Incidence of infantile spinal muscular atrophy on Shikoku Island of Japan

Background

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by homozygous mutations in the SMN1 gene. SMA has long been known to be the most common genetic cause of infant mortality. However, there have been no reports on the epidemiology of infantile SMA (types 1 and 2) based on genetic testing in Japan. In this study, we estimated the incidence of infantile SMA on Shikoku Island, which is a main island of Japan and consists of four prefectures: Ehime, Kagawa, Tokushima and Kochi.

Survey of patients with spinal muscular atrophy on the island of Shikoku,Japan

BackgroundSpinal muscular atrophy (SMA) is an inherited neuromuscular disorder associated with spinal motor neuron loss and characterized by generalized muscle weakness. Only a few reports exist on SMA epidemiology in Japan. Additionally, nusinersen recently became available as a treatment for this condition. We estimated the prevalence of each type of SMA on Shikoku, Japan’s fourth-largest major island.MethodsWe sent a questionnaire to all 131 hospitals in Shikoku that have pediatrics or neurology departments from March to September 2019, asking whether each hospital had SMA patients at that time. If so, we sent a second questionnaire to obtain more detailed information on the clinical data and treatment of each patient.ResultsA total of 117 hospitals (89.3%) responded to our first questionnaire, and 21 SMA patients were reported, 16 of whom had homozygous deletion of SMN1. Of the 21, nine had SMA type 1, five were type 2, five were type 3, one was type 4, and one was unidentified. The estimated prevalence for all instances of SMA and 5q-SMA was 0.56 and 0.43 per 100,000 people, respectively. Thirteen patients had received nusinersen therapy. Its outcomes varied from no obvious effects and being unable to sit to being able to sit independently.ConclusionOur data showed the prevalence of SMA types 2 and 3 was relatively low on Shikoku compared with previous reports from other countries, suggesting delayed diagnosis may affect the results. Remaining motor function may be one predicting factor. Greater awareness of SMA among clinicians and patients seems necessary for more accurate epidemiological studies.     

Genetic investigations on chronic forms of infantile and juvenile spinal muscular atrophy

Summary A material of 247 cases selected from 260 cases of spinal muscular atrophy in the Warsaw Department of Neurology in 1960–1974 was analyzed. The size of sibships was established and calculations were made of the mean distribution of the age at onset, also according to sex, for the different clinical forms, genetical proportions by the method of siblings and of probands, and coefficient of sib-sib correlation for the material as a whole and separately for males, femals and male-female pairs.The analysis shows the course of the disease to differ between the sexes and to be mild in males more often than in females, as is particularly noticeable in the higher age groups. Cases of Kugelberg-Welander's disease are predominantly male. The hypothesis is advanced that a proportion of male patients have a sex-linked modifying gene of a fairly high frequency (possibly of the range of 1 in 5 males, and 1 in 25, in the homozygous state, in females).Although it would not disprove conclusively the nosological distinctness of different forms of infantile and juvenile spinal muscular atrophy, the existence of the modifying gene, if proved, would tend rather to add to the likelihood of their constituting a single recessive autosomal disease.From Genetic Laboratory of Institute of Psychoneurology.     

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.     

A new polygenic disturbance: Cystinuria,leucinuria and spinal muscular atrophy

Summary The association of cystinuria, leucinuria, agromegalic characteristics and spinal muscular atrophy is reported in three girls. The pathological characters are segregated having an autosomal recessive mode of inheritance.No causal relationship could be established between the symptoms, without excluding such a possibility.

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Zusammenfassung Es werden die ersten Fälle von gleichzeitigem Auftreten von Cystinurie-Leucinurie und spinaler Amyotrophie mit getrenntem autosomal recessivem Erbmodus mitgeteilt.Alle Fälle gehören dem II. Typus von Cystinurie an und koexistieren mit Leucinausscheidung, einem akromegaloiden Aussehen und progressiver spinaler Muskelatrophie. Mit Ausnahme des Probanden 1.1.P₁, welcher für Cystinurie homozygot ist, erscheint der Defekt in heterozygoter Form. Die spinale Amyotrophie wurde ebenfalls autosomal recessiv vererbt, ohne feststellbare Expressivität bei den Heterozygoten.Aus den vorhandenen Befunden kann eine kausale Verbindung zwischen den einzelnen Komponenten des Krankheitsbildes gefolgert werden.

     

Pregnancy and spinal muscular atrophy

Summary We investigated the course and outcome of pregnancy and its influence on muscle weakness in 12 females with proximal spinal muscular atrophy (SMA) who delivered a total of 17 infants when aged 18–32 years. In 4 females the SMA clearly followed an autosomal recessive mode of inheritance. The disease was autosomal dominantly inherited in 2 patients; the other 6 were sporadic cases. Ages of onset of SMA ranged from 8 months to 29 years; all the females learned to walk, and 10 out of 12 are still ambulatory aged 30–60 years. Pregnancy and delivery were complicated in 10 out of 12 patients by premature labour (4), prolonged labour (3) and delayed postpartum recovery (6). Caesarean section was performed in 3 cases. No deleterious effects on fetal outcome could be detected. Exacerbation of muscle weakness after the second trimester of pregnancy was experienced by 8 females: 5 noticed a persistent deterioration of SMA; in 3 muscle weakness worsened temporarily during pregnancy and was followed by marked improvement in the puerperium. The psychological perceptions, in retrospect, of 10 females concerning their decision to have children were evaluated.     

Prominent fatigue in spinal muscular atrophy and spinal and bulbar muscular atrophy: Evidence of activity-dependent conduction block

ObjectivesTo clarify whether patients with spinal muscular atrophy (SMA) or spinal and bulbar muscular atrophy (SBMA) suffer disabling muscle fatigue, and whether activity-dependent conduction block (ADCB) contributes to their fatigue. ADCB is usually caused by reduced safety factor for impulse transmission in demyelinating diseases, whereas markedly increased axonal branching associated with collateral sprouting may reduce the safety factor in chronic lower motor neuron disorders.MethodsWe assessed the fatigue severity scale (FSS) in 22 patients with SMA/SBMA, and in 100 disease controls (multiple sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy (CIDP), and axonal neuropathy). We then performed stimulated-single fibre electromyography (s-SFEMG) in the extensor digitorum communis (EDC) muscle of 21 SMA/SBMA patients, 6 CIDP patients, and 10 normal subjects.ResultsThe FSS score was the highest in SMA/SBMA patients [4.9 ± 1.1 (mean ± SD)], with 81% of them complaining of disabling fatigue, compared with normal controls (3.5 ± 1.0), whereas patients with multiple sclerosis (4.3 ± 1.6), myasthenia gravis (4.0 ± 1.6) or CIDP (4.3 ± 1.4) also showed higher FSS score. When 2000 stimuli were delivered at 20 Hz in s-SFEMG, conduction block of single motor axons developed in 46% of patients with SMA/SBMA, and 40% of CIDP patients, but in none of the normal controls.ConclusionSMA/SBMA patients frequently suffer from disabling fatigue presumably caused by ADCB induced by voluntary activity.SignificanceADCB could be the mechanism for muscle fatigue in chronic lower motor neuron diseases.     

Sleep disorders in spinal muscular atrophy

ObjectiveTo estimate the frequency of sleep disorders in young persons with type 2 and type 3 spinal muscular atrophy (SMA), and to evaluate the relationship between sleep disorders and different variables such as motor impairment, age, use of ventilation, and use of night orthoses.MethodsA total of 85 young persons (6–25 years of age) with type 2 and type 3 SMA were assessed using the Sleep Disturbance Scale for Children (SDSC), a scale assessing different sleep factors, and the Hammersmith Functional Motor Scale Expanded (HFMSE), a scale evaluating motor impairment.ResultsAn abnormal total sleep score was found in 16.4% of children with SMA; an additional 16.7% had an abnormal score on at least one of the sleep factors assessed by the SDSC. No specific correlation was observed between sleep disturbances and functional level as expressed by the SDSC and total HFMSE scores, but the relationship with individual items on the scale was different. The SDSC total score was significantly associated with the ability to half roll on both sides and to roll from prone to supine on the HMFSE.ConclusionOur results demonstrate that sleep disorders are common in children with SMA.     

Clinical phenotypes of spinal muscular atrophy patients with hybrid SMN gene

BackgroundSpinal muscular atrophy (SMA) is a neuromuscular disease caused by homozygous deletion of SMN1 exons 7 and 8. However, exon 8 is retained in some cases, where SMN2 exon 7 recombines with SMN1 exon 8, forming a hybrid SMN gene. It remains unknown how the hybrid SMN gene contribute to the SMA phenotype.MethodWe analyzed 515 patients with clinical suspicion for SMA. SMN1 exons 7 and 8 deletion was detected by PCR followed by enzyme digestion. Hybrid SMN genes were further analyzed by nucleotide sequencing. SMN2 copy number was determined by real-time PCR.ResultsSMN1 exon 7 was deleted in 228 out of 515 patients, and SMN1 exon 8 was also deleted in 204 out of the 228 patients. The remaining 24 patients were judged to carry a hybrid SMN gene. In the patients with SMN1 exon 7 deletion, the frequency of the severe phenotype was significantly lower in the patients with hybrid SMN gene than in the patients without hybrid SMN gene. However, as for the distribution of SMN2 exon 7 copy number among the clinical phenotypes, there was no significant difference between both groups of SMA patients with or without hybrid SMN gene.ConclusionHybrid SMN genes are not rare in Japanese SMA patients, and it appears to be associated with a less severe phenotype. The phenotype of patients with hybrid SMN gene was determined by the copy number of SMN2 exon 7, as similarly for the patients without hybrid SMN gene.     

Nemaline bodies in spinal progressive muscular atrophy

Summary Numerous nemaline bodies were demonstrated in the pectoralis major muscle of an autopsy case of a 52-year-old woman, who died of respiratory failure after having suffered from spinal progressive muscular atrophy for 1 year. Rod-like structures ultrastructurally indistinguishable from classical nemaline bodies were abundant in both normal-appearing and atrophic myofibers of the pectoralis major muscle but not in the appendicular skeletal muscles. Morphometric analysis of spinal anterior horn cells clearly showed severe depopulation of somatic motor neurons in the lower cervical cord segments. The present case may provide further support for the neurogenic nature of nemaline body formation.     

The natural history of type I (severe) spinal muscular atrophy

The clinical features of 36 patients who satisfied the diagnostic criteria for type I (severe) spinal muscular atrophy (Werdnig-Hoffmann disease) are reported. Survival data for both the whole cohort and for groups within the cohort subdivided on the age of onset are presented. These data suggest that the patients with onset at birth or within the first 2 months of life have a more uniformly poor prognosis with earlier death. This is of potential importance in any therapeutic trials in the future whose outcome may be based on length of survival.     

Spinal muscular atrophy carriers with two SMN1 copies

Background

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Over 95% of SMA patients have homozygous deletions of the SMA-causative gene, SMN1. Thus, SMA carriers are usually diagnosed based on SMN1 copy number, with one copy indicating SMA carrier status. However, two SMN1 copies do not always exclude carrier status. In this study, we identified SMA carriers with two SMN1 copies.

Pregnancy and delivery in women with spinal muscular atrophy

Objectives: To expand the limited available knowledge about pregnancy and delivery in women with spinal muscular atrophy (SMA) using a cohort of genetically proven SMA patients from USA.

Methods: This was a cross-sectional questionnaire-based study. We mailed questionnaires to 58 women with confirmed SMA.

Results: Thirty-two women responded, reporting 35 pregnancies, including 19 women with at least one pregnancy. In this cohort, preterm labor and delivery by cesarean section were more common in mothers with SMA particularly SMA type 2. Seventy-four percent of mothers reported increased weakness during pregnancy that persisted after delivery in 42%. SMA mothers generally had a positive experience and good outcomes and elected to have more than one pregnancy.

Conclusion: This information regarding pregnancy in women with genetically confirmed 5q SMA will prove useful in guiding future research and in providing counseling to women with SMA.     

The mutation properties of spinal and bulbar muscular atrophy disease alleles

We studied the gene for the trinucleotide repeat disorder X-linked spinal and bulbar muscular atrophy (SBMA) to quantify the spectrum of mutations and gain insight into genetic anticipation. This analysis was performed using single sperm typing from an affected individual. This method allows the quantification of large numbers of meioses and therefore provides accurate information about genetic instability of the CAG repeat expansions which cause SBMA. Among 198 X chromosome-containing sperm cells, 20% had a CAG repeat number equal to the donor's somatic DNA of 49 CAG repeats, 56% were expansions, and 24% contractions. Most of the expansions (84%) and contractions (94%) were between 1 and 3 CAG repeats. These results are consistent with those obtained from one previously studied SBMA patient and reveal greater CAG repeat instability in sperm than in somatic tissue. Our results indicate that in SBMA, in contrast to sperm typing analysis of Huntington's disease, there is relative stability of the CAG repeat number during paternal transmissions and that the spectrum of mutations is narrow. These results are in agreement with the limited available clinical data and suggest that anticipation may not be a significant feature of this disease. Accepted: April 1, 1998     

Pathogenesis of proximal autosomal recessive spinal muscular atrophy

Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new findings regarding the dual cellular role of the SMN protein (translocation of beta-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axono- and dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally ("heterotopic motoneurons") and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype modifier genes and their products, cause the clinical SMA spectrum through differential degree of motoneuron functional loss.     

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.     

Assessment of motor unit loss in patients with spinal muscular atrophy

ObjectiveTo assess motor unit (MU) changes in patients with spinal muscular atrophy (SMA) using compound muscle action potential (CMAP) scans.MethodsWe performed CMAP scan recordings in median nerves of 24 treatment-naïve patients (median age 39; range 12–75 years) with SMA types 2–4. From each scan, we determined maximum CMAP amplitude (CMAP_max), a motor unit number estimate (MUNE), and D50 which quantifies the largest discontinuities within CMAP scans.ResultsMedian CMAP_max was 8.1 mV (range 0.9–14.6 mV), MUNE was 29 (range 6–131), and D50 was 25 (range 2–57). We found a reduced D50 (<25) in patients with normal CMAP_max (n = 12), indicating MU loss and enlarged MUs due to reinnervation. Lower D50 values were associated with decreased MUNE (P < 0.001, r = 0.68, n = 43). CMAP_max, MUNE and D50 values differed between SMA types (P < 0.001). Lower motor function scores were related to patients with lower CMAP_max, MUNE and D50 values (P < 0.001).ConclusionsThe CMAP scan is an easily applicable technique that is superior to routine assessment of CMAP_max in SMA.SignificanceThe detection of pathological MU changes across the spectrum of SMA may provide important biomarkers for evaluating disease course and monitoring treatment efficacy.     

婴儿型脊肌萎缩症22例临床分析

目的 探讨婴儿型脊肌萎缩症的发病机制、临床与病理特征及诊断.方法 对22例确诊为婴儿型脊肌萎缩症患者的临床表现、实验室资料、病理资料进行了回顾性分析.结果 本病临床特点患儿大多为8个月内起病,四肢呈对称性、迟缓性瘫痪,下肢重于上肢,近端重于远端;有肌萎缩,血清CK、LDH正常或增高;肌电图显示神经源性损害,肌活检见肌纤维萎缩、变性、坏死,符合脊肌萎缩症的改变.结论 婴儿型脊髓性肌萎缩症有较典型的临床及电生理特征,肌电图检查是重要的诊断方法,肌活检可为脊肌萎缩症的诊断提供客观的诊断依据,目前对本病主要采取对症治疗.     

Sleep disordered breathing in spinal muscular atrophy

Sleep disordered breathing is a common but under-diagnosed complication causing sleep disturbance and daytime symptoms in children with spinal muscular atrophy. Non-invasive (positive pressure) ventilation is an established treatment of respiratory failure; its role in treatment of sleep disordered breathing though remains controversial. Aim of this study was to verify the hypothesis that nocturnal non-invasive ventilation has beneficial impact on breathing during sleep, sleep quality and daytime complaints in children with spinal muscular atrophy. Twelve children with spinal muscular atrophy type I or II (7.8±1.9 years) underwent polysomnography and were asked to fill out a symptom questionnaire. Seven patients (six with spinal muscular atrophy I and one with spinal muscular atrophy II) had sleep disordered breathing and received non-invasive ventilation during sleep. Five less severely affected patients (one with spinal muscular atrophy I and four with spinal muscular atrophy II) had no sleep disordered breathing and served as reference group. Patients were restudied after 6–12 months. In patients with sleep disordered breathing both sleep architecture and disease related symptoms were significantly worse than in the reference-group. Non-invasive ventilation during sleep completely eliminated disordered breathing, normalized sleep architecture and improved symptoms (P<0.05 for all). In children with spinal muscular atrophy sleep disordered breathing may cause relevant impairment of sleep and well-being. Both can be highly improved by nocturnal non-invasive ventilation.