Paula and Bobby
Parents of Lillie
Warburg Micro syndrome 1
What is Warburg Micro syndrome?
It is a rare neurodevelopment syndrome that affects mainly the eyes and brain development. Issues with vision and intellectual disability are the main symptoms of the syndrome as a result. There are currently less than 100 cases recorded of the syndrome worldwide, making it extremely rare.
This syndrome is also known as:
Micro Syndrome WARBM
What gene changes cause Warburg Micro syndrome?
The genes responsible for causing the syndrome have been identified as RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20. However the syndrome has also been diagnosed in individuals without mutations in any of these genes which suggests other genes might also be responsible for causing it.
The syndrome is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
What are the main symptoms of Warburg Micro syndrome?
The main symptoms include vision and eye abnormalities including small eyes and small corneas. In some affected infants, cataracts (a clouding of the cornea) is often present at birth. Optic atrophy, degeneration of the optic nerve between the eyes and the brain, can also be associated with the syndrome. This in turn affects an individual's vision.
In some individuals with the syndrome atronic pupils are present. These are pupils that are very large, shaped irregularly and react poorly to the light.
Severe intellectual disability is also common to the syndrome. This includes developmental delays and in severe cases an inability to sit, walk or talk. Autistic features are also associated with the syndrome in some individuals.
Anomalies in brain development associated with the syndrome include an underdevelopment of the bridge that connects the right and left parts of the brain, a shrinkage of the brain and a shrinkage of the part of the brain responsible for coordination and balance, as well as anomalies involving too many folds in the brain and folds that are exceptionally small.
Unique facial features associated with the syndrome include a narrow mouth, wide bridge of the nose and deep set eyes.
Progrssive muscle weakness is also a symptom of the syndrome and this leads to individuals not being able to move their arms and legs. While infants with the syndrome often present with reduced muscle tone and floppiness, over time this muscle tone goes to another extreme and increases to the point where it causes spasticity or stiffness in the legs. This in turn cases the permanent fixture of joints in a bent or straightened position. In time this also spreads to the arms.
Underdeveloped genitals are common with the syndrome. In males this includes a small penis, underdeveloped scrotum and undescended testes. In females this may affect the development of the clitoris and labia minora.
How does someone get tested for Warburg Micro syndrome?
The initial testing for Warburg Micro syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Warburg Micro syndrome 1
Warburg et al., (1993) reported two sibs and a cousin, from an inbred Pakistani family, who all had a similar condition. There was microcephaly, microcornea with congenital cataracts, optic nerve atrophy, retinal dystrophy and small pupils which were bound by posterior synechiae. All the patients were severely mentally retarded and most are blind. Other features included hypertrichosis, a beaked nose with a prominent root, and prominent ears. All three patients had agenesis of the corpus callosum and one patient was reported to have lissencephaly. There are similarities to COFS, but differs in that the neurological abnormalities are not progressive. (Graham et al., 2004). These authors also point out that the MRI imaging in MICRO is characteristic in that the gyral pattern is simplified and irregular, with a diminished number of abnormally shallow sulci, subtle microgyri and pachygyri over the frontal lobes. Four children from an inbred Shiite Muslim community from Lebanon were reported by Megarbane et al., (1999). They had ptosis as well as the other features of the condition. MRI scans showed ""gyration abnormalities"", the cerebellum was normal.
Rodr¡guez Criado et al., (1999) reported two sisters with features of the condition. They also had hypogenesis of ther cerebellar vermis, retinal colobomas, and spastic tetraparesis.
Pavone et al., (2000) reported a three and half year old girl with microcepahly, microphthalmia, coloboma of the iris and mild developmental delay. She was found have to marked cerebellar and wormian atrophy. The authors concluded that she had a new clinical entity, but they noted the similarity to Micro syndrome.
Fourteen children, from 11, north Pakistan families were reported by Ainsworth et al., (2001). Neurologically, the microcephaly was not always evident from birth and all were initially floppy, but then developed spasticity. The lens abnormalities were similar in all patients in that the lens was small, and the cataract was reported as being diffuse, with a dense small central opacity. All had atonic pupils.
An autopsy on a patient with Micro syndrome was reported by Hamano et al., (2003). The child had in addition ""brownish-pigmented spots scattered throughout the body surface. The brain showed a simplified gyral pattern and the thalami were fused.
Three Pakistani sibs reported by Aligianis et al., (2006) had congenital cataracts, microphthalmia, micropenis and cryptorchidism, noted from birth. Development was delayed. One sib had small puplils, hypermetropia and secondary glaucoma. The other sibs were very similar and 2 were microcephalic. The clinical picture was similar to both Martsolf and MICRO syndromes and a mutation was found in the catalytic subunit of RAB3GAP the same gene that is mutated in MICRO syndrome. These 2 syndromes, concluded the authors, could be variable expressions of the same scondition. The Hennekam et al., (1988) patients were also examined, but no mutations were found. RAB3GAP is heterodimeric (it is a regulator of calcium-mediated hormone and neurotransmitter exocytosis) and the mutation here is in RAB3GAP1 as opposed to RAB3GAP2 in Martsolf syndrome. Mutations in RABGAP2 can also cause MICRO syndrome. The Turkish boy (with a RAB3GAP mutation) reported by Yuksel et al., (2007) had skin hyperelasticity and joint hypermobility. Seven Egyptian patients, with severe mental retardation were reported by Abdel-Salam et al., (2007). MRI findings were agenesis of the corpus callosum, an abnormal gyral pattern, a small vermis, and delayed myelination.
Mutations in RAB18 have also been found to cause this syndrome (Bem et al., 2011).
Fifty-two new MICRO families and 3 Martsolf families were reported by Handley et al., (2013) - all with mutations - the authors again note the overlap with Martsolf syndrome. Not too that out of 144 families with MICRO (some from the literature) no mutations were found in 67.
Mutations in TBC1D20 have also been found (Liegel et al., 2013)
A patient reported byArroyo-Carrera et al., (2015) had microcephaly, spasticity and microcornea, cataract and a cleft palate. A clinical diagnosis of MICRO syndrome was made, but a 1q43-44 microdeletion was found.
* This information is courtesy of the L M D.
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