AssessmentsZellweger spectrum disorders (NORD)
USMLE® Step 1 style questions USMLE
A 1-year old girl is brought to the pediatrician’s clinic for evaluation of gross motor delay. Her parents are concerned because she has not been able to sit up yet and feels “limp” when they hold her. They report that she has had seizures in the past. Upon physical exam, she has both hypotonia and hepatomegaly. No other family members had similar symptoms during development. Genetic testing is performed, and she is found to have a mutation in the PEX gene. What is the inheritance pattern of the patient’s condition?
Zellweger spectrum disorders, also called ZSDs, are a group of rare genetic diseases that impair the development of peroxisomes, which are structures found in almost every cell of the body.
A low level of peroxisomes in the body causes visual, auditory, and neurological deterioration as well as liver and kidney dysfunction.
For this reason, ZSDs are also known as peroxisome biogenesis disorders, or PBDs. ZSDs are named after Dr. Hans Zellweger, who first described the disease in 1964.
ZSDs were originally characterized as individual diseases of varying severity, however it was later determined that all of these diseases are part of the same disease spectrum.
ZSDs affect many parts of the body. In severe cases, symptoms can present shortly after birth, whereas less severe forms may have symptoms that do not appear until late infancy or childhood.
Infants with severe ZSD often, but don’t always have cranial abnormalities such as flattening of the face, high forehead, widely spaced eyes, broad nose bridge, and an abnormally small jaw.
The roof of the mouth may be unusually high and narrow, and the fontanelles may feel abnormally large.
Infants with ZSD may experience deteriorating visual, auditory, and neurological symptoms.
Progressive vision loss may manifest as difficulty following objects with the eyes and eyes pointing in different directions.
Hearing loss may present as a lack of a startle response to loud noises and not turning towards sounds.
Other symptoms include a lack of muscle tone, called hypotonia, and affected children may appear limp and lethargic.
Infants may have difficulty sucking or swallowing, causing problems in feeding and gaining weight.
Infants with ZSD may also develop liver and kidney-related disorders, causing liver dysfunction, enlarged liver, bleeding problems, and kidney cysts.
Individuals with intermediate or milder forms of ZSD often have a slower disease progression and may exhibit milder symptoms.
Some symptoms that may become noticeable in childhood include adrenal insufficiency, skeletal and dental abnormalities, and continued developmental delay as individuals approach school age.
ZSDs are genetic disorders caused by mutations in any of 13 of the 14 PEX genes, which encode for peroxins, proteins involved in peroxisome assembly.
Most children with ZSD have mutations in the PEX1 gene, though mutations can also occur in PEX2, PEX3, PEX5, PEX6, PEX10, PEX11, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26.