What are Zellweger Spectrum Disorders?
Zellweger Spectrum Disorders or ZSDs are referred to as a group of rare genetic diseases that impairs development of peroxisomes.
Peroxisomes are structures or small organelles found in the cytoplasm of many cells of our body. They contain enzymes that are responsible for a lot of biochemical pathways like fatty acid metabolism and lipid synthesis crucial for nervous system development.
When there is low level of peroxisomes in our body, it results in worsening of visual, auditory, neurologicaL, liver and kidney functions. Due to this, Zellweger Spectrum Disorders are also called Peroxisome Biogenesis Disorders or PBDs.
The term “Zellweger Spectrum Disorders” was coined after Dr. Hans Zellweger who was the first person to discover this in 1964. This disorder was initially identified as individual diseases with varying severity, but behind time, it was characterized that many diseases are a part of the same spectrum of disease.
What are the symptoms of Zellweger Spectrum Disorders?
Zellweger Spectrum Disorders affect many body parts. In severe cases, symptoms are reflected soon after birth whereas in less severe forms, symptoms do not appear till late infancy or childhood.
Infants having severe ZSDs usually have cranial abnormalities like flattening of face, high forehead, eyes that are broadly spaced, nose bridge that are wide and a jaw that is abnormally small.
Their mouth roof might be abnormally high and narrow and the fontanelles might be unusually large. However, it is not necessary that every infant have all of these features!
Infants with Zellweger Spectrum Disorders often experience worsened visual, auditory and neurological functions.
Visual deterioration includes glaucoma, cataracts, nystagmus and progessive vision loss, which might be demonstrated as trouble in following objects with eyes.
Auditory loss may be manifested as a shortfall of immediate response towards loud noises and not turning towards sounds.
Neurological symptoms include seizures and slowing down in certain developmental turning points like crawling, sitting or walking.
Other symptoms include hypotonia (which is an abnormally low muscle tone level), limp (which is difficulty to walk), lethargy (which is lack of energy or enthusiasm) , trouble in swallowing or sucking resulting in feeding problems and weight gain.
Zellweger Spectrum Disorder Infants may also develop kidney and liver disorders leading to liver dysfunction, enlarged liver, bleeding issues and kidney cysts.
Intermediate or mild forms of Zellweger Spectrum Disorders have a decreased progression of diseases and might present milder symptoms.
Few noticeable symptoms developing in childhood are adrenal insufficiency, skeletal and dental abnormalities and continued developmental delay as they approach school age.
What causes Zellweger Spectrum Disorders?
So we now know that ZSDs are a group of rare genetic diseases that impairs development of peroxisomes. Interestingly, these ZSDs are caused by mutations in any 13 of the 14 PEX genes which encode for peroxins. Peroxins are proteins that are essential for peroxisome assembly.
Most children with ZSD have mutations in the PEX1 gene. These mutations can also occur in PEX2, PEX3, PEX5, PEX6, PEX10, PEX11, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26.
And these mutations deteriorate the peroxisome function leading to very long chain fatty acids build up and nerve degeneration causing multiple system complications.
Importantly, ZSDs are inherited in an autosomal recessive pattern and therefore, a kid should have 25% risk to inherit altered genes from both parents who are carriers, in order to be affected.
How is ZSDs diagnosed?
Diagnosis starts with assessing clinical signs and symptoms of the individual. It is then followed by biochemical and genetic testing. High levels of very long chain fatty acids will be displayed in biochemical testing. Genetic testing is done to confirm ZSD.
Newly adopted neonatal screening for X-linked adrenoleukodystrophy can detect ZSD ahead of clinical observation of symptoms.
What is the treatment for Zellweger Spectrum Disorders?
Therapy includes oral bile acid replacement therapy using cholic acid as the first line treatment. Adrenal monitoring is recommended annually along with adrenal replacement therapy whenever necessary.
Following treatment is supportive and it differs based on the symptoms. Offering Special Education, Physical, Orthopedic and Speech therapies and other Medical, Social or Vocational services can benefit the affected people.
Also, genetic counseling is advised to help families acknowledge the genetics and natural history of ZSD and to bestow psychosocial support.
Quick summary
Zellweger Spectrum Disorders, or ZSDs, are rare autosomal recessive disorders caused by mutations of PEX genes.
It impairs the functioning of peroxisomes leading to very-long-chain fatty acids build up and nerve degeneration, causing multiple system complications.
In severe cases, symptoms are reflected soon after birth whereas in less severe forms, symptoms do not appear till late infancy or childhood.
Symptoms often include cranial abnormalities, visual and auditory impairments, developmental delays, hypotonia, seizures, kidney and liver dysfunction.
Diagnosis involves a detailed clinical examination followed by biochemical and genetic testing.
Early diagnosis is important for effective ZSD treatment and the treatment involves oral bile acid replacement therapy with cholic acid. Other treatments are supportive and based on symptoms.
Reference
Encyclopedia of Molecular Mechanisms of Disease by Florian Lang
Encyclopedia of Molecular Biology by Thomas E. Creighton
Rare Diseases: Integrative PPPM Approach as the Medicine of the Future from Springer
