PAK3 mutation in nonsyndromic X-linked mental retardation.

Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but genetically heterogeneous disorders, whose genetic bases are largely unknown. Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase. PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal reorganization and to nuclear signalling. The mutation produces premature termination, disrupting kinase function. MRI analysis showed no gross defects in brain development. Immunofluorescence analysis showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. Signal transduction through Rho GTPases and PAK3 may be critical for human cognitive function.

Fragile X syndrome without CCG amplification has an FMR1 deletion.

We describe a patient with typical clinical features of the fragile X syndrome, but without cytogenetic expression of the fragile X or an amplified CCG trinucleotide repeat fragment. The patient has a previously uncharacterized submicroscopic deletion encompassing the CCG repeat, the entire FMR1 gene and about 2.5 megabases of flanking sequences. This finding confirms that the fragile X phenotype can exist, without amplification of the CCG repeat or cytogenetic expression of the fragile X, and that fragile X syndrome is a genetically homogeneous disorder involving FMR1. We also found random X-inactivation in the mother of the patient who was shown to be a carrier of this deletion.

Rett syndrome in monozygotic twins.

The evolution of the Rett syndrome in 29-year-old twin girls is presented. Evidence for monozygosity is given together with a brief account of the problems these girls posed to their family in early childhood.

The fragile X syndrome II: preliminary data on growth and development in males.

Growth data--stature, body weight, occipito-frontal circumference (OFC), ear length and mean testicular volume (MTV)--in 61 males with the fragile X syndrome are presented. Small increases in the mean OFC and ear length and large increases in the MTV were found. The overgrowth of the head was evident in childhood. The characteristic facial appearance was deemed to be present in 60% of the subjects and was recognizable in childhood. Macro-orchidism (MTV of greater than or equal to 30 ml) was present in 80% of the adults but none of the children. Five subjects had a cleft palate, 11 serious eye disorders (3 with congenital nystagmus), and 4 had torticollis and/or kyphosis. Limited information on development suggested that mental retardation was present from early life and was not progressive. Although 3 subjects were autistic (2 with self abuse) most were pleasant, even tempered and cooperative men and boys.

Female relatives in families with the fragile X syndrome.

Three problems--mental retardation, having retarded children, and fear of having retarded children--are described in women in families with the fragile X syndrome. The investigation of one family with a counselling dilemma is presented in detail.

Fragile (X) expression, age and the degree of intellectual handicap in the male.

The proportion of cells expressing the fra(X) was compared to the guardian's opinion of who was the "brighter" in 31 sibships of 2 or more affected males. Six fra(X) positive males in the normal workforce were compared in a similar way to other affected relatives. A correlation was found between lower values of expression and "brightness" by the Wilcoxson signed rank test (less than 0.01, 2-tail). A decline in fra(X) expression occurs with age. Some apparently normal non-expressing transmitting males may be accounted for by these findings.

X-linked cutaneous amyloidosis: further clinical and pathological observations.

A 10-year follow-up of a family with X-linked cutaneous amyloidosis confirmed no more than streaks or spots of brown pigmentation of the skin in females but much more varied and severe manifestations in males. These included neonatal colitis, infantile diarrhea, recurrent respiratory infections, corneal dystrophy, photophobia, unruly hair with a frontal upsweep, dry skin, and mottled, muddy-brown pigmentation seen first on the inner thighs and spreading diffusely to the buttocks, trunk, and arms. Amyloid was found in the pigmented skin of adults of both sexes but not in children. An autopsy of a 50-year-old man, subject to recurrent pneumonia, confirmed the presence of amyloid in the skin, but it was not found in other organs. Changes in the lungs were those of late-stage diffuse pulmonary fibrosis. The pattern of inheritance is X-linked, but the pathogenesis remains obscure.

The fragile X syndrome I: familial variation in the proportion of lymphocytes with the fragile site in males.

A review of 61 males with the fragile X positive form of the Martin Bell syndrome from 30 families seen in the past 4 years suggests that the number of lymphocytes with the fragile site on the X chromosome (fra(X) ) in retarded males tends to be characteristic for the individual and similar to that found in other retarded males in the same family. The number of lymphocytes with fra(X) was not correlated with height, weight, occipitofrontal circumference, ear length or mean testicular volume in adults nor with age over the whole series.

Is there a fragile(X) negative Martin-Bell syndrome?

During the course of the preventative screening program for the fra(X) syndrome, we identified 32 men with the phenotype but who were fra(X) negative. These were reviewed and none fitted the full criteria, so we were unable to confirm the existence of the fra(X) negative Martin-Bell syndrome. The literature and 4 families previously thought to have the fra(X) negative Martin-Bell syndrome were also reviewed. We were unable to make a concrete diagnosis of the fra(X) negative Martin-Bell syndrome.

Fragile-X syndrome III: dermatoglyphic studies in males.

Dermatoglyphics of 39 males with the fragile-X syndrome were compared with those of 3 groups of control subjects; 497 school boys, 15 males with non-specific mental retardation, and 15 with Down syndrome. Compared with the control males, there was an increased frequency of radial loops, whorls, and arches on the fingers and of third interdigital patterns and abnormal creases on the hands, and a decreased frequency of ulnar loops and fourth interdigital patterns in the patients with the fragile-X syndrome. The mean a-b ridge count was lower than in controls and there were more patients than controls with an a-b ridge count less than 70. All of these differences were significant at p less than 0.01. There was no differences between patients and controls with respect to total ridge count on the fingers and the dermatoglyphics in other areas of the hands or feet. From this small study a preliminary index was developed that attempts to distinguish male patients with the fragile-X syndrome from normal male controls and males with non-fragile-X forms of mental retardation. The patterns on the left and right third fingers, the a-b ridge count, and the palmar creases were used in the index. Sixty-four % of patients with the fragile-X syndrome would be selected out if greater than or equal to + 0.5 was used as the criterion and 90% of these males would be expected to have the fragile-X chromosome.

Mortality in the fragile X syndrome: preliminary data.

Mortality was studied among 348 males and 433 females who had or who carried the gene for the fragile X syndrome. The average age of death was about 12 years lower than in the general population for both men and women but this was likely a bias of ascertainment. The commonest causes of death were cardiovascular, cerebrovascular and malignant disease similar to those in the general population. No evidence for any specific disease susceptibility was found in this preliminary study.

Confirmation of early menopause in fragile X carriers.

Fragile X carriers have a median age of menopause 6 to 8 years earlier than women in the general population, with 28% experiencing premature ovarian failure defined as menopause before the age of 40 years. This information was obtained from 203 returned questionnaires from women in the UK Fragile X Society.

A new syndrome with mental retardation, short stature and an Xq duplication.

We describe a new X-linked syndrome of marked short stature, severe intellectual handicap and an unusual facial appearance. High resolution prometaphase banding showed affected males to have an X chromosome tandem duplication; their karyotypes were designated 46,dup(X) (q13.1-q21.1)Y. In carrier females the abnormal X chromosome was late replicating. To verify the duplication, gene dosage studies were performed using an enzyme assay and DNA techniques. Prenatal diagnosis is available for carrier females using chromosome analysis of amniocytes or chorionic villi.

X-linked mental retardation with dystonic movements of the hands.

We describe a family with a syndrome of mental retardation, dystonic movements of the hands and dysarthria inherited in an X-linked recessive pattern. DNA marker studies gave a maximum lod score of 2.11 at theta of 0.00 for DXS41 with a likely localization of the gene to Xpter----Xp21.

A family with the Coffin Lowry syndrome revisited: localization of CLS to Xp21-pter.

We revisited a family with the Coffin-Lowry syndrome (CLS) first reported by Procopis and Turner in 1972. Twelve affected members are now known in 3 generations of which 9 were seen personally. DNA marker studies supported X-linkage with localization of CLS to Xp near DXS43 at p22.2-22.1 (theta = 0.001 Z = 2.71). Such linkage is reinforced by positive lod scores for DXS28 (theta = 0.00, Z = 0.90) and for DXS84 (theta = 0.09, Z = 1.56). Recombination with DXS84 and DXS164 places CLS distal to DMD in Xp21-pter.

Familial cutaneous amyloidosis with systemic manifestations in males.

We describe a family in which two males and seven females have brown pigmentation of the skin. In the females, the type and distribution of the pigmentation mimicked incontinentia pigmenti; in the males, the pattern was reticulate. The histological appearance was the same in both sexes with amyloid deposits in the papillary dermis, melanin in the basal layer, and slight hyperkeratosis. The females were otherwise normal. Both males had thrived poorly as infants but had survived. One had severe gastroenteritis with blood in the stools starting at the age of three weeks followed by seizures, hemiplegia, and developmental delay; the other had recurrent pneumonia throughout life, a urethral stricture, inguinal herniae, and near-blindness from amyloid deposition in the cornea. Five other males in the family had had severe illnesses. Two died of pneumonia by three months. One died at three months from colitis. Both remaining boys had colitis as infants, failed to thrive, and developed recurrent pneumonia from which one died at three years. We think all of these relatives had the same disease carried by a single gene with pleiotropic effects. The most likely form of inheritance is X-linked.

Localisation of the gene for X-linked reticulate pigmentary disorder with systemic manifestations (PDR), previously known as X-linked cutaneous amyloidosis.

X-linked reticulate pigmentary disorder (PDR), previously reported as X-linked cutaneous amyloidosis (MIM#301220), is characterized by brown pigmentation of the skin which follows the lines of Blaschko in females but appears as reticulate sheets in males. Males may suffer severe gastrointestinal disorders in infancy with failure to thrive and early death. Nowadays symptomatic treatment allows survival and other manifestations may appear such as corneal dystrophy with severe photophobia or chronic respiratory disease. Amyloid deposition in the skin may be no more than an age-dependent secondary manifestation. The PDR gene was localised by linkage analysis to Xp21-p22. The background genetic map is Xpter-DXS996-22.5-DXS207-3.3-DXS999-3.3-DXS36 5-14.2-DXS989-4.1-3'DMD-3.5- DXS997-1.0-STR44-9.3-DYSI-2.3-DXS1068-11.0-DX S228 with distances between markers given in cM. Recombinants detected with DXS999 distally and DXS228 proximally, define the limits to the localisation. Linkage was found with several markers within this interval. Peak lod scores of 3.21 at theta = 0.0 were obtained between PDR and DXS989 and between PDR and 5'DYSI within the dystrophin locus.

Regional localisation of two non-specific X-linked mental retardation genes (MRX30 and MRX31).

Two genes responsible for X-linked mental retardation have been localised by linkage analysis. MRX30 maps to a 28 cM region flanked by the loci DXS990 (Xq21.3) and DXS424 (Xq24). A significant multipoint lod score of 2.78 was detected between the loci DXS1120 and DXS456. MRX31 maps to a 12 cM region that spans the centromere from DXS1126 (Xp11.23) to DXS1124 (Xq13.3). Significant two-point lod scores, at a recombination fraction of zero, were obtained with the loci DXS991 (Zmax = 2.06), AR (Zmax = 3.44), PGK1P1 (Zmax = 2.06) and DXS453 (Zmax = 3.31). The MRX30 localisation overlaps that of MRX8, 13, 20 and 26 and defines the position of a new MRX gene on the basis of a set of non-overlapping regional localisations. The MRX31 localisation overlaps the localisations of many of the pericentromeric MRX loci (MRX 1, 4, 5, 7, 8, 9, 12, 13, 14, 15, 17, 20, 22 and 26). There are now at least 8 distinct loci associated with non-specific mental retardation on the X chromosome defined, in order from pter to qter, by localisation for MRX24, MRX2, MRX10, MRX1, MRX30, MRX27, FRAXE and MRX3.

Barth syndrome: clinical features and confirmation of gene localisation to distal Xq28.

Barth syndrome is an X-linked disorder characterised by cardioskeletal myopathy of variable severity usually fatal in childhood, and neutropenia. We ascertained a large pedigree with affected males in 3 generations. All affected males had dilated cardiomyopathy, with endocardial fibroelastosis (EFE) in some. The locus for Barth syndrome in this family was found to be closely linked to DXS52 (z = 2.78, theta = 0.0). The family was nonrecombinant for DXS52 in distal Xq28, but recombinant for DXS374 which maps proximal to DXS52. This localised Barth syndrome distal to DXS374, confirming a previous localisation to distal Xq28. As yet there is no evidence for genetic heterogeneity of Barth syndrome.

Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1.

Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBN1, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span; middle finger, hand, and foot length in the affected members of the family, compared with unaffected sibs of the same sex. Analysis of linkage to intragenic FBN1 markers was inconclusive because they were relatively uniformative. Construction of a multipoint background map from the CEPH reference families identified microsatellite markers linked closely to FBN1 which could demonstrate linkage of EL in this family to the FBN1 region. LINKMAP analysis detected a multipoint lod score of 5.68 at D15S119, a marker approximately 6 cM distal to FBN1, and a multipoint lod score of 5.04 at FBN1. The EL gene in this family is likely to be allelic to Marfan syndrome, and molecular characterization of the FBN1 mutation should now be possible.