A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudi-specific mutations.

Wilson disease (WD) is a hereditary disorder, with recessive transmission and genetic heterogeneity. Several mutations of ATP7B, the gene underlying WD, were reported in many ethnic groups. In this study, mutation screening in ATP7B of 56 Saudi Arabian WD patients was undertaken. The clinical data of all patients were recorded. The entire ATP7B coding sequence, including intron-exon boundaries were screened for mutation by the polymerase chain reaction (PCR)-based mutation detection technique and DNA sequencing. Thirty-nine patients were symptomatic at presentation and 17 subjects were pre-symptomatic siblings of affected patients. Fourteen patients had neurological, 11 patients had mixed (hepatic and neurological), and 14 patients had hepatic presentations. Family history suggestive of WD was present in 72% of cases and 68% had consanguineous parents. Genetic analysis showed disease-causing mutations in three exons (exons 8, 19 and 21) of the ATP7B gene in 28 patients (50%). Mutations in exons 21 (18 cases) and 19 (one case) were unique for Saudis. This large series of Saudi patients with WD has shown wide variability in the genomic substrate of WD. There is no correlation between genotype and clinical presentation.

Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature.

High dose intravenous immunoglobulin (IVG) is increasingly used in a broad range of immune mediated diseases. Thrombosis was exceptionally reported as a complication of this therapy. We describe three cases of thrombotic complications during or soon after IVIG treatment: myocardial infarction in a man and cerebral infarctions in an elderly man, associated with peripheral ischemia in a woman. In addition we review the published cases in the literature and discuss the possible etiologic factors.

The prevalence of epilepsy and other seizure disorders in an Arab population: a community-based study.

PURPOSE: To determine the prevalence of epilepsy and other convulsive disorders and the causes of symptomatic epilepsies in a Saudi Arabian population. METHODS: Door to door survey of a restricted area inhabited by 23 700 Saudi nationals. The World Health Organization (WHO) protocol designed to detect neurological disorders was used as screening instrument. All patients with probable seizures were examined by a neurologist and 92% of positive cases were investigated by brain computed tomography (CT) and electroencephalogram (EEG). RESULTS: Prevalence rate (PR) for active epilepsy was 6.54 /1000 population (95% confidence interval 5.48-7.60). Twenty-eight percent of the patients had partial seizures, 21% generalized seizures and in 51%, it was not possible to determine if the generalized seizures had focal onset or not. The epilepsy was symptomatic in 32% of the cases: pre or perinatal encephalopathy 23%, head injury 4%, childhood neurological infection 4% and stroke 1%. Febrile convulsions PR was 3.55 /1000 children under the age of 6 years and isolated seizures were documented in only 0.18 /1000 population. CONCLUSIONS: The PR of epilepsy in Saudi Arabs is within the range of the values reported in most communities. The causes of symptomatic epilepsies revealed a predominance of perinatal and inherited factors. Isolated and non-convulsive seizures were probably under-recognized due to various social and cultural factors as well as to lack of sensitivity of the questionnaire for non-convulsive seizures.

A novel deletion mutation within the carboxyl terminus of the copper-transporting ATPase gene causes Wilson disease.

In patients with Wilson disease (WD), an autosomal recessive disorder, toxic accumulation of copper results in fatal liver disease and irreversible neuronal degeneration. ATP7B, the gene mutated in WD, contains 21 exons and encodes a copper-transporting ATPase. In this study, all exons of the ATP7B gene of nine WD patients were screened for alterations by conventional mutation detection enhancement (MDE) heteroduplex analysis, followed by direct sequencing of the regions that showed heteroduplex formation. For the first time, a novel deletion mutation (4193delC) in exon 21, causing a frameshift leading to premature truncation of the protein was detected in four of nine patients. The 4193delC removes several signals within the carboxyl terminal domain that may disrupt trafficking of ATP7B protein through trans-Golgi network at the cellular level.

The Saudi Stroke Data Bank. Analysis of the first 1000 cases.

OBJECTIVES: To determine the types of stroke, their risk factors and their most likely causes in Saudi patients. METHODS: Data on stroke cases admitted to 2 major hospitals in Saudi Arabia since 1982 were collected retrospectively up to 1991 then prospectively since then. By January 1995, the number of cases with first-ever-stroke stored in our Saudi Stroke Data Bank reached 1280. This article describes the findings in the first 1000 Saudi patients investigated by brain computed tomography. RESULTS: Males (68%) outnumbered females. There was no significant difference between the retrospective cases and the prospective ones in relation to the types of stroke or the risk factors. Ischemic strokes accounted for 76% of the cases and one third of them were lacunar infarcts. Most of the hemorrhagic strokes were intracerebral hemorrhages (ICHs) and only 2% of all strokes were subarachnoid hemorrhages (SAHs). Hypertension (52%), diabetes mellitus (41%) and cardiac disorders were common risk factors. The commonest causes of cerebral infarcts were atherosclerosis 36%, hypertensive and/or diabetic arteriolopathy 24% and cardiac embolisms 19%. Hypertensive arteriolopathy accounted for two-thirds of the cerebral hemorrhages. Strokes related to small artery disease, i.e. lacunar infarcts and ICHs accounted for 47% of the cases. CONCLUSION: The overall distribution of stroke types in Saudis is not very different from that reported in western studies, except for the low frequency of SAH. However, the important role of small artery disease in stroke pathogenesis and the high number of diabetic patients are quite distinctive.

Application of DNA-based tests for diagnosis of spinal muscular atrophy in Saudi Arabia.

We examined the deletion of the survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes in patients with spinal muscular atrophy (SMA) using polymerase chain reaction followed by restriction site assay methods. The study included 16 Saudi patients (9 SMA type I and 7 SMA type II) and 6 healthy Saudi volunteers. The homozygous deletions of exons 7 and 8 of the telomeric SMN gene, and exon 5 of the NAIP gene were found in all SMA type I patients. Exons 7 and 8 of telomeric SMN were deleted in all SMA type II patients. However, exon 5 of NAIP was deleted in three of the seven cases. All control volunteers and all family members of the patients had normal SMN and NAIP. The incidence of NAIP deletion was higher in the more severe SMA cases and the dual deletion of the SMN and NAIP genes was more common in Saudi SMA type I patients compared with patients of other ethnic groups.

Motor terminal latency index in carpal tunnel syndrome.

We determined the motor terminal latency index (MTLI) of the median nerve across the carpal tunnel in 41 upper extremities of 31 patients with carpal tunnel syndrome. Changes in motor nerve conduction velocity (MNCV), motor terminal latency (MTL), sensory action potential and the amplitude of the compound muscle action potential recorded from the abductor pollicis brevis muscle were all suggestive of proximal and distal segment involvement of the nerve across the carpal tunnel. There was no correlation between forearm MNCV and MTL (r = 0.40), although MTLI was correlated with MTL (r = 0.67) but not with MNCV, indicating a disproportionate conduction across the carpal tunnel.

Terminal Latency Index: A distinctive diagnostic criterion for carpal tunnel syndrome.

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Application of DNA-based tests for diagnosis of spinal muscular atrophy in Saudi Arabia

We examined the deletion of the survival motor neuron [SMN] and neuronal apoptosis inhibitory protein [NAIP] genes in patients with spinal muscular atrophy [SMA] using polymerase chain reaction followed by restriction site assay methods. The study included 16 Saudi patients [9 SMA type I and 7 SMA type II] and 6 healthy Saudi volunteers. The homozygous deletions of exons 7 and 8 of the telomeric SMN gene, and exon 5 of the NAIP gene were found in all SMA type I patients. Exons 7 and 8 of telomeric SMN were deleted in all SMA type II patients. However, exon 5 of NAIP was deleted in three of the seven cases. All control volunteers and all family members of the patients had normal SMN and NAIP. The incidence of NAIP deletion was higher in the more severe SMA cases and the dual deletion of the SMN and NAIP genes was more common in Saudi SMA type I patients compared with patients of other ethnic groups

Motor terminal latency index in carpal tunnel syndrome

We determined the motor terminal latency index [MTLI] of the median nerve across the carpal tunnel in 41 upper extremities of 31 patients with carpal tunnel syndrome. Changes in motor nerve conduction velocity [MNCV], motor terminal latency [MTL], sensory action potential and the amplitude of the compound muscle action potential recorded from the abductor pollicis brevis muscle were all suggestive of proximal and distal segment involvement of the nerve across the carpal tunnel. There was no correlation between forearm MNCV and MTL [r = 0.40], although MTLI was correlated with MTL [r = 0.67] but not with MNCV, indicating a disproportionate conduction across the carpal tunnel

Dementia in Saudi Arabia: experience from a university hospital.

OBJECTIVES: To describe the pattern of presentation, the types of dementia and the associated conditions in Saudi patients. MATERIALS AND METHODS: Hospital-based study using DSM-IV and ICD 10 criteria for consensus diagnosis of cases from clinical information and results of investigations. Dementia subtypes were made according to NINCDS-ADRDA, NINDS-AIREN and ICD 10 criteria while CDR was used for severity grading. RESULTS: A total of 77 demented patients (49 males, 28 females) were studied. The hospital frequency was 19.3/100,000 patients. The mean age at presentation was 74.6 years and age at onset was below 65 years in 17 patients. The types of dementia were: Alzheimer's disease (51.9%), vascular dementia (18.2%), mixed cases (15.6%), dementia with Parkinson's disease (7.8%) and treatable dementia (5.2%). Only 3 patients were in the severe clinical stage and infections were important causes of deterioration. CONCLUSION: The hospital frequency appears to be low probably because of the relatively young population. The pattern of dementia with preponderance of AD is similar to that in western countries and intervention directed at the risk factors for stroke could reduce the burden of vascular dementia.

Risk factors of stroke at high and low altitude areas in Saudi Arabia.

BACKGROUND: The epidemiology of stroke at different geographical locations in the Kingdom of Saudi Arabia has not been adequately investigated. METHODS: In this study, clinical types and risk factors of stroke were compared among patients at low-altitude (Riyadh, 620 m) and high-altitude (Al Baha > 2000 m) areas using a case-control study design. One-hundred ninety recently diagnosed cases (109 from Riyadh and 81 from Al Baha) were verified and subjects were interviewed. An equal number of age- and sex-matched controls from the corresponding areas were also interviewed using a specific standard questionnaire. RESULTS: The frequency of thrombotic stroke at high altitude was 93.4% as compared to 79.3% at low altitude (P < 0.05). The odds ratios (OR) for the different risk factors at high and low altitudes, respectively, were: hypertension 4.4 and 2.1; diabetes mellitus: 2.7 and 1.9; ischemic heart disease (IHD): 2.4 and 1.9; atrial fibrillation: 3.9 and 3.3, and smoking: 2.3 and 2.5. The mean hematocrit values were 45.3% at high altitude and 41.0% for low altitude patients (P < 0.001) and its association with stroke at high altitude remained significant even after adjusting for age, gender and occupation. CONCLUSIONS: The study's finding of an increased frequency of thrombotic stroke at high altitude was explained by increased hematocrit which might have caused this in conjunction with other factors such as hypertension and IHD. Larger studies are recommended for better clarification of interaction between high altitude and other established risk factors not included in this study, such as sickle cell anemia and congenital heart diseases in young patients.

Molecular analysis of the SMN and NAIP genes in Saudi spinal muscular atrophy patients.

In this study we examined the deletion of the SMN and NAIP genes in 14 Saudi families (16 patients and 38 relatives of the patients, including parents and siblings) and six healthy Saudi volunteers. The homozygous deletions of exons 7 and 8 of the telomeric SMN gene and exon 5 of the NAIP gene were found in seven out of eight spinal muscular atrophy (SMA) type-I patients. In seven SMA type-II patients, exons 7 and 8 of telomeric SMN were deleted in six cases and exon 5 of NAIP was deleted in three cases. Three patients with SMA diagnosis did not show either of the above deletions. All control Saudi volunteers and all but two family members of the patients had both normal SMN and NAIP genes. Our results show that the incidence of NAIP deletion is higher in the more severe SMA cases and the dual deletions of the SMN and NAIP genes are more common in Saudi SMA type-I patients compared to patients of other ethnic groups.

Pattern of presentation of multiple sclerosis in Saudi Arabia: analysis based on clinical and paraclinical features.

We studied 89 MS patients comprising 38 males and 51 females seen over a 10-year period. The hospital frequency was 25/100,000 patients. The diagnosis was mainly clinical and was supported by neuroimaging, cerebrospinal fluid analysis and neurophysiological tests. Sixty-five patients (73%) were Saudis and the peak age of onset was in the third decade. Fifty-two patients (58.4%) had clinically definite MS, 17 (19.1%) had laboratory-supported definite MS, 15 (16.9%) were clinically probable MS cases and the remaining 5 (5.6%) had laboratory-supported probable MS. The mean age at onset of Saudi patients (25.9 years) was lower than that of the non-Saudis (29.4 years; p < 0.001). Involvement of the pyramidal system was the commonest mode of presentation. The clinical course was relapsing-remitting in 60.7%, progressive-relapsing in 20.2% and primary progressive in 19.1%. The number of systems involved was significantly associated with the duration of disease (p < 0.001). The demographic features and the variability of clinical presentation of Saudi MS patients is similar to the results from neighbouring countries. Combination of clinical features and paraclinical tests is essential for accurate determination of extent of dissemination and for unmasking clinically silent lesions.

Stroke register: experience from the eastern province of Saudi Arabia.

A stroke registry was established in the Eastern Province of Saudi Arabia with an estimated population of 750,000 inhabitants of whom 545,000 are Saudi citizens. The register started in July 1989 and ended in July 1993. The Gulf war led to its interruption from August 1990 to August 1991. Four hundred eighty-eight cases (314 males, 174 females) of first-ever strokes affecting Saudi nationals were registered over the 3-year period. The crude incidence rate for first-ever strokes was 29.8/100,000/year (95% CI: 25.2-34.3/100,000 year). When standardized to the 1976 US population, it rose up to 125.8/100,000/year. Ischemic strokes (69%) predominated as in other studies but subarachnoid hemorrhage (SAH) was extremely rare (1.4%). The important risk factors were: systemic hypertension (38%), diabetes mellitus (37%), heart disease (27%), smoking (19%) and family history of stroke (14%). Previous transient ischemic attacks (3%) and carotid bruits (1%) were uncommon. The 30-day case fatality rate was 15%. The study showed that the age-adjusted stroke incidence rate for Saudis in this region is lower than the rates reported in developed countries but within the range reported worldwide. The pattern of stroke in Saudi Arabia is not different from that reported in other communities with the exception of the low incidence of SAH. The risk factors are similar to findings in other studies except for the high frequency of diabetes mellitus in our cases. The lower mortality rate was probably due to the younger age of the population and the availability of free medical services for management of cases.

Evolution of brain tuberculomas under standard antituberculous treatment.

The treatment of brain tuberculomas is primarily medical. Surgery, excision or biopsy, is generally performed when the diagnosis is in doubt or there is no response to medical therapy. The aim of this study was to determine the radiological evolution of intracranial tuberculomas under standard anti-tuberculous drug therapy and to establish guidelines for better management of these patients. Eighteen patients were studied retrospectively. None of them had surgical intervention and all were treated by standard antituberculous drugs and had serial computed tomography (CT) scans until disappearance or stabilization of brain lesions. The regression of lesions' size and number was slow in the first month (mean -7.3%) then became rapid after this (-15% to -20% per month). A paradoxical increase in size was noted in three patients in the first month. All three had associated meningitis. All tuberculomas disappeared on CT scan after 12 months of therapy. Most of the edema images disappeared by 6 months. This study would suggest that a long treatment regimen of 15-18 months may not be necessary in most intracranial tuberculomas occurring in non-immunocompromised patients. It also demonstrates that medical trial in well tolerated suspected cases should last for at least 2 months before considering other etiologies or surgical exploration.

Epilepsy classification and factors associated with control in Saudi adult patients.

There is insufficient information on the epilepsies in Saudi Arabia. The objectives were to classify the patients according to seizure types and epilepsies as well as to determine the factors associated with control. In a hospital-based study, clinical information, electroencephalographic and neuroimaging findings were utilized to classify the cases into seizure types and epilepsies according to ILAE criteria and to determine the factors statistically associated with control. In the study there were 826 patients (454 males and 372 females; mean age = 28.7 years; >80% below 30 years at onset). The seizure types were: generalized tonic-clonic (43.8%), partial seizure secondarily generalized (41.9%), myoclonic (8.4%), simple partial (1.3%), complex partial (1.3%) and absence (0.4%). About 15% of the classifiable epilepsies were symptomatic. Most symptomatic epilepsies occurred in people over the age of 50 years. One-year remission rate was 80% and the factors associated with control were: compliance, monotherapy, therapeutic drug level and seizure type. The results showed that epilepsy predominantly affected young adults and confirmed the association of partial epilepsy with clinical and CT abnormalities. The 1-year remission rate was comparable with reports from other studies as well as the factors associated with control in our patients.

Nontraumatic cerebral hemorrhage in the young: a study of 107 cases.

BACKGROUND: Reports on intracerebral hemorrhage (ICH) in the young are rare, and information on the cause and prognosis of ICH in this age-group is sparse. METHODS: All cases of ICH admitted to three major hospitals in Saudi Arabia over a 15-year period were retrospectively reviewed. Patients aged between 6 months and 45 years at stroke onset were studied. Pooling of our data with those published from other centers was used for final analysis. RESULTS: One hundred seven cases (69 male, 38 female), including 12 children younger than 10, were analyzed. The causes of hemorrhage were as follows: arteriovenous malformations (AVMs), 23%; systemic hypertension, 20%; blood dyscrasias, 16%; berry aneurysms, 8%; other causes, 7%. No cause was found in 26%. Sixty-two percent of the ICHs were lobar and 3% multiple. Early death rate was high (27%). Twelve percent of the patients were lost to follow-up, and only 26% returned to a state of complete autonomy. CONCLUSION: The pooling of the causative data from our cases and the 253 others reported in the literature showed that even before 45 years of age systemic hypertension is the leading cause of ICH. It accounts for approximately 30% of the cases, with AVMs (20%) being next. The pooled overall early mortality rate is approximately 20%, and only one third of the patients return to independent living.