What is Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)?
Subacute necrotizing encephalomyelopathy (SNE), or Leigh syndrome, is a disease with a variety of genetic causes that mainly impacts the brain and nervous system. This condition was first identified in 1951. Leigh syndrome is defined by specific areas of tissue damage (also known as “necrotic” lesions) that are present on both sides of the body and are found in specific parts of the brain and the back part of the spinal cord.
What Causes Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)?
ATP is like the main battery of our body’s cells, providing them with the energy they need to function. Our cells make ATP by pushing hydrogen ions from a crowded to a less crowded area, similar to water flowing down a waterfall. This process takes place within tiny structures in our cells called mitochondria, specifically during a process called ‘oxidative phosphorylation’.
In a condition called subacute necrotizing encephalomyelopathy (SNE), changes in the genetic structure of the mitochondria disrupt the production of these energy batteries (ATP). The disruption in ATP production results in the specific problems seen in SNE.
The causes behind SNE are complex, as changes, or mutations, can occur in many different parts of the mitochondria, disrupting the entire energy production process. Scientists have identified changes in over 85 different genes that can lead to this condition, and these changes can be inherited in several ways, including through autosomal (from both parents), X-linked (mainly from mother), or mitochondrial DNA patterns.
Risk Factors and Frequency for Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)
Subacute necrotizing encephalomyelopathy, more commonly known as Leigh Syndrome, usually starts showing symptoms in infants between three and 12 months of age. Cases in adults have been reported but are very rare. The chance of a child having the disease depends on what type of inheritance pattern is involved.
- If the disease is passed down through genes in the cell nucleus, it affects about 1 in 40,000 newborn babies.
- If the disease comes from the mitochondrial inheritance pattern, it’s much less common, affecting about 1 in 100,000 to 1 in 140,000 babies.
- The rate of the disease is much higher in certain areas, such as the Faroe Islands between Norway and Iceland, where it affects about 1 in 1,700 babies.
- In Lac-Saint-Jean region in Quebec, Canada, the disease affects about 1 in 2,000 newborns.
It’s also worth noting that the disease seems to start earlier in people who have changes or mutations in their nuclear DNA compared to mitochondrial DNA.
Signs and Symptoms of Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)
Subacute necrotizing encephalomyelopathy, a condition affecting the brain and spinal cord, usually results in specific signs and symptoms related to nervous and muscle functions. The condition causes a delay in development or a regression that is seen in over half of the patients. Other symptoms include slow movement progression, cognitive decline, abnormal involuntary muscle contractions, lack of coordination, and brainstem dysfunction.
- Developmental delay or regression (most common)
- Slow movement progression
- Cognitive decline
- Abnormal involuntary muscle contractions
- Lack of coordination
- Brainstem dysfunction
- Epileptic seizures and respiratory problems (found in roughly one-third of cases)
- Muscle weakness and fatigue
- Low muscle tone
- Tremors
- Poor sucking and feeding
- Drooping of the eyelid (ptosis)
- Repeated eye movements
- Failure to thrive
Additionally, these patients can also experience heart issues such as an enlarged heart, irregular heart rhythm, and dilated cardiomyopathy (weak heart muscles). It is important to note that due to the high mortality rate associated with this condition at an early age, it is often difficult to trace a family history of this ailment. In some exceptional cases, the mother of the affected child may exhibit mild symptoms later in life or remain symptom-free even though they carry the variant of the disease in their mitochondrial DNA.
Testing for Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)
Subacute necrotizing encephalomyelopathy, a serious neurological disorder, can be detected through numerous laboratory, genetic, and imaging tests. Although there aren’t any universally agreed-upon criteria for diagnosis, patients with this condition do tend to exhibit certain common features.
One significant finding from recent research indicates that up to 72% of patients often have higher than usual levels of lactate in both their blood and cerebrospinal fluid (CSF) – the fluid that surrounds your brain and spinal cord.
On a genetic level, the condition is typically characterized by faulty genetic material in the cells. Most people with this disorder (about 80%) have incomplete sets of the enzymes required by our cells’ mitochondria – “energy factories” of our cells – to generate energy. Researchers have found that these gaps are usually caused by genetic mutations either in the mitochondria (32%) or the cell nucleus (38%).
Imaging scans also play a significant role in diagnosing this condition. Patients with this condition often have distinct brain and spinal cord damage that shows up on these scans. Computer Tomography (CT) and Magnetic Resonance Imaging (MRI) scans often reveal irregular areas in the spinal cord, the basal ganglia (the part of the brain responsible for movement), the cerebellum (the part which controls balance), the brainstem (connecting the brain to the spinal cord), and the diencephalon (involved in sensory perception and motor function).
On CT and T1-weighted MRI scans, these unusual areas appear as spots of low signal intensity (hypointense), whereas on T2-weighted MRI scans, they appear as high signal intensity spots (hyperintense).
Besides these, changes can also be observed in muscle tissue, such as abnormal build-up in the sarcoplasm (the ‘cytoplasm’ of the muscle fiber). Microscopic examination may reveal normal and abnormal shaped mitochondria, or unusually large, swollen mitochondria with irregular internal structures.
Treatment Options for Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)
Currently, there is no cure for subacute necrotizing encephalomyelopathy, a serious and rare condition that affects the brain and spinal cord. However, there are different ways to manage the condition and its symptoms. The treatment approach largely depends on how the condition is passed on in families.
The focus of treatment is two-fold: dealing with underlying issues related to metabolism (the body’s process of turning food into energy), and caring for symptoms such as acidosis (too much acid in the body), seizures, and dystonias (involuntary muscle contractions).
When there is too much acid in the body, it can be lessened with minerals such as sodium bicarbonate or sodium citrate. Seizures can be managed with medications that control electrical activity in the brain, though certain drugs like sodium valproate and barbiturates are not recommended as they may further disturb the mitochondria (the “powerhouse” of the cell).
Dystonias can be treated with a range of drugs, including benzhexol, baclofen, tetrabenazine, and gabapentin. In cases where these drugs don’t work, injections of botulinum toxin (Botox) may be considered.
In cases where subacute necrotizing encephalomyelopathy involves nuclear DNA (the genes in the cell’s nucleus), the treatment strategy can be different depending on the subtype. For example, patients with a deficiency in thiamine transporter-2 or biotinidase have been known to respond well to lifelong treatment with supplements of thiamine and biotin, or just biotin alone. Furthermore, individuals with a deficiency in coenzyme Q10 biosynthesis (a process that creates an important molecule for energy production) have shown positive responses to coenzyme Q10 supplementation.
There are also new therapies for this condition being developed. In 2012, a phase 2A trial saw promising results with a new drug called EPI-743. Among the children with SNE involved in the trial, those treated with this drug showed significant improvements and reversal in disease progression, as compared to untreated children.
What else can Subacute Necrotizing Encephalomyelopathy (Leigh syndrome) be?
Subacute necrotizing encephalomyelopathy, a rare brain disorder, can be imitated by many other conditions. Thus, during the diagnosis process, it’s important to keep in mind diverse possible diseases. Some diseases affecting the energy-producing parts of our cells, known as mitochondria, can show symptoms similar to both nuclear DNA and mt-DNA variants. This includes diseases such as mitochondrial depletion syndrome, mitochondrial translation defect, and MEGDEL syndrome.
What to expect with Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)
The outlook for subacute necrotizing encephalomyelopathy, a rare and severe brain disease, is unfortunately not good. On average, the age of death is slightly over 2 years, primarily due to complications with breathing. Heart failure and difficulties in breathing also contribute to the death of about half of the affected individuals by the time they reach three years old.
This condition bears similarities to other diseases related to mitochondria (the powerhouses of our cells), with an average survival period of about 90 days. The chances of surviving become even less when the disease shows up before 6 months of age, when the child fails to grow and develop normally, when there are lesions or injuries on the brainstem, and when the patient needs to be admitted to the Intensive Care Unit (ICU).
Though rare, this disease can also affect adults. When it does, it’s generally less severe.
Possible Complications When Diagnosed with Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)
Most of the complications from subacute necrotizing encephalomyelopathy, a type of brain disease, are connected to the central and peripheral nervous systems. These include problems like hearing loss, a eye disease called retinitis pigmentosa, developmental delays, and difficulty in swallowing. The nervous system issues can even extend to other areas of the body, causing conditions such as polyneuropathy and myopathy (nerve and muscle disorders). Other less common complications can include heart issues (hypertrophic cardiomyopathy) and hormonal imbalances.
Common complications:
- Problems with the central and peripheral nervous systems
- Hearing loss
- Retinitis pigmentosa (eye disease)
- Developmental delays
- Difficulty swallowing
- Polyneuropathy and myopathy (nerve and muscle disorders)
- Heart issues
- Hormonal imbalances
Preventing Subacute Necrotizing Encephalomyelopathy (Leigh syndrome)
SNE, also known as Subacute Necrotizing Encephalomyelopathy, is a rare and life-threatening disease. Because of this, it’s critical that if a child is affected, their parents are tested for any genetic abnormalities that could have contributed to the disease. Moreover, it’s important to discuss the risks of having more children with affected families. Once the disease appears, it’s crucial to determine which specific version of the disease the child has. This information can influence the direction and effectiveness of the treatment.
