Neuromuscular disorders such as spinal muscular atrophy (SMA) and myotubular myopathy (MTM) can be challenging to diagnose. Their signs and symptoms are often very similar, so health care professionals rely on physical exams, medical histories, and genetic testing to help make a diagnosis.

Here, we will explore what makes SMA and MTM different, including their symptoms, diagnoses, and treatment.

What Are Spinal Muscular Atrophy and Myotubular Myopathy?

SMA is a genetic (inherited) disease that affects the nerves and muscles. It affects the central nervous system (the brain and spinal cord), the peripheral nervous system (nerves in other parts of the body), and a person’s voluntary muscle movement. Over time, SMA causes the muscles to atrophy (become weak and waste away).

MTM is the common term used for X-linked myotubular myopathy (XLMTM), a rare genetic neuromuscular disorder. XLMTM belongs to a larger group of disorders called “centronuclear myopathies.” Although XLMTM is rare, it’s the most common — and most severe — of the centronuclear myopathies. This condition usually appears in newborns. It mostly affects boys, but girls may be carriers (able to pass the condition along to their children). Along with general muscle weakness, XLMTM causes problems with breathing and swallowing. Most people with MTM have a severe form of the disorder, and respiratory failure almost always occurs.

Common Symptoms of SMA and XLMTM

SMA symptoms can vary greatly in their impact on a person’s physical function, quality of life, and life expectancy. Two of the most important variables that determine the severity of SMA symptoms include the type of SMA a person has and their age at diagnosis.

Generally, a person living with SMA will experience a progressive loss of muscle movement, control, and strength that worsens with age. The muscles located the closest to the neck and torso tend to be the most severely affected. Some people with SMA will never sit, stand, or walk, while others may gradually lose these abilities. SMA may also cause other problems related to muscle coordination and function, including difficulty speaking and swallowing, and breathing problems.

There are five main types of SMA: types 0, 1, 2, 3, and 4. Type 0 is the most severe form of SMA and begins before birth. Type 4 is the mildest and begins in adulthood. Life expectancy is often reduced in more severe SMA types — most babies with SMA type 1, for instance, do not live past the age of 2.

MTM usually occurs in the newborn stage or shortly after. Before birth, a mother may notice a decrease in fetal movement. After birth, the baby will have difficulties with swallowing, breathing, and feeding. They can have mild to profound weakness in their muscles and weak muscle tone (hypotonia, also called “floppiness” or “floppy infant syndrome”). As with SMA, weakness of the muscles involved in feeding and swallowing may lead to trouble breathing.

Other potential symptoms or signs of XLMTM may include:

• An abnormal electromyogram (EMG), a test used to evaluate electrical activity in nerves and muscles
• Absence of muscle reflexes
• Weak eye muscles (ophthalmoplegia) or drooping of the upper eyelid (ptosis)
• Weak face muscles
• Bent joints that cannot be straightened (flexion contracture)
• Larger head circumference or body length
• Decreased liver function
• Scoliosis
• Toes or fingers that are slender and long (“spider fingers”)
• Genital abnormalities

Babies and children with XLMTM usually need a machine to help them breathe and a feeding tube to deliver nutrition directly into the body. As with SMA, these needs can vary — some children with XLMTM only need help breathing while sleeping, while others need help continuously.

Many infants with XLMTM die due to severe breathing difficulties, while others may survive into early childhood. There have even been a few individuals with XLMTM who have lived into adulthood.

It is extremely rare for girls to have XLMTM, but signs or symptoms of the condition in girls include:

• A family history suggesting an X-linked inheritance (but not always)
• Ptosis and other eye abnormalities, such as ophthalmoplegia
• Facial weakness
• Asymmetrical muscle growth
• Muscle weakness in the arms and legs

Like symptom severity, these signs and symptoms can vary from person to person.

What Causes SMA and XLMTM?

Both SMA and XLMTM are inherited genetic disorders. They result from mutations or problems with certain genes that have been passed down from parent to child.

SMA types 0 to 4, which account for 95 percent of cases of SMA, are caused by a mutation in the survival motor neuron (SMN) genes on both copies of chromosome 5 (from both the mother and the father). SMN genes tell the body to make SMN protein. This protein is crucial for the function of motor neurons — nerve cells that transmit signals from the brain and spinal cord to the muscles. Without sufficient SMN protein, motor neurons die, and the brain cannot signal the muscles to function.

There are two SMN genes on chromosome 5: SMN1 and SMN2. A mutation on both copies of a person’s SMN1 gene determines whether a person will have SMA. The type of SMA a person develops, the severity of symptoms, and life expectancy are often — but not always — related to the number of SMN2 copies they have.

MTM is caused by mutations in the MTM1 gene, which lead to deficiencies or defects of the protein myotubularin. This protein is believed to promote muscle development. XLMTM disease mainly affects boys who inherit the disorder from their mothers. The disease rarely affects girls, but when it does, it’s typically much less severe.

Diagnosing SMA and XLMTM

Because the signs and symptoms of SMA and XLMTM can also signal other rare diseases and neuromuscular disorders, doctors need to perform tests to determine the right diagnosis. They start by reviewing a person’s personal and family medical history, asking about their signs and symptoms, and conducting a physical exam.

Tests To Diagnose SMA

Several laboratory tests can be used to confirm an SMA diagnosis. SMA may also be diagnosed during pregnancy if there is a family history of the condition.

Blood Tests

When muscles deteriorate, they release the enzyme creatine kinase into a person’s bloodstream. An enzyme and protein blood test checks for high or elevated levels of this enzyme, which may point to a diagnosis of SMA.

Newborn Screening

In the United States, all newborn babies undergo blood testing to identify any metabolic (chemical processing) or genetic abnormalities. Some states include testing for issues with the SMN1 gene as part of this panel.

Electromyogram

An EMG is used to record electrical activity in the muscles. This indicates how responsive the muscles and nerves are.

Muscle Biopsy

Though rarely used, a muscle biopsy can help reveal atrophy (loss of muscle) caused by conditions like SMA. This test involves removing a small amount of the muscle cells and muscle tissue for lab analysis.

Tests To Diagnose MTM

Diagnosing MTM may also rely on an EMG, blood tests to detect the enzyme creatine kinase, and a muscle biopsy. Other tests may also be used to confirm a diagnosis if symptoms of XLMTM are present or if there’s a family history that may suggest the condition.

Neurological and Physical Exams

Neurological exams and physical exams may be conducted to check for muscle weakness and its causes. These tests can help a doctor rule out the possibility of other health conditions.

Genetic Testing

Genetic testing can be used to verify mutations in certain genes that may point to a diagnosis of XLMTM.

Treatments for SMA

Recently, three disease-modifying therapies were approved for the treatment of SMA. More research is needed to learn more about SMA and to develop more therapies to treat it. Assessment tools like the Hammersmith Functional Motor Scale can help researchers measure improvements from new therapies or medications.

Other therapies or assistive devices may also be used to help a person with SMA get around, complete everyday tasks, or breathe or eat easier.

Treatments for XLMTM

Treatment for XLMTM is generally based upon the individual’s unique symptoms. Occupational therapy, physical therapy, and assistive devices can help with eating, getting around, and breathing.

Clinical trials have shown some promise for future treatments. One small clinical trial used gene therapy to deliver normal MTM1 genes into the muscles of nine boys with MTM. About a year after receiving this treatment, muscle biopsies showed that the boys’ muscle cells were producing the myotubularin protein in much higher amounts than before — at about 85 percent of normal levels. Their muscle fibers also grew larger. These changes led some of the boys to be able to sit up unassisted, take steps with some assistance, eat a small amount of food, and even vocalize sounds.

Another clinical trial using an investigational gene therapy called AT132 has also shown promising results. Two years after receiving treatment, the majority of children in the study were able to reduce their use of a respirator. Muscle biopsies also showed higher amounts of myotubularin, and the majority of children had improved functional assessment scores compared to their scores before the trial began.

It Takes a Team

At mySMAteam, you’ll find people from around the world who are also living with SMA. Here, members come together to ask questions, offer support and advice, and share their experiences living with SMA.

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