What is Zellweger Spectrum Disorder?
Zellweger spectrum disorder, also known as cerebrohepatorenal syndrome, is a rare genetic condition. This disorder means that cells lack or have reduced numbers of peroxisomes, which are little compartments inside cells that help break down very long-chain fatty acids (a type of fat in our body). This condition is inherited in an autosomal recessive manner, meaning a child needs to inherit a copy of the defective gene from each parent to have the disease.
The Zellweger spectrum includes several disorders based on their symptoms and severity. These include Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata type 1 (RCDP1).
What Causes Zellweger Spectrum Disorder?
Zellweger spectrum disorder is caused by changes or mutations in various genes needed for the creation of a part of the cell called the peroxisome. There have been links to mutations in at least 13 different PEX genes which make proteins known as peroxins. These are like a construction team for the peroxisome. The most common mutations occur in the genes known as PEX1 or PEX6, found in about 65% of patients. These genes make a protein that helps transport other proteins into the peroxisome.
Peroxisomal disorders can be divided into three groups based on how the peroxisome is affected:
1. In conditions like Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease, the peroxisome function is usually lost.
2. Adrenoleukodystrophy is a similar disorder where the peroxisome doesn’t function properly. This results in significant problems with the nervous system and adrenal glands. Neonatal adrenoleukodystrophy is considered part of Zellweger spectrum disorder because it also results from a PEX mutation. Other adrenoleukodystrophy disorders are caused by mutations in ABCD1, another gene responsible for transporting very long-chain fatty acids into peroxisomes.
3. Rhizomelic chondrodysplasia punctata is associated with multiple defects in the enzymatic functions of the peroxisome.
Risk Factors and Frequency for Zellweger Spectrum Disorder
Zellweger spectrum disorder is a common disorder that affects the peroxisomes, small parts of cells. It usually shows up in babies just after they’re born. Approximately 1 in 50,000 newborns in the United States are diagnosed with this disorder, but the numbers can be quite different in other parts of the world.
- Zellweger spectrum disorder is common in the United States, affecting 1 in 50,000 newborns.
- Quebec sees a higher incidence with 1 in 12,000 newborns affected.
- Japan has a lower incidence, diagnosing the disorder in 1 in 500,000 newborns.
- The overall incidence of this disorder in newborns ranges between 1 in 50,000 to 100,000.
Signs and Symptoms of Zellweger Spectrum Disorder
The disorder we refer to impacts almost every system in the body because it affects peroxisomes, which are present in almost all our cells. This can lead to a wide variety of symptoms, including:
- Severe abnormalities in the skull and face
- Very weak muscle tone, or hypotonia
- Significant delay in brain development
- Loss of sense of hearing
- Eye abnormalities
- Irregularities in tooth enamel
- Enlarged liver, or hepatomegaly (in 80% of cases)
- Increased levels of liver enzymes and bilirubin
- Kidney cysts (in 70% of cases)
Patients can be categorized into three groups based on their age at presentation:
- Neonatal-infantile presentation: Most children show signs such as weak muscle tone, reduced movement, and a weak cry. They often struggle with feeding and may have seizures in the neonatal phase. They may have an unusual facial structure, including a high forehead, large soft spots on the skull, wide cranial sutures, underdeveloped ridges above the eyes, and a wide nasal bridge. They may also have ocular abnormalities such as glaucoma, cataracts, and retinopathy; along with varying levels of deafness.
- Childhood presentation: These children may face developmental delays, have difficulties growing and thriving, and experience eye, hearing abnormalities. They may also suffer from liver dysfunction, adrenal gland insufficiency, and kidney stones made of calcium oxalate. Furthermore, they may experience regression of neurological milestones due to the loss of their nerve’s white matter, a condition known as leukodystrophy.
- Adolescent and adult presentation: Older individuals may also exhibit developmental delay, regression in their neurological functions, or issues with balance and coordination due to damage to the cerebellum (cerebellar ataxia). They might also present peripheral neuropathy, adrenal gland insufficiency, and leukodystrophy.
Testing for Zellweger Spectrum Disorder
The first step in diagnosing a disease is identifying signs and symptoms, and testing the blood for specific markers. In this case, the markers are called very-long-chain fatty acid (VLCFA). These are large molecules of fat that might be found in the blood during a test we do on newborns.
If high levels of VLCFA are found, the next step is to conduct genetic testing. It’s possible to identify certain changes or mutations in genes known as PEX genes that signal the presence of the disease.
Further testing is then conducted to look for other signs of the disease. This includes checking for high levels of VLCFA, certain kinds of acids (like phytanic or pristanic acid), pipecolic acid, and bile acid intermediates. The test also checks for low levels of plasmalogen, a specific type of molecule, in red blood cells.
Still, some patients with a milder form of the disease might show normal levels in these biochemistry tests. In such cases, if there’s still a strong suspicion of the disease, a special test would be done on skin cells, known as fibroblasts. These cells would be grown in a lab in 40 °C temperature to confirm the diagnosis.
Once the diagnosis is confirmed, genetic counselling becomes important for the patient and their family to understand the implication of the diagnosis. Prenatal diagnosis is also significant since this disease can be passed from parents to their children.
Treatment Options for Zellweger Spectrum Disorder
Zellweger spectrum disorder is a severe condition that progresses quickly, and unfortunately, it often results in death. Currently, there’s no cure for this disorder, so doctors focus on providing care that aims to make patients more comfortable and enhance their quality of life.
Various treatments have been studied, including:
- Docosahexaenoic acid: This is a type of unsaturated fatty acid that’s vital for brain and eye development and is typically low in patients with Zellweger spectrum disorder. However, trials have shown that supplementing this acid doesn’t improve neurological symptoms or vision problems.
- Lorenzo’s oil: This is a combination of certain types of fats that were initially used to treat a different condition called X-linked adrenoleukodystrophy. Although it can reduce the levels of certain harmful fats in the blood, it doesn’t seem to slow down the progression of the disease.
- Cholic acid: This is a type of bile acid that helps the body absorb vitamins that dissolve in fat. People with Zellweger spectrum disorder often have trouble absorbing these vitamins, due to liver problems. Although the FDA has approved the use of cholic acid, there’s not enough evidence yet to show it’s effective.
There are also various supportive measures that can help manage specific symptoms, including:
- Hearing aids or cochlear implants for hearing loss
- Eye doctor visits, cataract surgery, and glasses to improve vision
- Regular epilepsy medication for seizures
- Vitamin K supplements for blood clotting problems
- Cortisone for adrenal gland disorders
- A feeding tube to ensure sufficient calorie intake
- Supplements to increase levels of vitamins A, D, E, which are important for various body functions and tend to be low in patients with Zellweger spectrum disorder
What else can Zellweger Spectrum Disorder be?
When trying to determine if a person has Zellweger spectrum disorder, doctors look at the main symptoms, and consider other health issues that could cause the same symptoms. These health conditions vary based on the key symptom that the person is showing:
For example, if a newborn has low muscle tone (hypotonia), the doctors would think about the following possibilities:
- Chromosomal abnormalities such as Down Syndrome or Prader-Willi Syndrome
- Spinal muscular atrophy
- Hypoxic-ischemic encephalopathy, a type of brain injury
- Other disorders related to peroxisomes (tiny parts of cells that help break down fats), like acyl-CoA oxidase type 1 deficiency or D-bifunctional protein deficiency
If the person displays signs of sensorineural hearing loss with retinitis pigmentosa (a gradual loss of vision), the doctors may consider:
- Usher syndrome type 1 or 2
- Cockayne syndrome
- Alport syndrome
- Waardenburg syndrome
- Classical Refsum disease
If the person has cataract in both eyes (bilateral cataract), they will think about:
- Lowe syndrome
- Galactosemia, a rare genetic disorder that affects how the body processes a simple sugar called galactose
- Congenital infections
- Rhizomelic chondrodysplasia punctata, a rare genetic disorder that affects many parts of the body
Lastly, if someone has signs of adrenocortical insufficiency (when the adrenal glands don’t produce enough hormones), the differential diagnoses would include:
- Adrenal hemorrhage, or bleeding within the adrenal gland
- X-linked adrenoleukodystrophy, a genetic disorder that affects the nervous system and the adrenal glands
- Infectious adrenalitis, or inflammation of the adrenal glands due to an infection
What to expect with Zellweger Spectrum Disorder
Babies who show symptoms right after birth usually have a very poor chance of survival, often passing away within their first year. Children who start showing symptoms later in life can develop serious and progressive liver disease. However, they might live a bit longer after diagnosis compared to infants. Teens with this condition may live a bit longer but generally develop worsening nerve-related symptoms, like muscle stiffness (spasticity) and nerve damage in the arms and legs (peripheral neuropathy), later in life.
Possible Complications When Diagnosed with Zellweger Spectrum Disorder
Zellweger spectrum disorder can lead to various complications which include:
- Bleeding in the digestive tract
- Failing liver
- Pneumonia, an infection that inflames the air sacs in your lungs
- Respiratory distress, a severe breathing difficulty
- Infections
Preventing Zellweger Spectrum Disorder
Zellweger spectrum disorder is a severe, progressive illness that affects many parts of the body from birth. Sadly, even with advanced medical care, individuals with this disease often don’t survive long, and it’s common for affected children to live up to only 2 years. This duration can vary based on their genetic makeup. The common causes of death include breathing failures, a severe form of sleep apnea, or complications due to infections.
Because this disease cannot be specifically treated and generally leads to severe outcomes, it is advised for anyone who might carry the genes for this disease to undergo genetic testing and counseling when considering starting a family. This way, they can understand their risks and make informed decisions. For those identified as potential carriers, prenatal or preimplantation genetic diagnosis, which is a way of testing the fetus or embryo for the disease before pregnancy is also an available method.
