Hypertrophic type of peroneal muscular atrophy and spinal muscular atrophy in siblings

We describe a family with one brother suffering from a hypertrophic type of peroneal muscular atrophy, and a sister suffering from a late infantile from of spinal muscular atrophy. There are no other affected members in the relatives studied. This association has not been previously described, and has appeared as a result of a consanguineous marriage.     

Depletion and sizes of motor units in spinal muscular atrophy

Motor unit number estimation (MUNE) was applied to the biceps brachii muscles of 13 young patients (age 5--24 years) with spinal muscular atrophy (SMA) and the results compared with those of healthy control subjects matched for age and gender. In the SMA patients, all motor unit (MU) estimates fell below the control range, and there was good correspondence between the values for the two arms in the same subject. No correlation could be found between the MUNEs and the severity of the weakness. This unexpected result was attributed to the presence of small and normal-sized MUs in the muscles of patients, in addition to MUs that appeared to be considerably enlarged. The threefold mean increase in MU potential size was insufficient to compensate for the MU loss. In addition, the study confirmed that there are, on average, approximately 130 MUs in the healthy biceps brachii muscle.     

Hybrid survival motor neuron genes in Japanese patients with spinal muscular atrophy

Spinal muscular atrophy (SMA) is a frequently occurring autosomal recessive disease, characterized by the degeneration of spinal cord anterior horn cells, leading to muscular atrophy. Most SMA patients carry homozygous deletions of the telomeric survival motor neuron gene (SMN) exons 7 and 8. In the study presented here, we examined 20 Japanese SMA patients and found that 4 of these patients were lacking in telomeric SMN exon 7, but retained exon 8. In these 4 patients, who exhibited all grades of disease severity, direct sequencing analysis demonstrated the presence of a hybrid SMN gene in which centromeric SMN exon 7 was adjacent to telomeric SMN exon 8. In an SMA family, a combination of polymerase chain reaction and enzyme-digestion analysis and haplotype analysis with the polymorphic multicopy marker Agl-CA indicated that the patient inherited the hybrid gene from her father. In conclusion, hybrid SMN genes can be present in all grades of disease severity and inherited from generation to generation in an SMA family.     

Compound muscle action potential and motor function in children with spinal muscular atrophy

Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials. Maximum ulnar compound muscle action potential (CMAP) data were collected at two visits over a 4–6‐week period in children with SMA types II and III, 2–17 years of age, at four academic centers. Primary functional outcome measures included the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS‐Extend. CMAP negative peak amplitude and area showed excellent discrimination between the ambulatory and non‐ambulatory SMA cohorts (ROC = 0.88). CMAP had excellent test–retest reliability (ICC = 0.96–0.97, n = 64) and moderate to strong correlation with the MHFMS and MHFMS‐Extend (r = 0.61–0.73, n = 68, P < 0.001). Maximum ulnar CMAP amplitude and area is a feasible, valid, and reliable outcome measure for use in pediatric multicenter clinical trials in SMA. CMAP correlates well with motor function and has potential value as a relevant surrogate for disease status. Muscle Nerve, 2010     

Failure of lower motor neuron radial outgrowth precedes retrograde degeneration in a feline model of spinal muscular atrophy

Feline spinal muscular atrophy (SMA) is a fully penetrant, autosomal recessive lower motor neuron disease in domestic cats that clinically resembles human SMA Type III. A whole genome linkage scan identified a ～140-kb deletion that abrogates expression of LIX1, a novel SMA candidate gene of unknown function. To characterize the progression of feline SMA, we assessed pathological changes in muscle and spinal cord from 3 days of age to beyond onset of clinical signs. Electromyographic (EMG) analysis indicating denervation occurred between 10 and 12 weeks, with the first neurological signs occurring at the same time. Compound motor action potential (CMAP) amplitudes were significantly reduced in the soleus and extensor carpi radialis muscles at 8-11 weeks. Quadriceps femoris muscle fibers from affected cats appeared smaller at 10 weeks; by 12 weeks atrophic fibers were more prevalent than in age-matched controls. In affected cats, significant loss of L5 ventral root axons was observed at 12 weeks. By 21 weeks of age, affected cats had 40% fewer L5 motor axons than normal. There was no significant difference in total L5 soma number, even at 21 weeks; thus degeneration begins distal to the cell body and proceeds retrogradely. Morphometric analysis of L5 ventral roots and horns revealed that 4 weeks prior to axon loss, motor axons in affected cats failed to undergo radial enlargement, suggesting a role for the putative disease gene LIX1 in radial growth of axons.     

The motor neuron response to SMN1 deficiency in spinal muscular atrophy

Introduction: The purpose of this study was to measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA). Methods: Sixty‐two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE. Results: Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (?6.32 μV/year, P = 0.10), and stable CMAP amplitude. Conclusions: The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis studies, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology. Muscle Nerve 49 : 636–644, 2014     

Intestinal pseudo-obstruction in adult spinal muscular atrophy

A 42-Year-old woman sith negative family history had the insidious onset of weakness in her lower extremities 8 years before, in 1983. The disorder slowly progressed to include cramps and muscle twitches. The diagnosis of adult spinal muscular atrophy (SMA) was made when electromyography showed large rapidly firing motor unit potentials, positive waves, and fibrillation potentials, and when muscle biopsy of the quadriceps revealed severe alterations consistent with neurogenic atrophy. The patient also had severe chronic constipation for many years. More recently she had developed unremitting diarrhea. Gastrointestinal studies showed no evidence of peristaltic contractions in the rectum, delayed gastric emptying, and abnormal jejunal manometry with altered propagation of the migrating myoelectrical complex. © 1994 John Wiley & Sons, Inc.     

Gene conversion events in adult-onset spinal muscular atrophy

OBJECTIVE: To investigate the possible occurrence of a conversion event in three patients with adult-onset spinal muscular atrophy (SMA) type IV, which represents the mildest form within the spectrum of the SMA phenotype. MATERIAL AND METHODS: We observed three patients with adult onset SMA and apparent isolated deletion of telomeric survival motor neuron (SMN1) exon 7. To distinguish between a deletion and a sequence conversion event of exon 7, these patients were analyzed in greater detail by a simple PCR-based assay. RESULTS: Analysis by DdeI digestion showed products for both telomeric and centromeric copies of exon 8. These findings indicated a gene conversion event as the site for primer R111 was retained at least in one of two alleles. CONCLUSIONS: These results provide first evidence that a conversion event may be also associated with adult-onset SMA, and further support the notion that a gene conversion event is usually associated with a milder SMA phenotype and a later onset of disease.     

儿童型脊肌萎缩症的临床特点

目的 探讨儿童型脊肌萎缩症(CSMA)的临床特点.方法 回顾性分析11例CSMA患者的临床资料.结果 本组患者平均发病年龄为(6.1±5.5)岁,均为慢性起病,主要临床表现为四肢无力、变细及行走不稳;血清肌酶水平5例轻度升高;肌电图检查结果显示8例为神经源性损害,3例未见异常;肌肉病理学检查显示11例患者均出现肌纤维大...     

Emerging concepts underlying selective neuromuscular dysfunction in infantile-onset spinal muscular atrophy

Infantile-onset spinal muscular atrophy is the quintessential example of a disorder characterized by a predominantly neurodegenerative phenotype that nevertheless stems from perturbations in a housekeeping protein.Resulting from low levels of the Survival of Motor Neuron(SMN)protein,spinal muscular atrophy manifests mainly as a lower motor neuron disease.Why this is so and whether other cell types contribute to the classic spinal muscular atrophy phenotype continue to be the subject of intense investigation and are only now gaining appreciation.Yet,what is emerging is sometimes as puzzling as it is instructive,arguing for a careful re-examination of recent study outcomes,raising questions about established dogma in the field and making the case for a greater focus on milder spinal muscular atrophy models as tools to identify key mechanisms driving selective neuromuscular dysfunction in the disease.This review examines the evidence for novel molecular and cellular mechanisms that have recently been implicated in spinal muscular atrophy,highlights breakthroughs,points out caveats and poses questions that ought to serve as the basis of new investigations to better understand and treat this and other more common neurodegenerative disorders.     

成人型脊髓性肌萎缩症临床及遗传学研究

目的总结成人型脊髓性肌萎缩症(SMA,Ⅳ)的临床及遗传学特征。方法收集46例经肌肉活检证实的SMAⅣ进行临床和病理学分析,并对其中3个家系进行遗传学分析。结果SMAⅣ平均发病年龄38.7岁,起病与进展隐匿,预后相对良好,以四肢近端肌萎缩无力为主,肌电图(EMG)检查示神经源性损害,肌活检示小群性肌萎缩,其中2个家系分别为常染色体显性遗传、X-连锁隐性遗传。结论依据临床表现、肌肉病理可确诊SMAⅣ。     

Motor function-muscle strength relationship in spinal muscular atrophy

The relationship between motor function and muscle strength in patients with spinal muscular atrophy (SMA) is still controversial. In 120 genetically proven SMA patients, aged 5 years or older, we measured muscle strength in the arms and legs by a hand-held dynamometer, forced vital capacity by a spirometer, and the time needed to walk 10 m, arise from the floor, and climb steps. SMA patients had markedly reduced muscle strength, approximating 20% of that predicted from age- and gender-matched normative data. Knee extensors were the weakest muscles in SMA patients. The young ambulant SMA patients performed better than adults in all the timed tests and had greater muscle strength on knee extension. This study shows a good relationship between motor ability and muscle strength in SMA and confirms that age-related loss of function in SMA is due to loss of muscle strength.     

Dominant congenital benign spinal muscular atrophy

The affected members of the family described in this article exhibit congenital nonprogressive atrophy and weakness of lower limb muscles in association with contractures. Clinical and laboratory findings support a dominant lower motor neuron disorder. DNA analysis excluded linkage of the disease with SMA markers on the long arm of chromosome 5. The condition must be differentiated from congenital and infantile SMA, from “arthrogryposis multiplex congenita, distal type,” and from non hereditary types of congenital arthrogryposis. © 1994 John Wiley & Sons, Inc.     

Sleep related breathing patterns in patients with spinal muscular atrophy

A clinical and polygraphic study of nocturnal sleep was performed in 8 (4 males, 4 females; age range 10–37 years) patients with spinal muscular atrophy, whose baseline respiratory function assessment during wakefulness showed restrictive ventilatory syndrome but blood-gas tension within normal limits. No patient reported any significant sleep complaint suggestive of sleepdisordered breathing. However, in 4 patients HbSaO2 desaturations below 90% (HbSaO2 nadir 68%) were detected during nocturnal polysomnography. The HbSaO2 desaturations occurred during brief central apneas or hypopneas, mainly during REM sleep, the apnoea hypopnea index being within normal limits in all cases. The data suggest that nocturnal polysomnography can detect otherwise clinically silent hypoxemia in SMA patients without any predisposing factor to sleep-disordered breathing other than their illness and still showing normal blood-gas tensions during wakefulness. Further studies are needed to determine the long-term evolution and the prognostic significance of nocturnal hypoxemia in these patients.

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Sommario Sono illustrati i risultati di una indagine clinica e polisonnografica sugli aspetti del sonno notturno e della respirazione durante sonno in 8 pazienti affetti da Amiotrofia Spinale (4 maschi, 4 femmine, di età compresa tra 10 e 37 anni) e che mostravano in veglia una sindrome restrittiva toracica ma valori emogasanalitici ancora nei limiti della norma. Nessun paziente riportava disturbi soggettivi del sonno tra quelli suggestivi di un sottostante disordine respiratorio sonno-relato. In 4 pazienti sono state documentate ricorrenti desaturazioni emoglobiniche di O2 sotto il 90% (valore minimo osservato 68%) nel corso della polisonnografia notturna, in relazione ad apnee o ipopnee non ostruttive, principalmente durante sonno REM. L'Indice di Apnea/Ipopnea è risultato essere nei limiti in tutti i pazienti. I dati suggeriscono che una iniziale tendenza alla desaturazione di O2 sonno relata può essere presente in pazienti con Amiotrofia Spinale senza apparenti disturbi clinici del sonno e che mostrano ancora un quadro di compenso emogasanalitico in veglia. L'evoluzione, la rilevanza clinica e dunque il significato prognostico di tali patterns di ipossiemia notturna andranno verificati in studi clinici e polisonnografici più estesi e con sviluppo longitudinale.

     

进行性脊肌萎缩症129例临床分析

目的探讨进行性脊肌萎缩症(PSMA)的临床特点、诊断与鉴别诊断。方法回顾性分析129例PSMA患者的临床资料。结果本组患者均隐袭起病,逐渐加重,男性多见,发病年龄65.9%患者>50岁。首发症状以单侧上肢无力和肌萎缩为多见(65.9%),均表现为下运动神经元损害的症状和体征,51.9%患者出现延髓麻痹症状;肌电图检查均提示神经源性损害;易误诊为颈或腰椎病。结论本病是一组慢性进行性下运动神经元疾病,病变可累及延髓。诊断主要依据临床表现和肌电图。     

Leg muscle function and fatigue during walking in spinal muscular atrophy type 3

Introduction: Spinal muscular atrophy (SMA) causes muscle weakness and fatigue. Better understanding of the relationship between weakness and fatigue may help identify potential targets for rehabilitation. Methods: Gait and surface electromyography (EMG) from 4 muscle groups were measured during the Six‐Minute Walk Test (6MWT) in 10 ambulatory participants, aged 9–49 years. Average root mean square amplitude (RMS) of muscle activity was calculated. Strength was assessed using manual and quantitative methods. Results: RMS, stride length, and velocity decreased during the 6MWT. Knee flexor and hip abductor strength was associated with fatigue‐related changes; overall strength correlated with disease duration; and leg strength was associated with 6MWT distance. Conclusions: Clinical measures are valid in assessing fatigue and function in SMA, and these assessments can be enhanced by use of gait analysis and EMG. Disease duration and strength measures may represent further stratification refinements when enrolling patients in clinical trials. Muscle Nerve 50 : 34–39, 2014     

Serum cholinesterase activity in infantile and juvenile spinal muscular atrophy

Serum acetylcholinesterase (AChE) and pseudocholinesterase (ChE) activity in infantile and juvenile spinal muscular atrophy (SMA) was determined. The total AChE activity was either normal or decreased in the childhood SMA (Type 1), the other SMA groups and disease controls (ALS, X-linked SMA). In the majority of SMA Type 1 cases (6/7 tested) an absence of the asymmetric A12 form was found. This was accompanied by changes in the other asymmetric and globular forms. The latter was, however, not specific for SMA Type 1 cases. The ChE activity was increased in the majority of SMA cases as well as disease controls. The asymmetric A12 ChE form was increased in all SMA Type 3 cases, the values of this form in SMA Type 1 was variable. A change in the ChE globular forms in SMA Type 1 and SMA Type 2 was a frequent finding. It is suggested that the absence of the asymmetric A12 AChE form in SMA Type 1 arises because of muscle cell immaturity and undeveloped muscle-nerve interactions. The reason of ChE changes is obscure.     

Cognitive functions in duchenne muscular dystrophy: A reappraisal and comparison with spinal muscular atrophy

In order to clarify cognitive functions in Duchenne muscular dystrophy (DMD), we performed a new controlled neuropsychological study. IQ (WISC-R), verbal skills (fluency, confrontation naming and syntax comprehension) and memory abilities (BEM) were studied in two matched groups; 24 DMD children and 17 spinal muscular atrophy (SMA) children aged 12–16 yr. A significant difference appeared between the DMD and SMA patients: only in the DMD group were there significant disabilities in certain specific functions and normal scores in others. Despite similar education, the DMD children more often had significantly greater learning disabilities. There were more DMD left-handers. Verbal IQ was significantly low whereas performance IQ was at a normal level. DMD children also performed poorly in reading tasks and in some memory functions such as story recall and verbal recognition. Specific cognitive disabilities in certain DMD children, not seen in SMA children, suggest a relationship with a DMD genetic disorder.     

Sensory axonopathy in hereditary distal spinal muscular atrophy

A girl of 14 year is presented with a distal spinal muscular atrophy (SMA) with autosomal recessive inheritance. The technical findings are in agreement with the diagnosis. Light microscopical examination of sural nerve biopsy, including teased fiber studies and morphometry, showed no abnormalities. Electron microscopical investigation however demonstrated axonal pathology. The question arises if distal SMA is a distal axonopathy mainly of motor nerves, but to some extent also of sensory nerves.