Dysphagia and Lung Disease in Children With Spinal Muscular Atrophy Treated With Disease-Modifying Agents.

OBJECTIVES: Disease-modifying agents (DMAs) for the treatment of spinal muscular atrophy (SMA) have evolved the SMA phenotype with improved survival. Ongoing oropharyngeal dysphagia and respiratory complications are reported. The extent of dysphagia and respiratory morbidity in this population, since DMAs' introduction, has not been well described. METHODS: A whole-population study involved all children with treated SMA types 1-3 in our facility. Videofluoroscopic swallow studies (type 1 alone), chest CT scans, and clinical data were collected. RESULTS: Thirty-six children were included (n = 9 type 1, n = 14 type 2, and n = 13 type 3; age range 0.3-15.4 years). Abnormal swallowing characteristics were demonstrated in all children with type 1 (n = 8; 100%). Bronchiectasis was found on chest CT: 3 of 9 (33.3%), 2 of 14 (14.3%), and 2 of 13 (15.4%) of type 1, 2, and 3, respectively. Atelectasis, mucus plugging, bronchial wall thickening, and parenchymal changes were common. DISCUSSION: Swallow impairments were universal in children with type 1. Bronchiectasis was common in all pediatric SMA types, with a prevalence of 1 in 5. Routine monitoring and management of dysphagia/recurrent respiratory infection should be implemented for improvement in lung health.

[A case of proximal-type Hirayama disease associated with neck axial rotation].

Hirayama disease is characterized by juvenile onset of unilateral muscular atrophy of a distal upper extremity. The pathogenic mechanism of Hirayama disease is cervical cord compression by the posterior dura with forward displacement in the neck flexion position. A few cases of 'proximal-type Hirayama disease' have been described as showing muscular weakness and atrophy of the proximal upper extremities caused by the pathogenic mechanism similar to that of Hirayama disease. We report herein the case of a 16-year-old boy with proximal-type Hirayama disease, who developed symptoms after he began kyudo (Japanese traditional archery). Neurological examination revealed bilateral weakness of the muscles innervated by C5 and C6 segments (the deltoid, biceps brachii, brachioradialis), bilateral mild sensory disturbance in the radial side of the forearm, absent tendon reflexes of the biceps brachii and brachioradialis with preserved triceps reflex, pyramidal signs of the bilateral lower extremities (pathologically brisk reflexes of lower extremities, Babinski's signs). MR images in the neck flexion position showing expansion of the posterior extradural space and forward displacement of the spinal cord at the C3/4, C4/5, C5/6 and C6/7 disk levels. CT myelogram revealed spinal cord compression not only in neck flexion but also in neck left axial rotation. His symptoms improved after the restriction of neck flexion and axial rotation. Weakness of the upper extremities improved after 2 months. Pyramidal signs of the lower extremities disappeared after 18 months. The pathogenic mechanism in this case may be associated with not only neck flexion but also neck axial rotation.

The Quantitative Assessment of Imaging Features for the Study of Hirayama Disease Progression.

OBJECTIVE: To evaluate the forward shifting of cervical spinal cords in different segments of patients with Hirayama disease to determine whether the disease is self-limiting. METHODS: This study was performed on 11 healthy subjects and 64 patients. According to the duration, the patients were divided into 5 groups (≤1 year, 1-2 years, 2-3 years, 3-4 years, and ≥ 4 years). Cervical magnetic resonance imaging (MRI) of flexion and conventional position was performed. The distances between the posterior edge of the spinal cord and the cervical spinal canal (X), the anterior and posterior wall of the cervical spinal canal (Y), and the anterior-posterior (A) and the transverse diameter (B) of spinal cord cross sections were measured at different cervical spinal segments (C4 to T1). RESULTS: In cervical flexion position, a significant increase in X/Y of C4-5 segments was found in groups 2-5, the C5-6 and C6-7 segments in groups 1-5, and the C7-T1 segments in group 5 (P < 0.05). The degree of the increased X/Y and cervical flexion X/Y of C5-6 segments were different among the 5 groups (P < 0.05), which was likely due to rapid increases in X/Y during the course of Hirayama's disease. CONCLUSION: The X/Y change progression indicates that Hirayama disease may not be self-limiting.

Clinical characteristics of three subtypes of spinal muscular atrophy in children.

BACKGROUND: The severity of spinal muscular atrophy (SMA) is highly variable and children with heterogeneous clinical features can be classified into three phenotypes (type I-III) on the basis of age of onset and maximum motor function achieved. The aim of this study was to compare the clinical characteristics of three phenotypes in children with SMA. METHODS: One hundred and thirty-two SMA patients were classified as type I, II or III according to the SMA classification criteria. The clinical features, deletion of survival motor neuron 1 (SMN1) gene and electrophysiology were analyzed and compared. The survival and functional status were obtained through telephone follow up. RESULTS: In our study, 90.6% of the patients lacked both copies of SMNl. No difference in the deletion frequency among the 3 groups was observed. Although most of the neurophysiological parameters showed no differences among the groups, the amplitudes of compound muscle action potential (CMAP) was lower in type III SMA. Absent sensory nerve action potential (SNAP) amplitude of the sural nerve was observed in 26 (25.4%) of the patients. The survival pattern and functional status of 66 cases were obtained. Two type II SMA patients could walk unaided during follow-up. The functional ability of lower extremities improved in 4 patients with type III SMA. CONCLUSIONS: In this study, we confirm that EMG examination and homozygous deletion of SMN1 do not correlate with the subtypes. Motor function of patients with SMA type II and III can improve. A period of follow-up is necessary before rendering accurate classification and prognosis.

Alterations of thoraco-abdominal volumes and asynchronies in patients with spinal muscle atrophy type III.

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons resulting in muscle weakness. For the mild type III form, a sub-classification into type IIIA and IIIB, based on age of motor impairment, was recently proposed. To investigate if SMA IIIA (more severe) and IIIB differ also in terms of respiratory function, thoracoabdominal kinematics was measured during quiet breathing, inspiration preceding cough and inspiratory capacity on 5 type IIIA and 9 type IIIB patients. Four patients with SMA II (more severe than types III) and 19 healthy controls were also studied. Rib cage motion was similar in SMA IIIB and controls. Conversely, in SMA IIIA and SMA II it was significantly reduced and sometime paradoxical during quiet breathing in supine position. Our results suggest that in SMA IIIA intercostal muscles are weakened and the diaphragm is preserved similarly to SMA II, while in SMA IIIB the action of all inspiratory muscles is maintained. Sub-classification of type III seems feasible also for respiratory function.

Nosology of juvenile muscular atrophy of distal upper extremity: from monomelic amyotrophy to Hirayama disease--Indian perspective.

Since its original description by Keizo Hirayama in 1959, "juvenile muscular atrophy of the unilateral upper extremity" has been described under many nomenclatures from the east. Hirayama disease (HD), also interchangeably referred to as monomelic amyotrophy, has been more frequently recognised in the west only in the last two decades. HD presents in adolescence and young adulthood with insidious onset unilateral or bilateral asymmetric atrophy of hand and forearm with sparing of brachioradialis giving the characteristic appearance of oblique amyotrophy. Symmetrically bilateral disease has also been recognized. Believed to be a cervical flexion myelopathy, HD differs from motor neuron diseases because of its nonprogressive course and pathologic findings of chronic microcirculatory changes in the lower cervical cord. Electromyography shows features of acute and/or chronic denervation in C7, C8, and T1 myotomes in clinically affected limb and sometimes also in clinically unaffected contralateral limb. Dynamic forward displacement of dura in flexion causes asymmetric flattening of lower cervical cord. While dynamic contrast magnetic resonance imaging is diagnostic, routine study has high predictive value. There is a need to lump all the nomenclatures under the rubric of HD as prognosis in this condition is benign and prompt diagnosis is important to institute early collar therapy.

Recommendations for the diagnosis and management of typical childhood spinal muscular atrophy.

Typical childhood spinal muscular atrophy is a disease that affects the anterior horn of the spinal cord related to SMN1 gene defects. Since no etiological treatment is currently available, its management is necessarily symptomatic and involves multidisciplinary care. The national plan on rare diseases for 2005-2008 developed by the French Ministry of Health resulted in the creation of 12 reference centres for neuromuscular diseases, mainly to improve their diagnosis and management. During the first one-day clinical research meeting on neuromuscular disorders, organized by the French Association to fight myopathies (AFM) in May 2007, clinicians from the 12 national reference centers led workshops for each of the main neuromuscular diseases. Concerning spinal muscular atrophy, discussions involving specialists from medical and allied professions were led by clinicians in charge of the workshop sessions. This paper reports the final version of their recommendation regarding the diagnosis, monitoring and management of typical infantile spinal muscular atrophy, which is necessarily multidisciplinary, including orthopedic, pulmonary, gastroenterology and nutrition care.

Molecular prenatal diagnosis of autosomal recessive childhood spinal muscular atrophies (SMAs).

Autosomal recessive childhood spinal muscular atrophy (SMAs) is the second most common neuromuscular disorder and a common cause of infant disability and mortality. SMA patients are classified into three clinical types based on age of onset, and severity of symptoms. About 94% of patients have homozygous deletion of exon 7 in survival motor neuron (SMN1) gene. The neuronal apoptosis inhibitory protein (NAIP) gene was found to be more frequently deleted in the severest form of the disease. This study aimed to comment on the implementation of genetic counseling and prenatal diagnosis of SMAs for 85 fetuses from 75 Egyptian couples at risk of having an affected child. The homozygous deletion of exon 7 in SMN1 gene and the deletion of exon 5 of the NAIP gene were detected using PCR-REFLP and multiplex PCR methods respectively. Eighteen fetuses showed homozygous deletion of exon 7 in SMN1 gene and deletion of exon 5 in NAIP gene. In conclusion prenatal diagnosis is an important tool for accurate diagnosis and genetic counseling that help decision making in high risk families.

Tracheotomy and children with spinal muscular atrophy type 1: ethical considerations in the French context.

Spinal muscular atrophy (SMA) type 1 is a genetic neuromuscular disease in children that leads to degeneration of spinal cord motor neurons. This sometimes results in severe muscular paralysis requiring mechanical ventilation to sustain the child's life. The onset of SMA type 1, the most severe form of the disease, is during the first year of life. These children become severely paralysed, but retain their intellectual capacity. Ethical concerns arise when mechanical ventilation becomes necessary for survival. When professionals assess the resulting life for the child and family, they sometimes fear it will result in unreasonably excessive care. The aim of this article is to present an analysis of ethical arguments that could support or oppose the provision of invasive ventilation in this population. This examination is particularly relevant as France is one of the few countries performing tracheotomies and mechanical ventilation for this condition.

Assessing spinal muscular atrophy with quantitative ultrasound.

OBJECTIVE: To assess the value of quantitative ultrasound in patients with type 2 and 3 spinal muscular atrophy (SMA). METHODS: Twenty-five patients with SMA (15 type 2 and 10 type 3) and 21 normal subjects were enrolled for this observational study. Strength of biceps brachii, wrist extensors, quadriceps, and tibialis anterior were measured with hand-held dynamometry. In addition, these 4 muscles were studied with a standard ultrasound system using a 5-MHz probe, and luminosity values for each muscle and the overlying subcutaneous fat were obtained by subsequent image analysis. A luminosity ratio (LR) for each muscle was calculated by dividing the muscle by the subcutaneous fat luminosity. The LR and strength scores for all 4 muscles were averaged to provide a single summary value for each patient. RESULTS: The LRs increased with disease severity: 1.27 +/- 0.26 for normal subjects, 2.43 +/- 0.78 for type 3 SMA, and 3.85 +/- 1.3 for type 2 SMA (p < 0.001). Taking all the normal subject and patient data together, there was a good correlation between strength and LR (r = -0.711, p < 0.001). There was also a moderate relationship between LR and strength in the patients with SMA alone (r = -0.588, p = 0.008), and, as expected, a nonsignificant relationship between LR and strength in normal subjects (r = -0.011). CONCLUSIONS: Quantitative ultrasound has the potential of serving as a marker of SMA severity and may be useful in future clinical trials.

Spinal muscular atrophy.

Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterised by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalised weakness. It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation. Although no medical treatment is available, investigations have elucidated possible mechanisms underlying the molecular pathogenesis of the disease. Treatment strategies have been developed to use the unique genomic structure of the SMN1 gene region. Several candidate treatment agents have been identified and are in various stages of development. These and other advances in medical technology have changed the standard of care for patients with spinal muscular atrophy. In this Seminar, we provide a comprehensive review that integrates clinical manifestations, molecular pathogenesis, diagnostic strategy, therapeutic development, and evidence from clinical trials.

Clinical trials in spinal muscular atrophy.

PURPOSE OF REVIEW: Spinal muscular atrophy is a neuromuscular disorder manifesting as weakness and hypotonia across a broad spectrum of severity. Mutations in the telomeric copy of the survival motor neuron gene (SMN1) cause the autosomal recessive form. Disease severity is modified by the number of centromeric copies of the gene (SMN2) and the quantity of survival motor neuron protein. This has given rise to a number of treatment strategies. RECENT FINDINGS: Histone deacetylase inhibitors appear to increase the expression of SMN2, with an increase in survival motor neuron protein in various cell types. Clinical trials have been performed with three histone deacetylase inhibitors which are already licensed in the USA. Phenylbutyrate showed promise in a mouse model and an open-label pilot study, but was not effective in a phase 2 trial. Valproate may enhance transcription and reverse SMN2 splicing pattern, and has induced promising motor-function improvement in patients. Hydroxyurea may enhance splice function and increase the number of nuclear 'gems', small nuclear organelles in which survival motor neuron protein concentrates. SUMMARY: Discoveries regarding the genetics and pathogenesis of spinal muscular atrophy have identified potential targets for pharmacotherapy, raising hope that better treatments will eventually be developed.

Perspectives on clinical trials in spinal muscular atrophy.

Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.

Spinal muscular atrophy: survival pattern and functional status.

OBJECTIVE: Spinal muscular atrophy (SMA) is common. The prevalence of SMA in southern Chinese is 1 in 53,000. The clinical course is variable. The traditional classification of SMA includes age of onset, age of death, achievement of motor milestones, and ambulatory status as criteria. There was a lack of inclusion of the best lifetime functional status of any child with SMA. With the advances in medical care, the life expectancy and ambulatory status of patients with SMA have improved. The objective of this study was to assess the survival pattern, ambulatory status, and functional status of children with SMA. METHODS: Patients with SMA were recruited from the neuromuscular clinic of the Duchess of Kent Children's Hospital, which is a university-affiliated hospital, and the Families of SMA in Hong Kong. By September 2002, 102 SMA cases had been registered in the Duchess of Kent Children's Hospital neuromuscular clinic and Families of SMA registry, and 83 patients were analyzed. Among them, 39 were recruited for the administration of Functional Independence Measure for Children (WeeFIM), an assessment tool for functional status that has been previously validated by us for Chinese children. The diagnosis of SMA was made from clinical history, serum muscle enzyme, electromyography, muscle biopsy, and, recently, by molecular studies. In Hong Kong, molecular tests of the survivor motor neuron gene was available since 1995. A total of 36 in our cohort of 83 patients had the diagnosis confirmed with molecular analyses. We adopted the classification of SMA from previous studies in which the criteria were based on the International SMA consortium (1992) with modifications according to the 59th European Neuromuscular Center International Workshops. As only SMA patients with childhood onset were studied, we did not include any type IV patients in our study. Parents were interviewed and records were reviewed for demographic and clinical data, including age of onset, gender, family history, motor milestones, disease progression, loss of motor function, and involvement of respiratory or bulbar muscles. We define the age of disease onset as the age in which the first abnormalities were obvious from the medical records or from the descriptions of the parents about the first signs of weakness, eg, age of achievement of certain motor milestones or loss of functions. For the ambulatory status, we define "being ambulatory" as having the ability to walk for 100 meters, either with assistance such as calipers or walkers or without assistance. Actuarial survival curves were obtained by using the Kaplan-Meier method for calculating survival probabilities and probabilities of remaining ambulatory. The parents or the chief caregivers were interviewed for functional status using WeeFIM at the last registered date in September 2002. The WeeFIM consists of 3 domains: 1) self-care, 2) mobility, and 3) cognition. The self-care domain consists of 8 items, namely eating, grooming, bathing, dressing (upper body), dressing (lower body), toileting, and bladder and bowel management. The mobility domain consists of 5 items: transfer from chair or wheelchair, transfer to toilet, transfer to tub or shower, walking/wheelchair/crawling distance, and moving up and down stairs. The cognition domain assesses comprehension, expression, social interaction, problem solving, and memory. A scoring scale from 1 to 7 was used (1 = total assistance, 2 = maximal assistance, 3 = moderate assistance, 4 = minimal contact assistance, 5 = supervision, 6 = modified independence, and 7 = complete independence). The maximum total WeeFIM score is 126, and the maximum score for self-care, mobility, and cognition are 56, 35, and 35, respectively. RESULTS: For type I SMA (n = 22), the survival probabilities at 1, 2, 4, 10, and 20 years were 50%, 40%, 30%, 30%, and 30%, respectively. For type II SMA (n = 26), the survival probabilities at 1, 2, 4, 10, and 20 years were 100%, 100%, 100%, 92%, and 92%, respectively. Sixteen of the SMA I patients and 4 of the SMA II patients died of cardiorespiratory failure. The 5 surviving SMA I patients all were ventilator dependent. All SMA III patients were surviving at the time of study. The probability of remaining ambulatory at 2, 4, 10, and 20 years after onset was 100%, 100%, 81%, and 50% for type IIIa (age of onset <3 years) and 100%, 100%, 84%, and 68% for type IIIb (age of onset between 3 and 30 years), respectively. The interval between disease onset and inability to walk was 15.0 +/- 10.9 years (mean +/- standard deviation) and 21.2 +/- 11.7 years for patients with SMA IIIa and IIIb, respectively. Only 39 patients participated in the WeeFIM interview as 20 had already died at the time of study and 24 refused participation. No difference could be found in the age of onset, gender, or types of SMA between those who participated (n = 39) and those who did not (n = 24). The mean total WeeFIM quotients were 24% for SMA type 1, 57% for SMA type 11, 75% for SMA type IIIa, and 78% for SMA type IIIb. For the self-care domain, 100% SMA type I and 73% SMA type II patients required assistance, whereas 55% and 63% of SMA types IIIa and IIIb patients achieved functional independence. Bathing and dressing (upper and lower body) were items with which most SMA children required help or supervision. For the mobility domain, assistance was needed in >90% of SMA types I, II, and IIIa and in 63% of SMA type IIIb patients. Stair management was the major obstacle for independence in achieving mobility for all types of SMA. For the cognition domain, performance was the best among the 3 domains, and 60% of SMA type II, 78% of SMA type IIIa, and 90% of SMA type IIIb patients achieved functional independence. However, except for SMA type IIIb, a significant proportion of patients still need assistance or supervision in the area of problem solving. Statistically significant differences were found in the WeeFIM scores between type I and type II and between type IIIa and IIIb patients. However, no significant difference could be observed between type II and type IIIa SMA patients in the overall WeeFIM scores or performance in any of the 3 domains. CONCLUSION: We found that there was improvement in survival in SMA patients as compared with other studies. Assistance or supervision was needed for the majority of SMA patients for both mobility and self-care domains. With improvement in survival as a result of medical advances, assessment of the most current or the best-ever functional status at a designated age might be an important criterion for classification of SMA.

Respiratory capacity course in patients with infantile spinal muscular atrophy.

STUDY OBJECTIVES: To describe the clinical and respiratory course in infantile spinal muscular atrophy (SMA) type I, type II, and type III, and to evaluate the respiratory needs for these patients, using noninvasive or tracheostomy ventilation. DESIGN: Retrospective cohort study. METHODS: We report 33 patients with SMA true type I (onset before age 3 months), 35 patients with SMA intermediate type I (onset between 3 months and 6 months), 100 patients with SMA type II (onset between 6 months and 18 months), 12 patients with SMA type III (onset after age 18 months). We report the clinical symptoms, respiratory course, and respiratory management: respiratory physiotherapy, periodic hyperinsufflation, nasal nocturnal ventilation (NNV), and tracheostomy. Also, we measured the FVC over several years during childhood and adolescence. RESULTS: In patients with SMA true type I, 82% of patients died, one third of whom underwent tracheostomy. In patients with SMA intermediate type I, 43% needed NNV, 57% underwent tracheostomy, and 26% died. In patients with SMA type II, 38% needed NNV, 15% underwent tracheostomy, and 4% died. In patients with SMA type III, respiratory impairment was moderate and began during the second decade of life. CONCLUSION: This data shows the progressively worsening course of restrictive respiratory insufficiency in patients with SMA, and the importance of early respiratory management to limit pulmonary complications and improve the quality of life for these patients.

Classical infantile spinal muscular atrophy with SMN deficiency causes sensory neuronopathy.

OBJECTIVE: Classic infantile spinal muscular atrophy (SMA) is believed to be a purely motor disorder, affecting neurons of the spinal anterior horn and nuclei of the lower cranial nerves. Other organ malformations or peripheral nerve involvement have been regarded as exclusion criteria for infantile SMA. Whether SMN protein deficiency can also lead to loss of sensory neurons has not been systematically addressed. METHODS: The authors evaluated the sural nerve biopsies of 19 patients with infantile SMA of varying severity. The diagnosis of SMA was confirmed by the presence of a homozygous deletion of the SMN1 gene in all patients. RESULTS: In seven unrelated infants with SMA type I, axonal degeneration of the sural nerve was noted. Five patients showed abnormal sensory conduction, thus prompting sural nerve biopsy. Sural nerves showed different degrees of axonal loss: fiber density ranged from 3.482 to 22.076/mm2 and was markedly reduced in four patients. There was no evidence of primary demyelination: the ratio of total myelinated fiber thickness to axon diameter (g-ratio) was normal in the patients examined. In seven patients with SMA II and five patients with SMA III, no sural nerve alterations were seen, and conduction velocity was normal. In addition to SMN1 gene deletions, homozygous NAIP gene deletions were detected in six out of seven infants with peripheral neuropathy, whereas there was no evidence of a large deletion including the multicopy markers C212 and Ag1-CA in two out of three families tested. CONCLUSIONS: In this series of patients with SMA I through III who underwent sural nerve biopsy, there was significant sensory nerve pathology in severely affected patients with SMA type I, whereas there were no sensory nerve alterations clinically or morphologically in patients with milder SMA type II or III.