• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
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  • Diagnosis
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Warburg Micro Syndrome

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Last updated: 4/24/2024
Years published: 2016, 2020, 2024


Acknowledgment

NORD gratefully acknowledges John M. Graham, Jr., MD, ScD, Consulting Medical Geneticist, Cedars-Sinai Medical Center, Professor Emeritus, Department of Pediatrics, David Geffen School of Medicine at UCLA, for assistance in the preparation of this report.


Disease Overview

Summary

Warburg micro syndrome (WARBM) is a rare autosomal recessive genetic disorder. It is primarily characterized by problems with the eyes and with the growth and development of the brain, resulting in neurodevelopmental delay. Affected children have severe intellectual disability, and they experience delays in reaching, or fail to reach, normal developmental milestones. They may also have microcephaly, a condition that indicates that the head circumference is significantly smaller than would be expected based upon an infant’s age and gender. Most children exhibit underdevelopment and reduced activity of the testes or ovaries (hypothalamic hypogonadism), and in some children with WARBM1 there is a peripheral neuropathy leading to lower limb spasticity and/or cardiomyopathy. Changes in one of at least four different genes, RAB3GAP1 (WARBM1), RAB3GAP2 (WARBM2), RAB18 (WARBM3) or TCB1D20 (WARBM4) cause this disorder and Warburg micro syndrome is inherited in an autosomal recessive manner. The 4 different types are clinically indistinguishable from each other, so molecular testing is required to distinguish between them. In 1993

Introduction

Warburg used the term MICRO syndrome to describe an autosomal recessive syndrome of microcephaly, microcornea, congenital cataract, intellectual disability, optic atrophy and hypogenitalism. This disorder is part of a spectrum of disease that includes Martsolf syndrome at the mild end and variants in the RAB3GAP2 gene have been linked to Martsolf syndrome.

 

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Synonyms

  • micro syndrome
  • WARBM type 1-4
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Signs & Symptoms

With over 100 published families, researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, intellectual disability and hypogonadism. It is important to note that affected individuals may not have all of the symptoms discussed below. Every child is unique. Parents should talk to their child’s physicians and medical team about their specific case, associated symptoms and overall prognosis.

Children with Warburg micro syndrome have problems with vision and their eyes. This includes abnormally small eyes (microphthalmia) and abnormally small corneas. The corneas are the clear (transparent) outer layer of the eyes. Some infants have clouding of the lenses of the eyes at birth (congenital cataracts). Cataracts usually affect both eyes. Degeneration of the optic nerve can also occur (optic atrophy). The optic nerve is the main nerve of the eyes that carries impulses from the eyes to the brain to form images. An affected individual’s vision is usually very poor due to optic atrophy and defects in the part of the brain that controls vision (cortical visual impairment). Some children may develop glaucoma, a condition characterized by increased pressure within the eyes.

Affected children may also have atonic pupils. Atonic pupils are abnormally large, irregularly shaped pupils that react poorly to light. Normally, the pupil gets smaller (constricts) in the presence of light or when focusing on nearby objects. The pupil normally opens wider (dilates) in dim light or darkness, when focusing on far away objects, or when a person is excited.

Affected children have intellectual disability that is often severe. They may fail to reach developmental milestones on time (developmental delays). Some children will be unable to sit independently, walk or talk. Some children will eventually display autistic features. Although less common, seizures can also occur. There are several abnormalities of brain development associated with Warburg micro syndrome. These include underdevelopment of the ‘bridge’ that connects the right and left halves (cerebral hemispheres) of the brain (hypoplasia of the corpus callosum), shrinkage of the brain (cortical atrophy), progressive shrinkage of the area of brain that controls coordination and balance (cerebellar atrophy) and polymicrogyria, a condition in which there are too many folds in the brain, and the folds are abnormally small. Some infants may experience a delay in the formation of the myelin sheath (delayed myelination). The myelin sheath covers and protects nerve fibers, acts as an insulator, and increases the speed of transmission of nerve signals. These brain findings may differ from one child to another.

Affected infants have growth failure and may have diminished muscle tone (hypotonia) so that they appear floppy. As they get older, they may have increased muscle tone and stiffness (spasticity), particularly in the legs. Spasticity can lead to the development of contractures, in which joints become fixed in a bent or straightened position. Contractures can partially or completely restrict the movement of the affected joint. Eventually the arms become involved. Progressive muscle weakness will develop and affected individuals may not be able to move their arms and legs (quadriplegia).

Most children will have underdevelopment and reduced activity of the testes or ovaries (hypothalamic hypogonadism). Affected boys may have a small penis, underdeveloped scrotum and their testes may fail to descend into the scrotum (cryptorchidism). Affected girls may have underdevelopment of the clitoris and labia minora, and an abnormally small opening that leads to the vagina (small introitus). In girls, hypogonadism can be mild and may go unnoticed.

Some infants and children with Warburg micro syndrome may have distinctive facial features including a narrow mouth, a wide bridge of the nose and deep-set eyes.

Additional symptoms have been reported including abnormal front-to-back and/or sideways curving of the spine (kyphoscoliosis) and excessive hair growth (hypertrichosis).

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Causes

Warburg micro syndrome is caused by changes (variants) in one of at least four different genes. The four genes known to be associated with this disorder are RAB3GAP1 (75% of cases), RAB3GAP2, RAB18 and TBC1D20. In some people, no variants in any of these genes have been found. This suggests that additional genes may cause this disorder.

Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant occurs in a gene, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain and the eyes.

Warburg micro syndrome is 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.

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Affected populations

Warburg micro syndrome is an extremely rare disorder. As with many rare disorders, the exact incidence or prevalence of this disorder is unknown. The disorder probably goes misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. About 100 families have been reported with this disorder in the medical literature, and a founder splicing mutation in RAB3GAP1 (c.748+1G>A) has been reported in 6 families of Turkish origin.

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Diagnosis

A diagnosis of Warburg micro syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Key findings of this disorder (microcephaly, cataracts, and microcornea) can also occur because of congenital viral infections and chromosomal abnormalities. Initial tests should be done to rule out congenital viral infections and chromosomal abnormalities.

Clinical Testing and Workup
A thorough eye (ophthalmological) examination is necessary in infants suspected of Warburg micro syndrome. Such an exam can reveal characteristic changes in the eyes. Specialized imaging techniques can also be performed and may include magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of the brain and can reveal characteristic changes such as cortical malformations, polymicrogyria and hypoplasia of the corpus callosum.

Molecular genetic testing with whole exome sequencing or whole genome sequencing can confirm a diagnosis of Warburg micro syndrome. Molecular genetic testing can detect variants in the specific genes known to cause this disorder but is available only as a diagnostic service at specialized laboratories. Molecular diagnosis permits adequate genetic counseling and appropriate management for predicted complications such as adequate sex steroid supplementation therapy for hypogonadism, in addition to standard supportive therapies for developmental delay and visual dysfunction, therefore molecular studies are recommended for this rare condition.

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Standard Therapies

The treatment of Warburg micro syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, eye specialists (ophthalmologists), clinical geneticists, speech pathologists, physical therapists, psychologists and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.

Genetic counseling is recommended for affected individuals and their families.

Treatment options that may be used to treat individuals with Warburg micro syndrome can be complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.

Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.

Additional treatment is symptomatic and supportive. Surgery may be performed to remove cataracts. However, vision remains poor despite successful cataract removal. Surgery may also be used to treat contractures. Medications that treat seizures (anticonvulsants) can be tried, but seizures may persist.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.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:

Toll-free: (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, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Nian FS, Li LL, Cheng CY, et al. Rab18 collaborates with Rab7 to modulate lysosomal and autophagy activities in the nervous system: an overlapping mechanism for Warburg Micro syndrome and Charcot-Marie-Tooth neuropathy type 2B. Mol Neurobiol. 2019 Sep;56(9):6095-6105.

Dejgaard SY, Presley JF. Rab18: new insights into the function of an essential protein. Cell Mol Life Sci. 2019 May;76(10):1935-1945.

Gumus E. Case report of four siblings in southeast Turkey with a novel RAB3GAP2 splice site mutation: Warburg micro syndrome or Martsolf syndrome? Ophthalmic Genet. 2018 Jun;39(3):391-395.

Kabzińska D, Mierzewska H, Senderek J, Kochański A. Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy. Folia Neuropathol. 2016;54(3):273-281.

Asahina M, Endoh Y, Matsubayashi T, et al. Novel RAB3GAP1 compound heterozygous mutations in Japanese siblings with Warburg Micro syndrome. Brain Dev. 2016 Mar;38(3):337-340.

Wu Q, Sun X, Yue W, et al. RAB18, a protein associated with Warburg Micro syndrome, controls neuronal migration in the developing cerebral cortex. Mol Brain. 2016 Feb 16;9:19.

Arroyo-Carrera I, de Zaldívar Tristancho MS, Bermejo-Sánchez E, et el. Deletion 1q43-44 in a patient with clinical diagnosis of Warburg-Micro syndrome. Am J Med Genet A. 2015 Jun;167(6):1243-1251.

Imagawa E, Fukai R, Behnam M, et al. Two novel homozygous RAB3GAP1 mutations cause Warburg micro syndrome. Hum Genome Var. 2015 Sep 17;2:15034. doi: 10.1038/hgv.2015.34. eCollection 2015.

Handley MT, Carpanini SM, Mali GR, et al. Warburg micro syndrome is caused by RAB18 deficiency or dysregulation. Open Biol. 2015;5:150047. http://www.ncbi.nlm.nih.gov/pubmed/26063829

Carpanini SM, McKie L, Thomson D, et al. A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton. Dis Model Mech. 2014 Jun;7(6):711-722.

Handley MT, Morris-Rosendahl DJ, Brown S, et al. Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18, and genotype-phenotype correlations in Warburg micro syndrome and Martsolf syndrome. Hum Mutat. 2013;34:686-696. http://www.ncbi.nlm.nih.gov/pubmed/23420520

Liegel RP, Handley MT, Ronchetti A, Brown S. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013;93:1001-1014.

Bem D, Yoshimura S, Nunes-Bastos R, et al. Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Am J Hum Genet. 2011;88:499-507. http://www.ncbi.nlm.nih.gov/pubmed/21473985

Morris-Rosendahl DJ, Segel R, Born AP, et al. New RAB3GAP1 mutations in patients with Warburg micro syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010;18:1100-1106. http://www.ncbi.nlm.nih.gov/pubmed/20512159

Abdel-Salam GM, Hassan NA, Kayed HF, Aligianis IA. Phenotypic variability in Micro syndrome: report of new cases. Genet Couns. 2007;18:423-435. http://www.ncbi.nlm.nih.gov/pubmed/18286824

Aligianis IA, Johnson CA, Gissen P, Chen D, Hampshire D. Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet. 2005;37:221-223. http://www.ncbi.nlm.nih.gov/pubmed/15696165

Cinleti T, Uzan GS , Bürçe B, Küçümen Y et al. Phenotypic comparison of a novel variant (p.P164R) and a founder mutation (c.748+1G>A) in Warburg Micro syndrome. Neurology Asia 2023; 28(4) : 1085 – 1094.

Graham JM Jr., Hennekam R, Dobyns WB, Roeder E, Busch D. MICRO syndrome: an entity distinct from COFS syndrome. Am J Med Genet A. 2004;128A:235245. http://www.ncbi.nlm.nih.gov/pubmed/15216543

Arroyo-Carrera I, de Zaldívar Tristancho MS, Bermejo-Sánchez E, et al. Deletion 1q43-44 in a patient with clinical diagnosis of Warburg-Micro syndrome. Am J Med Genet A. 2015;167:1243-12451.

INTERNET

WARBM1. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:600118; Last Update:  07/08/2021. Available at: http://omim.org/entry/600118 Accessed April 9, 2024.

WARBM2.Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:614225; Last Update:  09/25/2015. Available at: omim.org/entry/614225 Accessed April 9, 2024.

WARBM3. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:614222; Last Update: 01/18/2017. Available at: omim.org/entry/614222 Accessed April 9, 2024.

WARBM4. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:615663; Last Update:  06/07/2021. Available at: omim.org/entry/615663 Accessed April 9, 2024.

MARTS1. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:212720; Last Update: 12/04/2023. Available at: https://www.omim.org/entry/212720 Accessed April 9, 2024.

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