Spinal muscular atrophies are autosomal recessive disorders that were previously classified according to clinical findings supported by neurophysiological examinations and muscle biopsies. The incidence of spinal muscular atrophy type 1 (SMA1), or Werdnig-Hoffmann disease varies: in Sweden it has been found to be approximately 1/28 000 live births (4).
The most common cause of spinal muscular atrophy is mutations in the SMN1 gene, but 5 % of patients have no mutations in this gene (5). Among these there is a clinical group in whom respiratory distress occurs at an early stage. This is called spinal muscular atrophy with respiratory distress, or SMARD. Some patients with SMARD are clinically normal at birth, but they develop respiratory distress because of failing diaphragm function at a very early age. This group is now called SMARD type 1 (3).
The paralysis of the diaphragmatic muscle results in eversion of the diaphragm and paradoxical movements. These patients also have degeneration of the peripheral nerves, including the sensory and autonomic nerves, and frequently the distal muscles are most affected. Deep tendon reflexes may be preserved (6, 7). It has been shown that about one-third of these patients have mutations in the so-called immunoglobulin μ-binding protein 2 gene (IGHMBP2) (3, 6) – (10), and the combination of respiratory distress in the period from six weeks to six months of age and eventration of the diaphragm, or premature birth, are predictors of mutation in this gene with 98 % sensitivity and 92 % specificity (8). Those who do not have the mutation are of different age at onset of the disease, or might have congenital symptoms or multiple contractures, an indication of an early intrauterine development of the disease.
A differential diagnosis of SMARD1 that has recently been described is EMARDD (early onset myopathy, areflexia, respiratory distress and dysphagia), which is due to mutations in another gene called MEGF10 (11). These patients also have a weakness of the diaphragm, but myopathy is a dominant feature. It is assumed that new genetic differential diagnoses of SMARD will be reported, based on further genetic mapping of this patient group using new sequencing technology.
Approximately 60 different mutations of the IGHMBP2 gene have been described and the number is increasing. This might be of relevance to the phenotypic variations. A new mutation was also found in our patient. Like ours, the patients are homozygotes or complex heterozygotes for the mutations. Patients who have the mutation in only one allele have been reported, but the clinical significance of this is not clear (7). A few patients have the onset of symptoms as early as two weeks old (7), while in a few the symptoms occur considerably later (8). There are also rare juvenile forms with less serious clinical manifestations (12). A significant clinical variation is described even among siblings with the same mutations (8, 10, 13), and modifying genes influence the course of the disease (14).
Our patients were assessed as clinically normal at birth. In retrospect we think that the twitching might have been the first signs of the disease. All three developed respiratory distress at the age of 4 – 6 weeks. Paradoxical movements of the diaphragm were diagnosed, and all could be clinically classified as patients with SMARD1.
Genetic causes of SMARD1 were not known until several years after the death of our youngest patient. The history of the girl shows how difficult it is to reach a definitive diagnosis without genetic diagnostics. Various specialists made different findings and made partly diverging assessments and conclusions. Even after autopsy of two of the patients, with assessments by experienced neuropathologists, it was difficult to reach a final diagnosis.
The neuropathological findings vary in these patients. Muscular atrophy is found in all, and many describe changes in the peripheral nerves. Although the condition is classified as a spinal muscular atrophy, the expected changes in the anterior horn motor neurons of the medulla are not found in all cases (7). Loss of neurons was found in our two patients who were examined. Both neuropathological findings and neurophysiological results indicate peripheral axonal changes and/or progressive affection of both motor and sensory nerves, where motor nerves are affected first and most severely.
Neurophysiological investigation still has a place in the diagnostic assessment of children with atypical neuromuscular diseases when genetic analyses have not provided a diagnosis (15, 16). However, where there is a specific clinical suspicion, relevant genetic investigations should be the primary course of action (17).
For the parents it was an inconceivable tragedy to lose their three children. The parents were supported in their choice of treatment for their sons. If the correct diagnosis and prognosis of the first child had been known, the decision to start mechanical ventilation would have been more difficult. Evaluation and practice vary (18), since these patients can also live for many years with ventilator treatment (19, 20). There is no established treatment, but the increasing understanding of the genetic background of the SMA group has led to trials of potentially useful medicines (21).
Carrier frequency and the frequency of spontaneous mutations in our population are not known. To our knowledge our patients are the first to be diagnosed with SMARD type 1 in Norway.
These cases show the importance of keeping patient material (spleen sample, skin biopsy or blood sample) for later DNA analyses. In this case the cause was found more than ten years after the death of the first patient.
The parents have been informed about the result. The confirmation of the very serious prognosis provides retrospective support for the choices they made together with the health personnel.