Last updated:
08/25/2025
Years published: 2025
NORD gratefully acknowledges Esha Mahal, MS, Carolyn Bell, MS, Jazmine Newson, MS and MaryAnn Campion, EdD, MS, CGC, Stanford University MS Program in Human Genetics and Genetic Counseling and Dr. Peter Huppke, University of Göttingen, for the preparation of this report.
Summary
Huppke-Brendel syndrome (HBS), also known as congenital cataract-hearing loss-severe developmental delay syndrome, is a rare disorder with most symptoms being noticeable at birth or during infancy. As the name suggests, the primary features are cataracts, hearing loss and severe developmental delay. HBS is caused by changes (variants) in the SLC33A1 gene and the condition is passed down in families in an autosomal recessive manner. This means parents who are carriers for the condition have a 25% chance of having an affected child with each pregnancy. While there is no specific treatment for the condition, management is based on an individual’s symptoms.1
HBS has a broad range of symptoms and severity. Not every person will have the same features, but key symptoms include: 1, 2
Other symptoms that have been reported in some people include:
In most people, HBS is a neurodegenerative disorder leading to death before age 10 years. Developmental regression often follows an infection in early childhood.
Huppke-Brendel syndrome is caused by changes (variants) in the SLC33A1 gene. The SLC33A1 gene contains instructions to make (codify) the acetyl-CoA transporter protein (AT-1) which interacts with other proteins necessary for normal eye and brain development. AT-1 also seems to be related to ceruloplasmin, a copper-transporting protein in the blood, but the connection is not well understood at this time. Variants that cause Huppke-Brendel syndrome lead to a loss of AT-1 protein function, and this results in the symptoms.1, 2
Inheritance
HBS is passed down (inherited) in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
As of 2025, only ten cases of Huppke-Brendel syndrome have been reported in the medical literature. The true number of people affected is unknown.1
A diagnosis of Huppke-Brendel syndrome may be suspected in a child who has cataracts in both eyes that are present at birth, abnormal eye movements (nystagmus), sensorineural hearing loss or deafness, severe developmental delay and/or intellectual disability and low muscle tone (hypotonia), as well as seizures. A diagnosis may be further supported by brain MRI findings of cerebellar hypoplasia, hypomyelination and wide subarachnoid spaces. A blood test may show low copper and ceruloplasmin levels.1
A diagnosis of HBS can be confirmed with molecular genetic testing when two disease-causing (pathogenic) variants in the SLC33A1 gene are identified. Genetic testing to determine carrier status and for prenatal diagnosis is not available until variants in SLC33A1 have been identified in an affected family member.
Clinical Testing and Work-Up
When someone is diagnosed with Huppke-Brendel syndrome (HBS), doctors might recommend the following assessments to get a complete picture of health and any specific needs:
Treatments are available for specific symptoms that may be present in individuals with Huppke-Brendel syndrome including:1
The ongoing care of individuals with HBS may include different types of healthcare providers and specialists such as:
All the specialists should work together as a team in a coordinated way for the best management.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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