NORD gratefully acknowledges Danielle Terek, NORD Editorial Intern from the University of Notre Dame; Barb Calhoun, MSN, RN, NP, Nurse Practitioner and Outreach Coordinator, Boler-Parseghian Center for Rare and Neglected Diseases at the University of Notre Dame; and Hemant Sawnani, MD, Associate Professor, Department of Pediatrics, University of Cincinnati, College of Medicine, Division of Pulmonology, Section of Sleep Medicine, The Comprehensive Neuromuscular Program, Cincinnati Children’s Hospital Medical Center, for the preparation of this report.
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an extremely rare type of spinal muscular atrophy (SMA) that results from irreversible deterioration of alpha motor neurons of the spinal cord. Alpha motor neurons supply nerves to skeletal muscle and stimulate muscle contraction. The symptoms of SMARD1 primarily begin with infants experiencing difficulty breathing between the ages of 6 weeks and 6 months of age. Unless they are not supported with mechanical ventilation, most affected children die from respiratory failure before 13 months of age. Progression of muscle weakness typically stops within two years, but it should be understood that, in a young child, the consequences of severe neuromuscular weakness are progressive. SMARD1 is known to be caused by changes (mutations) in the IGHMBP2 gene and is inherited in an autosomal recessive pattern. A majority of children with SMARD1 have early onset in infancy, but there have been many children reported with a later onset juvenile form of SMARD1.
SMARD1 was first reported in medical literature in 1974 by Mellins, et al, who described two newborns presenting with an atypical variant of SMA type 1 (Wernig-Hoffmann disease). However, SMARD1 was not recognized as a separate disease from SMA until 1996. The first research showing IGHMBP2 gene mutations in relation to the characteristics of SMARD1 was reported in 2001 by Grohmann, et al.
Symptoms of SMARD1 generally begin during infancy. Early features of SMARD1 include a weak cry, feeding problems, difficult and noisy breathing- especially when inhaling (inspiratory stridor) and recurrent pneumonia. Between 6 weeks and 6 months of age, affected infants typically experience sudden onset of shortness of breath with progressive respiratory distress. This is due to paralysis of the diaphragm, (primary inspiratory muscle) and abdomen resulting in ineffective breathing with an increased respiratory rate (tachypnea) and eventual inability to breathe (respiratory failure). Diaphragmatic paralysis can result from a dysfunction of the phrenic nerve that supplies the diaphragm. This paralysis (phrenic nerve palsy) usually starts on the right side of the chest, although it can affect one or both halves of the diaphragm.
Following respiratory failure, muscle weakness occurs in muscles farther from the midline of the body (distal), usually beginning in the lower limbs, spreading to all muscles. The decline of muscle weakness stabilizes within two years. The retention of muscle function following this period is variable among individuals. Patients often experience complete paralysis of all limbs and trunk muscles.
A majority of affected individuals lose their deep tendon reflexes (areflexia) by the age of one. Children may also develop an abnormal sideways curvature of the spine (scoliosis), an excessive outward curvature of the spine (kyphosis), or both (kyphoscoliosis). Other features include a loss of bladder and bowel control (incontinence), irregular heartbeat (arrhythmia), low muscle tone (hypotonia), excessive sweating (hyperhidrosis), a reduced pain sensitivity, and deformities of feet and hands.
A variety of other symptoms and physical findings can develop in individuals with SMARD1:
Symptoms of SMARD1 is typically present in infancy, but there is a significant amount of variability in the timing of the onset, and numerous SMARD1 patients have been diagnosed later in childhood. Only a few have been reported with late onset or mild presentation.
SMARD1 is caused by mutations in the IGHMBP2 gene. Researchers have found more than 60 different mutations in the IGHMBP2 gene that cause SMARD1. The IGHMBP2 gene is responsible for providing instructions necessary for making the IGHMBP2 protein that is involved in DNA replication and production of RNA and proteins. However, the exact role of the IGHMBP2 protein is currently unknown.
The abnormal IGHMBP2 protein leads to damage and death of the alpha-motor neurons of the brain stem and spinal cord. These neurons are responsible for controlling muscle movements. The mechanism is currently unknown as to how the abnormal IGHMP2 proteins lead to damage and death of the alpha neurons. Affected individuals with some functional protein are more likely to have a higher level of muscle function and a later onset of SMARD1 symptoms.
SMARD1 is inherited as an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
The exact prevalence of SMARD1 is currently unknown. Studies show that diaphragmatic paralysis affects about 1% percent of individuals diagnosed with early onset spinal muscular atrophy. As of 2015, greater than 60 cases of SMARD1 have been described in scientific literature.
A diagnosis of SMARD1 is based upon the presence of characteristic features. Diagnosis usually follows severe and rapidly progressive respiratory distress caused by diaphragm paralysis, which often requires ventilation. An abnormally high position of the diaphragm can be indicative of SMARD1 if this occurs with one or more of the following signs: an infant with respiratory distress; family history of sudden infant death syndrome; close familial relation (consanguinity) of parents; and foot and hand muscle weakness and/or distal articular retractions. Genetic testing can detect the presence of mutations in the IGHMBP2 gene and confirm a clinical diagnosis. Further testing- such as an x-ray, electromyogram (EMG), and nerve conduction study (NCS), or muscle biopsy- may be performed to rule out related disorders.
Of all of the therapies that may be implemented, the evaluation for respiratory insufficiency is perhaps of most critical importance for overall successful management. This evaluation should include the measurements of random and early morning (prior to awakening) blood gas data to evaluate for alveolar hypoventilation/respiratory insufficiency. The features of respiratory insufficiency of neuromuscular disease include frequent nighttime awakening or arousals, REM (dream) sleep suppression, reduction in airflow from shallow or obstructed breathing, respiratory paradox, low saturations with our without apneas (respiratory pauses) and elevated CO2 levels. The gold standard for such evaluation is the sleep study (polysomnogram or PSG). The interpretation of this study should be done in light of the global diagnosis, and needs to be done (ideally) by a sleep medicine specialist with expertise in the management of neuromuscular disease.
There is currently no effective treatment available for SMARD1. Treatment is primarily supportive, focusing on the symptoms present in the affected individual. Patients with urinary retention need catheterization. Patients with diaphragm paralysis require early and adequate support with mechanical ventilation to reduce the likelihood of thoracic dystrophy. Unless they receive mechanical ventilation, a majority of affected individuals will die from respiratory failure before 13 months of age. Recurrent airway infections are treated with antibiotic therapy and other preventative measures (prophylaxis).
Ventilation strategies include the goals of reducing work of breathing and providing optimal respiratory muscle rest during sleep. Maintenance of appropriate resting lung volumes will lead to stabilization of ventilation (CO2 levels) and saturations (oxygen levels). Optimizing pulmonary care includes the incorporation of airway clearance therapies. Intubated patients require frequent nebulizer treatments that deliver liquid medications in the form of mist to loosen mucous. Suctioning is also used to clear the secretions from the upper airways. In addition, the use of cough augmentation devices (example Cough Assist) assist patients with producing an effective cough. The machine provides positive pressure when the patient breathes in to expand the lungs. When the patient breathes out, the machine exerts negative pressure that pulls the air back and out of the lungs. This change in pressure elicits a strong effective cough, thereby removing secretions. It is essential to remove mucous from the lungs in order to prevent obstruction as well as infections such as bronchitis and pneumonia.
Treatment also focuses on nutrition for these patients because of difficulty swallowing and digesting food due to muscle weakness and gastrointestinal dysfunction. If necessary, nutrition is given through a nasogastric tube (tube through nose to stomach) or gastrostomy tube that is surgically placed through wall of abdomen directly into stomach. Other vital aspects of treatment include physical and occupational therapy.
Genetic counseling is recommended for affected individuals and their families.
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