Spinal muscular atrophy with respiratory distress syndrome (SMARD1)

Last updated Feb. 7, 2023, by Susie Strachan
Fact-checked by Patricia Silva, PhD

Spinal muscular atrophy with respiratory distress type 1 — also known as SMARD1 or SMARD disease — is an inherited disorder that causes muscle weakness and respiratory failure, typically beginning in infancy. It is extremely rare, having been diagnosed in approximately 100 children around the world.

SMARD1 is caused by mutations in the IGHMBP2 gene, which provides instructions for making a protein that is involved in DNA replication.

There are several types of spinal muscular atrophy (SMA), which differ by the age of onset and severity of symptoms. SMA types 0-4 are caused by mutations in the SMN1 gene. This gene provides instructions to build a protein that is essential for the survival of motor neurons.

SMARD1 is inherited in an autosomal recessive pattern. This means that a child will only develop this disease if both copies of the gene, one inherited from the mother and the other from the father, are mutated.

SMARD1 is sometimes referred to as severe infantile axonal neuropathy with respiratory failure or distal SMA type 1. Without mechanical ventilation, babies with SMARD1 usually die in the first year of life.

What are the symptoms of SMARD1?

SMA is a genetic condition that causes progressive muscle weakness and wasting. Living with SMA can pose many challenges in day-to-day life.

SMARD1 is characterized by respiratory failure and muscle weakness, usually beginning between 6 weeks and 6 months of life.

The first noticeable symptoms of SMARD1 are usually the rapid onset of breathing issues in infants. Children with SMARD1 disease can develop symptoms later in life, but this is rare.

An infant may have:

• noisy breathing
• trouble inhaling
• a weak cry
• recurring pneumonia
• difficulty feeding.

The respiratory difficulty is caused by a paralysis of the diaphragm muscle that normally helps in breathing. The diaphragm is the thin muscle that separates the chest cavity from the abdomen and is essential for breathing. Children with SMARD1 typically, and suddenly, progress to respiratory failure, meaning they are not able to breathe without breathing support.

Muscle weakness usually becomes apparent shortly after respiratory failure. The weakness typically starts in distal muscles, or those that are furthest from the center of the body, such as the muscles in hands and feet, and continues to spread to all other muscles. But this steady decline in muscle strength stops typically within two years and stabilizes.

Muscular weakness causes problems with:

• swallowing
• crawling
• sitting
• standing
• walking.

The impact of the condition depends on the individual, as some children retain the ability to move, while others do not. Some children develop an abnormal side-to-side (scoliosis) or back to front (kyphosis) curvature of the spine.

Other symptoms of SMARD1 can include reduced pain sensitivity, loss of bladder and bowel control, excessive sweating, and an irregular heartbeat (arrhythmia).

Some children may also have:

• distal extremity deformities, such as clubfoot
• permanent flexion of the finger
• front half of the foot turning inward
• curved/bent fingers or toes
• elbow, ankle, and knee stiffness
• excessive saliva production, and persistent spitting up
• fatty finger pads.

SMARD1 is one of the rare types of SMA, with most cases falling within SMA types 0-4. Other rare types include lower extremity dominant (SMA-LED), Finkel type, Kennedy’s disease, and X-linked infantile SMA.

What causes SMARD1?

SMARD1 is caused by mutations in a recessive gene, which means both parents must be carriers of the gene mutation, while not showing any symptoms themselves. Each parent must pass a copy of the mutated gene onto their child for him or her to be affected.

When two carriers have a baby, there is a 1 in 4, or 25%, chance they will have an affected baby.

SMARD1 is different from SMA in that the former is caused by mutations in the IGHMBP2 gene, while SMA is caused by mutations in or the absence of the SMN1 gene.

Clinically, an infant with SMARD1 will present with respiratory distress, and then weakened muscles. An infant with SMA is the opposite, starting with weakened muscles, and then developing trouble breathing.

More than 60 different mutations in the IGHMBP2 gene have been found to cause SMARD1. Most of these affect either the amount or efficiency of the IGHMBP2 protein produced by the IGHMBP2 gene. It’s thought that not enough of this protein leads to degeneration of the lower motor neurons, although other factors also may come into play.

How is SMARD1 diagnosed?

Because SMARD1 is a very rare condition, it is difficult to diagnose, so a diagnosis can take a long time. Many infants with the condition are diagnosed after being admitted to hospital with breathing difficulties.

A conclusive diagnosis is only possible with genetic testing to identify mutations in the IGHMBP2 gene. More than 60 different mutations on this gene are linked to SMARD1.

When testing an infant for SMARD1, a blood sample is taken and sent to a lab for genetic testing. Further tests may be conducted, including an electromyogram (EMG) or muscle biopsy.

Following a diagnosis, genetic counseling will be offered to explain the disorder and its progression, along with counseling about future pregnancies.

What treatment options are available for SMARD1?

At this point, symptom management is the only treatment option available for SMARD1. Options include using a mechanical ventilator, maintaining a clear airway, which may require having a tracheostomy, and undergoing physical therapy to strengthen the muscles. A tracheostomy is a surgical procedure to create an opening at the front of the neck and into the windpipe to facilitate breathing.

Gene therapy via gene correction may have the potential to halt or possibly prevent neurodegenerative disease in SMARD1 patients. A recently approved gene therapy for SMA associated with mutations in the SMN1 gene could potentially be applied to SMARD1.

In 2022, the Nationwide Children’s Hospital in the U.S. launched a Phase 1/2a gene replacement clinical study (NCT05152823) to evaluate the safety of a gene therapy for IGHMBP2-related diseases, specifically SMARD1 and Charcot-Marie-Tooth disease type 2S (CMT2S).

What is the life expectancy for people with SMARD1?

The life expectancy of a child diagnosed with SMARD1 is variable, but many die younger than 13 months due to respiratory failure if they don’t receive respiratory support.

Almost all children who live with SMARD1 past 1 year of age require a tracheostomy, and are dependent on a ventilator and wheelchair.

Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1, and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1.

SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.