the homeobox Al (HOXA1) gene may influence susceptibility to autism. We have determined the frequencies of the A and G alleles of the HOXA1 A218G polymorphism in both white and black patients from the South Carolina Autism Project (SCAP) and controls. Marked differences were found in allele frequencies between the races, but no deviations from Hardy-Weinberg equilibrium were seen in either white or black SCAP family members. More direct tests, comparing genotype frequencies between probands and controls and tracking transmission of the A versus G alleles to affected offspring, did not support the contention that allele status for the HOXA1 A218G polymorphism influences ones susceptibility to autism.

Prenatal Diagnosis of L1 Cell Adhesion Molecule Mutations

Objective: Discuss the capability for and limitations of prenatal detection of L1 cell adhesion molecule (L1CAM) mutations. Methods: Haplotype analysis by PCR and PAGE. Mutation detection by SSCP, followed by dideoxy sequencing. Confirmation of sequencing results with PCR and NcoI digestion. Results: A 1-bp deletion was found in exon 2 of L1CAM in all affected males and obligate carriers in the pedigree. Prenatal detection is now possible for subsequent pregnancies. Conclusion: In a large gene with widespread mutations such as L1CAM, a mutation must be detected in another family member before direct prenatal mutation testing can be done within the required timeframe. If the proper family members are available, haplotyping offers a fast but indirect test with several limitations.