Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome.

BACKGROUND: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. The aim of this study was to describe the cerebrovascular phenotype of HANAC. METHODS: Detailed clinical data were collected in 14 affected subjects from the 3 families. MRI and magnetic resonance angiography (MRA) were performed in 9 of them. Skin biopsies were analyzed by electron microscopy in affected subjects in the 3 families. RESULTS: Only 2 of 14 subjects had clinical cerebrovascular symptoms: a minor ischemic stroke at age 47 years and a small posttraumatic hemorrhage under anticoagulants at age 48 years. MRI-MRA showed cerebrovascular lesions in 8 of 9 studied subjects (mean age 39.4 years, 21-57 years), asymptomatic in 6 of them. Unique or multiple intracranial aneurysms, all on the carotid siphon, were observed in 5 patients. Seven patients had a CSVD characterized by white matter changes (7/7) affecting subcortical, periventricular, or pontine regions, dilated perivascular spaces (5/7), and lacunar infarcts (4/7). Infantile hemiplegia, major stroke, and porencephaly were not observed. Skin biopsies showed alterations of basement membranes at the dermoepidermal junction associated with expansion of extracellular matrix between smooth vascular cells in the arteriolar wall. CONCLUSION: The cerebrovascular phenotype in hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome associates a cerebral small vessel disease and a large vessel disease with aneurysms of the carotid siphon. It is consistent with a lower susceptibility to hemorrhagic stroke than in familial porencephaly, suggesting an important clinical heterogeneity in the phenotypic expression of disorders related to COL4A1 mutations.

Genes for left-handedness: how to search for the needle in the haystack?

Although several genes that determine left-right asymmetry for structural syndromes such as situs inversus have been characterised in recent years (Supp, Witte, Potter, & Brueckner, 1997), there has been little progress in determining which genes or loci predispose to left-right handedness in humans. Linkage analysis has been used widely for the localisation of genes followed by their positional cloning. The complex genetics of handedness is one of the greatest problems for standard linkage analysis. Several genetic models have been proposed for the inheritance of handedness in humans. On the basis of these models, left-handedness can be considered a common single gene trait with a high gene frequency and a non-mendelian inheritance pattern. We report here a possible strategy, using these genetic models, that can be applied for the identification for genes determining handedness in humans.

The gene for Pendred syndrome is located between D7S501 and D7S692 in a 1.7-cM region on chromosome 7q.

Pendred syndrome is an autosomal recessive disorder characterized by goiter and congenital deafness. The primary defect is not yet known, although the gene causing Pendred syndrome has been localized very recently on chromosome 7q, a region that also contains a gene responsible for nonsyndromal hearing loss (DFNB4). We confirmed linkage to this chromosome 7 region in five Pendred families originating from different ethnic groups, with a highest cumulative lod score of 8.26 for marker D7S501. In combination with previous reports, our results define a candidate region for the Pendred gene of 1.7 cM flanked by markers D7S501 and D7S692.

Identification and characterization of a novel member of the EXT gene family, EXTL2.

Recently, two homologous genes, EXT1 and EXT2, with a putative tumor suppressor function have been described. Mutations in both genes are responsible for multiple exostosis syndrome (EXT), an autosomal dominant condition characterized by the presence of multiple osteochondromas, bony excrescences that sometimes undergo malignant transformation to chondrosarcoma. This family of EXT genes has been extended by the identification of an EXT-like (EXTL) gene showing a high degree of homology with the EXT genes. We report here a second EXT-like gene (EXTL2) which is homologous to the EXT and EXTL genes. EXTL2 consists of 5 exons encoding an ubiquitously expressed protein of 330 amino acids. In addition, a putative pseudogene, EXTL2P was also identified. The EXTL2 gene was assigned to chromosome 1p11-p12, whereas EXTL2P was mapped on chromosome 2q24-q31.