Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is becoming the most common form of adult onset hereditary syndrome characterized by recurrent transient ischemic attacks (TIA) and strokes, leading to progressive dementia, migraine with aura and psychiatric disturbances 123. Symmetrical white matter abnormalities are invariably seen, while small subcortical infarcts are often reported 4. The extent of the MRI lesions increases with age. Atypical anteriopathy with electron-dense granular deposition in the media of small cerebral arteries underlies the pathology of this disorder 5. This initial thickening and expansion of the extracellular matrix can be found to a lesser extent in extracerebral arteries, such as skin arterioles 6. Mutation in the NOTCH3 gene is usually linked to CADASIL 1. NOTCH3 encodes a 300-kd transmembrane protein with a receptor and cell signal transduction function. This receptor is expressed in vascular smooth muscle cells 7. Mutations are almost always mis-sense mutations causing the loss or gain of a cysteine residue and are detected in over 90% of patients 89. All mutations were located within the epidermal growth factor (EGF) repeats in the extracellular domain of the NOTCH3 gene and a strong clustering of the mutations were observed in exons 3 and 4 8910. Thus, there are more than 81 NOTCH3 mutations reported on the human genome mutation database 11 to-date. Therefore, CADASIL is far more common than previously perceived and it may often be misdiagnosed because it can present under various guises 10.

CADASIL cases have been identified in most countries of Western and Central Europe, the Americas, Japan, Australia, Tanzania, South America, the Caribbean, Turkey 12, South Africa 6 and Southeast Asia 13141516. To our knowledge, there are no published reports of CADASIL in native Arabs yet. Here we describe the clinical and genetic findings in three families from various Arab countries.

Nineteen (19) affected individuals, 9 males & 10 females, were examined by at least one of the authors. The mean age of onset was 31 ± 6 years. Stroke or TIA were noted in 68% of cases, the majority of episodes led to motor syndrome (hemiparesis, pseudobulbar palsy, dysphagia and incontinence) followed by sensory deficit and ataxia. 22% of examined patients had prominent cognitive decline and met the diagnostic criteria for vascular dementia 17 with stepwise deterioration, gait problems and urinary incontinence. Depression was the prominent affective disorder (25%) and in few patients was the only presenting symptom. Age of death was retrospectively identified and the mean age of death was 56 ± 11 years in the 8 patients studied. Migraine with aura was the predominant feature in members of Family B and affected members had histories of at least one vascular headache attack starting in the early 20s, followed by TIA or stroke 8 – 12 years later. One individual with depression and one with psychosis and ischemic changes in their MRIs (Figure 2a, 2b). Interfamilial and intra-familial variability with regards to presenting symptoms and of age at death was noted in most of the participants.

The following is the clinical and molecular findings summary of the three (3) families studied.

The families described in this report showed various characteristics that are typical of CADASIL, an autosomal dominant syndrome, with migraine, recurrent ischemic strokes, cognitive impairment, depressive disorder and premature death within 10 – 20 years after onset 4. CADASIL affects young and old adults, irrespective of vascular risk factors. In two of our families the affected sibling of probands had migraine with aura in their early 20s, followed by recurrent ischemic attacks in their mid 30s. Young onset of this syndrome had been reported previously 1216. The clinical course of the disease is heterogeneous, even within the same family as noted previously 15 (Figure 1).

MRI findings in our families include focal lacunar infarct and diffuse T2 weighted hyperintensity, usually including the temporal lobes and external capsules (Figure 2b, 2d). Positive MRI findings in asymptomatic individuals or in-patients who presented with depression or a psychiatric problem (Family B) indicated that NOTCH3 gene signalling may start early and may have different clinical presentations. The reported penetrance of MRI abnormalities is usually complete after age 35 and the mean age of clinical onset was 45 ± 10 years 34.

NOTCH3 mutations have been identified as a genetic cause of CADASIL. Numerous mutations in this gene have been described in recent years along with genetic heterogeneity of the disease 9; however, until now no genotype-phenotype relationship has been described 9.

The molecular findings in our families are in agreement with previous studies in other populations from different ethnic groups. All reports have found exon 4 to be the most common site of mutation and exon 3 to be the second most common site 7818.

CADASIL has been reported across various ethnic groups, with predominance among the French, German and Italian populations 26. It has seldom been reported from Asia 14. Families from Japan 6, Korea 13, Taiwan 14, Turkey 12 and Thailand 15 have also been reported.

We conclude that CADASIL can be seen in Arabs, and is probably under-diagnosed with similar clinical and genetic presentation as seen in other ethnic groups.

CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy

EDTA Ethylene Diamine Tetraacetic Acid

EGF Epidermal Growth Factor

MRI Magnetic Resonance Imaging

PCR Polymerase Chain Reaction

TIA Transient Ischemic Attacks

The author(s) declare that they have no competing interests.

SB, AS, AE, AA, TK, WS and SF were all involved in diagnosing the cases and carrying out the clinical evaluations. SB was in charge of recruiting patients and writing the clinical part of the manuscript. KAA performed the mutation analysis and laboratory work associated with it and writing the genetic part of this manuscript. All authors have read and approved the final manuscript.