Zellweger spectrum disorder is a genetic disorder. Severe Zellweger syndrome symptoms include distinctive facial features, such as a flattened face and widely spaced eyes. Read about Zellweger syndrome treatment at Meri Sehat.

Zellweger Spectrum Disorders

Overview

Zellweger spectrum disorders is a group of rare genetic diseases that affect multiple parts of the body. The most severe form of the disease is known as Zellweger syndrome, the moderate form of the disease is called neonatal adrenoleukodystrophy, whereas the mild form of the disease is called infantile Refsum disease or Heimler syndrome<a href="#accordion">[1]</a>.

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The Zellweger spectrum affects multiple parts of the body. Zellweger Syndrome is a genetic disorder that is characterized by the defect in any one of the ZSD-PEX genes. The children have all the signs and symptoms from birth, but they worsen overtime. It is common for kids with Zellweger spectrum disorder to develop other life-threatening issues, in multiple organs such liver, heart, and kidneys<a href="#accordion">[4]</a>.

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Zellweger Syndrome disorder is not highly prevalent and occurs in 1 out of 50,000 individuals. The disorder has many different names including:

<ul>
	<li>PBD-ZSD</li>
	<li>PBD, ZSS</li>
	<li>Zellweger spectrum</li>
	<li>Zellweger syndrome spectrum</li>
	<li>ZSD</li>
	<li>Peroxisome biogenesis disorder</li>
</ul>

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Since it is an autosomal recessive disorder, it means that the children have a 50% chance of becoming a carrier and a 25% chance of actually getting the disease if both parents carry the mutated gene.

Pakistan follows the same pattern of prevalence i.e., 1 in 50,000<a href="#accordion">[2]</a>. The rate of neonatal mortality in Pakistan has only declined by 0.9% throughout the years. Hypoxic-ischaemic encephalopathy (HIE) is one of the leading causes of neonatal mortality, however, HIE is often over-diagnosed since the clinical presentation of the inherited metabolic disorders overlaps with clinical features of HIE and sepsis. Hence, to effectively decrease rates of neonatal mortality, neonates with sepsis and HIE-like clinical presentation should also be evaluated for inherited metabolic disorders<a href="#accordion">[3]</a>.

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Types of Zellweger Spectrum Disorders include:

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<h5>Zellweger Syndrome</h5>

This is the most severe form of the disease. The syndrome mainly targets the nerves and the metabolism of the newborn baby. The brain, liver, and kidneys are the most affected organs in Zellweger syndrome. This is also known as cerebrohepatorenal syndrome. There is no cure for Zellweger syndrome and the treatment has a symptomatic approach for the maintenance of the disease. In most cases, the infants rarely survive for more than 6 months<a href="#accordion">[5]</a>.

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<h5>Neonatal Adrenoleukodystrophy</h5>

In the Zellweger spectrum, this is considered the moderate form of the disease. The abnormal features of the disease, present at birth include psychomotor retardation, muscle hypotonia, and stunted growth. It is also common for children to be blind and deaf. They can also experience frequent seizures. A retinopathic leopard spot is most commonly used to identify neonatal adrenoleukodystrophy<a href="#accordion">[6]</a>.&nbsp;

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<h5>Infantile Refsum Disease (IRD)</h5>

Also known as Mild peroxisome biogenesis disorder-Zellweger spectrum disorder (Mild PBD-ZSD) or Heimler Syndrome, this is the mildest form of Zellweger Spectrum Syndrome<a href="#accordion">[7]</a>. Symptoms may include nystagmus, hypotonia, sensorineural hearing loss, growth retardation, mild facial dysmorphism, and hepatomegaly. Hepatic dysfunction is first displayed in infants and in childhood, progressive retinitis pigmentosa, developmental deficits, and hypotonia are seen. Since the main issue is the breakdown of phytanic acid, a chemical that is not produced by the body, avoiding foods that contain phytanic acids is the primary treatment. IRD is a fatal disease, but with proper and rigorous treatment children can survive till adolescence and even early adulthood<a href="#accordion">[8]</a>.

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Signs And Symptoms

The symptoms of the Zellweger spectrum vary on the basis of its severity. Some of these symptoms include:

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<ul>
	<li>Hypotonia</li>
	<li>Difficulty feeding</li>
	<li>Seizures</li>
	<li>Hearing loss</li>
	<li>Vision loss</li>
	<li>Distinctive facial features (flat midface)</li>
	<li>Skeletal abnormalities</li>
	<li>Delayed psychomotor development&nbsp;</li>
	<li>Diffuse encephalopathy</li>
	<li>Muscle weakness</li>
	<li>Numbness</li>
	<li>Dry and scaly skin</li>
	<li>Liver cysts and/or kidney cysts</li>
	<li>Involuntary eye movement</li>
	<li>Hepatomegaly and/or splenomegaly</li>
</ul>

<div>&nbsp;</div>

Causes

Zellweger Syndrome is a genetic disorder that is caused due to mutations in the genes involved in peroxisome biogenesis. They are also known as pexins or PEX. Faulty PEX genes mean that the assembly of the proteins required for the formation of peroxisomes is going to be faulty. This also results in malfunctioning of the peroxisomes. 60% of the cases of Zellweger syndrome have mutations in the PEX1 gene. There are around 90 different variations of the mutations identified. Other affected genes include PEX2, PEX5, PEX6, PEX12, and PEX26<a href="#accordion">[10]</a>.

Most ZSD patients are found to accumulate very long-chain fatty acids and have a plasmalogens deficiency. In cases of infantile Refsum disease, the patients are mostly phytanic acid resistant<a href="#accordion">[9]</a>.

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Diagnosis

Diagnosis of ZSD can be very difficult; considering the wide range of symptoms and the rarity of the disease, it&rsquo;s never the primary suspect. The distinct facial features can be a prominent sign seen in the physical examination<a href="#accordion">[9]</a>. The disorder is then confirmed by the following tests:

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<ul>
	<li>Blood And Urine Tests: High levels of different fat molecules, especially the ones that are not metabolized by the body due to the mutated genes, indicate Zellweger spectrum disorder.</li>
</ul>

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<ul>
	<li>Biochemical Testing Of Skin Fibroblasts: This is useful to confirm the abnormalities seen in the body fluid samples e.g. blood and urine</li>
</ul>

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<ul>
	<li>Imaging Tests: Ultrasound is an ideal way to assess the size of the liver and spleen as well as the condition of other organs of the body. An MRI is preferred for an overall complete assessment of the patient.</li>
</ul>

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<ul>
	<li>Genetic Test: This is used to fully confirm the diagnosis e.g. Next generation sequencing methods. The test looks for the mutated PEX genes in the baby<a href="#accordion">[2]</a>.</li>
</ul>

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<ul>
	<li>Prenatal Testing: Certain tests (biochemical or genetic) can be performed prenatally in the first or second trimester using chorionic villus sampling or amniocentesis.</li>
</ul>

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Treatment

The treatment for all the disorders that come under the Zellweger syndrome is usually symptomatic and depends on several factors starting off from the age of onset, the rate of progression of the disease, and the type of disorder in the spectrum. This is because the options are highly limited and focused towards supportive care for a patient with the most severe form of the spectrum.&nbsp;

Docosahexaenoic acid is administered because the levels are low in ZS patients. It does not improve the already depleting condition; rather, the supplement helps to manage it. Lorenzo&rsquo;s oil aids in reducing very long-chain fatty acid levels, whereas cholic acid is used to aid in the absorption of fat-soluble vitamins<a href="#accordion">[11]</a>.&nbsp;

In case of infantile refsum disease, the treatment is solely based on modifying the diet of the patient in a way that there is no phytanic acid intake. Plasmapheresis is suggested; however, cascade filtration is also an option to eliminate the need for albumin replacement therapy. Other ointments and drugs may be prescribed for the skin scaling<a href="#accordion">[12]</a>.

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Infants with Zellweger syndrome may have several complications depending on the severity of their conditions. These include:

<ul>
	<li>Inability to eat</li>
	<li>Inability to move</li>
	<li>Underdeveloped muscles</li>
	<li>Liver failure</li>
	<li>Breathing difficulties</li>
	<li>Digestive tract bleeding</li>
</ul>

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There are no specific risk factors that lead to the development of autosomal recessive disorders. The main issue is of the parents being carriers that is later passed onto the children.&nbsp;

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While a person with Zellweger spectrum disorders can opt for genetic counseling, there is no actual way to prevent it<a href="#accordion">[2]</a>.&nbsp;

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The prevalence of Zellweger spectrum disorders is increasing with an estimated annual growth rate of 6% during the forecast period of 2022-2031. This increase is not reflective of more babies getting sick, but rather an indication of the improvement in diagnostic accuracy and increased awareness. The increased percentage is also related to the fact that researchers all over the world now have an aggressive approach towards diseases which were previously understudied<a href="#accordion">[13]</a>.

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Key Points

<ul>
	<li>Zellweger Spectrum Syndrome is used as an umbrella term that covers 3 major genetic disorders. It is an autosomal recessive disease.</li>
	<li>It is caused due to mutations in the PEX genes. There are around 12-13 PEX genes in which PEX1 mutation is the cause of 60% of Zellweger spectrum disorders; there are about 90 other distinct mutations.</li>
	<li>The spectrum contains 3 diseases based on the overall severity of the disorder. The most severe disease is known as Zellweger syndrome, the moderate stage of the disease is called neonatal adrenoleukodystrophy, and the mildest form of the disease is Infantile Refsum disease.</li>
	<li>There is no cure for the disease and a more symptomatic approach is taken for its treatment. For instance, drugs that control the metabolism of some compounds as well as replace the deficient compounds are prescribed by the doctor.</li>
	<li>The treatment does not cure the symptoms that involve blindness, deafness, mental retardation, flattened face, etc.&nbsp;</li>
	<li>This disorder cannot be prevented. However, only children whose parents are carriers are at risk of developing this disease. Even then there is a 50% chance of the child being just a carrier and a 25% chance of the child actually getting affected by the disease.</li>
</ul>

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[1] Zellweger Spectrum Disorders. NORD (National Organization for Rare Disorders).

[2] Zellweger syndrome: Causes, symptoms, diagnosis &amp; complications. Cleveland Clinic.

[3] Zahid M, Khan AH, Yunus ZM, et al. Inherited metabolic disorders presenting as hypoxic ischaemic encephalopathy: A case series of patients presenting at a tertiary care hospital in Pakistan. JPMA. 2019;69(3):432-436.

[4] Steinberg SJ, Raymond GV, Braverman NE, et al. Zellweger Spectrum Disorder. 2003 Dec 12 [Updated 2020 Oct 29]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.

[5] Zellweger syndrome. National Institute of Neurological Disorders and Stroke.

[6] Farrell DF. Neonatal adrenoleukodystrophy: A clinical, pathologic, and Biochemical Study. Pediatric Neurology. 2012;47(5):330-336.

[7] Refsum disease: Medlineplus Genetics. MedlinePlus.

[8] Infantile Refsum Disease | National Institute of Neurological Disorders and Stroke [Internet].

[9] Henderson AMRby E. What are zellweger spectrum disorders? News.

[10] Zellweger syndrome - about the disease. Genetic and Rare Diseases Information Center.

[11] Elumalai V, Pasrija D. Zellweger Syndrome. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

[12] Robert A Schwartz MD. Refsum disease treatment &amp; management: Medical care, surgical care, consultations. Refsum Disease Treatment &amp; Management: Medical Care, Surgical Care, Consultations.

[13] Zellweger spectrum disorder market segmentation by therapy (pediatricians, neurologists, surgeons, audiologists, ophthalmologists, and orthopedists); by diagnosis (Blood &amp; Urine Test, ultrasound, and genetic tests) and by end-user (hospitals, clinics, diagnostic centers, and Genetic Testing Laboratories) – Global Demand Analysis &amp; Opportunity Outlook 2031. Zellweger Spectrum Disorder Market Insights, Size &amp; Growth Forecast To 2031.