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Spinal Muscular Atrophy with Respiratory Distress Type 1

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Last updated: November 22, 2022
Years published: 2019, 2022


Acknowledgment

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, Professor, Department of Pediatrics, University of Cincinnati, College of Medicine, Division of Pulmonology, Section of Sleep Medicine, The Comprehensive Neuromuscular Program, Cincinnati Childrenโ€™s Hospital Medical Center, for the preparation of this report.


Disease Overview

Summary

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 presents as infants having trouble breathing between the ages of 6 weeks and 6 months of age. Unless they are 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, in a young child, the consequences of severe neuromuscular weakness are progressive. SMARD1 is known to be caused by changes (called mutations or variants) 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.

 

Introduction

 

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.

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Synonyms

  • autosomal recessive distal spinal muscular atrophy 1s
  • DHMN6
  • diaphragmatic spinal muscular atrophy
  • distal hereditary motor neuronopathy type VI
  • distal spinal muscular atrophy type 1
  • DSMA1
  • HMN6
  • HMNVI
  • severe infantile axonal neuropathy with respiratory failure
  • SIANRF
  • SMARD1
  • spinal muscular atrophy with respiratory distress type 1
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Signs & Symptoms

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 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.

Most 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:

 

Prenatal/Natal Features

 

โ€ข Intrauterine growth retardation (unborn not growing as expected)
โ€ข Premature birth
โ€ข Reduced fetal movements
โ€ข Birth weight, length and head circumference values less than the 10th percentile (small for their gestational age)
โ€ข Inability to gain weight or grow at the expected rate (failure to thrive)

 

Respiratory Abnormalities

 

โ€ข Respiratory paradox due to diaphragmatic weakness/paralysis
โ€ข Respiratory failure
โ€ข Persistent or recurrent atelectasis (collapse of lung segments or lobes) due to weak cough and reduced ability to clear respiratory secretions even without an illness.
โ€ข Spine and chest wall deformities due to chest wall muscle involvement that further reduce respiratory efficiency

 

Orthopedic abnormalities

 

โ€ข Distal extremity deformities, such as clubfoot (talipes equinovarus)
โ€ข Permanent flexion of the finger (camptodactyly of finger)
โ€ข Front half of the foot turning inward (metatarsus varus)
โ€ข Limitation of the range of motion of joints (joint contractures) in hands or feet (hand/foot arthrogryposis)
o Wrist retraction
o Elbow, ankle, and knee stiffness
โ€ข Curved/bent fingers or toes (claw hands or toes)
โ€ข Elbow, ankle, and knee stiffness.

 

Gastrointestinal features

 

โ€ข Excessive production of saliva (hyper salivation)
โ€ข Difficulty swallowing (dysphagia)
โ€ข Gastroesophageal reflux (persistent spitting up)
โ€ข Inability of the stomach to empty food in the usual way (gastroparesis)
โ€ข Inability to empty the bladder (urinary retention)
โ€ข Constipation

 

Neuromuscular features

 

โ€ข Fatty finger pads
โ€ข Loss of nerve supply to the diaphragm (denervation of the diaphragm)
โ€ข Abnormal elevation of the diaphragm (diaphragmatic eventration)
โ€ข Muscle wasting of arms and legs
โ€ข Spinal muscle deterioration (spinal muscular atrophy)
โ€ข Decreased nerve conduction velocity (slowed ability for nerves to send messages to parts of body)
โ€ข Involuntary twitching of the tongue and weakness of facial muscles
โ€ข Decreased degree of facial expression (hypomimia)

 

Other Characteristics

 

โ€ข Thoracospinal deformities (scoliosis, thoracic dystrophy)
โ€ข Seizures occurring during or after a hypoxic or anoxic (little to no oxygen) episode
โ€ข High blood pressure
โ€ข Dislocated hip

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.

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Causes

SMARD1 is caused by variants (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 as to how the abnormal IGHMP2 proteins lead to damage and death of the alpha neurons is currently unknown. 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 of having 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.

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Affected populations

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.

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Diagnosis

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 mechanical 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.

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Standard Therapies

Treatment

The evaluation for respiratory insufficiency is of 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 (elevated levels of carbon dioxide or CO2). 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, rapid breathing, respiratory paradox (see saw moments of the chest and abdomen), low saturations with or 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 initiation of adequate support with mechanical ventilation to reduce the likelihood or degree of thoracic dystrophy. Unless they receive mechanical ventilation, most 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. Suctioning is needed to clear the secretions from the upper airways. In addition, the use of cough augmentation devices (for example the Cough Assist machine) assists 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 stronger effective cough, thereby removing secretions. The use of such a machine requires patient interaction and cooperation and may therefore prove to be a little more challenging to use in infants and toddlers. It is essential to remove mucous from the lungs 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 the nose to the 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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Clinical Trials and Studies

Any information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Vanoli F, Rinchetti P, Porro F., et al. Clinical, molecular features, and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1. J. Cell. Mol. Med. Vol 19, No 9, 2015 pp. 2058-2066.

Grohmann K, Varon R, Stolz P., et al. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann of Neurol. Vol 54, Issue 6, 2003 pp. 719-724.

Viguier A, Lauwers-Cances V, Cintas P., et al. Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study. Neuromuscular Disorders. Vol 29, Issue 2, 2019 pp. 114-126.

Pitt M, Houlden H, Jacobs J., et al. Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1. Brain. Vol 126, Issue 12, 2003 pp. 2682-2692.

Porro F, Rinchetti P, Magri F., et al. The wide spectrum of clinical phenotypes of spinal muscular atrophy with respiratory distress type 1: A systematic review. J. of the Neurological Sciences. Vol 346, Issues 1-2, 2014 pp 35-42.

Sathasivam S. Brown Vialetto-Van Laere syndrome. Orphanet J Rare Dis. Vol 3, No 9, 2008. Pp.3-9.

INTERNET

Spinal muscular atrophy with respiratory distress type 1. Genetics Home Reference. Reviewed: March 2019.
https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy-with-respiratory-distress-type-1#diagnosis Accessed Nov 22, 2022.

IGHMBP2 gene. Genetics Home Reference. Reviewed: January 2013. https://ghr.nlm.nih.gov/gene/IGHMBP2#conditions Accessed Nov 22, 2022.

Spinal muscular atrophy with respiratory distress 1. Genetic and Rare Diseases Information Center. Last updated: Nov 8, 2021. https://rarediseases.info.nih.gov/diseases/8592/spinal-muscular-atrophy-with-respiratory-distress-1 Accessed Nov 22. 2022.

Spinal muscular atrophy, distal, autosomal recessive, 1. Online Mendelian Inheritance in Man. Last updated 03/25/2016.
https://omim.org/entry/604320 Accessed Nov 22, 2022.

Charcot-Marie-Tooth Disease. National Organization for Rare Disorders. Published: 2021. https://rarediseases.org/rare-diseases/charcot-marie-tooth-disease/ Accessed Nov 22, 2022.

Charcot-Marie-Tooth Disease, Axonal, Type 2s. Online Mendelian Inheritance in Man. Last updated: May 2017.
https://www.omim.org/entry/616155 Accessed Nov 22, 2022.

Myopathy, Areflexia, Respiratory Distress, and Dysphagia, Early-Onset. Online Mendelian Inheritance in Man. Last updated: January 2018. https://www.omim.org/entry/614399 Accessed Nov 22, 2022.

Pompe Disease. National Organization for Rare Disorders. Published: 2020. https://rarediseases.org/rare-diseases/pompe-disease/ Accessed Nov 22, 2022.

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Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโ€™s mission.

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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National Organization for Rare Disorders