Inherited leukoencephalopathies with clinical onset in middle and old age

Journal of the Neurological Sciences 347 (2014) 1–13

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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns

Review article

Inherited leukoencephalopathies with clinical onset in middle and old age Serena Nannucci a, Ida Donnini a, Leonardo Pantoni b,⁎ a b

NEUROFARBA Department, Neuroscience section, University of Florence, Florence, Italy Stroke Unit and Neurology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy

a r t i c l e

i n f o

Article history: Received 29 May 2014 Received in revised form 20 August 2014 Accepted 15 September 2014 Available online 20 September 2014 Keywords: Leukoencephalopathy White matter disease Genotype Phenotype Inherited Adulthood

a b s t r a c t The currently widespread use of neuroimaging has led neurologists to often face the problem of the differential diagnosis of white matter diseases. There are various forms of leukoencephalopathies (vascular, inflammatory and immunomediated, infectious, metabolic, neoplastic) and sometimes white matter lesions are expression of a genetic disease. While many inherited leukoencephalopathies fall in the child neurologist’s interest, others may have a delayed or even a typical onset in the middle or old age. This field is rapidly growing and, in the last few years, many new inherited white matter diseases have been described and genetically defined. A nondelayed recognition of middle and old age inherited leukoencephalopathies appears important to avoid unnecessary tests and therapies in the patient and to possibly anticipate the diagnosis in relatives. The aim of this review is to provide a guide to direct the diagnostic process when facing a patient with a suspicion of an inherited form of leukoencephalopathy and with clinical onset in middle or old age. Based on a MEDLINE search from 1990 to 2013, we identified 24 middle and old age onset inherited leukoencephalopathies and reviewed in this relation the most recent findings focusing on their differential diagnosis. We provide summary tables to use as a check list of clinical and neuroimaging findings that are most commonly associated with these forms of leukoencephalopathies. When present, we reported specific characteristics of single diseases. Several genetic diseases may be suspected in patients with middle or old age and white matter abnormalities. In only few instances, pathognomonic clinical or associated neuroimaging features help identifying a specific disease. Therefore, a comprehensive knowledge of the characteristics of these inherited white matter diseases appears important to improve the diagnostic work-up, optimize the choice of genetic tests, increase the number of diagnosed patients, and stimulate the research interest in this field. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Review results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is the MRI pattern useful in the differential diagnosis of middle and old age onset inherited leukoencephalopathies? 5.1. Cerebral infarcts and infarct-like lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Hemorrhages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. White matter lesions location and other peculiar neuroimaging features . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: ADLD, Adult onset autosomal dominant leukodystrophy; CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL, Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; FAF, Familial amyloidosis of Finnish type; FBD, Familial British dementia; FLAIR, Fluid-attenuated inversion recovery; FXTAS, Fragile X-associated tremor/ataxia syndrome; HCHWA-D, Hereditary cerebral hemorrhage with amyloidosis of Dutch type; HCHWA-I, Hereditary cerebral hemorrhage with amyloidosis of Icelandic type; LE, leukoencephalopathies; MELAS, Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF, Myoclonic epilepsy and ragged red fibers syndrome; MRI, Magnetic resonance imaging; RVCL, Retinal vasculopathy with cerebral leukodystrophy; SVD, Small vessel disease; TIA, Transient ischemic attack. ⁎ Corresponding author at: Stroke Unit and Neurology, Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134 Florence, Italy. Tel.: +39 055 7945519; fax: +39 055 4298461. E-mail address: pantoni@unifi.it (L. Pantoni).

http://dx.doi.org/10.1016/j.jns.2014.09.020 0022-510X/© 2014 Elsevier B.V. All rights reserved.

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S. Nannucci et al. / Journal of the Neurological Sciences 347 (2014) 1–13

1. Introduction The widespread use of neuroimaging (particularly magnetic resonance imaging (MRI)) has brought to discover the presence of white matter abnormalities in many patients and to increase the request of etiologic clarification. The differential diagnosis of white matter diseases is complex and may represent a relevant challenge for the neurologist. The term “leukoencephalopathies” embraces a long list of diseases that have in common the presence of alterations entirely or predominantly located in the cerebral white matter, may be seen in different age groups, and are heterogeneous in terms of the possible etiologies and the causative mechanisms. White matter abnormalities are associated with different possible clinical phenotypes ranging from asymptomatic pictures to severe ischemic or hemorrhagic stroke. In middle and old age, most leukoencephalopathies are sporadic, commonly caused by small vessel disease (SVD), and mainly associated with aging and hypertension [1]. However, also in these age groups, some white matter lesions represent the expression of a genetically transmitted disease. Although these inherited leukoencephalopathies are rare if individually considered and data about some of them are still limited, in the last two decades their number has considerably increased also in more advanced age-groups because their phenotypic and genotypic recognition is improved. Many genetic leukoencephalopathies pertain to the child neurologist’s interest but others may have a delayed or even a typical onset in middle or old age. The recognition of inheritable white matter diseases in agegroups in which the presence of a genetically transmitted disease is less intuitive is important if one considers the possible implications on the offspring in terms of genetic counseling. Furthermore, the identification of a genetic disease allows to avoid a number of unnecessary diagnostic tests and treatments. The precise individuation of the age of onset is sometimes difficult because a few mild clinical features may start years before the diagnosis is hypothesized or made. On the other side, in the case of leukoencephalopathies for which the onset, and therefore the suspicion of the disease, is uncommon in old age, the diagnostic difficulty is that the phenotype may be different from the classical pediatric or juvenile picture. In only few instances, the presence of peculiar clinical or neuroimaging features may help identifying a specific form of inherited leukoencephalopathy. For the above reported reasons, a more comprehensive knowledge of the characteristics of these inherited forms seems essential in the diagnostic work-up of white matter diseases. The aims of this review are to increase awareness that inheritable white matter diseases may manifest and can be suspected for the first time in middle and old age and to provide a clinical practice oriented guide (exemplified by the diagnostic management of the clinical case reported below) to help selecting the best genetic tests. 2. Methods We reviewed the literature on inherited diseases that may present with: 1) leukoencephalopathy on neuroimaging and 2) typical or possible clinical onset in middle and old age. For this purpose, we set the beginning of middle age at 45 years consistently with PubMed age groups limits. Diseases were included in this review only if the literature search clearly showed documented cases with onset after the age of 45. PubMed review was performed including papers published between 1990 and 2013 using the following key-words: “familial”, “inherited”, “genetic”, “adulthood”, “late-onset”, “adult-onset”, “leukoencephalopathy”, “leukodystrophy” and “white matter disease”. Only English-written papers were reviewed. 3. Review results Twenty-four forms of middle and old age onset inherited leukoencephalopathies were finally individuated from the literature

review. In Tables 1 and 2 we report, together with the affected gene, their clinical, neuroimaging, and distinctive features, distinguishing between those with typical and those with uncommon onset in middle and old age. As stated in the Introduction, the clinical-neuroimaging picture of some inherited leukoencephalopathies may be different in case of a childhood or a middle-old age onset. In this sense, given the purpose of this review, typical infantile or juvenile clinical features (e.g., psychomotor retardation, macrocephalia) were omitted. In Tables 3 and 4, we summarize the clinical and neuroimaging features of these white matter diseases. How Tables 3 and 4 can be used in the differential diagnostic process of leukoencephalopathies is exemplified by means of a case report. Criteria for the pre-genetic diagnosis of a few specific inherited white matter diseases with clinical onset in middle and old age are reported in the Appendix A. 4. Case report A 55-year-old Caucasian woman was admitted to the hospital for an episode of psychosis with sudden onset. The patient was afebrile and standard blood examinations, folic acid and vitamin B complex dosage, and toxicological tests were within normal ranges. She underwent a brain MRI showing white matter changes, apparently without specific characteristics, and a lumbar puncture that showed normal cerebrospinal fluid examination including tests for neurotropic infective agents and absence of oligoclonal bands. No epileptic abnormalities were seen on electroencephalogram. She was successfully treated with antipsychotic drugs. Two weeks later, she came to our attention for the re-evaluation of the brain white matter disease. The MRI showed a moderate degree of white matter hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences, symmetrically involving the centrum semiovale and, partially, the external capsules. On T1-weighted sequences, there were two round hypointensities consistent with lacunar infarcts, one in the pons and one in the right thalamus. Gradient echo sequences revealed a few hypointense lesions in the left cerebellar hemisphere, the right thalamus and the left occipital lobe. She did not complain of neurological symptoms and had no abnormal sign on physical examination. She had a history of migraine without aura beginning at the age of 20 and a 3-year history of diabetes mellitus and hypertension, both treated with medical therapy. To define the leukoencephalopathy etiology, we performed other laboratory and instrumental investigations. A search for thrombophilic factors and autoantibodies were negative. A 24hour blood pressure monitoring revealed a good control of daily pressure levels. Neck vessels and transcranial Doppler showed no sign of stenosis. We then better investigated her family history with the hypothesis of an inherited form of leukoencephalopathy. Her mother had a history of migraine without aura and had presented with a transient episode of right limbs weakness with sudden onset and lasting about 30 minutes that was not followed by headache. Her maternal grand-mother suffered from an ischemic stroke at the age 58 and developed cognitive decline from the age of 65. One brother was on treatment with antidepressants. Her 20-year-old daughter was affected by epilepsy. The family history was suggestive of an autosomal dominant or a maternal pattern of inheritance. Comparing the clinical characteristics of our patient with those of the 24 forms of middle and old age inherited leukoencephalopathies reported in Table 3, only 4 may manifest with psychiatric disturbances and migraine: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL), familial British dementia (FBD), with an autosomal pattern of inheritance, and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), with maternal transmission. Among possible clinical distinctive features of these 4 diseases (Table 3), our patient had only diabetes

S. Nannucci et al. / Journal of the Neurological Sciences 347 (2014) 1–13

mellitus, typical, but not specific, of MELAS, while she did not have the Raynaud’s phenomenon (typical of RVCL) or the triade of dementia, cerebellar ataxia, and spastic tetraparesis (typical of FBD). Considering the neuroimaging findings (Table 4), CADASIL, FBD, and SVD associated with COL4A1 mutations may all present with a supratentorial location of white matter hyperintensities, lacunar infarcts, and microbleeds. Because there are no data in the literature about the presence of hemorrhagic lesions in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), we could not exclude this disease considering only the neuroimaging. Regarding the possible distinctive neuroimaging features, the MRI of our patient showed only white matter hyperintensities involving the external capsules, typical, although not pathognomonic, of CADASIL. Matching all the different leukoencephalopathies that we previously identified and taking into account the clinical and neuroimaging features and the pattern of inheritance, we found CADASIL to be the most probable disease in our patient and we decided to perform NOTCH3 gene analysis. A heterozygous cysteine-involving 3140A N G mutation on exon 19 was detected. Should this genetic test had resulted negative, we should have considered the other leukoencephalopathies such as FBD, that has a more common onset in middle-old age, and SVD associated with COL4A1 mutations, that, although not commonly, may have an onset in middle-old age and for which the limited data in literature do not permit to exclude with certainty the presence of psychiatric disturbances as part of its clinical spectrum. 5. Is the MRI pattern useful in the differential diagnosis of middle and old age onset inherited leukoencephalopathies? Despite the presence of white matter changes is a conditio sine qua non for the diagnosis of inherited leukoencephalopathies, other neuroimaging features are seen in many of these forms and may be useful for their differential diagnosis. Specific aspects (e.g., location) of white matter lesions are also helpful to take into account. It is important to note that, for many inherited white matter diseases with uncommon onset in middle and old age, the majority of available data on neuroimaging are relative to the findings in childhood and we based on these data our review. 5.1. Cerebral infarcts and infarct-like lesions The presence of lesions consistent with infarcts is quite typical of middle and old age onset inherited leukoencephalopathies that have a vascular pathogenesis. In most instances, vascular forms are due to SVD and, therefore, the most common type of infarct is lacunar. This is the case of CADASIL and CARASIL, in which multiple lacunar lesions are frequently present and mainly located in basal ganglia, thalamus, and brainstem [3,17]. Lacunar infarcts have been reported also in FBD and SVD associated with COL4A1 mutations [18,54,57]. In hereditary cerebral hemorrhage with amyloidosis of Dutch type (HCHWA-D) small cortical and subcortical infarcts have been described [21]. In Fabry disease, brain infarcts, mainly located in posterior regions, have heterogeneous pathogenesis and thus both lacunar and corticosubcortical infarcts can be observed [97]. In MELAS, during stroke-like episodes, cortico-subcortical lesions are seen usually in posterior brain areas, with an infarct-like appearance but, typically, no vascular distribution [99], and correspond to areas of hyperemia on perfusion MRI [111]. Furthermore, these abnormalities may evolve into well-defined lesions or resolve completely [112]. Dilated perivascular spaces are common in SVD associated with COL4A1 mutations, mainly located in basal ganglia and more rarely in the gray-white matter junction [57]. In CADASIL, in the anterior part of temporal lobes, FLAIR images may show multiple hypointense lesions at the cortico-subcortical junction that are consistent with lacunes related to dilated perivascular spaces; these lesions are considered by some authors the most specific feature of CADASIL [3].

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5.2. Hemorrhages Hemorrhagic lesions are frequently seen in middle and old age onset inherited leukoencephalopathies caused by SVD where the location of the underlying pathological process is reflected in the location of hemorrhages. Lobar, cortico-subcortical, micro- and macro-hemorrhages are typical of all familial forms of cerebral amyloid angiopathy except the British and the Finnish type [18,22–24,27,28]. In CADASIL and SVD associated with COL4A1 mutations, multiple microbleeds or large hemorrhages are seen in basal ganglia, thalamus, and brainstem but also at the cortical-subcortical junction [12,14,15, 54,57]. 5.3. White matter lesions location and other peculiar neuroimaging features Some specific locations of white matter changes can help identifying some middle and old age inherited white matter diseases. Many CADASIL patients have white matter hyperintensities in the anterior part of temporal lobes and external capsules [3,13]. Hyperintensities of middle cerebellar peduncles are typical of adult onset autosomal dominant leukodystrophy (ADLD) and fragile X-associated tremor/ ataxia syndrome (FXTAS) [41,43,51]. Gyriform, also called “tram-line”, occipital cortical calcifications are typical of the inherited form of cerebral amyloid angiopathy due to the Iowa mutation [26,27]. Poroencephalic cysts, as result of antenatal hemorrhages, associated with multiple dilated perivascular spaces, are typical of SVD due to COL4A1 mutations [57]. Multiple intracranial aneurysms, mainly of the anterior circulation, are also commonly observed in this inherited form of SVD [54,56]. A diffuse cystic degeneration of hemispheric white matter that is replaced by fluid and shows a radiating, stripe-like pattern, due to the remaining tissue strands, is typical of vanishing white matter disease in childhood [81]. However, in the few patients with clinical onset in middle or old age, this feature can be missing or mild [85–88]. A similar feature with a typical tigroid aspect of the affected white matter together with relatively spared areas (“leopard-skin” aspect) is suggestive of metachromatic leukodystrophy [77]. Subcortical tumor-like contrast-enhancing lesions with surrounding edema, mainly located in frontal and parietal lobes, are typical of RVCL [59,60]. Tumor-like lesions have been described also in Alexander disease, in which they are typically located in brainstem, and, in some instances, can be the only or predominant neuroimaging manifestation [69,70]. In this disease, medulla oblongata and cervicothoracic spinal cord involvement with either signal abnormalities or atrophy is almost invariably present [69–71]. Another sign highly suggestive of Alexander disease is the presence of ventricular garlands, characterized by contrast enhancement along the ventricular wall [69,70]. Symmetric signal abnormalities of cerebellar dentate nuclei are reported in cerebrotendinous xanthomatosis patients [119,120]. They usually present with T2-hyperintensities of cerebellar dentate nuclei, but, in advanced stages, it is possible to observe low signal on T2weighted imaging in the same sites because of the deposition of calcium or hemosiderin [119]. Symmetric hyperintensities of globus pallidus and latero-dorsal columns of spinal cord are also frequently seen in cerebrotendinous xanthomatosis [119]. Symmetric basal ganglia, thalamus, and brainstem hyperintensities are typical of Leigh syndrome [121,122]. 6. Conclusions In this review, we offered an overview of the many inherited diseases that may present with white matter lesions and have the clinical onset of disturbances in middle or old age. These diseases belong to the broad category of white matter diseases, the vast majority of which

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Disease [references]

Affected gene (chromosome), pattern of inheritance

Clinical features

Neuroimaging findings

Distinctive features

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [2–15]

NOTCH3 (19q12) AD

Stroke, TIA, cognitive impairment, migraine with aura, psychiatric disturbances, pseudobulbar syndrome, seizures, cerebral hemorrhage (rare)

Widespread subcortical WMH involving external capsule and temporal pole, lacunar infarcts, subcortical microbleeds, dilated perivascular spaces at temporal cortico-subcortical junction

Imag: WMH involving external capsule and temporal pole; round hypointensities at temporal cortico-subcortical junction Path/Lab: GOM and accumulation of NOTCH3 protein in skin biopsy

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) [16,17]

HTRA1 (10q25) AR

Stroke, pseudobulbar syndrome, cognitive impairment, acute lumbago, spondylosis deformans, disc herniation, alopecia, personality changes

Diffuse subcortical WMH (sometimes involving external capsule and temporal pole), lacunar infarcts

Clin: Acute lumbago, disc herniation, spondylosis deformans, premature and diffuse alopecia

Familial British dementia (FBD) [18,19]

BRI (13q14) AD

Typical triade: progressive dementia, spastic tetraparesis, cerebellar ataxia; seizures, headache, depression, cerebral hemorrhage (rare)

Patchy or confluent WMH, mainly located around the frontal and occipital poles of lateral ventricles, lacunar infarcts, corpus callosum atrophy, hemorrhagic lesions (uncommon)

Clin: Typical triade Path/Lab:ABri amyloid peptide fibrils in brain biopsy

Hereditary cerebral hemorrhage with amyloidosis of Dutch type (HCHWA-D) [20–22]

Amyloid β precursor protein (AβPP) (21) AD

Recurrent lobar hemorrhages, dementia, seizures

Diffuse periventricular and subcortical WMH; lobar hemorrhages (tending to spare frontal lobe), microbleeds at gray-white matter junction (rare in cerebellum, never in basal ganglia, thalamus, or brainstem), small cortical and subcortical infarcts

Path/Lab: Aβ42 amyloid fibrils in brain biopsy

Hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I) [23–25]

Cystatin C (20) AD

Recurrent cerebral hemorrhages, dementia, headache, seizures, ischemic stroke (rare)

Widespread WMH, multiple micro- and macro-depositions of hemosiderin

Path/Lab: Depositions of cystatin-C amyloid protein in skin biopsy

Dementia and severe cerebral amyloid angiopathy due to the Iowa amyloid precursor protein mutation (including previously described familial occipital calcifications, hemorrhagic strokes, leukoencephalopathy, arterial dysplasia, and dementia (FOCHS-LADD)) [26,27]

Amyloid β precursor protein (AβPP) (21) AD

Dementia, speech disturbances, personality changes, seizures, myoclonic jerks, cerebral hemorrhage, episodes of mental confusion after general anaesthesia

Extensive WMH (worse posteriorly), gyriform occipital calcifications, cortical and subcortical hemosiderin deposition, possible dysplasia-like appearance of external carotid arteries

Imag: Gyriform or “tram-line” occipital calcifications; dysplasia-like appearance of external carotid arteries Path/Lab: Round-shaped calcifications in capillary basal membrane in skin biopsy

S. Nannucci et al. / Journal of the Neurological Sciences 347 (2014) 1–13

Table 1 Genetic, clinical, neuroimaging, and laboratory features of inherited leukoencephalopathies with common onset of disturbances in middle and old age.

Gelsolin (9) AD

Facial palsy, mild peripheral neuropathy, corneal lattice dystrophy, atrophic bulbar palsy, gait ataxia, vibration sense loss, cognitive impairment, visual loss, psychiatric disturbances, cutis laxa, mild renal dysfunction, cardiac conductive disorders

Diffuse hemispheric WMH (+++ in frontal lobes and pons), focal cerebellar WMH; spinal cord posterior column hyperintensities

Clin: Spinal involvement, corneal lattice dystrophy

Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids [29–33]

Colony stimulating factor receptor 1 (CSFR1) (5q) AD

Psychiatric disturbances, cognitive impairment, seizures, impaired balance, gait disturbances, ataxia, urinary incontinence

Ill defined, patchy, bilateral WMH, most pronounced in frontoparietal regions; cortical (mainly frontoparietal) and corpus callosum atrophy

Path/Lab: Neuroaxonal spheroids

X-linked adrenoleukodistrophy (adult cerebral, adrenomyeloneuropathy, and women forms) [34–38]

ABCD1 (Xq28) X-linked recessive

Spastic paraparesis, sensory ataxia, sphincter disturbances, impotence, sensory-motor mostly axonal peripheral neuropathy, behavioral disturbances, cognitive impairment, Addison disease, testicular insufficiency

Various degree of WMH (+++ in frontal and parieto-occipital regions) with wallerian degeneration of corticospinal tracts in brainstem and internal capsule; cerebellar atrophy with or without cerebellar WMH

Clin: Addison disease and testicular insufficiency Imag: wallerian degeneration of corticospinal tracts in brainstem and internal capsule Path/Lab: Increased VLCFA levels in plasma and tissues

Adult-onset autosomal dominant leukodystrophy (ADLD) [39–43]

Lamin B1 (LMNB1) (5q23) AD

Autonomic and pyramidal dysfunction, cerebellar ataxia, cognitive impairment

Symmetrical extensive WMH (+++ frontal and parietal lobes, middle cerebellar peduncles), corpus callosum, brainstem, and spinal cord atrophy

Imag: Middle cerebellar peduncles hyperintensity

Adult polyglucosan body disease [44–47]

Glycogen branching enzyme (GBE1) (3p12) AR

Neurogenic bladder, impaired balance, tetraparesis, sensory neuropathy in lower extremities, cognitive impairment

Diffuse hemispheric WMH (+++ occipital lobes, posterior limb of internal capsule, medial edges of inferior and middle cerebellar peduncles), moderate cortical atrophy, severe atrophy of corpus callosum, cerebellum, brainstem, and spinal cord

Imag: Medial edges of inferior and middle cerebellar peduncles hyperintensity Path/Lab: Polyglucosan bodies in skin biopsy

Fragile X-associated tremor/ataxia syndrome (FXTAS) [48–52]

FMR1 (50 to 200 CGG triplet repeats) X-linked

Males: cerebellar ataxia, parkinsonism, cognitive impairment, psychiatric disturbances, autonomic dysfunction, peripheral neuropathy Females: primary ovarian insufficiency

Multifocal WMH, hyperintensities in middle cerebellar peduncles and surrounding dentate nuclei; cerebral and cerebellar cortex, corpus callosum, pons atrophy

Imag: Middle cerebellar peduncles hyperintensity

AD: autosomal dominant; AR: autosomal recessive; Clin: clinical; Imag: neuroimaging; Path/Lab: pathologic/laboratory; GOM: granular osmiophilic material; TIA: transient ischemic attack; WMH: white matter hyperintensities; +++: especially

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Familial amyloidosis of Finnish type (FAF) [28]

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Table 2 Genetic, clinical, neuroimaging, and laboratory features of inherited leukoencephalopathies with possible but uncommon onset of disturbances in middle and old age. Affected gene (chromosome), pattern of inheritance

Clinical features

Neuroimaging findings

Distinctive features

Small vessel disease associated with COL4A1 mutations (including also hereditary angiopathy,nephropathy, aneurysms, and muscle cramps (HANAC)) [53–57]

COL4A1 (13q34) AD

Spontaneous, traumatic, or anticoagulation associated cerebral hemorrhage, ischemic stroke (rare), migraine with aura, retinal hemorrhages, Axenfeld-Rieger type ocular malformations, glomerulopathy and renal cysts, muscle cramps, Raynaud’s phenomenon, cardiac arrhythmias

Variable degree of WMH with a possible predominantly posterior pattern, subcortical microbleeds, cerebral macrohemorrhagic lesions, lacunar infarcts, dilated perivascular spaces, intracranial cerebral aneurysms, poroencephalic cysts

Imag: Cerebral poroencephalic cysts, dilated perivascular spaces combined with cerebral hemorrhages Other: Renal cysts

Retinal vasculopathy with cerebral leukodystrophy (RVCL) (now including cerebroretinal vasculopathy, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), and hereditary vascular retinopathy) [58–62]

TREX1 (3p21) AD

Progressive visual loss, focal neurologic deficits, cognitive impairment, seizures, stroke, psychiatric disturbances, migraine, kidney dysfunction, Raynaud’s phenomenon

Subcortical contrast-enhancing lesions with surrounding edema mainly in fronto-parietal lobe; multifocal deep WMH or only slight periventricular WMH without mass lesions

Imag: Subcortical contrast-enhancing lesions with surrounding edema

Alexander disease [63–72]

Glial fibrillary acidic protein (GFAP) (17q21) AD

Spastic paresis, bulbar or pseudobulbar syndrome, cerebellar ataxia, ocular motor abnormalities, palatal myoclonus, autonomic dysfunction

WMH prevalent in frontal lobe (uncommon in adult), severe atrophy of medulla oblongata and cervicothoracic spinal cord, contrast enhancement of ventricular lining (garlands), periventricular rim, frontal WM, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, cerebellar cortex; tumor-like lesions in brainstem (rare)

Clin: Palatal myoclonus Imag: Severe atrophy of medulla oblongata and cervicothoracic spinal cord; periventricular garlands Path/Lab: Rosenthal fibers in brain biopsy

Metachromatic leukodystrophy [36,73–77]

Arylsulfatase A (ASA) (22q13) or saposin B (10) AR

Psychiatric disturbances, hallucinations, cognitive impairment, spastic paraparesis, cerebellar ataxia, seizures, peripheral neuropathy

Bilateral diffuse WMH, more pronounced in periventricular regions; radiating pattern (“tigroid” appearance, similar to PelizaeusMerzbacher disease) of spared WM in centrum semiovale with areas of relatively normal-appearing WM (“leopard-skin” aspect)

Imag: Hemispheric WM “tigroid” appearance Path/Lab: Decreased arylsulfatase A activity

Vanishing white matter disease [78–88]

Eukaryotic translation initiation factor (EIF2B1-5) (respectively on 12q24.3, 14q24, 1p34.1, 2p23.3, 3q27) AR

Cerebellar ataxia, spasticity, cognitive impairment, episodes of rapid and major neurological deterioration provoked by stress, psychiatric disturbances, dysgenesis and ovarian failure, cataracts, hepatosplenomegaly, pancreatitis, kidney hypoplasia

Widespread bilateral and symmetric rarefaction and cystic degeneration of hemispheric WM, replaced by fluid; remaining tissue strands within the rarefied WM, as a radiating, stripe-like pattern; cerebellum and brainstem atrophy.

Clin: Episodes of rapid neurological deterioration provoked by stress Imag: Widespread cystic degeneration of hemispheric WM, replaced by fluid, radiating and stripe-like pattern of remaining WM Path/Lab: foamy oligodendrocytes

Krabbe disease (or globoid cell leukodystrophy) [89–94]

β-galactocerebrosidase (GALC), (14q31) AR

Spastic tetraparesis, ataxia, blindness, deafness, limb weakness, sensory-motor demyelinating neuropathy, cognitive impairment, pes cavus

Symmetric or asymmetric WMH involving corticospinal tract, parieto-occipital regions, and splenium

Path/Lab: Low levels of β-galactocerebrosidase in peripheral blood leukocytes; globoid cells in brain biopsy

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Disease [references]

α-galactosidase A (GALA) X-linked

Common type: male, angiokeratomas, burning acroparesthesiae, hypohidrosis, corneal opacity, gastrointestinal disturbances, hearing loss, vascular disease of heart, kidneys and CNS, psychiatric disturbances. Adulthood: heart and kidneys involvement, cryptogenic stroke, cognitive impairment

Extensive WMH, dolichoectasia of vertebro-basilar arteries, lacunar and cortico-subcortical infarcts, diffuse brain atrophy, possible pulvinar hyperintensity on T1 images; significant increased CBF in posterior circulation on PET

Clin: Acroparesthesiae, angiokeratoma, cornea verticillata Imag: pulvinar T1-hyperintensity Path/Lab: α-galactosidase A deficiency in plasma or leukocytes

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) [99,102–114]

Mitochondrial DNA (A3243G mutation in 80%) maternal; Nuclear DNA mendelian

Stroke-like episodes, migraine, nausea/ vomiting, seizures, cognitive impairment, psychiatric disturbances, myopathy, cardiomyopathy, hearing loss, diabetes mellitus, short stature, ophthalmoparesis

Acute/chronic infarct-like cortical lesions without vascular territory distribution with hyperintensities on DWI and hyperemia on perfusion MRI typically in posterior regions. Elevated brain lactate on proton MRS. Progressive cortical and cerebellar atrophy. Diffuse WMH (occasionally)

Clin/Imag: Combination of stroke-like symptoms and cerebral lesions without vascular territories distribution

Myoclonic epilepsy and ragged red fibers syndrome (MERRF) [102,104,105,109,111,115]

Mitochondrial DNA (8344A N G mutation in 80%) maternal; Nuclear DNA mendelian

Myoclonus, generalized tonic-clonic seizures, cerebellar ataxia, cognitive impairment, muscle weakness, hearing loss, cardiomyopathy (occasional)

Cerebral, pallidal and cerebellar atrophy, WM and striatal T2 hyperintensities

Clin: Myoclonic epilepsy

Cerebrotendinous xanthomatosis [116–120]

Cytochrome P-450 enzyme sterol 27-hydroxylase (CYP27A1) AR

Tendon xanthomas, chronic diarrhea, cataract, cerebellar ataxia, spastic paraparesis, seizures (more common in adulthood), peripheral neuropathy, cognitive impairment (mental retardation if early onset), psychiatric disturbances, systemic atherosclerotic arteriopathy, osteoporosis, liver abnormalities, hypothyroidism (occasional)

Periventricular WMH, hyperintensities or hypointensities (hemosiderin or calcium deposits) of cerebellar dentate nuclei and WM; globus pallidus and latero-dorsal columns of spinal cord hyperintensities; choroid calcifications; cerebral, cerebellar, brainstem, and corpus callosum atrophy

Clin: Tendon xanthomas (typically Achilles tendon) Imag: hyper- or hypo-intensities of cerebellar dentate nuclei

Leigh syndrome [102,104,105,109,121–123]

Very heterogeneous (mitochondrial and nuclear DNA) maternal or mendelian

Heterogeneous (partially depending on the mutation): from severe neurologic problems (cognitive impairment, parkinsonism and pseudobulbar syndrome, vomiting, eye movement abnormalities, seizures, myoclonus altered state of consciousness, respiratory impairment) to nearly absence of abnormalities

Symmetric, focal or diffuse cerebral and cerebellar WM, basal ganglia, thalamus, and brainstem hyperintensities; cortical or subcortical grey matter atrophy with ventricular enlargement

Imag: Symmetric basal ganglia, thalamus, and brainstem hyperintensities

Leber hereditary optic neuropathy [124–127]

Mitochondrial DNA (G11778A mutation) maternal

+++ male, acute or subacute, bilateral, painless, central visual loss, postural tremor, peripheral neuropathy, myopathy, movement disorders (dystonia), abnormal cardiac conduction

Multifocal WMH (uncommon), most pronounced in periventricular regions

Clin: Acute or subacute bilateral painless optic neuropathy

S. Nannucci et al. / Journal of the Neurological Sciences 347 (2014) 1–13

Fabry disease [36,95–101]

AD: autosomal dominant; AR: autosomal recessive; Clin: clinical; Imag: neuroimaging; Path/Lab: pathologic/laboratory; CBF: cerebral blood flow; CNS: central nervous system; DWI: diffusion weighted imaging; MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; PET: positron emission tomography; WM: white matter; WMH: white matter hyperintensities; +++: especially

7

8

Table 3 Clinical features of inherited leukoencephalopathies with clinical onset in middle and old age. Disease (pattern of inheritance)

TIA or ischemic stroke

Psychiatric Motor Ataxia Ocular Renal Clinical distinctive features Cerebral Headache Seizures Cognitive disturbances disturbances disturbances abnormalities dysfunction hemorrhage or migraine

CADASIL (AD) CARASIL (AR) RVCL (AD) Small vessel disease associated with COL4A1 mutations (AD) FBD (AD)

+ + + −/+

−/+ +

+ + +

−/+ + -

+ + + -

+ + + -

+ + -

-

+ +

+ +

-

−/+

+

+

+

+

+

+

-

-

HCHWA-D (AD) HCHWA-I (AD) Dementia and severe cerebral amyloid angiopathy due to the Iowa amyloid precursor protein mutation (AD) Familial amyloidosis of the Finnish type (AD)

−/+ -

+ + +

+ -

+ + +

+ + +

+

-

-

-

-

-

-

-

-

+

+

+

+

+

Facial palsy, cutis laxa, peripheral neuropathy, cardiac conductive disorders

Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids (AD) Vanishing white matter disease (AR)

-

-

-

+

+

+

+

+

+ (corneal lattice dystrophy) -

-

-

-

-

-

-

+

+

+

+

+

+

Krabbe disease (AR)

-

-

-

+

-

+

+

+

-

Alexander disease (AD)

-

-

-

+

+

+

-

-

-

-

−/+in adult + +

-

Metachromatic leukodystrophy (AR) X-linked adrenoleukodystrophy (X-linked)

−/+in adult −/+in adult + -

Episodes of rapid and major neurological deterioration provoked by stress, dysgenesis and ovarian failure hepatosplenomegaly, pancreatitis Deafness, sensory-motor demyelinating neuropathy, pes cavus Palatal myoclonus, autonomic dysfunction

+ +

+ +

+ +

-

-

-

-

-

+ + +

+

+ + -

+ + -

+

(strokelike episodes) -

+

+

+

+

-

-

+ (cornea verticillata) +

-

+ +

+ +

+

+

+ +

+

-

-

-

-

-

+

+

+

+

-

-

-

-

-

-

-

-

+

-

+

-

-

-

-

+

+

-

+

+

+

-

MELAS (maternal)

MERRF (maternal) Cerebrotendinous xanthomatosis (AR) Fragile X associated tremor/ataxia syndrome (X-linked) Leber hereditary optic neuropathy (maternal) Leigh syndrome (maternal or mendelian)

-

Peripheral neuropathy Sphincter disturbances, impotence, sensory-motor mostly axonal peripheral neuropathy, Addison disease, testicular insufficiency Autonomic dysfunction Neurogenic bladder Angiokeratomas, burning acroparesthesiae, hypohidrosis, hearing loss Myopathy, cardiomiopathy, hearing loss, diabetes mellitus

Muscle weakness, hearing loss Tendon xanthomas, chronic diarrhea, peripheral neuropathy, osteoporosis, liver abnormalities, hypothyroidism Autonomic dysfunction, peripheral neuropathy, primary ovarian insufficiency Peripheral neuropathy, myopathy, abnormal cardiac conduction Altered state of consciousness episodes, respiratory impairment

AD: autosomal dominant; ADLD: adult onset autosomal dominant leukodystrophy; AR: autosomal recessive; CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; FBD: familial British dementia; HCHWA-D: hereditary cerebral hemorrhage with amyloidosis of Dutch type; HCHWA-I: hereditary cerebral hemorrhage with amyloidosis of Icelandic type; MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF: myoclonic epilepsy and ragged red fibers syndrome; RVCL: retinal vasculopathy with cerebral leukodystrophy; +: present; −: absent; −/+: possible but not typical.

S. Nannucci et al. / Journal of the Neurological Sciences 347 (2014) 1–13

ADLD (AD) Adult polyglucosan body disease (AR) Fabry disease (X-linked) +

Acute lumbago, spondylosis, disc herniation, alopecia Raynaud’s phenomenon Muscle cramps, cardiac arrhythmias, Raynaud’s phenomenon Triade (progressive dementia, spastic tetraparesis, cerebellar ataxia) Episodes of mental confusion after general anesthesia

S. Nannucci et al. / Journal of the Neurological Sciences 347 (2014) 1–13

9

Table 4 Neuroimaging findings of inherited leukoencephalopathies with clinical onset in middle and old age. Disease

White matter hyperintensities

Infarcts

Supratentorial Cerebellar Brainstem Spinal cord

Nonlacunar

Lacunar MacroMicrobleeds hemorrhages

Hemorrhagic lesions

Neuroimaging distinctive features

CADASIL

+

-

+

-

-

+

−/+

+

CARASIL RVCL

+ +

+ -

+ -

-

-

+ -

-

-

Small vessel disease associated with COL4A1 mutations

+

-

-

-

-

+

+

+

FBD HCHWA-D

+ +

-

-

-

+ -

−/+ +

−/+ +

HCHWA-I Dementia and severe cerebral amyloid angiopathy due to the Iowa amyloid precursor protein mutation Familial amyloidosis of the Finnish type Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids Vanishing white matter disease

+ +

-

-

-

+ (small cortical and subcortical) -

-

+ +

+ +

+

+

+

+

-

-

-

-

Gyriform or “tram-line” occipital calcifications, dysplasia-like appearance of external carotid arteries -

+

-

-

-

-

-

-

-

-

+

−/+

−/+

-

-

-

-

-

Krabbe disease Alexander disease

+ −/+in adult

−/+in adult

+ −/+in adult

−/+in adult

-

-

-

-

Metachromatic leukodystrophy

+

-

-

-

-

-

-

-

X-linked adrenoleukodystrophy

+

+/−

+

-

-

-

-

-

ADLD

+

+

+

+

-

-

-

-

Adult polyglucosan body disease

+

+

+

-

-

-

-

Fabry disease

+

-

-

−/+ (cervicalmedullary junction) -

Cystic degeneration of hemispheric WM, radiating and stripe-like appearance of remaining WM Medulla oblongata and cervicothoracic spinal cord atrophy, ventricular garlands with contrastenhancing “Tigroid” and “leopardskin” appearance of WM in centrum semiovale Wallerian degeneration of corticospinal tracts in brainstem and internal capsule, spinal cord atrophy Middle cerebellar peduncles hyperintensity Medial edges of inferior and middle cerebellar peduncles hyperintensity

+

+

-

-

MELAS

−/+

-

-

-

-

-

-

-

MERRF Cerebrotendinous xanthomatosis Fragile X associated tremor/ ataxia syndrome Leber hereditary optic neuropathy Leigh syndrome

+ +

+

-

+

-

-

-

-

+

+

-

-

-

-

-

-

−/+

-

-

-

-

-

-

-

+

+

+

-

-

-

-

-

WMH involving temporal pole and external capsule Tumor-like contrastenhancing lesions with surrounding edema Poroencephalic cysts, intracranial cerebral aneurysms -

Vertebro-basilar dolichoectasia, pulvinar T1-hyperintensity Infarct-like cortical lesions in posterior regions with hyperemia on perfusion MRI Hyper or hypo-intensity of cerebellar dentate nuclei Middle cerebellar peduncles hyperintensity Symmetric basal ganglia and thalamus hyperintensities

ADLD: adult onset autosomal dominant leukodystrophy; CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; FBD: familial British dementia; HCHWA-D: hereditary cerebral hemorrhage with amyloidosis of Dutch type; HCHWA-I: hereditary cerebral hemorrhage with amyloidosis of Icelandic type; MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF: myoclonic epilepsy and ragged red fibers syndrome; MRI: magnetic resonance imaging; RVCL: retinal vasculopathy with cerebral leukodystrophy; WM: white matter; +: present; −: absent; −/+: possible but not typical.

10

S. Nannucci et al. / Journal of the Neurological Sciences 347 (2014) 1–13

are of sporadic origin. Therefore, the premise in the differential diagnosis of middle and old age onset inherited leukoencephalopathies is that sporadic forms of white matter diseases (vascular, infective, inflammatory, demyelinating, neoplastic) have been already excluded. The identification of an inherited form of white matter disease also in a more advanced age-group is important in the proband to eliminate unnecessary exams and inappropriate therapies. Furthermore, it appears useful for the relatives who could take advantages of a genetic counseling and an early diagnosis to anticipate, when possible, adequate treatments and prevention strategies to delay the picture progression. Once a presumptive diagnosis of middle and old age onset inherited leukoencephalopathy is made, in order to guide the choice of the most appropriate genetic test, the clinical and neuroimaging features of the patient should be carefully analyzed. In many instances, the combination of clinical, neuroimaging, and type of genetic transmission allow to select a more limited number of diseases for which performing genetic tests, that are usually timeconsuming and expensive. In the future, one may hypothesize that advances in genetic assessment methodology will make genetic tests feasible in larger proportion of patients at lower cost. At present, we think that this review could be an useful tool to better select the genetic tests that have to be performed as first screening and, if negative, guide the choice of further genetic analyses. A more extensive knowledge about middle and old age onset inherited leukoencephalopathies, which are rare if singularly considered but likely currently underestimated, could improve their recognition and increase the number of diagnosed patients. Overall, this might also stimulate the research interest in the field of the inherited white matter diseases and improve the understanding of mechanisms causing leukoencephalopathies with potential implications in terms of treatment strategies.

At least four of the following five characteristics have to be present to make the diagnosis: 1. extensive white matter increased signal intensity on T2-weighted images, mainly in the frontal regions; 2. a periventricular rim that appears to be hyperintense in T1 scans and hypointense in T2 ones; 3. abnormalities of basal ganglia and thalami; 4. involvement of the brain stem; 5. contrast enhancement in the periventricular regions. Vanishing white matter disease (neuroimaging criteria) [81] Obligatory 1. Cerebral white matter shows either diffuse or extensive signal abnormalities; the immediately subcortical white matter may be spared. 2. Part or all of the abnormal white matter has a signal intensity close to or the same as cerebrospinal fluid on proton density or FLAIR images, suggestive of white matter rarefaction or cystic destruction. 3. If proton density and FLAIR images suggest that all cerebral white matter has disappeared, there is a fluid-filled distance between ependymal lining and the cortex, but not a total collapse of the white matter. 4. The disappearance of the cerebral white matter occurs in a diffuse “melting away” pattern. 5. The temporal lobes are relatively spared, in the extent of the abnormal signal, degree of cystic destruction, or both. 6. Cerebellar white matter may be abnormal, but does not contain cysts. 7. There is no contrast enhancement. Suggestive

Acknowledgements We have no organizations that funded our research. Appendix A Available diagnostic criteria of some forms of leukoencephalopathies with possible clinical onset in middle or old age Fragile X-associated tremor/ataxia syndrome (FXTAS) [50] Examination and degree Molecular Major: 55–200 CGG repeats (premutation) Radiological Major: MRI white matter lesions in middle cerebellar peduncle Minor: MRI white matter lesions in cerebral white matter Minor: Moderate-to-severe generalised atrophy Clinical Major: Intention tremor Major: Gait ataxia Minor: Parkinsonism Minor: Moderate-to-severe short-term memory deficit Minor: Executive function deficit Neuropathological Major: FXTAS inclusions Diagnostic category Presence of expanded CGG repeat (molecular), and: • Definite Presence of one major radiological sign plus (i) one major clinical symptom or (ii) the presence of FXTAS inclusions • Probable Presence of one major radiological sign and one minor clinical symptom, or two major clinical symptoms • Possible Presence of one minor radiological sign and one major clinical symptom Alexander disease (neuroimaging criteria)[69]

1. Within abnormal white matter there is a pattern of radiating stripes on sagittal and coronal T1-weighted or FLAIR images; on axial images dots and stripes are seen within the abnormal white matter as crosssections of the stripes. 2. Lesions within the central tegmental tracts in the pontine tegmentum. 3. Involvement of the inner rim of the corpus callosum, whereas the outer rim is spared. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) [103] Category A. Clinical findings of stroke-like episodes 1. 2. 3. 4. 5.

Headache with vomiting Seizure Hemiplegia Cortical blindness or hemianopsia Acute focal lesion observed via brain imaginga Category B. Evidence of mitochondrial dysfunction

1. High lactate levels in plasma and/or cerebral spinal fluid or deficiency of mitochondrial-related enzyme activitiesb 2. Mitochondrial abnormalities in muscle biopsyc 3. Definitive gene mutation related to MELASd Definitive MELAS Two items of Category A and two items of Category B (four items or more) Suspicion of MELAS One item of Category A and two items of Category B (at least three items) a b

Focal brain abnormalities in CT and/or MRI. 2 mmol/L (18 mg/dl) or more lactate in plasma at rest or in cerebral spinal fluid and/or deficiency of electron transport chain enzyme, pyruvate-related, tricarboxylic acid cycle-related enzymes or lipid metabolism-related enzymes in somatic cells (desirable for muscle cells).

S. Nannucci et al. / Journal of the Neurological Sciences 347 (2014) 1–13 c

d

RRF (ragged-red fiber) in modified Gomori's trichrome stain and/or SSV (strongly SDH-reactive blood vessels) in succinate dehydrogenase stain, cytochrome c oxidasedeficient fibers or abnormal mitochondria in electron microscopy. Definitive mitochondrial gene mutations reported in the literature (G583A, G1642A, G1644A, A3243G, A3243T, A3252G, C3256T, A3260G, T3271C, T3291C, G3481A, G3697A, T3949C, G4332A, G5521A, A5814G, G7023A, T7512C, A8296G, T8316C, T9957C, A12299C, A12770G, G13042A, A13084T, G13513A, A13514G, A13528G, and G14453A) as of 2010. [128]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) The CADASIL Scale has been proposed as a tool for the pre-genetic screening of CADASIL (with a reported sensitivity of 96.7% and specificity of 74.2%) [129]

Migraine Migraine with aura TIA or stroke TIA/stroke onset ≤50 y Psychiatric disturbances Cognitive decline/dementia Leukoencephalopathy Leukoencephalopathy extended to temporal pole Leukoencephalopathy extended to external capsule Subcortical infarcts Family history* in at least 1 generation Family history* in at least 2 generations

1 3 1 2 1 3 3 1 5 2 1 2

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