Proximal spinal muscular atrophy type 1 (ORPHA:83330)
A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with onset of severe and progressive muscle weakness in the first 6 months of life and presenting with severe, generalized hypotonia and weakness,. Dysphagia and respiratory impairment may also be present at presentation or appear at a later stage. Classically, before the advent of recent therapies, type 1 patients never achieved sitting without support.
Epidemiology
The average prevalence of proximal spinal muscular atrophy (SMA) is estimated at 1/12,000, of which approximately 60% account for type 1.
Clinical description
Disease onset occurs before 6 months of age. The severe, symmetrical muscle weakness affects predominantly proximal limbs but often also involves the extremities. Cries are weak. Poor sucking ability and reduced swallowing are frequent, leading to feeding difficulties. Deep tendon reflexes are absent. Patients have paradoxical breathing, a bell shaped chest and develop respiratory failure. Mild contractures (of the knees and, more rarely, of the elbows), and scoliosis may be present. Classically, patients were not able to achieve sitting without support but this has changed following the availability of new treatments.
Etiology
The disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport, and it is believed that motor neurons are particularly vulnerable to impairments in these processes. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. The number of copies of the SMN2 is inversely correlated to disease severity.
Diagnostic methods
The diagnosis is clinically suggested by muscle weakness and hypotonia with sparing of the facial muscles, loss of reflexes, typical respiratory pattern with predominance of diaphragmatic movements compared to poor intercostal movements, and tremor. Diagnosis is confirmed by genetic testing of SMN1 deletion/mutation and, if possible, SMN2 copy number testing. Muscle biopsy and electromyography should not be performed in patients with typical presentation.
Differential diagnosis
Differential diagnoses include, other spinal muscular atrophies with infantile onset (infantile-onset X-linked spinal muscular atrophy and spinal muscular atrophy with respiratory distress type 1), congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, some early-onset mitochondrial disorders, and carbohydrate metabolism disorders (glycogen storage disease due to acid maltase deficiency).
Antenatal diagnosis
Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples.
Genetic counseling
Transmission is autosomal recessive and thus the risk of transmission to offspring is 25% where both parents are unaffected carriers. However, around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to affected families.
Management and treatment
Symptomatic management is multidisciplinary and aims to improve quality of life. This includes respiratory support (noninvasive ventilation and airway clearance), physiotherapy, gastrostomy, and antibiotic treatment in case of pulmonary infection. In the last few years, nusinersen, an antisense oligonucleotide, has been approved and made available for treatment of all SMA types in Europe and the USA. Clinical trials and real world data have shown that it reduces the risk of death and improves motor milestones in type 1 patients, with a number of patients achieving sitting without support. The best results are seen following early intervention and in presymptomatic patients. Risdiplam (a small molecule) has a also recently successfully completed clinical trials and has become commercially available in US and, for compassionate use, also in Europe. A different approach, using gene therapy, onasemnogene abeparvovec, has also been approved in US and Europe. The results of the clinical trials in young patients also indicate a very high rate of survival beyond 2 years and an improvement of motor function. Real world data are being collected in older patients but are not yet publicly available.
Prognosis
The prognosis is generally poor with most patients dying within the first two years of life due to respiratory failure. Data on long term outcomes with nusinersen treatment and with other drugs are now becoming increasingly available, suggesting long term survival.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Pr Eugenio MERCURI | EURO-NMD*


                                * European Reference Network