What is Nonketotic Hyperglycinemia?
Nonketotic hyperglycinemia (NKH) is an uncommon genetic disorder that affects how the body processes the amino acid called glycine. Amino acids are the building blocks of proteins that the body needs for growth and repair. This disease is due to a mutation or change in one of the enzymes, which are proteins that speed up chemical reactions in the body. In this case, the affected enzyme is supposed to break down glycine. Because of the mutation, the patient’s body can’t break down glycine properly, leading it to build up around the body.
Most of the excessive glycine gathers in the spinal cord and brain, which is why the symptoms, as well as the long-term effects of this disorder, are usually related to the nervous system.
Unfortunately, there are no known treatments that can change the usual course of nonketotic hyperglycinemia. However, medications and therapies can help reduce the other health problems that can occur with this condition. Early detection and treatment can significantly improve the outcome in patients, which is why it’s important for doctors to recognize this disease as soon as possible.
What Causes Nonketotic Hyperglycinemia?
The classic form of nonketotic hyperglycinemia, a rare genetic disorder, typically happens because of problems in certain genes (GLDC and AMT). These genes are supposed to help create parts of an enzyme that breaks down an amino acid called glycine. If there’s an issue with these genes, the enzyme doesn’t work as well as it should.
Recently, newer kinds of gene changes have been found in Chinese and Turkish patients during studies. Nonketotic hyperglycinemia is a condition that is inherited, meaning it is passed down from parents to their children. It’s a type of disorder known as autosomal recessive, meaning a child has to inherit two copies of the abnormal gene, one from each parent, to have the condition. The disorder usually starts showing signs at a very early age.
Risk Factors and Frequency for Nonketotic Hyperglycinemia
Nonketotic hyperglycinemia is a rare disorder that affects approximately 1 in 76,000 people globally. However, in certain regions, between 1 in 12,000 to 1 in 63,000 newborn babies may have this condition. This disease can afflict people of any background, but it’s found more often in those of Finnish heritage.
Signs and Symptoms of Nonketotic Hyperglycinemia
When a doctor suspects a patient might have an inborn metabolic disorder called nonketotic hyperglycinemia, several key steps are taken. The doctor will take a thorough history, focusing on symptoms such as tiredness, difficulty feeding, muscle weakness, seizures that do not respond to treatment, episodes of encephalopathy (a type of brain disease) without a clear cause, and periods of stopped breathing if the patient is a newborn. The doctor will also ask about the patient’s diet, growth, and development.
Extra attention will be given to any developmental delays, particularly problems with speech, hyperactivity, and how the patient’s symptoms have progressed as they’ve grown older. The doctor will also ask about the patient’s family history, with special focus on instances of unexplained stillbirths or infant death, and any long-term illnesses in the family. Since nonketotic hyperglycinemia starts in the womb and can cause abnormalities present at birth, the mother’s health history is also important. Questions regarding fetal movement, especially any unexplained hiccups, could be a sign of nonketotic hyperglycinemia.
During the physical examination, signs that may point to nonketotic hyperglycinemia include lethargy and changes in mental status similar to those seen in encephalopathy. A neurological examination is necessary, as well as a detailed examination of the patient’s respiratory system checking for unusual breathing patterns, hypotonia (abnormally low muscle tonus), which could lead to respiratory failure.
The disease is categorized into two forms: severe and attenuated. Patients with severe Nonketotic hyperglycinemia usually experience unmanageable seizures and show no signs of developmental progress. On the other hand, those with the attenuated form show varied developmental progress and either no seizures or seizures that can be easily managed.
Testing for Nonketotic Hyperglycinemia
For those with a condition called nonketotic hyperglycinemia, a number of tests are often carried out to figure out the cause, as it’s often unknown when the symptoms first show up. Some of the standard checks the doctors may perform include complete blood count (CBC), blood sugar levels, electrolytes (levels of certain minerals in the body), checking blood urea nitrogen and creatinine levels (which can show how well kidneys are working), uric acid levels, arterial blood gas analysis (to check for oxygen and carbon dioxide levels in your blood), ammonia levels, and liver enzymes.
Once these basic tests are done, the doctors may recommend specialized tests under the guidance of a metabolic specialist. For nonketotic hyperglycinemia, these tests may include measuring the level of an amino acid called glycine both in your blood and in the fluid in your brain and spine (this helps them measure the abnormal CSF-to-plasma glycine ratio which can be an indication of the disease), carrying out a magnetic resonance imaging (MRI) scan of your brain (to look for changes in certain parts of your brain), genetic testing (which can identify changes in your genes that cause the disease), and in some cases, analyzing the activity of certain enzymes (which can help to know the extent of the damage caused by the disease).
If the patient has been experiencing seizures, further tests like an electroencephalogram (EEG – a test that monitors electrical activity in the brain) may also be carried out.
Treatment Options for Nonketotic Hyperglycinemia
Nonketotic hyperglycinemia is a disorder that currently has no treatments that can alter its progression. However, treatments are available which focus on reducing levels of a substance in the body called glycine. This is often achieved using a medication called sodium benzoate. Some types of medication, such as dextromethorphan or oral ketamine, work by reducing the activity driven by glycine. These therapies have been noted to improve control of seizures and help with brain development, but this is only in selective cases.
Once diagnosed with nonketotic hyperglycinemia, it becomes necessary for patients to regularly undergo examinations for developmental progress. As they grow older, checks for scoliosis, a condition which causes the spine to curve, and hip dislocation are especially important. Regular eye examinations are also performed to determine the presence of cortical blindness, a condition where the brain cannot process visual information despite the eyes working properly.
As the condition may lead to high blood pressure in the lungs, known as pulmonary hypertension, it might be necessary for a patient to undergo a heart check-up. This is to decide whether medication might be beneficial for treating this. Sometimes, a referral to a specialist in the digestive system might be needed to figure out if special access for nutrition is necessary. Patients are often required to take long-term anti-seizure medications and might need diet changes or special surgical procedures, such as the placement of a vagal nerve stimulator, a device used to control seizures.
What else can Nonketotic Hyperglycinemia be?
When doctors are evaluating the cause of seizures or confusion, several conditions are usually explored before considering inborn metabolic disorders. The common conditions to consider first include:
- Acute changes in body’s metabolism (like low blood sugar)
- Lack of oxygen supply to the body (hypoxia)
- Bleeding inside the skull (intracranial hemorrhage)
- Severe bacterial infections in the blood (sepsis)
- Blood clots (thrombosis)
- Newborn seizure disorders
- Abnormalities in baby’s brain present at birth (congenital brain malformations)
During routine screening of new borns or when a doctor suspects an inborn defects of metabolism, lab tests might show signs of a disorder called nonketotic hyperglycinemia. However, several other conditions can also show similar lab results. These conditions need to be ruled out, they include:
- Certain medications (like valproate, which reduces the activity of a specific enzyme known as glycine cleavage enzyme system)
- mistakesin how the laboratory sample was collected
- Starvation
- Use of fluids that contain glycine (for instance, fluids used to wash out the bladder)
- Temporary glycine encephalopathy (brain disease) due to internal brain bleeding or oxygen deprivation
- Temporary glycine encephalopathy due high levels of glycine due to the immaturity of a specific enzymatic system in new borns
- Excessive production of glycine in the urine due to defects in how the kidneys handle glycine (like in familial iminoglycinuria or benign hyperglycinuria)
There are also certain inherited metabolic conditions which display symptoms like nonketotic hyperglycinemia, but they have different mechanisms at play and might require different treatment approaches.These include:
- Organic acidurias
- Epilepsy that is dependent on a specific type of Vitamin B6 (Pyridoxine dependent epilepsy)
- Disorders that affect how the body handles a type of B-vitamin (Disorders of intracellular cobalamin metabolism)
- GLYT1 encephalopathy
- Lipoate deficiency
What to expect with Nonketotic Hyperglycinemia
The long-term outlook or prognosis of an illness depends on certain factors. For our purposes here, we’re particularly interested in an enzyme called the glycine cleavage enzyme system. This enzyme plays a crucial part in determining how the illness may progress.
If there’s a severe deficiency of this enzyme, the condition tends to show itself quite early in life – typically, during the newborn period. Unfortunately, this early onset generally suggests a poorer outlook, as threatening conditions like difficulty in breathing might occur.
Newborns who manage to breathe spontaneously may later show symptoms like notable sleepiness, brain function abnormalities, or even death. To make matters worse, surviving patients might face lifelong serious developmental issues and unmanageable seizures.
On a more hopeful note, patients who start showing symptoms later in life (around three months or later) are likely to have less severe forms of the enzyme deficiency. For these individuals, the progress of developmental issues and the severity of seizures can vary. A significant part of it depends on how promptly the disease is identified and treated early on.
Possible Complications When Diagnosed with Nonketotic Hyperglycinemia
In newborn babies, this disease can cause serious breathing difficulties that result in low oxygen levels, necessitating respiratory support. If the breathing issues improve, the child might then fall into a state of progressive drowsiness or brain dysfunction. The lifespan can extend to several years in some cases, but it varies widely according to disease severity. Death can potentially happen at any time.
For survivors or those who develop the disease later in life (usually three months or beyond), the severity can also vary significantly. Such individuals might never achieve normal development progress and suffer from persistent seizures, high blood pressure in the lungs, difficulty swallowing and problems with the digestive system movement necessitating surgical intervention, a curved spine, hip dislocation from muscle stiffness, and even blindness. In infants, some studies have also noted the presence of excessive cerebrospinal fluid in the brain, requiring surgical treatment to relieve the fluid buildup.
Common Conditions and Issues:
- Severe breathing difficulties
- Low oxygen levels
- Progressive drowsiness or brain dysfunction
- Persistent seizures
- High blood pressure in the lungs
- Difficulty swallowing
- Disruption with the digestive system movement
- Scoliosis (a curved spine)
- Hip dislocation from muscle stiffness
- Potential blindness
- Excessive cerebrospinal fluid in the brain
Preventing Nonketotic Hyperglycinemia
Doctors should explain to parents about the long-term outcomes of a condition known as nonketotic hyperglycinemia, specifically the chance of nervous system problems for the children who survive this condition. If a child with this condition develops chronic epilepsy, parents should be particularly cautious, making sure there is proper supervision to avoid any possible danger if a seizure were to occur.
Family counselling that focuses on genetic health might be needed to assist the parents and siblings of a child with nonketotic hyperglycinemia. This counseling will help them understand the possibility of this condition reoccurring in the family due to genetic reasons, which will aid them in making future health-related and personal decisions in an informed way.
