Di Donato N, Kuechler A, Velgano S, Heinritz W, Bodurtha J,
Merchant SR,
Breningstall G, Ladda R, Sell S, Altmüller J, Bögershausen N,
Timms AE, Hackmann K, Schrock E, Collins S, Olds C, Rump A, Dobyns WB. Update
on the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. Am J Med
Genet A. 2016 May 30. doi: 10.1002/ajmg.a.37771. [Epub ahead of print]
Abstract
Baraitser-Winter cerebrofrontofacial syndrome is caused by
heterozygous missense mutations in one of the two ubiquitous cytoplasmic
actin-encoding genes ACTB and ACTG1. Recently, we characterized the large
cohort of 41 patients presenting with this condition. Our series contained 34
patients with mutations in ACTB and only nine with ACTG1 mutations. Here, we
report on seven unrelated patients with six mutations in ACTG1-four novel and
two previously reported. Only one of seven patients was clinically diagnosed
with this disorder and underwent ACTB/ACTG1 targeted sequencing, four patients
were screened as a part of the large lissencephaly cohort and two were tested
with exome sequencing. Retrospectively, facial features were compatible with
the diagnosis but significantly milder than previously reported in four
patients, and non-specific in one. The pattern of malformations of cortical
development was highly similar in four of six patients with available MRI
images and encompassed frontal predominant pachygyria merging with the
posterior predominant band heterotopia. Two remaining patients showed mild
involvement consistent with bilaterally simplified gyration over the frontal
lobes. Taken together, we expand the clinical spectrum of the ACTG1-associated
Baraitser-Winter cerebrofrontofacial syndrome demonstrating the mild end of the
facial and brain manifestations.
Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M,
Abdul-Raman OA,
Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David
A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano
F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G,
Melis D, Lourenço CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC,
Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C,
Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer
B, Fry AE, Rump A, Hoischen A, Drunat S, Rivière JB, Dobyns WB, Pilz DT.
Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in
42 cases. Eur J Hum Genet. 2015 Mar;23(3):292-301.
Abstract
Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome
types 1 and 3 have recently been associated with heterozygous gain-of-function
mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB
and ACTG1 that encode β- and γ-actins. We present detailed phenotypic
descriptions and neuroimaging on 36 patients analyzed by our group and six
cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33
ACTB). The major clinical anomalies are striking dysmorphic facial features
with hypertelorism, broad nose with large tip and prominent root, congenital
non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or
retinal coloboma is present in many cases, as is sensorineural deafness. Cleft
lip and palate, hallux duplex, congenital heart defects and renal tract
anomalies are seen in some cases. Microcephaly may develop with time. Nearly
all patients with ACTG1 mutations, and around 60% of those with ACTB mutations
have some degree of pachygyria with anteroposterior severity gradient, rarely
lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk
and progressive joint stiffness is common. Early muscular involvement,
occasionally with congenital arthrogryposis, may be present. Progressive,
severe dystonia was seen in one family. Intellectual disability and epilepsy
are variable in severity and largely correlate with CNS anomalies. One patient
developed acute lymphocytic leukemia, and another a cutaneous lymphoma,
indicating that actinopathies may be cancer-predisposing disorders. Considering
the multifaceted role of actins in cell physiology, we hypothesize that some
clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial
syndrome is our suggested designation for this clinical entity.
Kemerley A, Sloan C, Pfeifer W, Smith R, Drack A. A novel mutation in ACTG1 causing Baraitser-Winter syndrome with extremely variable expressivity in three generations. Ophthalmic Genet. 2016 Apr 20:1-5.
ReplyDeleteAbstract
Baraitser-Winter syndrome (cerebrofrontofacial syndrome, type 3) is a rare developmental disorder typified by hypertelorism, ptosis, high-arched eyebrows, ocular coloboma, and brain malformations. Other common manifestations include hearing loss, short stature, seizures, intellectual impairment, muscle dysfunction, and abnormalities of the kidney and urinary system. This syndrome is caused by missense mutations in the genes ACTB or ACTG1, both of which encode for cytoplasmic actin proteins crucial for proper development of many organs in the human body. There are no reports of familial transmission; all reported cases have been new mutations. However, different mutations in ACTG1 have been reported to cause isolated non-syndromic hearing loss, with many reported cases of autosomal dominant (AD) inheritance. We have identified a three-generation pedigree segregating a novel mutation in the ACTG1 gene that causes Baraitser-Winter Syndrome with extremely variable expressivity, leading to an initial diagnosis of isolated AD hearing loss in two members. Subtle optic nerve signs not previously reported in this syndrome are also documented in one patient.
Rossi M, Guerrini R, Dobyns WB, Andria G, Winter RM. Characterization of brain malformations in the Baraitser-Winter syndrome and review of the literature. Neuropediatrics. 2003 Dec;34(6):287-92.
ReplyDeleteAbstract
Baraitser-Winter syndrome is a rare autosomal recessive disorder characterized by developmental delay, dysmorphic features, and multiple malformations also involving the brain. We report a further case and provide updated information about an unrelated girl reported in the original paper by Baraitser and Winter. Both of them presented with pachygyria and the latter case was recently found to have subcortical band heterotopia on high resolution brain MRI imaging. These two patients and a review of the previously reported cases indicate that a specific pattern of brain anomalies falling in the agyria-pachygyria-band spectrum is associated with this dysmorphic syndrome, which may be considered another example of syndromic neuronal migration defect.
Shiihara T, Maruyama K, Yamada Y, Nishimura A, Matsumoto N, Kato M, Sakazume S. A case of Baraitser-Winter syndrome with unusual brain MRI findings: pachygyria, subcortical-band heterotopia, and periventricular heterotopia. Brain Dev. 2010 Jun;32(6):502-5.
ReplyDeleteAbstract
Baraitser-Winter syndrome (BaWS) is characterized by iris coloboma, ptosis, hypertelorism, and mental retardation; it is a rare multiple congenital anomaly or a mental-retardation syndrome of unknown etiology. Patients suffering from this syndrome have been also found to show brain anomalies such as pachygyria, subcortical-band heterotopia (SBH), and hippocampal malformations; therefore, these anomalies have been included in the phenotypic spectrum of this syndrome. We report the case of a Japanese boy suffering from BaWS; the patient's brain magnetic resonance imaging scan revealed pachygyria, SBH, and periventricular heterotopia. However, the results of the genome-wide array comparative genomic hybridization did not reveal any chromosomal rearrangements.
Rivière JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4, S1-2.
ReplyDeleteAbstract
Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.
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