A Pedigree Study Of Frontotemporal Dementia And Retrospective Analysis Of The Clinical Features Of Frontotemporal Dementia

Background and purpose:Frontotemporal dementia （FTD） is an insidious onset, progressive neurodegenerative disease and the second most common early-onset dementia after Alzheimer’s disease（AD）, characterized by behavioral changes, the frontal executive function impairment and language dysfunction. Till now, there are more than 2400 people with dementia around the world. It is estimated that the prevalence of dementia would increase to four times, while FTD accounts for 20% in all dementia people. Compared with AD caregivers, burden among FTD caregivers is higher than among AD caregivers and related with neuropsychiatric symptoms. And, there are also some specific problems, including delayed diagnosis, young age of patients and social isolation. Furthermore, the rate of progression and death on FTD is more rapidly than AD.Till now, the etiology and pathogenesis of FTD has not been clearly illuminated. However, many studies suggested that FTD is associated with genetics changes. In recent years, it is reported that 40-50% of FTD patients in western countries have a family history of dementia, while 10% to 40% patients have an autosomal dominant inheritance pattern for the disease, in which 88% of patients have been identified causative mutations. While, the prevalence of FTD with family history in Asia is only 9.5%. FTD has clinical and genetic heterogeneity. Different gene mutations can lead to different clinical manifestations, while the same gene mutation can also lead to different clinical manifestations, which may be caused by the causative gene correlation with environment, random factors or other genes,. In recent years, with the rapid development of molecular genetics, seven single causative genes which could lead to FTD have been discovered, including microtubule-associated protein tau （MAPT）, valosin-containing protein（VCP）, charged multivesicular body protein 2B （CHMP2B）, progranulin （GRN）, transactive response DNA-binding protein （TARDBP）, fused in sarcoma （FUS）, chromosome 9 open reading frame 72 （C9ORF72）. Mapping of these gene mutations, carrying out scientific researches to its function and protein products, will provide important clues for the etiology and pathogenesis of FTD, also can provide references and enlightenment to the study of sporadic FTD. FTD is clinically and genetic heterogeneous disease, and there is no effective biomarkers and drug treatment, so early diagnosis, treatment and prevention is very important. Currently, no investigations and studies about epidemiology and demographic characteristics on Chinese FTD patients have been reported in our country. And the latest researches about FTD are confined to case reports and small sample retrospective studies. Furthermore, the further research development is hampered by low diagnostic accuracy and lacking of multi-center cooperation. So far, there are few reports about FTD pedigrees in China, particularly for the families who have multi-generation patients. Compared with western countries, disease spectrum in Chinese FTD is still unclear. So, it is very important to study the familial FTD related gene. The study made illustrations about clinical and genetic characteristics on a Chinese FTD family which have multi-generation patients, then performed gene tests to identify the causative gene. We can improve the implementation of clinical data and genotype-phenotype correlates will be established by the implementation of phenotypic ontology, which can allow to associate genetic variations with specific clinical characteristics. So, the study can provide the evidences and clues for the etiology, mechanism and genetics interrogation of FTD.AD is the most common type of dementia, characterized by progressive memory loss and cognitive impairment, followed by executive dysfunction, mental and behavioral abnormalities and other symptoms. The similar clinical manifestations, certain family history and no specific auxiliary examinations between FTD and AD in clinical practice make clinicians identify them very hard. Currently, there are no effective medicines to FTD. Cholinesterase inhibitors can relieve the symptoms of AD, but can aggravate patient’s condition or psychiatric symptoms. So, it is of great value to differentiate FTD from AD, At present, researches on the identification of FTD and AD mostly are made about analyzing the differences in imaging and neuropsychological assessment between FTD and AD, while the comparative studies about the clinical features of FTD and AD are less. Shea et al compared the clinical features between FTD and AD in 2014, attempting to find methods to distinguish them. But the sample size is small. This study retrospectively analyzed the clinical features of 16 cases of FTD patients, and compared the clinical features between FTD and AD and tried to find the identification points, then providing powerful help to the clinicians.Part 1 The clinical characteristics and genetic research of a Chinese FTD familyMethods:â… . Case recruitment:A FTD family was collected on Mar.2014. After written the informed consent, we collected history taking on family members. This study protocol was approved by the Ethic Committee of Nanfang Hospital.â…¡. Clinical data compilation:We drew the family tree, and confirmed that the inheritance pattern of the family was autosomal dominant inheritance, and organized the clinical data and summarized clinical characteristics of the pedigree. Then, we made a detailed clinical history taking, neuropsychological examinations, neuropsycho logical examinations, imaging studies and other auxiliary examinations about the proband. In order to follow up, we saved their constant connection methods.â…¢. Blood specimen collection:After written the informed consent, we collected venous blood specimen of the family members.â…£. Targeted next-generation sequencing technology:Targeted next-generation sequencing technology performed by BGI （Shenzhen, China） was conducted for testing the proband’s blood specimen to confirm whether there is causative genes leading to this FTD family. For the purpose of differential diagnosis between FTD and familial Alzheimer disease, we conducted for all exons of several known common causative genes which were responsible for frontotemporal dementia （MAPT、GRN、FUS、VCP、CHMP2B、TARDBP） and familial Alzheimer disease （amyloid precursor protein （APP）、presenilin 1 （PSEN1）、 presenilin 2 （PSEN2） and APOE）.（FTD caused by C9ORF72 mutation often combined with ALS, this family has no clinical symptoms about ALS or other motor nerve diseases, so we didn’t detect this gene）.â…¤. Sanger sequencing:After found causative genes, DNA was extracted from the family members’blood specimens. Primers were designed according to the detected causative gene and then amplified by PCR in the right conditions. Sanger sequencing were performed on all affected and unaffected subjects to justify the suspicious mutation. The sequencing results compared with the corresponding DNA sequence of the human gene of GenBank using Chromas Lite and Blast software analysis.â…¥. Statistical analyses:Measurement data were expressed as x ± s.Results:â… . Clinical features of the FTD family:The inheritance pattern of the pedigree （South China, Han） was autosomal dominant inheritance. Both men and women were affected. The inheritance condition was unrelated with sex. The pedigree consists of 65 family members over 5 generations. Ten members （4 male,6 female） of the first three generations among the pedigree were affected,8 of them were deceased. The fourth and fifth generations were not affected, given that the members were still young. The age at onset on the family ranged 50-58 years old （mean age 53.80±2.87 years）. The first symptom was memory loss, mainly in short term memory loss, and gradually aggravated, followed by abnormal mental behavior.1-5 years after onset （mean time 3.22±1.30 years）, all the affected people died.â…¡. The proband’s clinical features and auxiliary examinations:The proband was 61 years old female in the third generation and she was Illiterate. Her onset age was 58 years old. And the first sign was memory loss, followed by calculation, attention, orientation, execution and many other cognitive functions impairment, combined with indifference, unresponsiveness, little words, interpersonal skills reduction, personality changes, irritability, and neglect of personal hygiene. Neurological examinations were normal. The neuropsychological assessment indicated that her Mini-Mental Status Examination （MMSE） score was 9/30.The Frontal Assessment Battery （FAB） score was 3/18. Neuropsychiatric Inventory （NPI） score was 44/144. A Lawton activity of daily living scale （ADL） score was 26/56. Hamilton Depression Scale （HAMD） score was 5/79. Hachinski scale was 1/18. Brain MRI displayed bilateral frontal lobe atrophy, the right frontal lobe atrophy was more prominent than the left, the other cerebral cortex and bilateral hippocampus mild atrophy with the anterior horn the right lateral ventricles enlarged; SPECT revealed obvious decreased perfusion in the right frontal and parietal lobes, and mild decreased perfusion in bilateral temporal lobes.â…¢. The results of gene test:A missense mutation in MAPT（NM₀01123066, c.1907C>T, p.Pro636Leu）, a heterozygous C-to-T change at codon 301 in exon 10, was identified in the proband （111-10） and one presymptomatic individual. Furthermore, a missense mutation in APOE （NM₀00041, c.388T>C, p.Cys130Arg） a heterozygous T-to-C change at codon 130 in exon 4 in the proband, and her APOE genotype was ε3/4. The presymtomatic person’s APOE genotype was ε2/3. APOE genotype of other three members（Ⅲ-15、Ⅳ-1、Ⅳ-3） were ε3/4, and another two members were ε3/3. We failed to find any other pathogenic mutations in GRN、FUS、 VCP、CHMP2B、TARDBP、APP、PSEN1 and PSEN2.Conclusion:This study identifies a rare domestic FTD pedigree, and provides a detailed illustration about clinical features of the family and performs gene test analysis. The inheritance pattern of the pedigree is autosomal dominant inheritance. The age at onset on the family ranges 50-58 years old.1-5 years after onset of FTD, all the affected people died. The first symptom of the FTD family is memory loss, with the main sign of dementia. Structural imaging suggests asymmetrical frontotemporal atrophy, and functional imaging studies show frontal and parietal lobes asymmetrical hypoperfusion. A mutation in MAPT, a heterozygous C-to-T change at codon 301 in exon 10 which leads to the substitution of proline to leucine （P301L）, is identified in the family by targeted next-generation sequencing technology. This is the first report of familial FTD with the P301L mutation of MAPT in China.Part 2 Retrospective analysis of the clinical features of frontotemporal dementiaMaterials and methods:â… . Subjects:After devised the inclusion and exclusion criteria,16 cases of diagnosed FTD were collected from the department of neurology or clinic in our hospital during Jan.2006 to Dec.2014.26 cases of diagnosed AD during the same period were recruited as the controls.â…¡. Methods:Clinical data of FTD and AD individuals had been recorded and analyzed. Including demographic characteristics （gender, age, education level, duration）, clinical features （family history, clinical symptoms, neurological signs）, auxiliary examinations （routine, biochemistry, CT or MRI, electromyography, MMSE）, etc.â…¢. Statistical analyses:Measurement data were expressed as x ± s. Mean among 2 groups was compared by using two independent samples T test analysis. Enumeration data were demonstrated as percentages and used Fisher exact probability methods. Ranked data were analyzed by Wilcoxon rank sum test. P<0.05 was defined as statistically significant. All data were analyzed by using SPSS 19.0 Software package.Results:No difference was found as to sex distribution, disease duration, educational level, family history and MMSE score between FTD and AD. The age at onset of FTD was much earlier than AD. Cognitive impairment as the first symptom was more common in AD, while neuropsychiatric abnormalities were rare. Instead, cognitive dysfunction and neuropsychiatric abnormalities as the first sign were both common in FTD.100% of the FTD patients suffered from neuropsychiatric abnormalities, while only 46% of the AD patients suffered from neuropsychiatric abnormalities. There were no differences in apathy, impulsive behaviors, hallucinations, unresponsiveness and speech reduction between two groups. The incidence of pyramidal signs was 18.8% and 0%, respectively, with significant differences in FTD group and AD group. The misdiagnosis rate was higher in FTD than AD, and FTD patients were easily misdiagnosed as AD.Conclusion:FTD is a clinically heterogeneous disease, which can occur in conjunction with motor neuron disease, Parkinson’s syndrome and epilepsy. The age at onset of FTD is much earlier than AD. The first symptom of neuropsychiatric abnormalities is more common in FTD compared with AD. But, apathy, impulsive behaviors, hallucinations, unresponsiveness and speech reduction cannot effectively distinguish FTD from AD. Pyramidal signs may be used as specific clinical signs of FTD patients, and are expected to become the identification points between FTD and AD.