Spinal muscular atrophy (SMA) is a rare genetic condition characterized by the progressive loss of motor neurons, the specialized nerve cells that control voluntary movement, leading to muscle weakness and wasting.
The most common forms of SMA — types 0, 1, 2, 3, and 4 — are mostly caused by mutations in the SMN1 gene, which provides instructions to produce a protein essential for motor neuron and muscle health.
Rarer types of SMA are caused by mutations in genes other than SMN1.
X-linked infantile SMA
X-linked infantile SMA is a very rare and severe form of spinal muscular atrophy that mainly affects boys, starting before or shortly after birth. It partly resembles SMA types 0 and 1, the most severe, common forms of the condition.
This rare form is caused by changes in the UBA1 gene, which provides the instructions for making an enzyme of the same name that is essential for breaking down damaged or no-longer-needed proteins inside cells. These mutations are thought to impair normal protein breakdown, leading to a toxic buildup of waste material to which motor neurons are particularly vulnerable, dying as a consequence.
While still in the womb, affected babies may be less active (lesser movement) in the later stages of pregnancy. At birth, they typically have low muscle tone (lack of tension in the muscles, which can cause floppiness), absent reflexes, and multiple joint deformities that can be accompanied by bone fractures.
These deformities, along with progressive muscle weakness, affect the baby’s ability to move. While some early developmental milestones, such as being able to sit independently, may be reached, they will likely be loss as the condition progresses.
The muscles involved in sucking, swallowing, and breathing are also severely affected, leading to nutritional and breathing problems.
Other symptoms may include an unusually small chin, abnormal curvature of the spine, and testicles that fail to descend.
Most boys with X-linked infantile SMA do not survive beyond early childhood due to respiratory failure, but there have been rare reports of children surviving until adolescence.
SMA with respiratory distress type 1
SMA with respiratory distress type 1 (SMARD1) is an extremely rare and severe form of spinal muscular atrophy caused by mutations in the IGHMBP2 gene.
This gene provides instructions for making a protein that is involved in DNA replication, RNA production, and protein generation. DNA replication is the process by which DNA makes a copy of itself to allow for cell division, and RNA is a cousin molecule of DNA generated mainly to guide protein production. While it remains unclear how these mutations affect motor neurons in particular, motor nerve cells may be particularly vulnerable to problems in either of these vital processes.
Sometimes called severe infantile axonal neuropathy with respiratory failure and distal SMA type, SMARD1 closely resembles SMA type 1, a severe and more common, infantile-onset form of the disease. However, there are many reports of a later-onset juvenile form of SMARD1.
Typically, the first and most noticeable symptoms of SMARD1 are breathing difficulties, or respiratory distress, starting between the ages of 6 weeks and 6 months. These issues are caused by paralysis of the diaphragm, the thin muscle that separates the chest cavity from the abdomen and is essential for breathing.
Breathing problems are usually accompanied by weakness in distal muscles, or those furthest from the center of the body, such as those in the hands and feet. This muscle weakness rapidly spreads to all muscles — impairing motor skills such as sitting, standing, and walking — and typically stabilizes within two years.
Children with SMARD1 often experience complete paralysis of the limb and trunk muscles, but the retention of muscle function after age 2 is variable among patients.
Abnormal curvature of the spine, bone/joint problems, and absent deep tendon reflexes — such as the reflex that occurs when a person’s knee is tapped — are also common. Patients may also have reduced pain sensitivity, excessive sweating, loss of bladder control, gastrointestinal problems, and an irregular heartbeat.
The life expectancy of children with SMARD1 is difficult to predict because the progression of the disease differs among patients. Without mechanical ventilation, most affected infants die from respiratory failure before 13 months of age.
SMA with lower extremity predominance
SMA with lower extremity predominance (SMA-LED) is a slowly progressing form of spinal muscular atrophy that mainly affects the leg muscles.
It is caused by changes either in the DYNC1H1 gene (often called SMA-LED type 1) or in the BICD2 gene (called SMA-LED type 2). Both genes provide instructions for making proteins that are part of the dynein-dynactin complex, a protein complex involved in moving molecules and other materials within cells.
By reducing molecule transport, these mutations are thought to impair motor neuron growth and function, ultimately leading to their death. Notably, BICD2 mutations also affect the structure of the Golgi apparatus — the distribution and shipping center of a cell’s proteins and fatty molecules — which may further contribute to motor neuron death.
Still, it remains unclear why this condition primarily affects the motor neurons controlling the leg muscles.
SMA-LED is characterized by slowly progressing muscle weakness and atrophy in the leg muscles that typically become noticeable in infancy or early childhood. However, about one-quarter of affected individuals do not develop symptoms until adulthood.
The disease most severely affects the quadriceps, or the large muscles of the thighs, challenging a child’s ability to rise from a seated position, walk, and/or climb stairs. Some patients may also have weakness in upper limb muscles. Joint deformities and rigidity may also develop.
Most people with SMA-LED have a normal lifespan. Some may need support, such as braces or a wheelchair, for mobility later in life.
SMA with progressive myoclonic epilepsy
As the name suggests, SMA with progressive myoclonic epilepsy (SMA-PME) is characterized by a combination of progressive muscle weakness and myoclonic seizures — brief muscle “jerks” or spasms.
Also known as SMA plus, the disease is caused by mutations in the ASAH1 gene, which contains the instructions to produce an enzyme involved in fatty molecule breakdown inside cells. These mutations result in a reduced enzymatic activity that impairs the normal breakdown of these fatty molecules, which may trigger motor neuron death through still-unclear mechanisms.
After several years of normal development, children with SMA-PME develop muscle weakness in the legs that spreads first to the arms and later to muscles throughout the body.
This muscle weakness eventually affects their ability to swallow and breathe, increasing the risk of pneumonia and respiratory failure — the main causes of death in these patients. Pneumonia is an infection that inflames the air sacs in one or both lungs.
Seizures, which be of other types besides myoclonic, typically appear some years after the onset of muscle weakness, become more frequent over time, and are not well controlled with standard anti-seizure medication.
Affected children may also have episodes of tremors, usually in the hands, and lose their hearing due to neurological damage.
Life expectancy is affected in SMA-PME patients, who generally living into late childhood or early adulthood.
Finkel type SMA
Finkel type SMA — first described by Richard Finkel, MD, in 1962 and named after him — is an adult-onset, slowly progressive form of SMA associated with mutations in the VAPB gene.
The protein this gene works to produce, the VAPB protein, is thought to be involved in the detection of unfolded or misfolded proteins to activate cellular events that prevent their toxic accumulation inside cells. By preventing this process, VAPB gene mutations lead to the death of motor neurons, which appear to be particularly vulnerable to this toxic buildup.
Symptoms, often mild to moderate in severity, typically appear between the second and third decade of life and mainly affect the proximal muscles, or those closest to the body’s center, such as the muscles in the legs and arms. Symptoms include muscle weakness and cramping of the limbs and abdomen, tremors, and involuntary muscle twitching.
People with Finkel type SMA generally have a normal lifespan. They may eventually need assistance or support with daily activities, such as walking, as they get older.
Kennedy’s disease
Kennedy’s disease, named after William R. Kennedy — the first physician to describe the condition in 1966 — is an adult-onset form of SMA that mainly affects males and progresses very slowly.
It is caused by a mutation in the androgen receptor (AR) gene, which provides the instructions to make the receptor protein of androgens, a group of hormones, such as testosterone, that are important for normal male sexual development.
This mutation is characterized by excessive repeats of three nucleotides — the building blocks of DNA: one cytosine (C), one adenine (A), and one guanine (G). These excessive CAG repeats lead to the formation of an abnormally long, non-working receptor protein that cannot bind to androgens, thereby preventing the transmission of their signal and subsequently their biological action.
How this mutation causes motor neurons damage and leads to Kennedy’s disease remains poorly understood, but it is thought that the resulting abnormal protein may accumulate to toxic levels inside these cells, triggering their death.
Also known as spinal and bulbar muscular atrophy (SBMA), the disease’s hallmark is progressive weakness and atrophy of the proximal and bulbar muscles. Proximal muscles are those closer to the trunk, such as those in the legs and arms, while bulbar muscles, those of the mouth and throat, are involved in swallowing, chewing, and speech.
Symptoms usually begin between the ages of 30 and 50, and first affect the muscles in the legs and arms. Cramping, tremors, and involuntary twitches are common. As the disease progresses, patients may start to experience a risk of falls and walking difficulties that may later lead to the need of walking aids or a wheelchair to move around.
Bulbar muscles are typically affected later in the disease course, causing problems with speech and swallowing, which increase the risk of choking on food or liquids, and of aspiration pneumonia. Aspiration pneumonia is a lung infection that develops due to food or liquid being aspirated into the lungs.
Men with SBMA may also develop enlarged breasts, testicular shrinkage, a lesser sex drive, impotence, and reduced fertility.
These patients usually have a normal life expectancy, but some (less than 10%) die in their 60s or 70s due to asphyxiation or aspiration pneumonia related to swallowing difficulties.
Inheritance
Like the five main types of SMA, SMARD1 and SMA-PME are inherited in an autosomal recessive manner, meaning that a child must acquire two defective copies of the disease-causing gene — one from the mother and one from the father — to develop the disorder.
In these cases, people with only one mutated gene copy are typically healthy, but are considered to be carriers because they can still transmit the mutated gene to their own children. If both parents are carriers, each of their children have a 25% chance of inheriting two mutated copies and developing the disease, and a 50% risk of being a carrier.
SMA-LED and Finkel type SMA are autosomal dominant forms, meaning that a single mutated copy of the disease-causing gene is sufficient to cause the disease. Those with these diseases will have a 50% chance of transmitting the condition to their children. If both parents are affected by the disease and have a single mutated gene copy, their children would have a 3-in-4 risk of inheriting one or more faulty copies of the gene and developing the condition.
X-linked recessive forms, including X-linked infantile SMA and Kennedy’s disease, involve mutations in genes located in the X chromosome (one of the two sex chromosomes, the other being the Y chromosome).
Men who inherit the mutated gene will develop the condition, as they only have one X chromosome (inherited from the mother). In women — who have two X chromosomes, one from the mother and one from the father — the mutated gene copy can be compensated by a healthy copy, and they most likely will not show any disease symptoms.
However, female carriers have a 50% chance of having a son with the condition, and a 50% risk of having a daughter who will also be a carrier. Men with any of these X-linked diseases will transmit the mutation to all their daughters (who will be carriers), but not to their sons, because boys receive a Y sex chromosome from their fathers, instead of an X chromosome.
Diagnosis
When symptoms of any of these diseases are present and/or there is a history of such a condition in the family, a diagnosis can be confirmed through genetic testing, which screens for mutations in disease-related genes.
DNA testing also is highly reliable in identifying carriers — which can help to estimate a person’s chances of having a child affected by the disease — as well as affected babies, either while still in the womb or shortly after birth.
Currently, screening for mutations in genes associated with these rarer types of spinal muscular atrophy are not part of standard SMA genetic tests, but may be requested if a diagnosis is strongly suspected.
Treatment
There is currently no disease-modifying treatment for any of these rarer types of SMA. Disease management focuses on easing patients’ discomfort and maintaining or improving their quality of life.
Last updated: Nov. 8, 2021, by Marta Figueiredo PhD
***
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.
