Research On Clinical And Genetic Heterogeneity Of Hereditary Movement Disorders

In the broad sense,movement disorders include involuntary movement caused by damage to extrapyramidal system,as well as voluntary movement disorder caused by damage to the corticospinal tract,spinal cord,peripheral nerves or skeletal muscles.The etiology is complex,such as genetic,degeneration,toxicosis,metabolism,immunology and cancer.This research focuses on genetic factors leading to corticospinal tract and extrapyramidal dyskinesia.The former is more common in hereditary spastic paraplegia(HSP),and the latter is more common in hereditary Parkinson’s disease(PD)and dystonia.HSP is a syndromic designation for a clinically and genetically heterogeneous group of inherited neurodegenerative disorders in which the main neurological signs are lower-limb spasticity and weakness.To date,more than 80 genes or loci have been published.Depending on the presence of other neurological or non-neurological signs,HSP are classified as “pure” and“complicated” phenotypes.These signs include cerebellar dysfunction,peripheral neuropathy,cognitive impairment,extrapyramidal features,psychiatric disturbances,myopathy,epilepsy,brain and spine MRI abnormalities,skeletal malformations and skin abnormalities.Spastic paraplegia and these signs can be seen in a variety of hereditary neurologic diseases,such as spinocerebellar ataxia(SCA)and leukodystrophy(LD).The highly overlapping clinical manifestations result in great difficulties to diagnosis.Hereditary PD is a complex neurodegenerative disorder characterized by bradykinesia with tremor,rigidity or postural instability result from genetic factors.>90% of the presenting phenotypes are complex or atypical,with dystonia,cognition decline,pyramidal signs,psychiatric disorders,abnormal eye movements and abnormal imaging excluding PRKN associated PD.Among them,Parkinson-like manifestations of juvenile Parkinson’s disease(JPD,≤21 years)can be mild or atypical,often accompanied by dystonia,with obvious diurnal fluctuation and sleep benefit,which easily misdiagnosed as DRD in the early duration.In the meanwhile,adult-onset DRD often mimicking PD.At present,diurnal fluctuation and sleep benefit have also been found in some other hereditary neurodegenerative diseases,such as HSP and SCA.This study collected the inpatients developed spastic paraplegia with or without other neurologic signs and dopa-responsive parkinsonism/dystonia with diurnal fluctuation respectively and having a gene diagnosis in the Department of Neuromuscular Diseases of the Third Hospital of Hebei Medical University from January 2011 to June 2021,explored the genetic etiology of the two phenotypes and features in clinical,laboratory,neuro-electrophysiology and imaging of the diseases to make differential diagnosis,and expand the spectrum of hereditary movement disorders and improve the positive rate of diagnosis.Part one: Clinical and genetic heterogeneity of hereditary spastic paraplegiaObjective: This study aims to explore disease spectrum of HSP,and the clinical,laboratory,electrophysiological and imaging differences of various diseases to improve the positive rate of diagnosis.Methods: 28 cases were screened out to have definite or suspected pathogenic variants from clinically suspected HSP pedigrees through HSP-associated sequencing and/or expanded genetic testing or enzyme detection of leukodystrophy.In addition,detailed clinical,laboratorial,electrophysiological and radiological characteristics of the 28 patients were presented.Results: A total of five types of hereditary neurological disorders were confirmed in 28 patients,including 15 cases of HSP,five cases of Hcy remethylation disorders,five case of LD,two cases of HA,and one case of Charcot-Marie-Tooth atrophy.Lower limbs spastic paraplegia is the characteristic of all patients.Patients in the HSP group had chronic courses with a duration of 13.9 years,and accompanied by cerebellar involvement(3/15),cognitive decline(1/15),dysarthria(3/15),peripheral neuropathy(3/15)and abnormal brain MRI(5/15).Upper limbs involvement accounted for 3/15(hyperreflexia and/or positive Hoffmann’s sign).Mainly axonal neuropathy in nerve conduction studies and “ear of the lynx”,thinning corpus callosum,non-specific white matter lesions and cerebellar atrophy in brain MRI were observed.In non-HSP patients,some patients were complicated with cerebellar signs,cognitive decline,dysarthria,peripheral neuropathy and brain MRI.In the Hcy remethylation disorders group,the mean course of disease was 2.6 years,and 2/5 patients were involved in the upper limbs.The serum Hcy of all cases was higher than 53.1 umol/L,the nerve conduction studies were mainly demyelination,and brain MRI showed high signals around the ventricle and reversible signals.In LD group,the mean course of disease was2 years,and 4/5 patients were with upper limbs involvement.The serumβ-galactocerebrosidase of the patient with Krabbe’s disease significantly decreased to 2.6 nmol/17h/mg Pr.Brain MRI showed abnormal signals in the periventricular,corpus callosum and corticospinal tract region.In the HA group,the mean course of disease was 18.5 years,and all patients showed typical signs of cerebellum and pyramidal tract involvement with upper limbs involved.The EMG of SCAR8 showed extensive spontaneous potential(four spinal segments),suggesting involvement of the spinal anterior horn.Cerebellar atrophy in brain MRI was found in all cases,and ARSACS showed characteristic signals in pons.Patients with CMT was combined with gastrocnemius atrophy.EMG showed extensive spontaneous potential without abnormal nerve conduction in nerve conduction studies.A total of 12 new variants were obtained.Conclusions: HSP had clinical overlap with a variety of inherited neurological diseases,including Hcy remethylation disorders,LD,HA and CMT,which accounted for a significant proportion of the proposed HSP.These diseases had different characteristics in clinical,laboratorial,electrophysiological,and radiological aspects,which could help differential diagnosis.Expanded genetic testing can improve the diagnosis rate.Part two: Genetic etiology of parkinsonism or dystonia with diurnal fluctuationObjective: The study aims to explore disease spectrum of dopa-responsive parkinsonism/dystonia with diurnal fluctuation,and the clinical and imaging differences of various diseases to guide genetic testing and improve the positive rate of diagnosis.Methods: Nine patients with dopa-responsive parkinsonism or dystonia with diurnal fluctuation and definite genetic diagnosis were recruited.Their clinical,imaging and genetic data were retrospectively analyzed to summarize and compare the clinical phenotypic characteristics.Results: 6 cases of hereditary PD(PARK2/PRKN,PARK14/PLA2G6),and 3 cases of DRD(GCH1 and TH)were confirmed.The mean age at onset of DRD patients was 5.3 years old(4-9 years old),and all of them were female.The clinical manifestations were dystonia,with hyperreflexia(2/3),pyramidal sign(1/3)and foot pronation(1/3).One case was associated with episodic limbs stiffness,and all cases had no rigidity,bradykinesia or tremor.The average age at onset of hereditary PD was 22.8 years(13-33 years),and the male to female ratio was 2:4.The main clinical manifestations were typical Parkinson-like symptoms,and some patients were accompanied by hyperreflexia(5/6),dystonia(1/6),pyramidal sign(1/6)and foot pronation(3/6).All patients still had significant diurnal fluctuation and sleep benefit during the third or fourth decade.One case developed dopa-induced motor fluctuation and dyskinesia.A total of 3 new variants were found,PLA2G6/c.967G>A、TH/c.746C>T and GCH1/c.580 del A.Conclusions: Diurnal fluctuation and sleep benefit are typical features of DRD,but can also occur in patients with hereditary PD.In this study,dystonia,hyperreflexia,pyramidal sign,foot pronation,diurnal fluctuation and sleep benefit,and good response to dopa in patients with hereditary PD were similar to DRD,as well as female preference.However,the age at onset of hereditary PD was later,and the diurnal fluctuation lasted longer.Among hereditary PD,PRKN mutations were more common,and the manifestations of PLA2G6 mutations were more complex.Genetic testing can confirm the diagnosis,and the scope of genetic testing can be expanded if necessary.