KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotype-genotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa.     

西藏地区一个家族性痉挛性截瘫家系的连锁分析

目的对西藏地区的一个常染色体显性遗传的家族性痉挛性截瘫家系的致病基因进行定位研究。方法用常染色体显性遗传痉挛性截瘫的３个基因区域内的９个微卫星位点：Ｄ１４Ｓ２６４、Ｄ１４Ｓ７５、Ｄ１４Ｓ６９、Ｄ１４Ｓ２６６、Ｄ１４Ｓ６６、Ｄ２Ｓ２３４７、Ｄ２Ｓ２２５５、Ｄ１５Ｓ１２８和ＧＡＢＲＢ３对该家系进行连锁分析。结果各位点最大Ｌｏｄ值分别为：Ｄ１４Ｓ２６４：０．５１６３（θ＝０．０５）;Ｄ１４Ｓ７５：２．１０７２（θ＝０）;Ｄ１４Ｓ６９：０．２８４０（θ＝０．１０）;Ｄ１４Ｓ２６６：０．９３１１（θ＝０）;Ｄ１４Ｓ６６：０．７９９１（θ＝０）;ＧＡＢＲＢ３：０（θ＝０．４０）;Ｄ１５Ｓ１２８：０（θ＝０．４０）;Ｄ２Ｓ２２５５：０（θ＝０．４０）;Ｄ２Ｓ２３４７：０（θ＝０．４０）。结论本家系中的致病基因与ＳＰＧ３基因区域的Ｄ１４Ｓ７５位点连锁（θ＝０,最大Ｌｏｄ值为２．１０）。     

Spinal epidural hematoma following epidural anesthesia versus spontaneous spinal subdural hematoma. Two case reports

Two cases of lumbar hemorrhage with subsequent persistent neurologic sequelae are presented and their possible causes are discussed in the context of a literature review: one patient with spontaneous spinal subdural hematoma with no trauma or lumbar puncture and one with spinal epidural hematoma associated with preceding epidural catheterization for postoperative pain relief. The subdural hematoma was associated with a thrombocytopenia of about 90,000/microliters due to intraoperative blood loss. This might have been contributory to the formation or expansion of the hematoma, but it is not convincing since a platelet count of this amount should not lead to spontaneous bleeding. Both patients received low-dose heparin, but since coagulation tests were normal, prolonged bleeding does not appear to be a likely cause, although it cannot be excluded. In conclusion, the reasons for both hematoma remain unclear. With regard to the epidural hematoma and low-dose heparinization, the possible coincidence of spontaneous lumbar hematoma and lumbar regional block should be taken into consideration.     

大剂量氨溴索联合气管镜治疗高位截瘫患者肺部感染临床研究

目的观察大剂量氨溴索联合纤支镜在治疗高位截瘫患者合并肺部感染的临床效果。方法合并严重肺部感染的高位截瘫患者30例,随机分成3组：小剂量氨溴索组（氨溴索30mg,壶入3次／d）;大剂量氨溴索组（氨溴索300mg,壶入3次／d）;联合治疗组（氨溴索300mg,壶入3次,d）,联合纤支镜下吸痰治疗。比较各组患者治疗前以及治疗第3d,第7d的临床效果、体征、X线表现、血气分析及呼吸机使用时间等。结果大剂量组患者在临床效果、体征及X线表现好转程度明显优与小剂量组（均P〈0．05）,且感染控制及脱机时间均显示缩短。联合治疗组较大剂量组治疗效果更加明显。结论对高位截瘫合并肺部感染患者,应用大剂量氨溴索可以有效化痰,控制感染,减少控制感染时间,减少呼吸机辅助呼吸时间,联合纤支镜治疗效果更好。     

Hartnup disease presenting as hereditary spastic paraplegia and severe peripheral neuropathy

Hartnup disease cases were rare, and the genotype–phenotype correlation was not fully understood. Here we reported two unrelated young men diagnosed as Hartnup disease, who carried novel compound heterozygote mutations in the SLC6A19 gene and presented with new phenotypes. Other than intermittent encephalopathy and photosensitive rashes, they displayed symptoms and signs of spastic paraplegia and severe peripheral nerve damages. Magnetic resonance imaging showed mild bilateral cerebellar atrophy and thinning of the thoracic spinal cord. Electromyogram detected mixed sensorimotor polyneuropathy in lower limbs. Sural nerve biopsy and pathological study indicated the moderately reduced neural fibers in the periphery nerves. Urinary amino acid analysis showed increased levels of multiple neutral amino acids. Moreover, muscle strengths in the lower limbs and the walking ability have been improved in both cases (MRC 3/5 to 4/5 in Patient 1; walking distance elongated from 50 to 100 m in Patient 2) after the treatment with oral nicotinic acid and intravenous injection of multiple amino acids. Exome sequencing revealed and confirmed the existence of the novel compound heterozygous SLC6A19 mutations: c.533G>A (p.Arg178Gln) and c.1379-1G>C mutations in patient1, and c.1433delG (p.Gly478AlafsTer44) and c.811G>A (p.Ala271Thr) in patient 2. Taken together, these findings expanded the clinical, neuroimaging, pathology, and genetic spectrum of Hartnup disease. However, the co-existence of HSP and peripheral neuropathy was only inferred based on clinical observations, and pathological and molecular studies are needed to further dissect the underlying mechanisms.