Inherited retinal dystrophies in a Kuwaiti tribe.

PURPOSE: To evaluate the clinical and genetic spectrum of inherited retinal diseases (IRDs) in a Kuwaiti tribe. METHODS: Forty four patients with IRDs from 28 nuclear families from the tribe, were evaluated for presenting symptoms, visual acuity, fundus examination, OCT, microperimetry, full-field (ff), and multifocal electroretinography (mERG) and genotyping. RESULTS: Seventeen patients were diagnosed with autosomal recessive retinitis pigmentosa (arRP) associated with RP1 c.606C>A with onset of nictalopia in the third decade, myopia, and macular atrophy by the age of 50; eleven with autosomal recessive cone/rod dystrophy or macular dystrophy associated with RP1 c.606C>A (p.Asp202Glu) mutation with color and central vision deterioration in teenage, myopia, paracentral ring scotoma and macular atrophy; eleven were with arRP associated with PDE6B c.992 + 1 G > A mutation with onset around 5 years, myopia, cataract, retained central fixation, and ellipsoid zone and late perimacular atrophy; five-with Leber congenital amaurosis associated with homozygous RPGRIP1 for c.1107delA mutation with extinguished ffERG and electrophysiological phenotype of rod and cone; and one patient-with autosomal recessive rod-cone dystrophy associated with homozygous PDE6B c.992 + 1 G > A, who was homozygous ABCA4 c.5882 G > A and heterozygous EYS; c.2137 + 1 G > A. CONCLUSIONS: This study represents a typical tribe from the Middle East with high rate of consanguinity for many generations that harbors multiple mutated genes associated with IRD. It demonstrates the predominant phenotype and its variability in retinal disorders caused by identical mutations and illustrates the nuances in the clinical presentation and disease progression of patients with pathogenic mutations in more than one gene.

Distinguishing 3 classes of corpus callosal abnormalities in consanguineous families.

OBJECTIVE: We sought to create a classification system for pediatric corpus callosal abnormalities (CCA) based upon midline sagittal brain MRI. We used the term CCA for patients with structural variants of the corpus callosum, excluding patients with interhemispheric cyst variant or pure dysplasia without hypoplasia. Currently, no system exists for nonsyndromic forms of CCA, and attempts to create such a system have been hampered by highly variable morphology in patients with sporadic CCA. We reasoned that any useful strategy should classify affected family members within the same type, and that phenotypic variability should be minimized in patients with recessive disease. METHODS: We focused recruitment toward multiplex consanguineous families, ascertained 30 patients from 19 consanguineous families, and analyzed clinical features together with brain imaging. RESULTS: We identified 3 major CCA classes, including hypoplasia, hypoplasia with dysplasia, and complete agenesis. Affected individuals within a given multiplex family usually displayed the same variant of the class of abnormality and they always displayed the same class of abnormality within each family, or they displayed complete agenesis. The system was validated among a second cohort of 10 sporadic patients with CCA. CONCLUSIONS: The data suggest that complete agenesis may be a common end-phenotype, and implicate multiple overlapping pathways in the etiology of CCA.

Sanjad-Sakati syndrome/Kenny-Caffey syndrome type 1: a study of 21 cases in Kuwait.

We studied 21 patients with Sanjad-Sakati syndrome (SSS) from 16 families. Parental consanguinity was recorded in 2 families (12.5%). All patients had severe intrauterine growth retardation, short stature, small hands and feet, blue sclera, deep-set eyes, microcephaly, persistent hypocalcaemia and hypoparathyroidism. Medullary stenosis was detected in 2 patients. Cytogenetic and fluorescent in situ hybridization studies were normal. All affected persons had homozygous deletion of 12 bp (155-166del) in exon 3 of the TBCE gene. All of the parents were heterozygous carriers of this mutation. The high frequency of SSS and low frequency of consanguineous marriages in this study may reflect a high rate of heterozygous carriers.

Sanjad-Sakati syndrome/Kenny-Caffey syndrome type 1: a study of 21 cases in Kuwait

We studied 21 patients with Sanjad-Sakati syndrome [SSS] from 16 families. Parental consanguinity was recorded in 2 families [12.5%]. All patients had severe intrauterine growth retardation, short stature, small hands and feet, blue sclera, deep-set eyes, microcephaly, persistent hypocalcaemia and hypoparathyroidism. Medullary stenosis was detected in 2 patients. Cytogenetic and fluorescent in situ hybridization studies were normal. All affected persons had homozygous deletion of 12 bp [155-166del] in exon 3 of the TBCE gene. All of the parents were heterozygous carriers of this mutation. The high frequency of SSS and low frequency of consanguineous marriages in this study may reflect a high rate of heterozygous carriers

Profile of major congenital malformations in neonates in Al-Jahra region of Kuwait.

We investigated major congenital abnormalities in babies born in Al Jahra Hospital, Kuwait from January 2000 to December 2001. Of 7739 live and still births born over this period, 97 babies had major congenital malformations (12.5/1000 births): 49 (50.6%) babies had multiple system malformations, while 48 (49.4%) had single system anomalies. Of the 49 babies with multiple malformations, 21 (42.8%) had recognized syndromes, most of which were autosomal recessive and 17 had chromosomal aberrations. Isolated systems anomalies included central nervous system (12 cases), cardiovascular system (9 cases), skeletal system (7 cases) and gastrointestinal system (6 cases). Of the parents, 68% were consanguineous. Genetic factors were implicated in 79% of cases. Genetic services need to be provided as an effective means for the prevention of these disorders.

Profile of major congenital malformations in neonates in Al-Jahra region of Kuwait

We investigated major congenital abnormalities in babies born in Al Jahra Hospital, Kuwait from January 2000 to December 2001. Of 7739 live and still births born over this period, 97 babies had major congenital malformations [12.5/1000 births]: 49 [50.6%] babies had multiple system malformations, while 48 [49.4%] had single system anomalies. Of the 49 babies with multiple malformations, 21 [42.8%] had recognized syndromes, most of which were autosomal recessive and 17 had chromosomal aberrations. Isolated systems anomalies included central nervous system [12 cases], cardiovascular system [9 cases], skeletal system [7 cases] and gastrointestinal system [6 cases]. Of the parents, 68% were consanguineous. Genetic factors were implicated in 79% of cases. Genetic services need to be provided as an effective means for the prevention of these disorders

Fragile X syndrome: a clinico-genetic study of mentally retarded patients in Kuwait.

In a prospective study in Kuwait, 182 mentally retarded male patients who fulfilled 5 or more clinical criteria of fragile X syndrome were screened using polymerase chain reaction (PCR) testing. Twenty patients (11%) were highly suspected of having fragile X syndrome due to mutation at the FRAXA locus; none had mutation at the FRAXE locus. Of these, 11 (55%) were confirmed fragile-X-positive by both cytogenetic and PCR techniques. The most frequent clinical features were: prominent forehead, high arched palate, hyperextensible joints, long ears, prominent jaw, height > 10th centile and attention-deficit hyperactivity. Less common were avoidance of eye contact (45%), autism (45%) and seizures (30%). Large testes were found in 55% of cases. Pre-pubertal and post-pubertal clinical criteria were different.

Fragile X syndrome: a clinico-genetic study of mentally retarded patients in Kuwait

In a prospective study in Kuwait, 182 mentally retarded male patients who fulfilled 5 or more clinical criteria of fragile X syndrome were screened using polymerase chain reaction [PCR] testing. Twenty patients [11%] were highly suspected of having fragile X syndrome due to mutation at the FRAXA locus; none had mutation at the FRAXE locus. Of these, 11 [55%] were confirmed fragile-X-positive by both cytogenetic and PCR techniques. The most frequent clinical features were: prominent forehead, high arched palate, hyperextensible joints, long ears, prominent jaw, height > 10th centile and attention-deficit hyperactivity. Less common were avoidance of eye contact [45%], autism [45%] and seizures [30%]. Large testes were found in 55% of cases. Pre-pubertal and post-pubertal clinical criteria were different

Trisomy 18 in Kuwait.

BACKGROUND: Trisomy 18 (Edwards' syndrome, T18) is the second most common trisomy in man. We describe 118 children with regular T18 who were ascertained clinically and cytogenetically in the Kuwait Medical Genetics Centre during 1980-1997. METHODS: Ascertainment of T18 cases was performed shortly after birth. Chromosomal studies were carried out in addition to other relevant investigations. To investigate the factors associated with T18, a case-control study was carried out with 131 normal healthy newborns. Studied factors included maternal and paternal age, birth order, abortion, associated malformation, and survival. Multiple logistic regression analysis was used to adjust for confounding between variables. RESULTS: There was a preponderance of females among T18 cases (female:male ratio 2.1:1). The majority of T18 cases (53%) died before the second week of life. The most common associated anomalies were: congenital heart (38.1%) and gastrointestinal (25.4%). Multiplicity of malformations was also observed. Significant seasonal variation in T18 cases was detected with a peak in spring. Of the 118 T18 cases, 59 were delivered during 1994-1997 (average overall T18 birth prevalence rate 8.95 per 10 000 live births [95% CI: 6.66-11.23]). Concerning maternal age, 30.5% of the T18 cases' mothers were > or =35 years compared to 10.7% in the control group. The difference was statistically significant, P = 0.002. Logistic regression analysis showed that maternal age >30 years was a significant risk factor for T18, after adjusting for confounding with paternal age. Paternal age and abortion were not found to be significant risk factors. CONCLUSION: Trisomy 18 birth prevalence rate is high in Kuwait with advanced maternal age as a significant risk factor.

PIP: This paper describes associated factors of trisomy 18 (T18) or Edwards' syndrome among infants in Kuwait. A case control study of 131 normal newborn controls was undertaken. The study included information about gender, maternal age, paternal age, birth order, reproductive history, consanguinity, survival, and associated anomalies. Results showed a preponderance of females among T18 cases (female/male ratio, 2.1:1). The difference between the T18-case mothers and the control-group mothers was statistically significant (P = 0.002); however, there was no significant difference with regard to paternal age. The logistic regression analysis showed that the odds ratio for 2 abortions with reference to (0/1) abortion was 1.086, which is statistically significant as a risk for T18. The majority of children with T18 died before the second week of life. With regard to malformations, the most common associated anomalies were congenital heart and gastrointestinal abnormalities. Thus, the prevalence of T18 is high in Kuwait, with advanced maternal age as a significant risk factor.

Clustering of trisomy 18 in Kuwait: Genetic predisposition or environmental?

BACKGROUND: This study describes 59 newborns with regular trisomy 18 (EdwardsA centAA syndrome, T18) who were ascertained clinically and cytogenetically at the Kuwait Medical Genetic Centre from 1994 to 1997, out of 118 T18 cases identified from 1980 to 1997. MATERIALS AND METHODS: T18 cases were ascertained clinically and cytogenetically shortly after birth. In addition to assessing the T18 birth prevalence rate and confidence limits during the years 1994-1997, we investigated the possible etiological factors by a case-control study with normal healthy newborns. Studied factors included gender, parental age, birth order, abortion, clinical variables (presentation, amniotic fluid and mode of delivery), and survival. RESULTS: The average T18 birth prevalence rate during the period was 8.95 per 10,000 live births (95% confidence limits 6.66-11.23). The T18 cases were mostly females, with a male:female ratio of 1:2.1, and the majority (53%) died before the second week of life. Maternal age above 30 years was found to be a significant factor for T18. CONCLUSION: This high T18 birth prevalence rate suggests clustering of T18 in the highly inbred population of Kuwait. Such clustering may indicate a possible environmental, and to a lesser extent, genetic predisposition to aneuploidy nondisjunction.

Screening 25 dystrophin gene exons for deletions in Arab children with Duchenne muscular dystrophy.

Forty-two Arab children with Duchenne muscular dystrophy (DMD) were studied for intragenic deletions in 25 exons of the dystrophin gene using three different multiplex PCR sets each amplifying a total of 9, 9 and 6 different exons, respectively. Exon 22 was amplified individually. Deletions were found in 78, 76 and 12% of DMD patients with each of the three sets, respectively. With all the three sets, the detection rate increased to 86% (36 of 42 patients). Fifty percent of the deleted exons were located in the distal hot spot, 8% in the proximal hot spot while 42% were scattered over both. This study, the first in an Arab population and only the second to use three PCR multiplex sets, documents one of the highest deletion detection rates in DMD.

Unusual traits associated with Robinow syndrome.

We report on some members of two unrelated families showing the characteristic features of Robinow syndrome. In a consanguineous Kuwaiti family, the index case with Robinow syndrome showed some unusual features including severe IUGR, laxity of ligaments, hyperextensible joints, redundant skin folds, severe normocytic anaemia, repeated infection, increased percentage of total T cells and CD4 positive population, reduced percentage of CD8 positive cells, and EMG abnormality. In a Pakistani family with a high degree of multigenerational consanguinity, a single case with the Robinow phenotype also had congenital heart disease, mainly involving the right side of the heart, with pulmonary stenosis, tricuspid atresia, ASD, VSD, double outlet right ventricle, and right atrial isomerism. This report suggests that the disease profile of Robinow syndrome may be extended to accommodate the unusual traits mentioned above. The association of the Robinow phenotype with congenital heart disease in case 2 of this report is consistent with the previously reported finding that congenital heart disease, particularly involving the right side of the heart, may be a prominent component of Robinow syndrome in a subset of patients.

Deletion analysis of the SMN and NAIP genes in Kuwaiti patients with spinal muscular atrophy.

Two genes are known to be involved in spinal muscular atrophy (SMA), namely, SMN (survival motor neuron) and NAIP (neuronal apoptosis inhibitory protein). Deletion analysis of these genes has been reported for many ethnic groups. We have extended this analysis to include 15 Arabic patients (11 unrelated cases of type I, which represent practically all of the patients diagnosed within the last 2 years in Kuwait, and 4 type-II cases from a single kinship). Also, 41 healthy relatives (parents and sibs) and 44 control individuals of Arabic origin were analyzed. The homozygous deletions of exons 7 and 8 of the SMN gene were found in all SMA patients studied. Exon 5 of NAIP was homozygously absent in all type-I patients, but was retained in type-II cases. Among members of SMA families, one mother was found to be homozygously deleted for NAIP. All of the control individuals had both normal SMN and NAIP. Our results are in agreement with the general consensus that the incidence of NAIP deletion is higher in the more severe SMA cases. Furthermore, they suggest that SMA type-I chromosomes, with the dual deletion of the SMN and NAIP genes, are more common in Arabs than in patients of other ethnic origin.

Disease profile of 400 institutionalized mentally retarded patients in Kuwait.

In this preliminary report we summarize the results of a 4-year multidisciplinary systematic, etiological clinicogenetic survey of 400 institutionalized mentally retarded patients in Kuwait. All had an intelligence quotient below 50. A constitutional disorder, as the direct cause of the mental retardation, was found in 203 patients (50.75%)): a chromosomal abnormality in 37 (9.25%), Mendelian disorders in 137 (34.25%), MCA/MR in 22 (5.55%) and CNS malformations in 7 cases (1.75%). In 157 patients (39.35%) a pre-, peri or postnatal cause was ascertained. No etiological diagnosis was detected in 40 patients (10%). A detailed analysis of the "disease profile" is given and compared with the results of previous diagnostic genetic surveys among different institutionalized mentally retarded populations in Western and developing countries.