An X-linked recessive basal ganglia disorder with mental retardation

We report a previously apparently undescribed, X-linked recessive basal ganglia disorder segregating in three generations of one family. The affected patients were variably mentally retarded, although some showed strengths in oral reading and memory. Most affected males had frontal bossing and increased head circumference with large calvaria in relation to facial bones. Their height and weight did not differ from that of other relatives; testicular size was average, chromosomes were normal, and results of laboratory investigations for known metabolic disorders were normal. All patients examined had neurological impairment, including persistent frontal lobe reflexes, cogwheel rigidity, postural changes, and Parkinsonian-type tremors. Some had strabismus; several had seizures. Although carriers of the condition were not consistently abnormal, two had suggestive signs. No definitive indication of the disorder was documented in infancy in any affected male, and it is possible that this could be due to lack of careful prospective clinical evaluation rather than to the absence of symptoms in early life.     

Dandy-Walker variant malformation, spastic paraplegia, and mental retardation in two sibs

Two sibs, a boy and a girl, had both hypoplasia of the cerebellar hemispheres and partial agenesis of the cerebellar vermis with normal communication between the fourth ventricle and arachnoid spaces, i.e., the manifestations of the Dandy-Walker variant malformation associated with agenesis of the corpus callosum. Both sibs were mentally retarded and had spastic paraplegia. The occurrence of a distinct and similar pattern of congenital anomalies in sibs born to healthy parents points toward a "new" syndrome caused by the homozygous state of an autosomal recessive gene. Prenatal ultrasonographic diagnosis is possible at least for the more severe form of the brain anomalies.     

Spastic paraplegia with iron deposits in the basal ganglia: a new X-linked mental retardation syndrome.

We report on a family with X-linked mental retardation (XLMR) and severe spastic paraplegia. Appearance is normal but there is severe involvement of the lower limbs (affected relatives never walked), with minimal involvement of the upper limbs and unusual MRI findings including macrogyria, white matter hypoplasia, lack of myelination and a markedly increased paramagnetic signal suggestive of iron deposition. Linkage studies documented possible linkage, with no recombination, between the disease locus and DXS424. A 7-point linkage analysis yielded a maximum LOD score of 1.9, (theta = 0.00) for three loci spanning Xq22-q25. The combination of the unusual clinical and MRI findings and the tentative localization to a region different than other XLMR syndromes with spastic paraplegia, provide good evidence that this is a new XLMR syndrome.     

X-linked dysmorphic syndrome with mental retardation

We present a dysmorphic syndrome in eight males of the same family (four brothers, three cousins and one uncle) that is characterised by: mental retardation, facial dysmorphia, abnormal growth of teeth, skin dimple at the lower back, clinodactyly, patella luxation, malformation of lower limbs, abnormalities of the fundus of the eye and subcortical cerebral atrophy. These physical defects do not correspond to any previously described syndrome, which suggests that it is a new syndrome. According to the model of heredity this syndrome could be due to a mutant gene situated in the X-chromosome.     

X-linked mental retardation with marfanoid habitus

Here we report on two pairs of mildly to moderately mentally retarded brothers with marfanoid habitus and similar craniofacial changes. They had a long and narrow face, small mandible, high-arched palate, and hypernasal voice, as previously reported by Lujan et al (Am J Med Genet 17:311-322, 1984) in four mentally retarded males of a large kindred. The present data suggest the existence of a specific type of X-linked mental retardation with marfanoid habitus.     

X-linked skeletal dysplasia with mental retardation

A syndrome compatible with an X-linked trait is described, affecting four male cousins in three sibships. The boys had skeletal anomalies, including short stature, ridging of the metopic suture, fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sacral hypoplasia and short middle phalanges. In addition, they had moderate developmental retardation, and abducens palsies. Three of the four had glucose intolerance, and one was born with an imperforate anus.
Of five female obligate carriers studied, three had fusion of cervical vertebrae, three had some shortening of the middle phalanges and three had glucose intolerance.
The syndrome in this family was compared to previously reported syndromes, and the conclusion was reached that it represents a previously unreported X-linked syndrome with minor manifestations in carrier females.     

X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder

We report on a family with an apparently X-linked neuromuscular disease. Electrophysiologic tests and electron microscopic studies are consistent with the diagnosis of hereditary motor sensory neuropathy type II (HMSN-II), one form of Charcot-Marie-Tooth disease. The manner of inheritance, the observation that males are severely affected from infancy, and the frequent association of deafness and/or mental retardation with the neuromuscular disorder are not usual for HMSN-II and suggest that this family may have a previously undescribed genetic disorder. The peripheral neuropathy did not appear to be linked to the Xg blood group. Minor abnormalities of sensory nerve conduction, electromyography, and hearing were separately identified in female relatives in this family, but were not consistent enough to be useful in the identification of carriers for this gene.     

New X-linked syndrome of mental retardation, short stature, and hypertelorism

We present a three-generation family with five retarded, abnormally appearing males and two abnormally appearing females (presumably manifesting carriers). The phenotype of the patients is different from that of all other previously described types of X-linked mental retardation (XLMR). The patients had prominent forehead, frontal bossing, hypertelorism, broad nasal tip, and anteverted nares. Chromosomes were normal including fragile X analysis. Skeletal roentgenograms were normal.     

X-linked mental retardation associated with macro-orchidism.

Two families are described with an X-linked form of mental retardation in whom the affected males were found to have bilateral enlargement of the testes. No conclusive evidence of any endocrinological disturbance was found.     

X-linked mental retardation with macro-orchidism and marker-X chromosomes

The family of 2 men with X-linked mental retardation was investigated for the presence of the marker-X chromosome and macro-orchidism. Lymphocyte cultures were set up in media F-10 and 199. Chromosomes were G-band-stained and slides coded for blind analysis. Marker-X chromosomes and autosomal gaps were seen only in cultures prepared with medium 199. Autosomal gaps were seen in all family members and controls. The marker-X chromosome was present in affected male (3% and 15.5%) and female family members (0.5%–6.5%) but not in controls or a normal male family member. Bilateral macro-orchidism was present in 1 affected male and unilateral macro-orchidism in the other. Both had normal penile measurements. The replication pattern of the marker-X chromosome was studied in 1 woman by BrdU labelling. BrdU decreases the frequency of marker-X expression. As the marker-X chromosome was the late-replicating X in 9/20 cells, it appears that there is no preferential inactivation of the marker-X in this woman.     

X-linked cubitus valgus with mental retardation and typical face

In 1973, Jones and Smith described two maternal male first cousins with a similar pattern of malformation, including mental retardation, cubitus valgus, and unusual facies. The purpose of this report is to describe three additional cases, a 10-year-old male and his 30-year-old maternal uncle and an unrelated 15-year-old boy, bringing to five the total number of individuals with this disorder. The principal features include moderate mental retardation, mild microcephaly, a short philtrum, deep-set, downslanting palpebral fissures, multiple nevi, and striking cubitus valgus. Documentation of this disorder in two maternal male first cousins as well as in a male and his maternal uncle support an X-linked recessive mode of inheritance for this condition.     

Psychometric assessment of families with X-linked mental retardation

As part of an integrated approach to DNA-linkage analysis in X-linked mental retardation (XLMR), 29 members of five families suspected of having XLMR underwent psychometric assessment. Mental retardation was confirmed in all participants. The range of mental retardation varied from mild to profound within and between families. In addition, these preliminary results indicated family-specific cognitive profiles in MRX45 and MRX46. The fact that two non-overlapping loci were involved provides strong evidence that specific cognitive profiles are linked to specific loci (genes) in mental retardation. We therefore recommend the application of standardised psychometric tests for the assessment of XLMR.     

X chromosome inactivation and X-linked mental retardation

The expression of X-linked genes in females heterozygous for X-linked defects can be modulated by epigenetic control mechanisms that constitute the X chromosome inactivation pathway. At least four different effects have been found to influence, in females, the phenotypic expression of genes responsible for X-linked mental retardation (XLMR). First, non-random X inactivation, due either to stochastic or genetic factors, can result in tissues in which one cell type (for example, that in which the X chromosome carrying a mutant XLMR gene is active) dominates, instead of the normal mosaic cell population expected as a result of random X inactivation. Second, skewed inactivation of the normal X in individuals carrying a deletion of part of the X chromosome has been documented in a number of mentally retarded females. Third, functional disomy of X-linked genes that are expressed inappropriately due to the absence of X inactivation has been found in mentally retarded females with structurally abnormal X chromosomes that do not contain the X inactivation center. And fourth, dose-dependent overexpression of X-linked genes that normally “escape” X inactivation may account for the mental and developmental delay associated with increasing numbers of otherwise inactive X chromosomes in individuals with X chromosome aneuploidy. © 1996 Wiley-Liss, Inc.     

X-linked mental retardation and/or hydrocephalus

A family in which a brother and 5 sons of five sisters were mentally retarded without major physical abnormality, is reported. Two hydrocephalic males also occurred in the family. The possibility is entertained that in this family (and probably in others) an X-linked gene caused either non-specific mental retardation or hydrocephalus associated with mental retardation. Some minor physical and neurological abnormalities were found in some of the affected males, and their intelligence varied considerably within the retarded range.     

De novo pure 12q22q24.33 duplication: first report of a case with mental retardation, ADHD, and Dandy-Walker malformation

We present a patient with a de novo 12q nonmosaic pure duplication characterized by multiple minor anomalies and Dandy-Walker malformation. A neurological and behavioral assessment revealed psychomotor retardation and attention deficit/hyperactivity disorder (ADHD), with neurobehavioral abnormalities (auto- and heteroaggressive behavior). Fluoxetine therapy in this case markedly improved the neurobehavioral profile, with a decreased level of aggression. To define the extension of the duplicated region, we performed FISH analyses by using YAC probes. The analyses revealed a tandem duplication of the 12q22q24.33 region, with the proximal breakpoint located between 96.5 and 97.6 cM and the distal one between 154 and 161 cM. This is the first case of pure de novo duplication involving the 12q22q24.33 region. To better define the clinical phenotype associated with 12q partial duplication, we compared our case with the four patients with similar pure duplications previously described.     

A large kindred with X-linked mental retardation, marker X and macroorchidism

Thirty-eight members of a black kindred with mental retardation and the Marker X were studied. Ten of 14 affected males, 6 of 6 affected females, 18 carriers or possible carriers, and 7 normal males were examined. Eight of 9 affected males who could be measured had macroorchidism, but their ears and mandibles were not prominent. No distinct facies were evident, although minor anomalies, such as a slight pectus, were present in some. Clinical diagnosis in the absence of a strongly positive family history may be even more difficult among prepubertal black children than in whites. The risk of retardation among children of carriers was estimated at 20-40%.     

X-linked recessive nephritis with mental retardation, sensorineural hearing loss, and macrocephaly

A family with hereditary nephritis, sensorineural hearing loss, macrocephaly, and mental retardation is reported. X-linked recessive inheritance was suggested by the presence of two affected brothers and a maternal uncle. This association may be a previously unreported variant of Alport's syndrome.     

New X-linked syndrome with severe mental retardation,severely impaired vision,severe hearing defect,epileptic seizures,spasticity, restricted joint mobility,and early death

A family with an X-linked mental retardation syndrome involving seven children in two generations is reported. The syndrome includes microcephaly, severe mental retardation, optic atrophy with severely impaired vision or blindness, a severe hearing defect, spasticity, epileptic seizures, restricted movement of the large joints, and death in infancy or early childhood. We conclude that this is a distinct, previously unrecognized X-linked mental retardation syndrome. © 1993 Wiley-Liss, Inc.     

Large-scale sequencing to identify disease causing variants in X-linked mental retardation

A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation
Tarpey et al. (2009)
Nature Genetics 41: 535–543     

New X-linked mental retardation syndrome with the gene mapped tentatively in Xp22.3

X-linked mental retardation (XLMR) is genetically heterogeneous and clinically variable. We describe a new XLMR syndrome of severe mental retardation and multiple congenital anomalies. Two sisters have (with 3 different partners) 3 severely handicapped sons. In 2 cases, oligohydramnios and intrauterine growth retardation were noted. Common anomalies included a square-shaped face, high and broad forehead, frontal bossing, downward slant of palpebral fissures, hypertelorism, epicanthic folds, long philtrum, thin upper lip, and apparently low-set ears. One boy has bilateral microphthalmos and sclerocornea, and his cousin has atrophy of the optic nerve. All 3 patients are blind and have profound statomotor and mental retardation, seizures, and a grossly abnormal electroencephalographic pattern. Additional findings are short stature, delayed bone maturation, hydronephrosis, vesicorenal reflux, cryptorchidism, clinodactyly of the 5th fingers, and transverse palmar creases. The karyotype is normal (46,XY). Segregation analysis showed perfect coinheritance between the clinical phenotype and alleles at several loci in Xp22.3, whereas recombinants were identified with marker loci from Xp22.2-qter. Analysis of multiple informative meioses suggests that the disease locus maps in Xp22.3 distal to DXS16. © 1996 Wiley-Liss, Inc.