Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid, pancreatic islet and anterior pituitary tumours. To facilitate a screening programme for MEN1, we investigated 709 people (364 males and 345 females, age range 1-84 years) from 62 MEN1 families, and 36 non-familial MEN1 patients. Of those investigated, 220 (95 males and 125 females, age range 8-79 years) suffered from MEN1. Parathyroid, pancreatic and pituitary tumours occurred in 95%, 41% and 30% of the patients, respectively. Parathyroid tumours were the first manifestation of MEN1 in 87% of patients, and amongst the pituitary and pancreatic tumours, somatotrophinomas and gastrinomas were more common in patients above the age of 40 years, whilst insulinomas occurred more frequently in patients below the age of 40 years. Biochemical screening indicated that the penetrance of MEN1 by the ages of 20, 35 and 50 years was 43%, 85% and 94%, respectively, and that the development of MEN1 was confined to first-degree relatives in 91% of patients and to second-degree relatives in 9% of patients. These findings have helped to define a proposed screening programme for MEN1.
Spinocerebellar ataxia 2 (SCA2) belongs to the family of autosomal dominant cerebellar ataxias (ADCA), a genetically heterogeneous group of neurodegenerative diseases. The SCA2 gene maps to chromosome 12q24 and the causative mutation involves the expansion of a CAG repeat within the coding region of the gene. Pathologically, SCA2 presents as olivo-ponto-cerebellar atrophy (OPCA). We present the cases of a 41-year-old man and a 54-year-old woman who died after a long illness characterized by severe cerebellar ataxia. Diagnosis of SCA2 was confirmed by genetic analysis. The brains were moderately to severely atrophic and atrophy was particularly obvious in the cerebellum and brainstem. Histological examination revealed extreme loss of pontine and olivary nuclei and Purkinje cells, with preservation of the dentate nuclei, and of the pigmented cells in the substantia nigra. The whole spinal cord was also severely affected, with shrinkage of the dorsal columns and reduction in the number of neurones in the motor pool and Clarke's nuclei. Immunohistochemistry with 1C2 antibody showed granular neuronal cytoplasmic deposits in all the areas examined and widespread intranuclear inclusions, which were particularly numerous in the residual pontine nuclei. Intranuclear inclusions were not considered a feature in SCA2. Our results support the view that intranuclear inclusions are an integral part of the pathology of this mutation.
X-linked recessive nephrolithiasis is associated with kidney stones and renal tubular dysfunction in childhood progressing to renal failure in adulthood. The primary defect causing this renal tubular disorder is unknown and determining the chromosomal location of the mutant gene would represent an important step toward defining the biochemical basis. We have performed linkage studies in 102 members (10 affected males, 47 unaffected males, 15 obligate heterozygote females, and 30 unaffected females) from five generations of one family. As genetic markers we used 10 cloned human X chromosome fragments identifying restriction fragment length polymorphisms and seven pairs of oligonucleotide primers identifying microsatellite polymorphisms. Linkage with the locus DXS255 was established with a peak LOD score = 5.91 at 3.6% recombination, thereby localizing the X-linked recessive nephrolithiasis gene to the pericentromeric region of the short arm of the X chromosome (Xpl 1.22). Multilocus analysis indicated that the mutant gene was distal to DXS255 but proximal to the Duchenne muscular dystrophy locus on Xp. Thus, the gene that causes X-linked recessive nephrolithiasis maps to the pericentromeric region of the short arm of the X chromosome (Xpll.22), and further characterization of this gene will help to elucidate the factors controlling renal tubular function and mineral homeostasis. (J. Clin. Invest. 1993Invest. . 91:2351Invest. -2357
The development of some endocrine tumours, such as medullary thyroid carcinomas, phaeochromocytomas, anterior pituitary adenomas, and parathyroid adenomas involve a putative tumour suppressor gene located on chromosome lp32-pter, a region that represents 111 cM. In order to refine the location of this gene, 93 endocrine tumours (39 parathyroid adenomas, 40 anterior pituitary adenomas, seven pancreatic islet cell adenomas, and seven carcinoids) were investigated for loss of tumour heterozygosity (LOH) using the seven polymorphic loci lpter -D1S228 -DlS507 -D1S234 -D1S476 -DlS220 -D1S207 -DlS206 -Icen. LOH was detected in 27% of the parathyroid tumours and in 7.5% of the pituitary tumours, but in none of the pancreatic islet cell or carcinoid tumours. In addition, seven of the 10 parathyroid tumours that showed LOH of chromosome lp facilitated a more precise mapping of this putative tumour suppressor gene; five tumours involved a loss only of the telomeric locus D1S228, whereas two other tumours showed LOH at the centromeric loci D1S507, D1S234, D1S476, and DlS220, but not D1S228. Thus, our results have mapped this tumour suppressor gene implicated in endocrine tumours to a 4 cM region flanked by D1S228 and DlS507 on chromosome lp35-p36.
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