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J F Arena

Publications and source records attributed to J F Arena.

At least 19 recordsLinked to original sources
PubMed1999

XLMR database.

The computer database on X-linked mental retardation (XLMR) disorders developed by Arena and Lubs in 1991 has now been updated to include all currently known XLMR disorders and nonspecific (MRX) families. Currently, it includes 123 syndromes, 59 nonspecific XLMR families, and 60 families from the Miami/Greenwood study. The older clinical reports have been reviewed and revised. The search mechanism has also been revised and now includes 740 individual "keywords." Each of these keywords recognizes several of clinical descriptive terms, as used in published literature reports. Searches can be made according to any clinical finding or combination of findings. For each disorder, the database presents a graphic display that contains a revised and more complete set of clinical findings, references, keywords, map localization, molecular information, access to pictures, and OMIM number.

Chromosome Mapping↗
PubMed1999

X-linked mental retardation with variable stature, head circumference, and testicular volume linked to Xq12-q21.

Clinical and molecular studies are reported on a family with X-linked mental retardation (XLMR) in which there are eight affected males in three generations. Although the males have somatic manifestations, these are variable and in most cases do not allow clear distinction of affected and unaffected males. Affected males are shorter and have a smaller head circumference. Several also have a sloping forehead (5/8), hearing loss (3/8), cupped ears (2/8), and small testes (4/6). An LOD score of 4.41 with zero recombination was obtained at locus DXS1166 in Xq13.2. This family highlights the difficulty in classifying XLMR conditions as either nonsyndromic or syndromic because of the variable somatic manifestations observed in the affected males.

Abnormalities, Multiple↗
PubMed1999

X-linked mental retardation syndrome with seizures, hypogammaglobulinemia, and progressive gait disturbance is regionally mapped between xq21.33 and Xq23.

We identified a family with three males in two generations with moderate mental retardation. The two oldest were first cousins whose mothers were sisters. The third affected was a grandson through a daughter of one of the sisters, strongly suggesting X- linked inheritance. The affected males had prominent glabella, synophrys, prognathism, generalized hirsutism, and bilateral single palmar creases. All developed seizures in childhood. The two oldest have had a slow deterioration in neurological status with poor gait and balance and progressive weakness. No deterioration in their mental status has been observed. The oldest had cerebellar atrophy confirmed on computed tomography and magnetic resonance imaging scans of the brain and prolonged nerve conduction velocity. Two of the males had hypogammaglobulinemia (IgA deficient). Two-point linkage analysis using 27 microsatellite markers on the X chromosome resulted in a maximum LOD score of 2.23 at straight theta = 0 for locus DSX101. Recombination was observed at locus DSX1170 in Xq21.33 and locus DXS8067 in Xq23. We conclude that this family represents an X-linked disorder associated with a recognizable phenotype, progressive neurological deterioration, and variable hypogammaglobulinemia. The gene appears to lie between Xq21.33 and Xq23.

Abnormalities, Multiple↗
PubMed1999

Gene for apparently nonsyndromic X-linked mental retardation (MRX32) maps to an 18-Mb region of Xp21.2-p22.

We studied a family with 11 males having X-linked mental retardation (XLMR) using microsatellite markers. Aside from the mental retardation, the affected males do not appear to differ from their unaffected brothers or uncles. The gene for this XLMR condition has been linked to DXS451 in Xp22.13 with a lod score of 5.18 at straight theta = 0. Recombination was detected at DXS992 (Xp21.3) and DXS1053 (Xp22.2), thereby defining the limits of the localization. This family is considered to have nonsyndromic XLMR and has been assigned the designation MRX32.

Adolescent↗
PubMed1998

Renpenning syndrome maps to Xp11.

Mutations in genes on the X chromosome are believed to be responsible for the excess of males among individuals with mental retardation. Such genes are numerous, certainly >100, and cause both syndromal and nonsyndromal types of mental retardation. Clinical and molecular studies have been conducted on the Mennonite family with X-linked mental retardation (XLMR) reported, in 1962, by Renpenning et al. The clinical phenotype includes severe mental retardation, microcephaly, up-slanting palpebral fissures, small testes, and stature shorter than that of nonaffected males. Major malformations, neuromuscular abnormalities, and behavioral disturbances were not seen. Longevity is not impaired. Carrier females do not show heterozygote manifestations. The syndrome maps to Xp11.2-p11.4, with a maximum LOD score of 3.21 (recombination fraction 0) for markers between DXS1039 and DXS1068. Renpenning syndrome (also known as "MRXS8"; gene RENS1, MIM 309500) shares phenotypic manifestations with several other XLMR syndromes, notably the Sutherland-Haan syndrome. In none of these entities has the responsible gene been isolated; hence, the possibility that two or more of them may be allelic cannot be excluded at present.

Abnormalities, Multiple↗
PubMed1997

A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation.

X-chromosome inactivation is the process by which a cell recognizes the presence of two copies of an X chromosome early in the development of XX embryos and chooses one to be active and one to be inactive. Although it is commonly believed that the initiation of X inactivation is random, with an equal probability (50:50) that either X chromosome will be the inactive X in a given cell, significant variation in the proportion of cells with either X inactive is observed both in mice heterozygous for alleles at the Xce locus and among normal human females in the population. Families in which multiple females demonstrate extremely skewed inactivation patterns that are otherwise quite rare in the general population are thought to reflect possible genetic influences on the X-inactivation process. Here we report a rare cytosine to guanine mutation in the XIST minimal promoter that underlies both epigenetic and functional differences between the two X chromosomes in nine females from two unrelated families. All females demonstrate preferential inactivation of the X chromosome carrying the mutation, suggesting that there is an association between alterations in the regulation of XIST expression and X-chromosome inactivation.

Deoxyribonucleases, Type II Site-Specific↗
PubMed1997

Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis.

PTEN, a protein tyrosine phosphatase with homology to tensin, is a tumor-suppressor gene on chromosome 10q23. Somatic mutations in PTEN occur in multiple tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible for Cowden disease (CD), a rare autosomal dominant multiple-hamartoma syndrome. PTEN was sequenced from constitutional DNA from 25 families. Germ-line PTEN mutations were detected in all of five families with both breast cancer and CD, in one family with juvenile polyposis syndrome, and in one of four families with breast and thyroid tumors. In this last case, signs of CD were subtle and were diagnosed only in the context of mutation analysis. PTEN mutations were not detected in 13 families at high risk of breast and/or ovarian cancer. No PTEN-coding-sequence polymorphisms were detected in 70 independent chromosomes. Seven PTEN germ-line mutations occurred, five nonsense and two missense mutations, in six of nine PTEN exons. The wild-type PTEN allele was lost from renal, uterine, breast, and thyroid tumors from a single patient. Loss of PTEN expression was an early event, reflected in loss of the wild-type allele in DNA from normal tissue adjacent to the breast and thyroid tumors. In RNA from normal tissues from three families, mutant transcripts appeared unstable. Germ-line PTEN mutations predispose to breast cancer in association with CD, although the signs of CD may be subtle.

Adenoma↗
PubMed1997

Arch fingerprints, hypotonia, and areflexia associated with X linked mental retardation.

A syndrome with distinctive facies, poor muscle tone, absent deep tendon reflexes, tapered fingers, excessive fingerprint arches, genu valgum and mild-moderate mental retardation has occurred in four males in two generations of a white family of European ancestry. The facies are characterised by square configuration, tented upper lip, and thickening of the helices, upper eyelids, and alae nasi. At birth and at maturity, growth (head circumference, height, weight) of affected males is comparable to or greater than unaffected male sibs. Moderate impairment of cognitive function was documented (IQ scores between 40-51). Carriers show no heterozygote manifestations. This X linked condition appears to be different from other syndromes with mental retardation, although there are certain similarities with the alpha thalassaemia-mental retardation syndrome (ATR-X). Linkage analysis found tight linkage to DXS1166 and DXS995 in Xq13 and Xq21 respectively.

Abnormalities, Multiple↗
PubMed1997

A new X linked recessive syndrome of mental retardation and mild dysmorphism maps to Xq28.

Efforts to understand the genetic basis of mental retardation are greatly assisted by the identification of families with multiple relatives with mental retardation that clinical geneticists encounter in the routine practice of their profession. Here we describe a linkage study of a four generation family in which X linked recessive mental retardation (XLMR) is associated with minor dysmorphism and premature death of the affected males. Microsatellite based polymorphic loci evenly spaced over the entire X chromosome were used initially to detect linkage to Xq28. Further analysis identified a haplotype of Xq28 markers bounded proximally by locus DXS1113 and distally by DXS1108 that cosegregated with XLMR in this family. Two point lod scores > 3.0 provided strong evidence that the gene locus responsible for XLMR in this family is within this 7 Mb region of Xq28. The minor anomalies noted in some affected males were not distinctive enough to suggest a unique syndrome. None of our patients had features of the Waisman-Laxova syndrome or the PPM-X syndrome. The possibility of allelism with any of the five other non-specific XLMR syndromes (MRX3, MRX16, MRX25, MRX28, and MRX41) mapped to Xq28 could not be excluded. While the recognition of a gene responsible for this disorder needs much additional work, multiple female relatives at risk in this family benefit immediately from knowing their genotype and heterozygotes will have the opportunity to undergo prenatal diagnosis.

Adult↗
PubMed1996

XLMR genes: update 1996.

A current list of all known forms of X-linked mental retardation (XLMR) and a slightly revised classification are presented. The number of known disorders has not increased because 6 disorders have been combined based on new molecular data or on clinical grounds and only 6 newly described XLMR disorders have been reported. Of the current 105 XLMR disorders, 34 have been mapped, and 18 disorders and 1 nonspecific XLMR (FRAXE) have been cloned. The number of families with nonspecific XLMR with a LOD score of > or = 2.0 has more than doubled, with 42 (including FRAXE) now being known. a summary of the localization of presumed nonspecific mental retardation (MR) genes from well-studied X-chromosomal translocations and deletions is also included. Only 10-12 nonoverlapping loci are required to explain all localizations of nonspecific MR from both approaches. These new trends mark the beginning of a significantly improved understanding of the role of genes on the X chromosome in producing MR. Continued close collaboration between clinical and molecular investigators will be required to complete the process.

Chromosome Mapping↗
PubMed1996

Study of X-linked mental retardation (XLMR): summary of 61 families in the Miami/Greenwood Study.

The initial goal of this study was to localize as many genes as possible that lead to syndromic and nonspecific XLMR. More recently, this goal has been redefined to include narrowing these localizations and cloning specific genes. In the last 5 years, 61 families have participated in this study; 34 have a projected or actual lod score greater than 2.0. Restudy of 12 families reported previously has been a particularly productive aspect of this study and has led to clinical redefinition and new or improved localization of most of these syndromes. Five possible new XLMR syndromes have been identified. Five large families with nonspecific XLMR have been regionally localized. Since many XLMR conditions are based on only 1 or 2 family reports, one of the major purposes of this summary is to provide clinical data on the study families so that collaborative projects can be undertaken with other centers that have similar families.

Databases, Factual↗
PubMed1996

X-linked mental retardation with thin habitus, osteoporosis, and kyphoscoliosis: linkage to Xp21.3-p22.12.

We reevaluated a family previously described as having nonspecific X-linked mental retardation (XLMR) by Snyder and Robinson [1969: Clin Pediatr 8:669-674] (MIM 309583). Clinical and DNA studies were conducted on 17 relatives, including 6 males with mild-to-moderate mental retardation, 3 carrier females, and 8 normal males. In contrast to the normal appearance and minimal clinical findings reported 22 years ago, affected males were found to have a characteristic set of clinical findings. These developed gradually over the first 2 decades, and included thin body build with diminished muscle mass, osteoporosis and kyphoscoliosis, slight facial asymmetry with a prominent lower lip, nasal speech, high narrow or cleft plate, and long great toes. Carrier females were clinically normal. Multipoint linkage analysis indicated linkage to markers distal to the 3' end of DMD (DXS41 and DXS989), with a maximal lod score of 4.7. On the basis of these findings, this entity is redefined as XLMR syndrome.

Adult↗
PubMed1996

Nonsyndromic X-linked mental retardation: review and mapping of MRX29 to Xp21.

The gene responsible for nonsyndromic mental retardation in a family with 7 affected males has been localized to Xp21. The maximal two-point lod score was 3.31 for tight linkage to marker DXS1202 in Xp21.3-p22.3 with crossovers between the 3' portion of the DMD gene (DXS1234) proximally and locus DXS989 distally. The XLMR gene in this family has been assigned the designation MRX29. The localization overlaps with at least six other MRX entities linked to the distal short arm of the X chromosome.

Adult↗
PubMed1994

Aarskog-Scott syndrome: confirmation of linkage to the pericentromeric region of the X chromosome.

Aarskog-Scott syndrome was tentatively mapped to Xq13 on the basis of an X:8 translocation by Bawle et al. [Am J Med Genet 17:595-602, 1984]. A review of the cytogenetics and the use of molecular markers in that family have resulted in revision of the breakpoints of the translocation to Xp 11.2 and 8q11.21 [Glover et al., Hum Mol Genet 2:1717-1718, 1993]. Two families, including one of the two initial families with Aarskog-Scott syndrome [Scott, BD:OAS VII (6): 240-246, 1971], have participated in our study to evaluate the localization of the gene for Aarskog-Scott syndrome to the pericentromeric region of the X chromosome. Using a series of DNA probes, we have been able to confirm linkage to the X chromosome, with multipoint analysis indicating the most likely localization of the gene to be on the proximal short arm.

Abnormalities, Multiple↗
PubMed1994

XLMR genes: update 1994.

We provide a comprehensive list of all known forms of X-linked mental retardation. It comprises 127 entries, subdivided into 5 categories (syndromes, dominant disorders, metabolic disorders, neuromuscular disorders, and nonspecific mental retardation). Map location of 69 putative loci demonstrates several overlaps, which will only be resolved by more refined mapping or cloning of the respective genes. The ultimate goal of identifying all the genes on the X chromosome whose mutations cause mental retardation will require a concerted effort between clinical and molecular investigators.

Chromosome Mapping↗
PubMed1993

Agenesis of the corpus callosum associated with MASA syndrome.

MASA syndrome includes mental retardation, adducted thumbs, shuffling gait and aphasia or speech delay. MASA syndrome, X-linked hydrocephalus and X-linked spastic paraplegia have been linked to the same markers on Xq28 and perhaps represent variation in the clinical expression of the same gene or manifestations of different mutant alleles. The present family includes five males in two generations with borderline to mild mental retardation (5/5), speech delay (5/5), spastic paraplegia (5/5), adducted thumbs (2/5) and marked hydrocephalus (1/5). Of these males, four were evaluated by MRI or CT scan and all four were determined to have partial to complete agenesis of the corpus callosum (ACC). DNA studies confirm linkage to Xq28 probe St14 (DXS52) with a lod score of 2.86 and no recombination. It is not known if X-linked ACC is linked to the same Xq28 region.

Abnormalities, Multiple↗