遗传性痉挛性截瘫一家系的临床特点与遗传学分析

Objective To study the clinical and genetic features of a family with hereditary spastic paraplegia(HSP).Methods The patients were from a large Linyi family.Five members were clinically diagnosed with HSP according to Harding's criteria Blood samples were collected from family members.Genomic DNA was extracted from total blood samples using a standard phenol-chloroform extraction.The genetic linkage analysis was performed using microsatellite markers.Two-point linkage analysis was performed using the LINKAGE program.Five members underwent detailed neurological examinations and 4 members underwent electrophysiological analysis,cervical and thoracic MRI and serum enzymes.Results Linkage analysis mapped the AD-HSP locus to chromosome 2p12(SPG31)in this family.Positive LOD scores were obtained for SPG31 markers on chromosome 2 with a maximum multipoint LOD score of Z=1.8.Analysis of the REEP1 gene revealed a heterozygous G-to-A mutation at nucleotide position c417+1 donor site in exon 5.resulting in splice-site mutation.The symptoms of the patients manifested as stiffness,instability or weakness of the legs.MRI of the thoracic revealed atrophies of the spinal cord in the proband's son.Conclusions SPC31 patients have the clinical features of the typical HSP characteristics.REEP1 gene is the pathogenic gene.with REEP1 c417+1G＞A heterozygous mutation.     

遗传性痉挛性截瘫一家系的临床特点与遗传学分析

目的 探讨遗传性痉挛性截瘫(HSP)一家系的基因型和临床特点.方法 抽取1个HSP家系15名成员外周血,选择与已知HSP致病基因位点在物理距离上紧密连锁的微卫星分子进行标记[短串联重复序列(STR)],连锁分析并构建单体型.对患者进行观察,行心肌酶学、肌电图以及头颅、颈髓、胸髓MRI检查,总结其临床特点.结果 家系成员SIR的扩增产物进行基因分型,连锁分析发现与HSP 31型(SPG31)位点连锁,2个SIR(D2S2951、D2S2333)最大LOD值为1.8,表明连锁.经过连锁分析后得到的对应致病基因为REEP1基因,经过突变筛查发现了1个REEP1 c417+1G＞A杂合突变.SPG31临床特点以痉挛步态、下肢肌张力增高为主要表现,MRI显示胸髓萎缩.结论 SPG31患者临床特征表现为典型的HSP特征,致病基因为REEP1基因,存在REEP1 c417+1G＞A杂合突变.     

痉挛性截瘫并共济失调表型的家系基因分析

以该院门诊收治的5例具有痉挛性截瘫合并共济失调表型的家系先证者为研究对象,运用高通量测序芯片结合毛细管电泳技术对这些家系先证者进行致病基因动态突变检测。发现了一个家系先证者携带有ATXN3/MJD1基因CAG重复84次,其妹妹CAG重复82次,其父CAG重复73次,该家系拟诊为遗传性脊髓小脑共济失调3型(SCA3/MJD)家系,并具有明显的临床异质性及遗传早现现象。建议对于兼有痉挛性截瘫及小脑性共济失调表型的患者,特别是具有显性遗传家族史的患者,应进行SCA3致病基因的动态突变检测,同时对家系内表型正常的成员应仔细查体,以防漏诊。     

A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia

The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage‐gated K⁺‐channel, K_V1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow‐up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two‐electrode voltage‐clamp recordings of Xenopus laevis oocytes expressing mutant K_V1.2 channels showed loss of function with a dominant‐negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016     

Attenuated SEPs with no latency shifts in a family with hereditary spastic paraplegia

Five siblings with hereditary spastic paraplegia of autosomal-dominant inheritance were studied with somatosensory evoked potentials. Somatosensory evoked potentials were recorded from Cz', T12, and the left popliteal fossa following left posterior tibial nerve stimulation. The latency and amplitude of the corresponding potentials (i.e., P37, N20, and N7) were compared with normal values obtained from age- and height-matched controls. There was no significant difference in the values of N7, suggesting an intact afferent peripheral pathway; in contrast, the amplitudes of P37 and N20 were decreased with normal latencies. The degree of amplitude decrease correlated with the severity of vibration sense impairment in the lower limbs. These results appear to support selective axonopathy of the centrally directed axons of the dorsal root ganglion cells. Furthermore, our results suggest that different degrees of dorsal column involvement in hereditary spastic paraplegia can cause different types of somatosensory evoked potential abnormalities, namely, attenuated amplitudes with no latency shifts, as recorded in this family, and the prolonged latencies, as reported previously.     

A family of hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V)

Three siblings with hereditary motor and sensory neuropathy with spastic paraplegia (HMN V) were described. Their grandfather was suspected to have the similar symptoms. Their parents were normal and not consanguineous. The first case was a 54-year-old woman. She has suffered from difficulty in walking since the age of 10 years. Distal muscular weakness and wasting began at 20 years old. She was admitted to our hospital for investigation in 1988. Results of examination of the brain, cranial nerve, and cerebellar function were normal. The deep reflexes were hyperactive in the arm and knee, while absent at the ankle. Babinski's sign was definitely positive. Muscular weakness and wasting were noted in intrinsic hand muscles and in those below her knees. There were pes cavus and hammer toes, and the gait was spastic. Mild sensory disturbance was noted in distal limbs. The conduction velocity of motor nerve fibers of her limbs was below normal and that of sensory nerve fibers normal. Muscle biopsy of biceps brachii revealed neurogenic changes. Sural nerve biopsy showed decreased number of myelinated fibers of large diameter and formation of small oinion-bulb. The second and third cases were her brothers and proven to have the similar condition, but their onset of illness were earlier and their affections were more severe. A few cases of HMSN V with nerve biopsy findings have so far been reported and the family presented here is the first report in Japan.     

遗传性痉挛性截瘫一家系临床及spastin基因突变的特点

目的 探讨遗传性痉挛性截瘫(SPG)一家系临床及基因突变的特点.方法 回顾性分析一个SPG家系的临床资料.结果 该家系内5代共有5例SPG患者,各代均有发病.3例存活患者均为女性,发病年龄16 ～21岁,平均18.3岁;病程11 -58年,平均33.3年;3例患者临床表现为缓慢进展的双下肢无力,下肢肌张力明显增高.基因检测显示3例患者spastin基因c.1098+1～2gt→ctcaga突变,家系中正常成员未见该变异.结论 该SPG家系的遗传方式为常染色体显性,临床表现为单纯性SPG,为spastin基因c.1098+1 ～ 2gt→ctcaga突变所致.     

遗传性痉挛性截瘫的神经外科治疗

目的 ;探讨遗传性痉挛性截瘫的神经外科治疗方法及其疗效。方法对17例遗传性痉挛性截瘫患者施行周围神经缩窄术,其中单纯周围神经缩窄术12例,周围神经缩窄+矫形术5例。采用改良Asworth分级评定患者的痉挛程度,采用简化Fugl-Meyer量表评估患者下肢运动功能的改善。结果随访8~15个月,平均12个月。术后近期痉挛缓解率为98.5%,随访期间为92.7%。术后近期下肢运动改善率为86.5%,随访期间为90.8%。2例(11.8%)患者下肢出现短暂的感觉障碍,随访期间均消失。1例(5.9%)严重痉挛患者术后伴有肌力减低。2例(11.8%)患者随访期间痉挛复发。结论遗传性痉挛性截瘫患者适时适当的进行外科手术治疗能够较好地缓解痉挛,改善下肢运动功能,延缓病程进展。     

An autopsy case of hereditary ataxia (hereditary spastic ataxia)

An autopsy case of hereditary spastic ataxia is reported. There are four family members with similar symptomatology through three generations. A 36-year-old man developed atactic gait at the age of 22 years, with following dysarthria, scanning speech, pyramidal signs, dysmetria, dysdiadochokinesia, nystagmus and mild sensory disturbance. The clinical course was steadily progressive and terminated about 14 years after the onset. The gross examination showed smallness of the brain stem and spinal cord with marked symmetrical atrophy of the anterior and lateral columns, especially at thoracic level. Histologically, pronounced degeneration was found in the anterior and posterior spino-cerebellar tracts, spino-thalamic tracts, and spinal ganglia. The olivary nuclei, pons and cerebellum were spared. The dentate nuclei showed considerable loss of neurons with degeneration, however there were no clinical signs related to this pathology. This case is considered to fall in the group of hereditary spastic ataxia according to Greenfield's classification, however, there was no report on degeneration of the dentate nucleus in this disease for the present. Hereditary spastic ataxia is very rare disease and only four cases have well been documented in our country to the best of our knowledge. The presence of nystagmus and superficial sensory disturbance, and sparing of the posterior column of the spinal cord seems to be common clinico-pathology in Japanese cases, differing from those of foreign cases. The fact that reactive astrogliosis was immunohistochemistry demonstrated in the degenerative regions of the spinal cord and where is no discrepancy between degenerative and reparative processes as reported before is stressed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evoked potentials in hereditary spastic paraplegia

Pattern reversal visual evoked response (VER) and monaural stimulation of brainstem auditory evoked responses (BAER) were recorded from both sides in 25 patients (males 19; females 6) with hereditary spastic paraplegia (HSP). Their age ranged from 15–52 (mean±SD; 25.2±22.5) years and duration of symptoms 6 months-9 (mean±SD; 4.2±3.6) years. A prolonged P 100 latency was seen in 6 patients and BAER abnormality in 13. None of the patients had clinical evidence of brainstem involvement. It is suggested that VER and BAER abnormalities are due to segmental demyelination and fiber loss in central conduction pathways and could serve as an important tool for the diagnosis of this disorder.

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Sommario I potenziali evocati visivi (VER) e uditivi del tronco (BAER) sono stati registrati bilateralmente in 25 pazienti (19 maschi e 6 femmine) affetti da paraplegia spastica ereditaria (HSP). La loro età media era compresa tra 15 e 52 anni (media±DS=25.2±22.5) e con una durata di malattia compresa tra 6 mesi e 9 anni (media±DS=4.2±3.6). In 6 pazienti è stato riscontrato un aumento della latenza della P100 e in 13 i BAER erano anormali. Nessuno dei pazienti presentava segni clinici di coinvolgimento del tronco. Viene ipotizzato che le anormalità osservate ai VER e BAER sono dovute ad una demielinizzazione segmentaria o a perdita di fibre lungo le vie di conduzione cerebrale. Questi esami strumentali sarebbero quindi di grande utilità nella diagnosi di HSP.

     

Recent advances in hereditary spastic paraplegia

The hereditary spastic paraplegias are a group of rare disorders that are characterized by great clinical and genetic heterogeneity. There has been an exponential increase in the number of HSP loci mapped in recent years, with nine out of the 17 loci reported during the past 2 years. Eight loci have now been identified for the autosomal-dominant form, and seven of these are associated with pure HSP. Spastic paraplegia-4 remains the most frequent locus, and is usually associated with a pure phenotype. Although the corresponding spastin gene was only recently identified, over 50 mutations have been described to date, which renders molecular diagnosis difficult. Five loci are known for autosomal-recessive HSP, and four of these are associated with complex forms, all with different phenotypes. Two genes have been identified: paraplegin and sacsin. Finally, three loci have been identified in X-linked HSP, two of which are complex forms. The genes that encode L1 and PLP were the first to be identified in HSP disorders. Surprisingly, the five genes encode proteins of different families, making understanding and diagnosis of HSP even more difficult. The discovery of new genes should hopefully help to clarify the pathophysiology of these disorders.     

遗传性痉挛性截瘫一家系(SPG4)的临床与遗传学特点

目的 探讨遗传性痉挛性截瘫(HSP)4型患者的临床特点和基因突变. 方法观察HSP4型患者1个家系4例患者的临床特点,抽取家系5个成员的外周血,选择与已知HSP致病基因位点在物理距离上紧密连锁的微卫星分子STR进行标记.连锁分析并构建其单体型后进行突变筛选.结果 基因分型结果显示了D2S2351与D2S2255与致病基因不排除连锁.其他位点LOD值为负值排除连锁,因此初步定位于HSP致病基因(SPG)4,所对应的候选基因是spastin基因.突变筛查发现患者spastin基因第8外显子1168位置碱基A/G杂合突变.结论该HSP家系患者具有典型临床表现,为spastin基因第8外显子1168核苷酸的位置上A/G杂合突变所致.