Proximal spinal muscular atrophy type 2 (ORPHA:83418)
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 between 6 to 18 months of age with progressive, proximal muscle weakness, mild to moderate hypotonia and finger polymyoclonour tremor, with areflexia. Motor milestones are classically limited to independent sitting or standing.
Epidemiology
In Europe the average prevalence at birth of proximal spinal muscular atrophy (SMA) type 2 is estimated at 1/50,000. Worldwide the prevalence ranges from 1/11,00-175,000.
Clinical description
Disease onset occurs between the ages of 6 and 18 months. Classically, before the advent of the new therapies, affected children achieve sitting independently and may acquire standing but do not acquire independent walking. Progressive proximal muscle weakness is symmetrical and greater in the legs than the arms. Finger trembling is frequent. Scoliosis, joint contractures and ankyloses of the mandible are very common . Progressive respiratory muscle weakness can lead to restrictive lung disease. Cognition is normal.
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 disease is suspected based on clinical history and examination. The gold standard in diagnosis is genetic testing of SMN1 deletion/mutation and, if possible, SMN copy number testing. Muscle biopsy and electromyography should not be performed in patients with typical presentation.
Differential diagnosis
Differential diagnoses include, congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, neuromuscular junction disease (botulism), 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 cells.
Genetic counseling
Transmission is autosomal recessive but 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. Assisted airway clearance and non-invasive ventilations are helpful. Physiotherapy and occupational therapy are recommended to prevent scoliosis, maintain joint mobility and promote function and mobility. Antibiotic therapy is required in case of pulmonary infection. The scoliosis may require a corset/back brace for support, and almost invariably needs surgical correction. 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 improves motor function in type 2 patients, with a number of patients achieving walking. The best results are seen following early intervention and in presymptomatic patients. Risdiplam (a small molecule) has a also recently, successfully completed a clinical trials and has become commercially available in US and for compassionate use in Europe. Clinical trials are ongoing to identify other potential drug treatments.
Prognosis
Life expectancy for affected individuals is variable but, with the new standards of care, particularly for respiratory insufficiency, the majority of patients survive up to adulthood.

                            Last update: 
                            January 2021


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


                                * European Reference Network