- Donate
- Understanding Rare Disease
- Living with a Rare Disease
- Community Support
- Advancing Research
- Driving Policy
- Get Involved
- Rare Disease News
- Resource Library
- About Us
- For Clinicians & Researchers
- For Patient Organizations
Last updated: 10/17/2024
Years published: 2024
NORD gratefully acknowledges Wes Stephens, DO Candidate, Rocky Vista University, Alexis Poss, MS, CGC, University of North Carolina, Clara Hildebrandt, MD, University of North Carolina and Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for the preparation of this report.
Summary
NDUFB11-related disorders are a group of rare genetic conditions caused by changes (variants) in the NDUFB11 gene. Disease-causing variants in the NDUFB11 gene are associated with a range of symptoms and include the following four conditions:
Affected individuals may have overlap of these four conditions10. It is not yet possible to predict which condition a person will have based on the specific gene variant they have10.
There is no cure for NDUFB11-related disorders, but treatment can help manage symptoms.
Introduction
Linear skin defects with multiple congenital anomalies type 3 (LSDMCA3), first described in the medical literature in 2015, was the first reported condition caused by variants in the NDUFB11 gene (see Causes section) 12,13. This rare genetic disorder affects the skin, eyes and heart. Another medical paper in 2015 reported a NDUFB11 variant in a person with the heart condition histiocytoid cardiomyopathy2. In 2016, NDUFB11 variants were reported to be associated with a complex I mitochondrial disorder3 as well as sideroblastic anemia4,5.
The NDUFB11 gene variants can cause a range of different symptoms that can be associated with the following conditions:
Mitochondrial complex I deficiency nuclear type 30 (NDUFB11-related mitochondrial complex I deficiency)
This condition is caused by variants in the NDUFB11 gene which affect how the mitochondria (the energy-producing parts of cells) function. This can lead to a range of symptoms because different parts of the body rely on this energy. Symptoms can vary but commonly include:3,10,17,18
Some people may experience stroke-like episodes, changes in brain tissue (especially white matter), nerve damage, involuntary movements, exercise intolerance, or issues with the liver and kidneys.
X-linked sideroblastic anemia
Some individuals with a NDUFB11-related disorder develop a type of anemia called X-linked sideroblastic anemia4,5, a type of anemia characterized by the body’s inability to properly incorporate iron into hemoglobin, the protein in red blood cells that carries oxygen. This condition leads to the production of abnormal red blood cells known as sideroblasts, which are red blood cells that contain iron granules in their cytoplasm instead of properly using the iron to form hemoglobin. A lack of healthy red blood cells or hemoglobin leads to decreased oxygen delivery throughout the body because the red blood cells may not carry enough oxygen. Symptoms may include:4,5
Histiocytoid cardiomyopathy (foamy myocardial transformation of infancy; oncocytic cardiomyopathy; arachnocytosis of the myocardium)
A rare heart condition known as histiocytoid cardiomyopathy has been linked to NDUFB11 gene variants, especially in females under 2 years old. This condition can cause the following symptoms:1,2,9
Some children may need significant medical interventions like a heart transplant.
Linear skin defects with multiple congenital anomalies (LSDMCA type 3, microphthalmia with linear skin defects syndrome; linear skin defects with cardiomyopathy and other congenital anomalies; NDUFB1-related microphthalmia with linear skin defects; NDUFB1-related MLS syndrome)
Children with LSDMCA type 3 may have a combination of symptoms that affect the skin, eyes, heart and other body systems. Common symptoms may include:1,6,8
Some individuals may also have the following symptoms:8
The symptoms of NDUFB11-related disorders can vary widely in severity. Each person may have a unique combination of symptoms, so regular check-ups with healthcare providers are crucial for managing the condition and improving quality of life.
NDUFB11-related disorders are caused by a pathogenic variant in the NDUFB11 gene. In other words, there is a change in the DNA sequence of the gene that causes the gene not to function correctly. The NDUFB11 gene is part of a group of genes that help mitochondria make energy13. When this gene doesn’t work properly, cells can’t make enough energy and this affects organs that need a lot of energy, like the skin, eye, brain, heart and muscles6.
The NDUFB11 gene provides instructions for making a protein that is part of an important enzyme called NADH dehydrogenase, which is the biggest complex in the cell energy-producing system, known as the respiratory complex. This enzyme helps cells produce energy and is located in the mitochondria, the cell energy “powerhouse.” NADH dehydrogenase is also called complex I, and it is the largest of the five parts of the electron transport chain11. If the gene doesn’t work correctly, the body has trouble getting enough energy to organs that need it the most.
Inheritance
NDUFB11-related disorder is inherited in an X-linked pattern. X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
X-linked dominant disorders are caused by a disease-causing gene variant on the X chromosome and mostly affect females. Females are affected when they have an X chromosome with the gene variant. Males with a disease-causing gene variant for an X-linked dominant disorder are more severely affected than females and often do not survive.
In some people, a NDUFB11 variant has been found to occur de novo6, meaning the variant arises spontaneously and is not inherited from either parent. De novo variants occur during the formation of reproductive cells (eggs and sperm) or early in the development of the embryo, leading to the presence of the genetic change in the child without it being present in the family history.
NDUFB11-related disorder affects males and females and has been reported in individuals from various ethnic backgrounds around the world. The exact prevalence of this condition is not well established, but it is considered a rare disorder, with only a small number of cases documented in the medical literature. As awareness of this condition increases, more cases may be identified, helping to clarify its true frequency in the general population.
Doctors may suspect NDUFB11-related disorder based on symptoms like poor growth starting in the womb, respiratory failure and heart failure in a newborn boy3, severe heart arrhythmia and enlarged heart in a newborn girl2, early onset sideroblastic anemia and lactic acidosis4, linear skin defects that disappear in the first few months, low muscle tone, seizures, abnormal findings on brain MRI, cardiomyopathy, developmental delay with small head circumference, and poor growth1. Genetic testing can confirm the diagnosis by identifying a variant in the NDUFB11 gene. Sometimes, doctors will also use blood tests, muscle biopsies, or brain imaging to look for signs of mitochondrial disease17.
There is no cure for NDUFB11-related disorder; treatment focuses on managing symptoms and improving quality of life.
Complex I deficiency treatment, which may or may not be effective, can include such metabolic therapies as: riboflavin, thiamine, biotin, co-enzyme Q10, carnitine and the ketogenic diet. Therapies for the infantile multisystem form have been unsuccessful17.
X-linked sideroblastic anemia treatment is supportive and involves hematological monitoring, surveillance of iron levels and lifetime pyridoxine supplementation in those who respond and folic acid supplementation. Pyridoxine response varies in degree and is rarely complete. Occasional prophylactic phlebotomy can be performed to prevent iron overload if anemia is very mild or corrected by pyridoxine. If iron overload has already developed, phlebotomy, iron chelation or a combination of both can be used to normalize iron levels. In some people, iron depletion may simultaneously increase the hemoglobin level. Blood transfusions may be needed on occasion but are only required on a regular basis for those most severely affected16.
Histiocytoid cardiomyopathy may be treated with electrophysiological mapping, surgery to remove nodular lesions, radiofrequency ablation, catheter ablation, or heart transplant. Antiarrhythmics are generally ineffective, but one patient showed a good response to treatment with amiodarone15.
Linear skin defects with multiple congenital anomalies type 3
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving US government funding, and some supported by private industry, are posted on this government web site. At the time of this writing, October 2024, there are currently no clinical trials for NDUFB11-related disorder.
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: 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/
Show Your Stripes® this Rare Disease Day® with a gift to NORD
Your donation will help more than 30 million Americans with a rare disease navigate their diagnosis, receive financial assistance, and access the care and support they deserve. Make your tax-deductible gift today!