Cadasil, atypical and familial presentation – family case report
Authors: Iegoroff Renan , Vaca Rafael Herlan Terceros , Pinheiro Gustavo Araújo , Huanca Alvaro Marcelo Huchani , Coradini Matheus Henrique de Souza , Medeiros Leonardo Mariano Inácio 
Published: July 2023

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a non-atherosclerotic, nonamyloid, hereditary cerebral disease of small vessels and capillaries caused by mutations in the NOTCH-3 gene located on chromosome 19. The presence of granular osmophilic material (GOM) deposition in the smooth muscle cells of vessel walls is the pathological hallmark of arteriopathy in CADASIL. GOM deposits in the basal lamina of smooth muscle of small vessels are pathognomonic for CADASIL. The presence of GOM in capillary blood vessels of the skin and muscle in biopsy and genetic studies (NOTCH-3 analysis) plays a key diagnostic role. Biopsy tests have high specificity (up to 100%) and low sensitivity (less than 50%). The NOTCH-3 test has been proposed as the primary diagnostic approach, allowing detection of 90% of affected individuals. CADASIL has an estimated prevalence between 2 and 5 in 100,000, and the phenotypic study demonstrates different clinical symptoms in the course of the disease within the same family. The average age of onset of clinical symptoms varies between 48.3 years in men and 52.2 years in women. Characteristic symptoms of migraine, stroke or TIA (transient ischemic attack), behavioral changes, early and progressive cognitive changes associated with leukoencephalopathy on imaging studies. The large association of symptoms often causes the diagnosis of CADASIL to be delayed. In this case, we had an association of gait ataxia within the framework of motor alterations, demonstrating the wide range of symptomatology of the pathology. This case report presents a familial course that started outside the most prevalent age group in the studies described and with an atypical presentation in an affected generation. Case reports: Case 01: woman, 68 years old, started progressively forgetting to perform household activities after the age of fifty, associated with primarily generalized myoclonic epileptic seizures, evolving rapidly within five years to walking apraxia with the use of a wheelchair and tonic-tonic epileptic seizures. bilateral clonic disorders, comprehension aphasia and bradypsychism. Relatives report previous migraine without chronic aura and REM (rapid eye movement sleep) sleep behavior disorder (RMSD). On neurological examination, severe ataxia with bilateral dysdiadochokinesia associated with bilateral hypometric index-index. Bilateral ROT 4+/4+ with bilateral Hoffman and Babinski signs. MMSS and MMII with FGM 4/5 proximal and distal. Case 02: woman, 36 years old, pastry chef, had episodes of forgetting about everyday activities of her work, progressive in the last three years (cake recipes, budget accounts, orders placed) associated with confusion for spatial location on the way home/ work, evolving to apraxia in writing letters and words and difficulty with calculations associated with monoparesis of the right lower limb for twelve months with progression to paresis of the lower limbs after six months and evolution to paresthesia of the upper limbs for three months. Associated with the condition, he has migraine without chronic aura and RMSD. The neurological examination showed Mini-Mental State Examination 22/30 (expected score of 29), list of animals in one minute: 09 animals; list of words starting with “F”: 03 words; clock test: 2/4; difficulty with calculations and digital agnosia with right/left apraxia; Upper limbs: eutrophic, FMG 4/5, bilateral distal; FMG 5/5 bilateral proximal; Lower limbs: eutrophic, bilateral FMG 4/5 distal and proximal with positive Mingazini; atypical gait with evidenced weakness in heel, toe and tandem gait; Bilateral dysdiadochokinesia with eumetric, slowed indexindex; ROT 4+/4+ in the right side with positive Hoffman and Babinski signs. MRI Brain (17/09/2020): extensive area of hypersignal on T2 and FLAIR (T2- weighted-Fluid-Attenuated Inversion Recovery) involving the periventricular white matter in all lobes without atrophic or expansive effect; Case 03: woman, 45 years old, started behavioral arrest epileptic seizures at the age of thirty-two, progressing to focal dysperceptive seizures with progression to bilateral tonic clonic seizures after eight months and multiple episodes of anterograde amnesia, presenting forgetfulness related to everyday work activities (exchanged worksheets , payments, calculation errors and budgets); associated with the condition presented migraine without chronic aura and RMSD. Genetic Test (04/06/2017): Heterozygous alteration in exon 8 of the NOTHC – 3 gene. Discussion: CADASIL presents a rare cause of cognitive decline and is often overlooked in diagnosis, except in cases of high clinical suspicion in a familial course. Access to imaging tests becomes fundamental for the diagnostic segment and the primordial genetic test for etiological elucidation and family planning, in the report described the family presentation with the same course of satellite symptoms (migraine without aura, and RMSD) associated with cognitive alteration with anticipation of age of onset are hallmarks of clinical thinking. Cases described in the literature show that the clinical symptomatology is not necessarily related to the level of brain injury observed in the imaging exam, which could be explained by personal factors and which exon is affected. The NOTCH-3 gene has 24 exons, in which the literature reports exon 4 as the most common mutation, followed by 3, 5 and 6, mainly in the Caucasian population. In an Asian population, the most affected exon is 4 and 11, which is also found in Italian descendants. The mutation in exon 8, described in the clinical case, is found in a population of Portuguese origin, being the second most common mutation in this nationality, behind the mutation in exon 4. Brain MRI studies have tried to elucidate the most affected brain regions, aiming to trace a line of evolution. Involvement of the temporal lobe, external capsule and corpus callosum are described as probable markers of CADASIL, and can be used as an aid in the diagnosis due to its specificity of 86% and sensitivity of 89%. Studies also show that the frontoparietal area has frequent findings of hyperintensity (100%), followed by the temporal lobe (83%), less frequently affecting the brainstem, occipital lobe and cerebellum. Despite the great advances in the specialized literature, the causes of the important cognitive dysfunction presented in the course of the evolution of CADASIL remain unclear. However, studies have suggested that the process of cognitive decline is more related to the loss of cortico-subcortical connections than to brain atrophy itself, with these disconnections resulting from repeated transient ischemic accidents. Science has been looking for ways to change the prognosis of CADASIL, recent studies in gene therapy and neurogenetics show the importance of thinking about this pathology as a genetic disease of great importance to change the prognosis of this pathology.