Voluntary ambulation using voluntary upper limb muscle activity and Hybrid Assistive Limb® (HAL®) in a patient with complete paraplegia due to chronic spinal cord injury: A case report

Context: We sought to describe our experience with the Hybrid Assistive Limb® (HAL®) for active knee extension and voluntary ambulation with remaining muscle activity in a patient with complete paraplegia after spinal cord injury.

Findings: A 30-year-old man with complete paraplegia used the HAL® for 1 month (10 sessions) using his remaining muscle activity, including hip flexor and upper limb activity. Electromyography was used to evaluate muscle activity of the gluteus maximus, tensor fascia lata, quadriceps femoris, and hamstring muscles in synchronization with the Vicon motion capture system. A HAL® session included a knee extension session with the hip flexor and voluntary gait with upper limb activity. After using the HAL® for one month, the patient’s manual muscle hip flexor scores improved from 1/5 to 2/5 for the right and from 2/5 to 3/5 for the left knee, and from 0/5 to 1/5 for the extension of both knees.

Conclusion/clinical relevance: Knee extension sessions with HAL®, and hip flexor and upper-limb-triggered HAL® ambulation seem a safe and feasible option in a patient with complete paraplegia due to spinal cord injury.     

C19orf12 mutation causing mitochondrial membrane-protein Associated Neurodegeneration masquerading as spastic paraplegia

Mitochondrial Membrane-protein Associated Neurodegeneration (MPAN) is a rare disease, caused by C19orf12 mutations and up to 29 different mutations have been described. We report a young woman presented with spastic paraparesis due to C19orf12 gene. MPAN presenting like Hereditary spastic paraplegia-43 is rare and the genetic mutation had been described only once in the literature.     

A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3′UTR‐encoded,aggregation‐inducing motif

Single‐nucleotide variants that abolish the stop codon (“nonstop” alterations) are a unique type of substitution in genomic DNA. Whether they confer instability of the mutant mRNA or result in expression of a C‐terminally extended protein depends on the absence or presence of a downstream in‐frame stop codon, respectively. Of the predicted protein extensions, only few have been functionally characterized. In a family with autosomal dominant Charcot‐Marie‐Tooth disease type 2, that is, an axonopathy affecting sensory neurons as well as lower motor neurons, we identified a heterozygous nonstop variant in REEP1. Mutations in this gene have classically been associated with the upper motor neuron disorder hereditary spastic paraplegia (HSP). We show that the C‐terminal extension resulting from the nonstop variant triggers self‐aggregation of REEP1 and of several reporters. Our findings support the recently proposed concept of 3′UTR‐encoded “cryptic amyloidogenic elements.” Together with a previous report on an aggregation‐prone REEP1 deletion variant in distal hereditary motor neuropathy, they also suggest that toxic gain of REEP1 function, rather than loss‐of‐function as relevant for HSP, specifically affects lower motor neurons. A search for similar correlations between genotype, phenotype, and effect of mutant protein may help to explain the wide clinical spectra also in other genetically determined disorders.     

GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia

Various genetic defects can cause intellectual and developmental disabilities (IDDs). Often IDD is a symptom of a more complex neurodevelopmental or neurodegenerative syndrome. Identifying syndromic patterns is substantive for diagnostics and for understanding the pathomechanism of a disease. Recessive glutamate pyruvate transaminase (GPT2) mutations have recently been associated with IDD in 4 families. Here, we report a novel recessive GPT2 stop mutation p.Gln24* causing a complex IDD phenotype in a homozygous state in 5 patients from 2 consanguineous Arab families. By compiling clinical information of these individuals and previously described GPT2 patients a recognizable neurodevelopmental and potentially neurodegenerative phenotype can be assigned consisting of intellectual disability, pyramidal tract affection with spastic paraplegia, microcephaly and frequently epilepsy. Because of the consistent presence of pyramidal tract affection in GPT2 patients, we further suggest that GPT2 mutations should be considered in cases with complex hereditary spastic paraplegia.     

Functional Assessment of Lower Extremities in Hereditary Spastic Paraplegia

Braschinsky M, Parts K, Maamägi H, Gross-Paju K, Haldre S. Functional assessment of lower extremities in hereditary spastic paraplegia.

Objectives

To characterize the spasticity and range of motion (ROM) in patients with hereditary spastic paraplegia (HSP) and to correlate these parameters with walking speed.

Design

An observational population-based cohort study.

Setting

Patient data were acquired from a population-based epidemiologic study performed earlier in Estonia.

Participants

Persons (N=46) (mean age, 50.1y) with clinically confirmed HSP diagnosis (mean duration, 20.9y) participated in the study.

Interventions

Active and passive ROMs were measured with a plastic 360° goniometer. Spasticity was evaluated by using the modified Ashworth scale (MAS). The time it took a patient to walk 10m was recorded.

Main Outcome Measures

Measurements included testing of active and passive ROM as a marker for mobility, the MAS for spasticity, and time to complete a 10-m walk.

Results

A higher degree of spasticity in hip muscles was associated with lower values of active ROM and slower walking. Walking speed was negatively correlated to disease duration and participant age.

Conclusions

The present study provides analysis of the contributions of spasticity and ROM to walking speed in HSP, both factors negatively influence gait in persons with HSP.     

Proteolipid protein modulates preservation of peripheral axons and premature death when myelin protein zero is lacking

Protein zero (P0) is the major structural component of peripheral myelin. Lack of this adhesion protein from Schwann cells causes a severe dysmyelinating neuropathy with secondary axonal degeneration in humans with the neuropathy Dejerine‐Sottas syndrome (DSS) and in the corresponding mouse model (P0^null‐mice). In the mammalian CNS, the tetraspan‐membrane protein PLP is the major structural myelin constituent and required for the long‐term preservation of myelinated axons, which fails in hereditary spastic paraplegia (SPG type‐2) and the relevant mouse model (Plp^null‐mice). The Plp‐gene is also expressed in Schwann cells but PLP is of very low abundance in normal peripheral myelin; its function has thus remained enigmatic. Here we show that the abundance of PLP but not of other tetraspan myelin proteins is strongly increased in compact peripheral myelin of P0^null‐mice. To determine the functional relevance of PLP expression in the absence of P0, we generated P0^null*Plp^null‐double‐mutant mice. Compared with either single‐mutant, P0^null*Plp^null‐mice display impaired nerve conduction, reduced motor functions, and premature death. At the morphological level, axonal segments were frequently non‐myelinated but in a one‐to‐one relationship with a hypertrophic Schwann cell. Importantly, axonal numbers were reduced in the vital phrenic nerve of P0^null*Plp^null‐mice. In the absence of P0, thus, PLP also contributes to myelination by Schwann cells and to the preservation of peripheral axons. These data provide a link between the Schwann cell‐dependent support of peripheral axons and the oligodendrocyte‐dependent support of central axons. GLIA 2016;64:155–174     

贵州部分少数民族遗传性痉挛性截瘫Spastin基因突变研究

目的筛查及分析遗传性痉挛性截瘫(HSP)Spastin基因突变,了解贵州地区少数民族(彝族、布衣族、苗族)Spastin基因突变特点。方法应用PCR产物直接DNA测序法,对9例HSP患者(包括3个家系中7例现证者和2例散发患者)Spastin基因1-17号外显子进行突变筛查;被发现存在突变的外显子,其次行家系内其他成员相对应外显子的筛查。结果在9例HSP患者中发现家系3两例患者(Ⅴ24、Ⅴ25)的Spastin基因第4号外显子同一位点上发生错义突变c.847C>T,其他参与抽血的亲属均无该位点突变,推测该位点的突变为一多态。另外的突变位点均位于外显子序列前后的内含子区域。结论此次贵州地区部分少数民族spastin基因突变率低,与国内文献报道的汉族人群不同。