Cohen syndrome gene assigned to the long arm of chromosome 8 by linkage analysis.

Cohen syndrome is an autosomal recessive disorder characterized by mental and motor retardation, short stature, microcephaly, several dysmorphic features, major ocular symptoms and granulocytopenia. Major research challenges are the confusing nosology and the pleiotropy of the gene. We report the mapping of a locus (CHS1) by linkage analysis in as few as four two-generation pedigrees with uniform clinical features. CHS1 was assigned to an interval of approximately 10 cM between D8S270 and D8S521. Our results provide a tool to a more accurate definition of Cohen syndrome(s) and a starting point for the positional cloning of CHS1.

Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1.

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low frequency in many populations but is more common in Finland and the Mediterranean region. It is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures with onset at age 6-15 years, typical electroencephalographic abnormalities and a variable rate of progression between and within families. Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval, positional cloning identified the gene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutations uncharacterized. In this study, we report a novel type of disease-causing mutation, an unstable 15- to 18-mer minisatellite repeat expansion in the putative promoter region of the CST6 gene. The mutation accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length of the repeat array differs between chromosomes and families, but changes in repeat number seem to be comparatively rare events.

Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an autosomal recessive inherited form of epilepsy, previously linked to human chromosome 21q22.3. The gene encoding cystatin B was shown to be localized to this region, and levels of messenger RNA encoded by this gene were found to be decreased in cells from affected individuals. Two mutations, a 3' splice site mutation and a stop codon mutation, were identified in the gene encoding cystatin B in EPM1 patients but were not present in unaffected individuals. These results provide evidence that mutations in the gene encoding cystatin B are responsible for the primary defect in patients with EPM1.

Genome-wide linkage scan for loci of musical aptitude in Finnish families: evidence for a major locus at 4q22.

BACKGROUND: Music perception and performance are comprehensive human cognitive functions and thus provide an excellent model system for studying human behaviour and brain function. However, the molecules involved in mediating music perception and performance are so far uncharacterised. OBJECTIVE: To unravel the biological background of music perception, using molecular and statistical genetic approaches. METHODS: 15 Finnish multigenerational families (with a total of 234 family members) were recruited via a nationwide search. The phenotype of all family members was determined using three tests used in defining musical aptitude: a test for auditory structuring ability (Karma Music test; KMT) commonly used in Finland, and the Seashore pitch and time discrimination subtests (SP and ST respectively) used internationally. We calculated heritabilities and performed a genome-wide variance components-based linkage scan using genotype data for 1113 microsatellite markers. RESULTS: The heritability estimates were 42% for KMT, 57% for SP, 21% for ST and 48% for the combined music test scores. Significant evidence of linkage was obtained on chromosome 4q22 (LOD 3.33) and suggestive evidence of linkage at 8q13-21 (LOD 2.29) with the combined music test scores, using variance component linkage analyses. The major contribution of the 4q22 locus was obtained for the KMT (LOD 2.91). Interestingly, a positive LOD score of 1.69 was shown at 18q, a region previously linked to dyslexia (DYX6) using combined music test scores. CONCLUSION: Our results show that there is a genetic contribution to musical aptitude that is likely to be regulated by several predisposing genes or variants.

Monoamine oxidase deficiency in males with an X chromosome deletion.

Mapping of the human MAOA gene to chromosomal region Xp21-p11 prompted our study of two affected males in a family previously reported to have Norrie disease resulting from a submicroscopic deletion in this chromosomal region. In this investigation we demonstrate in these cousins deletion of the MAOA gene, undetectable levels of MAO-A and MAO-B activities in their fibroblasts and platelets, respectively, loss of mRNA for MAO-A in fibroblasts, and substantial alterations in urinary catecholamine metabolites. The present study documents that a marked deficiency of MAO activity is compatible with life and that genes for MAO-A and MAO-B are near each other in this Xp chromosomal region. Some of the clinical features of these MAO deletion patients may help to identify X-linked MAO deficiency diseases in humans.

Intestinal cancer in patients with a germline mutation in the down-regulated in adenoma (DRA) gene.

A recent study has revealed that germline mutations of the down-regulated in adenoma (DRA) gene are a likely cause of a recessive intestinal absorption defect, congenital chloride diarrhea. This finding was in accordance with previous works showing that DRA encodes a sodium independent transporter for sulfate and oxalate. Although DRA was originally reported as a candidate tumor suppressor, these studies have questioned the relevance of DRA in cancer. To evaluate whether further studies on the role of DRA in tumorigenesis are still of interest, we examined whether individuals carrying germline DRA mutations have an excess of intestinal cancer. Cancer status of 229 members of 36 Finnish congenital chloride diarrhea families (44 homozygous patients, 70 heterozygous parents, and 115 grandparents at 50% risk of being a DRA mutation carrier) was checked at the Finnish Cancer Registry and the risk of intestinal cancer was found slightly elevated (standardized incidence ratio 3.4, 95% confidence interval 1.4-7.0, P < 0.05). While this result does not unambiguously demonstrate an increased intestinal cancer risk in DRA mutation carriers, it should promote further studies to determine the possible role of DRA in cancer.

Refined mapping of the Cohen syndrome gene by linkage disequilibrium.

The Cohen syndrome is a rare autosomal recessively inherited disorder. Contrary to many case reports published elsewhere, the phenotype is uniform in Finland including nonprogressive mental and motor retardation, typical dysmorphic features, granulocytopenia and marked ophthalmological changes. By linkage analysis in five Finnish multiplex nuclear families, the COH1 locus for the Cohen syndrome was recently assigned to a 10-cM region between loci D8S270 and D8S521 on the long arm of chromosome 8. Here we present results of linkage disequilibrium and haplotype analysis in an extended panel of 16 Finnish COH1 families using new markers localized in the COH1 region. By inferring historical recombinations in conserved haplotypes the COH1 gene was assigned in the region of marker loci D8S1808, D8S1762 and D8S546. Calculations of genetic distances based on linkage disequilibrium suggest that the most likely localization of COH1 is in the immediate vicinity of marker locus D8S1762. Haplotype analysis suggests the occurrence of one main COH1 mutation and possibly one or two rare ones in Finland. This information will be useful in the positional cloning of the gene.

Linkage studies in progressive myoclonus epilepsy: Unverricht-Lundborg and Lafora's diseases.

The progressive myoclonus epilepsies (PME) are a heterogeneous group of rare genetic disorders. Unverricht-Lundborg disease and Lafora's disease are two major classic forms of PME. We recently assigned the gene for Unverricht-Lundborg disease (EPM1) to human chromosome 21 band q22.3. We have now refined the localization of EPM1 by linkage analysis between the disease phenotype and nine DNA markers in 13 Finnish families. Loci MX1 and CD18 flank the EPM1 interval, which spans a distance of about 3.5 megabases. In this 20-centimorgan interval, no recombinations were detected between EPM1 and marker loci BCEI, D21S19, D21S42, D21S113, D21S154, and PFKL. Within this interval a maximum multipoint lod score of 11.04 was reached at loci D21S154-PFKL. In two Swedish families with Unverricht-Lundborg disease no recombinations were detected. In three Italian families with Lafora's disease the linkage results suggested that EPM1 is not the locus for Lafora's disease.

Atrial myxoma in a family.

A family is described in which the mother and three of seven children had atrial myxoma. The mother had biatrial myxoma; surgical treatment resulted in massive intraoperative embolization and death. Surgery was sucessful in two sons with left atrial myxoma and systemic arterial embolization. A third son had calcified right atrial myxoma with destruction of the tricuspid valve and episodes of syncope and pulmonary embolism; surgery including valve replacement, was successful. The mother's father and a brother had died suddenly without a definite diagnosis. The family data are consistent with dominant transmission. The possibility of finding affected relatives should be borne in mind when studying patients with atrial myxoma.

The Meckel syndrome in Finland: epidemiologic and genetic aspects.

Estimates of the incidence of the Meckel syndrome (MS) from different parts of the world vary from 1:140,000 to 1:13,250 births. In this nationwide study performed in Finland, the incidence of 1:14,400 births was found by retrospective ascertainment during the period 1970-1979, while the incidence was 1:8,500 births when prospective monitoring was performed in 1980-1981. The most probable incidence in Finland is about 1:9,000 births. Autosomal recessive inheritance of MS is confirmed in this study. The ratio of affected sibs, corrected for truncate complete ascertainment, was 0.261. No consanguinity between parents was found, as marriages between close relatives are rare in Finland and the ancestors were not traced back far enough to find remote consanguinities.

RAPADILINO syndrome with radial and patellar aplasia/hypoplasia as main manifestations.

A new malformation syndrome is described in a pair of sibs and 3 sporadic patients. The characteristic manifestations are radial aplasia or hypoplasia, absence of thumbs, absent or hypoplastic patellae, dislocations of joints, unusual face, cleft or highly arched palate, diarrhea in infancy, small stature, and normal intelligence. Recessive inheritance seems the most plausible cause. The acronym RAPADILINO syndrome is proposed.

Cohen syndrome: essential features, natural history, and heterogeneity.

This article elucidates the clinical picture in Cohen syndrome (MIM 216550), an autosomal recessive disorder that is overrepresented in Finland. The diagnosis is based on the typical clinical picture: nonprogressive psychomotor retardation, motor clumsiness and microcephaly, typical facial features, childhood hypotonia and hyperextensibility of the joints, ophthalmologic findings of retinochoroidal dystrophy and myopia in patients over 5 years of age, and granulocytopenia. In a nationwide study, 29 Finnish patients were investigated. Magnetic resonance images of the brain with quantitative structure analyses revealed a relatively enlarged corpus callosum (CC). The youngest patients had normal EEGs, while all others had low-voltage EEGs. Of the patients, 22% had profound, 61% severe, 6% moderate, and 11% mild retardation. In an adaptive behavior scale (AAMD), patients had high scores in the positive domains (self-direction, responsibility, and socialization), whereas maladaptive behavior was almost lacking. Only the youngest patients had unimpaired visual function. Vision started to deteriorate early but slowly. Progressive myopia and retinochoroidal dystrophy were found in all of the patients over 5 years of age. All of the patients had isolated granulocytopenia. The heart anatomy was normal. However, decreased left ventricular function with advancing age was found. No significant endocrine abnormalities were discovered. Fingers were slender but short, with a typical metacarpophalangeal pattern profile. The manifestations vary at different ages. The Finnish Cohen patients are clinically highly homogeneous, their disease gene being located on chromosome 8. Heterogeneity probably exists among other patients claimed to have Cohen syndrome.

Familial congenital diaphragmatic defects: aspects of etiology, prenatal diagnosis, and treatment.

We present 14 familial cases from five Finnish families affected with a life-threatening congenital diaphragmatic defect (CDD) and review data on 53 previously published familial cases. CDD occurred in three sibs and their half brother's son, and probably in all four offspring of parents consanguineous as both first and second cousins. In the remaining three Finnish families and in the vast majority of the previously reported familial cases, only two sibs were affected. Two thirds of those affected were males both in the Finnish and the overall series. Pedigree data, delayed fusion of the diaphragm as the primary pathogenetic mechanism, varying anatomical structure of the defective hemidiaphragm, association with other congenital anomalies, and data on animal experiments are more in accordance with multifactorial determination than with recessive inheritance. This does not exclude other genetic causes in some familial cases. The recurrence risk for sibs after one affected sib is about 2%. As the prognosis, especially in familial cases of CDD has remained grave, the development of fetal surgical treatment is desirable. This emphasizes the future role of prenatal diagnosis by ultrasound.

The desmoid tumor. III. A biochemical and genetic analysis.

We have carefully examined four patients with desmoid tumor (DT) and their 31 relatives. In three of four cases, biopsies of the DT demonstrated low yet significant amounts of estrogen but not progesterone receptors in the tumor cytosol. In the fourth case, where the receptors were not demonstrable, the affected patient was a menopausal woman and the receptors may have been blocked by endogenous estrogen. Fourteen of their 31 relatives demonstrated multiple minor bone malformations in x-ray screening of the skeleton. The inheritance of these malformations was compatible with an autosomal dominant trait with variable penetrance. These findings are compatible with our suggestion that the basic underlying cause for DT is an inherited defect in growth regulation of the connective tissue. When a trauma is superimposed on such an individual, a DT may result. The growth of the tumor is, however, controlled primarily by sex hormones, estrogen predominance over progesterone being inducive to tumor growth.

PEHO syndrome (progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy): neuroradiologic findings.

PURPOSE: To investigate the radiologic characteristics of the clinical progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) symptom complex. This complex is nonspecific, but within this syndrome, a subgroup with a defined neuropathologic phenotype and apparently autosomal recessive inheritance exists. METHODS: Brain CT or MR studies were performed on 21 patients with the clinical PEHO syndrome. Their previous neuroradiologic studies were re-evaluated. RESULTS: Twelve patients (group A) showed uniform changes with early progressive brain atrophy accentuated infratentorially, and abnormal myelination. The gyral pattern was normal. Brain atrophy of nine patients (group B) differed by being less progressive, supra- rather than infratentorial, and often combined with abnormal gyral formation. CONCLUSIONS: Postmortem studies permitted correlation of radiographic and morphologic findings in three cases. Two autopsied group A patients were compatible with the true PEHO syndrome, while one group B patient was incompatible. Group A seems to correspond to the core group of the PEHO syndrome. During a patient's life, a suggestive diagnosis of the true PEHO syndrome is thus feasible, although neuropathologic studies are needed for a conclusive diagnosis.