CADASIL and migraine: A narrative review

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene and is clinically characterized by recurrent stroke, cognitive decline, psychiatric disturbances and migraine. The prevalence of migraine in CADASIL is slightly higher than in the general population, and the proportion of migraine with aura is much higher. The pathophysiological mechanism that leads to increased aura prevalence in CADASIL is unknown. Possible mechanisms of the excess of migraine with aura are an increased susceptibility to cortical spreading depression (CSD) or a different expression of CSD. It is also possible that the brainstem migraine area is involved in CADASIL. Last, it is possible that the NOTCH3 mutation acts as a migraine aura susceptibility gene by itself. In this narrative review we summarize the literature about migraine in CADASIL, with a special focus on what CADASIL might teach us about the pathophysiology of migraine.     

Interpretation of NOTCH3 mutations in the diagnosis of CADASIL

CADASIL is an autosomal dominant inherited disease, characterized by mid-adult onset of cerebrovascular disease and dementia. CADASIL is caused by mutations in the NOTCH3 gene, which encodes the NOTCH3 protein. Pathogenic mutations in CADASIL are highly distinctive in the sense that they lead to the loss or gain of a cysteine residue in 1 of the 34 EGFr domains of the NOTCH3 protein. The majority are missense mutations, but small deletions, insertions and splice-site mutations have been reported, which typically also lead to a numerical cysteine alteration. Whether numerical cysteine-altering mutations are a rule in CADASIL remains subject of debate, as there are reports suggesting pathogenicity of other types of mutations. However, for most of these the association with CADASIL was later revoked or is questionable. Here, we discuss and provide recommendations for the interpretation of NOTCH3 mutations in the diagnosis of CADASIL.     

MIGRAINE: EPIDEMIOLOGY, GENETICS, AND COMORBIDITY

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Knowledge of disease expression in young adult NOTCH3 mutation carriers (MCs) is limited.
Objective: To characterize clinical, neuropsychological, and radiological status in NOTCH3 MCs younger than 35 years.
Design: Clinical characterization and blinded survey comparing MCs with non-MCs.
Setting: Referral center.
Participants: Individuals younger than 35 years who were at a 50% risk of a NOTCH3 mutation, from our CADASIL database. Thirteen individuals, from 8 families, met the criteria.
Methods: Comprehensive clinical, genetic, neuropsychological, and radiological investigations. Magnetic resonance images were scored according to a standardized white matter hyperintensities rating scale.
Results: Six individuals, from 5 families, were MCs. Clinical symptoms consisted of migraine (with aura), stroke, and stroke-like episodes. We did not find evidence for psychiatric disturbances, functional disability, or cognitive dysfunction, compared with non-MCs. Radiologically, a characteristic magnetic resonance imaging lesion pattern emerged for all MCs. This comprised white matter hyperintensities in the anterior temporal lobes, the frontal lobes, and the periventricular frontal caps.
Conclusions: Migraine (with aura) and stroke can present in NOTCH3 MCs younger than 35 years; however, more importantly, physical function and cognition are intact. Possible subtle cognitive dysfunction needs to be assessed in a larger study. White matter hyperintensities on magnetic resonance imaging are characteristic, and are consistently visualized from the age of 21 years and onward. Awareness of the clinical and radiological features of CADASIL in those younger than 35 years should increase early diagnosis and allow for customized counseling of young adults from families with CADASIL.     

Recognizing CADASIL: a Secondary Cause of Migraine with Aura

Purpose of Review

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an important disease to consider in the differential diagnosis of migraine with aura. This review examines current literature regarding migraine in CADASIL, as well as diagnostic and treatment modalities.

Recent Findings

Recent studies have shown that smoking is a modifiable risk factor for progression of CADASIL (Chabriat et al. in Stroke 47:4–11, 2015). Specific imaging changes and findings on clinical exam can predict disease progression. However, migraine symptoms often precede MRI changes (Guey et al. in Cephalalgia 36:1038–47, 2015). A recent paper on migraine treatment in CADASIL reevaluates the prevailing belief that vasoconstrictive abortive medications are contraindicated in these patients (Tan and Markus in PLoS ONE 11:e0157613, 2016).

Summary

CADASIL is an autosomal dominantly inherited vasculopathy causing ischemic pathology in younger individuals due to a mutation in the NOTCH3 gene. The mutation results in impaired arterial contractility due to accumulation of granular osmiophilic extracellular material (GOM) in vascular smooth muscle cells (VSMCs). Clinical manifestations include migraine with and without aura, cognitive decline, ischemic events, and mood disorders. The presenting symptom is often migraine with aura. Characteristic MRI changes are often present. Genetic screening is available to confirm NOTCH3 mutation and pathognomic changes are often seen in skin biopsy. Treatment of migraine is similar to the general population, but with some notable and specific differences. Further studies in CADASIL, other small vessel arteriopathies, and migraine may help us understand more about the pathophysiology of these conditions and help with treatment development.

     

Acetazolamide for the prophylaxis of migraine in CADASIL: a preliminary experience

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by NOTCH3 mutations. It is characterized by migraine, with or without aura, ischemic events, psychiatric and cognitive disturbances. There is no approved treatment for migraine prophylaxis in CADASIL, but acetazolamide has been anecdotally reported to be effective. We retrospectively reviewed our database of patients with a genetic diagnosis of CADASIL to identify how many of them were treated with acetazolamide for the prophylaxis of migraine. The efficacy and the tolerability of this treatment were checked looking at the clinic reports. Acetazolamide was prescribed in seven patients; the mean duration of treatment was 6 months, and the daily dose ranged from 125 to 500 mg. Three patients had a total and sustained remission, while in two patients a reduction in attacks and an improvement of the headache intensity were recorded. In one of these, acetazolamide was deliberately taken only during the migraine attack and the beneficial effect started 1 h after administration. In two patients, the drug did not produce any beneficial effect. Mild side effects were recorded in two patients. Our preliminary experience expands previous reports and confirms the possible efficacy of acetazolamide in CADASIL migraine. Based on these data, a randomized controlled trial seems worthy to be carried out to test the efficacy and safety of this drug.     

GENETICS

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.
Comment: At least 400 families from countries around the world have been described with CADASIL. The four classic features are migraine with aura, stroke, dementia, and psychiatric disturbances. Migraine with aura, especially familial hemiplegic migraine and migraine with prolonged aura, is linked genetically to CADASIL on chromosome 19, occurs in up to 30% of patients, and when present is usually the earliest symptom. Definitive diagnosis is by skin biopsy, with characteristic depositions surrounding degenerating smooth muscle cells in the media. —Stewart J. Tepper, MD     

变性高压液相色谱分析在中国家族性CADASIL患者基因筛查中的应用

目的:探讨变性高压液相色谱分析(DHPLC)在伴皮质下梗死及白质脑病的常染色体显性遗传性脑动脉病(CADASIL)患者诊断中的方法和价值。方法:运用DHPLC及DNA直接测序技术,对CADASIL家系先证者、家系成员14例(CADASIL组)及健康对照者100例(对照组)进行Notch3基因检测。结果:CADASIL组发现3种致病性突变,其中Cys134Tyr为新的突变类型,同时发现15种多态类型;对照组中未发现突变。结论:DHPLC技术在筛查Notch3中起重要作用,但在筛查时应进行多个柱温的测试,温度调换以2℃为宜。     

ABCB4基因外显子12和23突变与妊娠期肝内胆汁淤积症的关系

目的：探讨ABCB4基因外显子12和23的突变与妊娠期肝内胆汁淤积症（ICP）发病的关系。方法：从31例ICP患者外周血标本中提取出基因组DNA，聚合酶链反应（PCR）扩增ABCB4基因外显子12和23，PCR产物经DNA序列测定检测突变情况。结果：31例ICP患者均扩增出ABCB4基因外显子12和23的靶基因片段，未见外显子12和23的缺失,DNA测序分析31例ICP患者ABCB4基因外显子12和23，未发现点突变。结论：ABCB4基因外显子12和23的突变与中国皖南地区的ICP发生无关或关联很小，皖南地区ICP患者中可能存在其他ABCB4基因突变热点。ABCB4基因的突变与中国人ICP发病的相关性仍应进行更大样本的研究和其他外显子的筛查。     

中国南方人群家族性偏瘫型偏头痛家系CACNA1A基因多态性相关研究

背景:偏头痛与遗传学之间的联系早已受到关注,遗传流行病学和分离研究证实,偏头痛存在显著的遗传危险性。目的:通过检测偏头痛患者和家族性偏瘫型偏头痛家族外周血CAC-NA1A基因3个常见的突变位点,分析探讨中国南方人群家族性偏瘫型偏头痛与CACNA1A基因突变之间的关系。设计:抽样调查。单位:中山大学附属第一医院和深圳市宝安西乡人民医院。对象:所有病例均来源中山大学附属第一医院门诊和深圳市宝安西乡人民医院。①家族性偏瘫型偏头痛患者组10例患者。②家族性偏瘫型偏头痛亲属组:家系A和B共12例。③无家族性偏瘫型偏头痛家族史的偏头痛患者组53例。④健康对照10名。方法:采用聚合酶链反应扩增CACNL1A4基因的第13,16,17外显子。采用SSCP方法对2个家族性偏瘫型偏头痛家族10例患者及12名无症状亲属和53例无家族性偏瘫型偏头痛家族史的有先兆偏头痛患者及10名健康对照的外周血标本进行检测,分析CACNA1A基因的3个常见突变位点(T666M,R583Q和D715E)在家族性偏瘫型偏头痛家族中的表现形式。主要观察指标:①聚合酶链反应扩增CACNL1A4基因第13,16,17外显子的结果。②SSCP分析13,16,17外显子的突变结果。结果:参加实验的家族性偏瘫型偏头痛患者10例,家族性偏瘫型偏头痛亲属12例,无家族性偏瘫型偏头痛家族史的偏头痛患者53例,健康对照组10名,均进入结果分析。①第13,16,17外显子的目的片段长度分别为247,268,204bp。②CACNA1A基因3个常见的突变T666M,R583Q和D715E在2个家族性偏瘫型偏头痛家族10例家族性偏瘫型偏头痛患者,12名无症状亲属和53例无家族性偏瘫型偏头痛家族史的有先兆偏头痛患者及10名健康对照者中均未检测到。结论:在中国人群家族性偏瘫型偏头痛家族中未发现有T666M,R583Q和D715E3个突变。     

Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders

Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2, and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome‐wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients.