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Case Study 1
This patient was diagnosed with type I spinal muscular atrophy (SMA) at six months of age.
She presented with progressive proximal weakness that affected her legs more than arms. There was poor head control, hypotonia resulting in a frog-leg posture when lying, and slip-through on vertical suspension and areflexia. She never sat. She had weakness of the intercostal muscles with relative sparing of the diaphragm, producing a bell-shaped chest and a pattern of paradoxic or ‘belly-breathing’. Her cognition was normal and she was noted to have a bright and alert expression at the time of diagnosis.
She exhibited tongue fasciculations. Failure to thrive was noted by nine months of age, which required nasogastric feeding supplementation. At 11 months of age she developed difficulty swallowing. Bilevel positive airway pressure (BiPAP) was pre-emptively introduced at eight months of age. She developed respiratory failure at 11 months of age. At 16 months of age, she requires at least 18 hours a day of BiPAP.
Case Study 2
This patient was diagnosed with SMA type II at 10 months of age. He was able to sit unsupported at 13 months, but was never able to stand alone or walk. He developed progressive proximal weakness affecting legs more than arms, hypotonia and areflexia. He exhibited tremor (polyminimyoclonus) of the hands. Progressive scoliosis developed, requiring surgical intervention at four years, which in combination with intercostal muscle weakness resulted in significant restrictive lung disease.
He required overnight BiPAP in late childhood. He developed joint contractures and ankylosis of the mandible. His body mass index was low (third centile). Cognition was normal and verbal intelligence was above average.
Classic proximal spinal muscular atrophy (SMA) is a heterogeneous genetic disorder characterised by progressive proximal muscle weakness and atrophy, which result from degeneration of the spinal and, in the most severe cases, bulbar lower motor neurons. Other forms of SMA (non-5q) exist but are beyond the scope of this review.
SMA results from homozygous deletions or pathogenic variants involving the ‘survival of motor neuron’ (SMN) gene at locus 5q13. The SMN gene is present in two copies on each chromosome 5, designated SMN1 and SMN2.
Due to a crucial single nucleotide change in exon 7 of SMN2 (creating an exon splicing suppressor), this gene produces less functional SMN protein than the SMN1 gene (approximately 10 per cent of total SMN produced). Most patients with 5q recessive SMA harbour homozygous deletions (of exon 7) of SMN1 gene but maintain at least one copy of SMN2. An approximate correlation exists between SMN2 gene copy number, which varies normally in the population, and the severity of the disease; 80 per cent of patients with type I SMA have one or two copies of SMN2, 82 per cent of patients with type II have three copies of SMN2, and 96 per cent of patients with type III have three or four SMN2 copies.
Although there is, in general, an inverse correlation between the level of SMN protein and severity of disease, this correlation does not seem to be as close as that between SMN2 copy number and phenotype. The role of SMN protein is still under active investigation. Indeed, SMA may involve dysfunction of more than lower motor neurons, with evidence for neuromuscular junction abnormalities seen.
SMA is the leading genetic cause of infant mortality. The incidence has been estimated to be between one-in-6,000 to one-in-11,000 live births for SMA type I. The carrier frequency for pathogenic variants in SMN1 gene has been estimated to be between 1:38 to 1:70. Despite this high frequency, the incidence is lower than expected. This may reflect some foetuses having a 0/0 SMN1/SMN2 genotype (ie, no SMN protein present), which is embryonically lethal.
A range of phenotypic severity permits division of SMA into four broad clinical subtypes. The maximal functional status approach has been used, which classifies type I patients as ‘non-sitters’, type II as ‘sitters’, and type III as ‘walkers’.
There has been some increase in survival in recent years in SMA type I patients with the use of assisted ventilation and improved nutritional care. Prior natural history studies reported shortened life span, with 68 per cent mortality within two years and 82 per cent by four years of age. With the application of respiratory and nutritional interventions, mortality has reduced to 30 per cent at two years, but approximately half of survivors are fully dependent on non-invasive ventilation at this stage.
In a recent observational study, the median age of reaching the combined endpoints of requiring at least 16 hours a day of non-invasive ventilation or death was 13.5 months. Infants with two SMN2 copies had a greater morbidity and mortality than those with three SMN2 copies. The need for nutritional support preceded that for ventilation support.
In a study of 240 type II SMA patients, survival rates were found to be 98.5 per cent at five years and 68.5 per cent at 25 years. Patients may live into the third decade but life expectancy is shortened due to the risk of respiratory compromise.
The much milder form of SMA, type III, is characterised by prolonged ambulation. Patients are able to stand alone and walk at some point. Symptom onset occurs after 18 months. They have progressive proximal weakness affecting legs more than arms and may ultimately need to use a wheelchair. In general, they do not develop severe respiratory muscle weakness or scoliosis. Loss of ambulation increases the risk of these complications, however. They may have tremor of the hands and hypertrophy of calves. Life expectancy is not significantly different from the general population.
A milder adult-onset type IV SMA has been described, with onset after 21 years of age and essentially normal life span.
Care of patients with SMA
In 2007, an international Consensus Statement for Standard of Care in Spinal Muscular Atrophy by multidisciplinary care was released regarding the current best recommendations for management of patients with SMA.
Respiratory failure is the major cause of mortality in patients with types I and II SMA. Infants with type I SMA have weak intercostal muscles and relatively preserved diaphragm strength. Patients with type II SMA have additional scoliosis, contributing to progressive restrictive lung disease. The restrictive lung disease results in insidious onset of sleep hypoventilation. Proper use of BiPAP has no significant haemodynamic side-effects. There should be a low threshold to starting antibiotics in times of acute illness due to the risk of pneumonia.
Growth failure and failure to thrive are common features in SMA type I and some severe SMA type II. Many patients with SMA type II may have excess fat mass relative to muscle mass, despite having normal body mass index.
Close attention must be paid to nutritional status.
Patients with SMA type I are extremely weak and tire during feeding. This can result in failure to thrive and aspiration, with recurrent respiratory infections. Laparoscopic Nissen fundoplication and gastrostomy may improve nutritional status, with evidence suggesting a trend towards fewer long-term aspiration events. Constipation can worsen reflux or respiratory symptoms.
Close orthopaedic follow-up for the development of scoliosis and contractures is needed. Surgical intervention is often required and careful co-ordination with perioperative respiratory and nutritional support can minimise complications. Fractures and hip dislocation can occur but management is often conservative.
A diagnosis can result in significant psychosocial issues for families. A range of emotional and practical supports are provided by Muscular Dystrophy Ireland (MDI), the national organisation for neuromuscular conditions.
Through the provision of information, support and advocacy, MDI seeks to promote a better quality of life for patients and their families — see www.mdi.ie.
Currently, there is no cure for SMA. There has, however, been great interest in identifying agents that can increase the amount of full-length SMN protein by up-regulating the expression of the SMN2 gene or promoting inclusion of exon 7 (of SMN2 gene).
Researchers are also actively exploring several other approaches to treatment.
Histone deacetylase inhibitors (HDACIs) have been extensively investigated as potential therapeutic agents in SMA.
Histones play a role in epigenetic regulation of gene expression via their acetylation status. HDACIs have been shown to increase full-length SMN2 transcript levels in cell lines from patients, by activating the human SMN2 promotor, enhancing transcription and correcting the splicing pattern. Clinical trials of HDACIs, phenybutrate and valproic acid have shown no difference in motor function scores compared with placebo group in a non-ambulatory cohort of type II SMA.
RG7800 (Roche/PTC/SMAF) is a small molecule that is designed to correct the SMN2 alternative splicing event, thereby increasing full-length SMN. This molecule extends the life expectancy of the SMN∆7 severe mouse model from 14 days to six months.
This compound was further developed for a phase 1b/2a trial (MOONFISH) in SMA II/III patients but is currently on hold due to unexpected eye findings during an animal study evaluating long-term safety of the compound.
A similar SMN2 splicing molecule RG7916 has been developed and a phase 1 study is underway.
The ß-adrenergic agonist albuterol was evaluated in a pilot study of 13 patients with type II and III SMA. At six months, a significant improvement was noted in muscle strength myometry, forced vital capacity and duel-energy x-ray absorptiometry scores, but there was no significant improvement in Medical Research Council strength scores.
Another pilot study of 23 patients with SMA type II treated with salbutamol for 12 months showed improvements on the Hammersmith Functional Motor Scale. However, this was not a placebo-controlled study and must be interpreted with caution.
Salbutamol has also been shown to increase full-length SMN mRNA and SMN protein by promoting inclusion of exon 7. The response was directly proportional to SMN2 gene copy number. This finding prompts further interest in exploring the effects of ß-agonists on SMA in randomised, controlled trials.
Neuroprotective survival of motor neuron protein stabilisation agents
A phase 2, multicentre, randomised, double-blind study is currently being conducted to assess efficacy and safety of the neuroprotective agents riluzole and olesoxime (TRO19622) in patients with SMA types II and III.
Antisense oligonucleotides (ASOs) have been developed that block an intronic splicing suppressor element, which, in turn, prevents skipping of exon 7.
These intronic suppressors were found to be located in intron 7 as tandem motifs, namely hnRNP A1/A2. Blocking of these motifs by ASOs enhance exon 7 inclusion in the SMA mouse model. Patients treated with ASOs were shown to enhance production of full-length SMN mRNA in fibroblasts. Periodic intracerebroventricular deliveries of ASOs in SMA mice models have been found to improve motor function. Biogen/Ionis are investigating this compound, Nusinersen (formerly ISIS-SMNRx). Currently, two phase 3, randomised, double-blind, placebo-controlled trials are underway in later-onset SMA (two-to-12 years) (CHERISH) and infants with SMA up to 210 days of age (ENDEAR).
In addition, pre-clinical animal SMA models have suggested that early intervention with ASOs results in greatest efficacy. A phase 2 clinical trial is currently underway (NURTURE) in pre-symptomatic SMA patients up to six weeks of age to examine the efficacy of Nusinersen.
Neonatal SMA model mice injected systemically with self-complementary adeno-associated virus 9 (scAAV9), engineered to carry the wild type SMN gene, expressed high levels of protein in multiple tissues and derived remarkable therapeutic benefit, surviving in some instances to 12 months or more, with no evidence of muscle weakness. Considering proof-of-concept studies demonstrating the ability of scAAV9 to penetrate the mature BBB and infect adult motor neurons, an SMN replacement strategy to treat SMA is a promising alternative to pharmacologic approaches. An open-label phase 1/2 trial is underway in SMA type 1 patients.
SMA is a chronic, inherited motor neuron disease for which there is no curative treatment. However, our knowledge about the molecular genetics and pathogenesis is ever increasing. Several groups are actively exploring pharmacological interventions. Standards of care guidelines have been developed. Although it may seem that a treatment for SMA is far in the future, advances made since gene identification in 1995 allow for some hope for patients, families and those privileged to care for patients with SMA.