Last updated:
10/7/2025
Years published: 2025
NORD gratefully acknowledges Samah Akhter, MS, LCGC, Genetic Counselor, and Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for the preparation of this report.
Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (PEBAT) is a rare and severe neurodegenerative condition that begins during the early stages of life, especially infancy.1
The characteristic features of this condition are severe developmental delays, or loss of skills (developmental regression), seizures (usually with onset in infancy), and progressive loss of brain volume, accompanied by a thin corpus callosum (nerve fibers connecting the left and right sides of the brain). Other features include decreased head size (microcephaly), low muscle tone (hypotonia), optic nerve damage (optic atrophy) resulting in loss of vision and some skeletal abnormalities such as multiple joint contractures (arthrogryposis), hip dislocation, abnormal shape of the head and an abnormal lateral curvature of the spine (scoliosis).1,2
PEBAT is caused by disease-causing changes (pathogenic variants) in the TBCD gene, which provides instructions for making the tubulin folding protein TBCD. The inheritance pattern of this condition is autosomal recessive.1,3
Diagnosis is based on a combination of clinical assessment, neuroimaging (MRI of the brain) and genetic testing. There is no cure for this condition, and treatment typically involves a symptom-based approach to enhance quality of life.1
PEBAT can cause a wide spectrum of clinical symptoms with varying levels of progression and severity, even within members of the same family. Symptoms can develop in a newborn or later in infancy. Numerous symptoms have been reported for this condition. Not all of them are seen in a single person, and they can differ from one person to another. The most common findings are developmental delays and seizures.2,3,4
The signs and symptoms that have been reported include:1-5
PEBAT is caused by disease-causing changes (pathogenic genetic variants) in the TBCD (tubulin folding cofactor D) gene.1 The TBCD gene is responsible for the production of the TBCD (tubulin cofactor) protein involved in the correct assembly and shaping of microtubules.6
Microtubules are structures giving shape and stability to the cell and are crucial for processes like cell division and nerve cell (neuron) functions, such as sending signals between neurons and building brain connections.7
Disease-causing TBCD variants affect TBCD protein stability and function, resulting in disturbed microtubule structure and functioning.1 When microtubules do not form and hold shape and structure properly, the neurons cannot maintain their structure or function. Hence, their ability to make connections and send signals gets disrupted leading to brain abnormalities, developmental delays, wasting of brain tissue and other related symptoms as seen in PEBAT.4-8
Inheritance
The inheritance pattern for PEBAT is autosomal recessive.1,2,3 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.
PEBAT is a rare condition with a prevalence of about <1/1,000,000. As of 2025, approximately 39 cases have been reported in the medical literature.1 Patients have been reported from different parts of the world and there does not appear to be a specific geographical or ethnic limitation; however, reports are sparse. One study reported a founder variant (a genetic change that started in a small group of ancestors and is passed down through generations in that population) in the Faroe Islands, located between Iceland and Norway in the North Atlantic Sea. The study showed that 2.6% of the Faroese population are carriers of a gene variant for PEBAT.8 Outside of these islands, the carrier frequency in the general population is extremely low, as no large population hotspots have been identified yet.
The diagnosis of PEBAT is based on a combination of typical signs and symptoms, medical evaluation, brain imaging and genetic testing.1,4
At present, there are no biomarkers (laboratory tests that directly confirm the disease). Instead, doctors look for characteristic clinical features together with findings on magnetic resonance imaging (MRI). MRI is a safe technique that uses magnets and radio waves to produce detailed pictures of the brain. In PEBAT and other tubulin-related disorders (conditions caused by problems in proteins important for brain cell structure), the MRI often shows changes that raise suspicion for the condition.
Once PEBAT is suspected, genetic testing is essential to confirm the diagnosis. This testing looks for variants in the TBCD gene. Testing can be done in several ways:1,4
If disease-causing variants in the TBCD gene are found in a family, doctors can offer carrier screening. This type of testing checks if relatives carry the gene variant, which can help with understanding their own health risks and with family planning.
For families who wish to have children in the future, doctors can also discuss options such as prenatal genetic diagnosis (testing during pregnancy) or preimplantation genetic diagnosis (testing embryos created by in-vitro fertilization before pregnancy begins).1,4
Although there is currently no treatment for PEBAT, an early diagnosis can provide families with more personalized counseling regarding prognosis and the likelihood of recurrence in future pregnancies.⁴ At present, there is no cure or gene therapy available. Care is therefore focused on symptom management through a multidisciplinary approach, with the goal of improving quality of life and reducing the impact of symptoms. The type of care needed depends on the severity of the condition and the specific symptoms the person has.¹
Seizures are a common concern, and children are usually referred to a neurologist for specialized care. Anti-seizure or anti-epileptic medications may be prescribed to help control these episodes. Nutritional support is also important and may involve referrals to specialists in nutrition and dietetics. Children are often evaluated for swallowing difficulties, and in some cases a gastrostomy tube (G-tube) may be recommended to support safe feeding. Management of constipation and regular monitoring of growth are also key aspects of nutritional care.
Respiratory support may be needed for some children, with referrals to a pulmonologist for further evaluation. Slow or shallow breathing (hypoventilation) may require close monitoring. Treatments might include medications or equipment to clear the airways, and in some children oxygen or breathing machines are used.
Therapies such as physical, occupational, speech and behavioral therapy play an essential role in care. These therapies can help manage stiff joints and muscles, maintain mobility and provide alternative methods of communication when speech is affected. Orthopedic evaluations may be necessary to address skeletal differences. Physical aids can assist with movement, while medications may be used to reduce muscle stiffness. In some people, surgical interventions are considered for musculoskeletal difficulties.
Because PEBAT can also affect vision and hearing, regular evaluations are important. Doctors may monitor for changes such as optic nerve damage.
Families are encouraged to access supportive and palliative care services to help manage complex needs and improve overall quality of life. Genetic counseling is strongly recommended for family planning, as it can help relatives understand their risk of carrying a gene variant for the condition. Finally, connecting with community resources and patient support groups can provide valuable emotional support and practical guidance for families living with PEBAT.
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 web site.
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/
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/No patient organizations found related to this disease state.
Please complete this form to access the requested resource.
