Causes
Agenesis of the corpus callosum is caused by disruption to development of the fetal brain between the 3rd and 12th weeks of pregnancy. [8] In most cases, it is not possible to know what caused an individual to have ACC or another callosal disorder. However, research suggests that some possible causes may include chromosome errors, inherited genetic factors, prenatal infections or injuries, prenatal toxic exposures, structural blockage by cysts or other brain abnormalities and metabolic disorders. [1]
Ciliopathies: rare genetic disorders
Until recently, the medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying symptoms apparent on clinical examination. Agenesis of the corpus callosum is one such disease, part of an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell organelles that are present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration. [9]
Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination.
Colpocephaly is a cephalic disorder involving the disproportionate enlargement of the occipital horns of the lateral ventricles and is usually diagnosed early after birth due to seizures. It is a nonspecific finding and is associated with multiple neurological syndromes, including agenesis of the corpus callosum, Chiari malformation, lissencephaly, and microcephaly. Although the exact cause of colpocephaly is not known yet, it is commonly believed to occur as a result of neuronal migration disorders during early brain development, intrauterine disturbances, perinatal injuries, and other central nervous system disorders. Individuals with colpocephaly have various degrees of motor disabilities, visual defects, spasticity, and moderate to severe intellectual disability. No specific treatment for colpocephaly exists, but patients may undergo certain treatments to improve their motor function or intellectual disability.
Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. The condition also occurs in other species.
Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellar maldevelopment presenting as early-onset non–progressive congenital ataxia, hypotonia and motor learning disability.
The cerebellar vermis is located in the medial, cortico-nuclear zone of the cerebellum, which is in the posterior fossa of the cranium. The primary fissure in the vermis curves ventrolaterally to the superior surface of the cerebellum, dividing it into anterior and posterior lobes. Functionally, the vermis is associated with bodily posture and locomotion. The vermis is included within the spinocerebellum and receives somatic sensory input from the head and proximal body parts via ascending spinal pathways.
Dandy–Walker malformation (DWM), also known as Dandy–Walker syndrome (DWS), is a rare congenital brain malformation in which the part joining the two hemispheres of the cerebellum does not fully form, and the fourth ventricle and space behind the cerebellum are enlarged with cerebrospinal fluid. Most of those affected develop hydrocephalus within the first year of life, which can present as increasing head size, vomiting, excessive sleepiness, irritability, downward deviation of the eyes and seizures. Other, less common symptoms are generally associated with comorbid genetic conditions and can include congenital heart defects, eye abnormalities, intellectual disability, congenital tumours, other brain defects such as agenesis of the corpus callosum, skeletal abnormalities, an occipital encephalocele or underdeveloped genitalia or kidneys. It is sometimes discovered in adolescents or adults due to mental health problems.
3C syndrome is a rare condition whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.
A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.
Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome that is usually lethal in the neonatal period. Fryns (1987) reviewed the syndrome.
Oculocerebrocutaneous syndrome is a condition characterized by orbital cysts, microphthalmia, porencephaly, agenesis of the corpus callosum, and facial skin tags.
Neuronal migration disorder (NMD) refers to a heterogenous group of disorders that, it is supposed, share the same etiopathological mechanism: a variable degree of disruption in the migration of neuroblasts during neurogenesis. The neuronal migration disorders are termed cerebral dysgenesis disorders, brain malformations caused by primary alterations during neurogenesis; on the other hand, brain malformations are highly diverse and refer to any insult to the brain during its formation and maturation due to intrinsic or extrinsic causes that ultimately will alter the normal brain anatomy. However, there is some controversy in the terminology because virtually any malformation will involve neuroblast migration, either primarily or secondarily.
Gómez–López-Hernández syndrome (GLH) or cerebellotrigeminal-dermal dysplasia is a rare neurocutaneous (Phakomatosis) disorder affecting the trigeminal nerve and causing several other neural and physical abnormalities. Gómez–López-Hernández syndrome has been diagnosed in only 34 people. Cases of Gómez–López-Hernández syndrome may be under-reported as other diseases share the characteristics of cerebellar malformation shown in Gómez–López-Hernández syndrome. Gómez–López-Hernández syndrome was first characterized in 1979.
13q deletion syndrome is a rare genetic disease caused by the deletion of some or all of the large arm of human chromosome 13. Depending upon the size and location of the deletion on chromosome 13, the physical and mental manifestations will vary. It has the potential to cause intellectual disability and congenital malformations that affect a variety of organ systems. Because of the rarity of the disease in addition to the variations in the disease, the specific genes that cause this disease are unknown. This disease is also known as:
L1 syndrome is a group of mild to severe X-linked recessive disorders that share a common genetic basis. The spectrum of L1 syndrome disorders includes X-linked complicated corpus callosum dysgenesis, spastic paraplegia 1, MASA syndrome, and X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS). It is also called L1CAM syndrome and CRASH syndrome, an acronym for its primary clinical features: corpus callosum hypoplasia, retardation, adducted thumbs, spasticity, and hydrocephalus.
Andermann syndrome, also known as agenesis of corpus callosum with neuronopathy (ACCPN), Charlevoix disease and KCC3 axonopathy among other names, is a very rare neurodegenerative genetic disorder that damages the nerves used to control muscles and related to sensation and is often associated with agenesis of the corpus callosum.
COACH syndrome, also known as Joubert syndrome with hepatic defect, is a rare autosomal recessive genetic disease. The name is an acronym of the defining signs: cerebellar vermis aplasia, oligophrenia, congenital ataxia, coloboma and hepatic fibrosis. The condition is associated with moderate intellectual disability. It falls under the category of a Joubart Syndrome-related disorder (JSRD).
Strømme syndrome is a very rare autosomal recessive genetic condition characterised by intestinal atresia, eye abnormalities and microcephaly. The intestinal atresia is of the "apple-peel" type, in which the remaining intestine is twisted around its main artery. The front third of the eye is typically underdeveloped, and there is usually moderate developmental delay. Less common features include an atrial septal defect, increased muscle tone or skeletal abnormalities. Physical features may include short stature, large, low-set ears, a small jaw, a large mouth, epicanthic folds, or fine, sparse hair.
Chudley–Mccullough syndrome is a rare genetic disorder which is characterized by bilateral congenital hearing loss associated with brain malformations. It is a type of syndromic deafness.
X-linked complicated corpus callosum dysgenesis is a genetic disorder characterized by dysplasia, hypoplasia or agenesis of the corpus callosum alongside variable intellectual disability and spastic paraplegia. Only 13 cases have been described in medical literature. Transmission is X-linked recessive. It is the mildest subtype of L1 syndrome.
