Agenesis Of The Corpus Callosum

Agenesis of the Corpus Callosum – 6 Interesting Facts

ACC (agenesis of the corpus callosum) is a congenital malformation that yields diverse clinical presentations depending on various factors
The severity of the malformation (eg, partial or complete) and the specific locations of the absent callosal fibers influence the clinical phenotype
The most common symptoms of ACC include social and language impairments, seizures, and delays in motor and cognitive development
Postnatal diagnosis of ACC can be challenging and may require clinical evaluation, neuroimaging, and genetic testing
Prenatal diagnosis of ACC using imaging (ultrasonography or MRI) and genetic analysis allows for planning appropriate care, especially in cases of metabolic illnesses
The primary goal of treatment is to alleviate symptoms and provide supportive measures to enhance quality of life

Introduction

The corpus callosum connects the 2 cerebral hemispheres with nearly 200 million axons, facilitating interhemispheric communication
It enables efficient coordination and communication between the right and left hemispheres, which is critical for complex tasks such as comprehension of sensory input and social interaction
- Right hemisphere
  - Specializes in nonverbal and spatial tasks and processes visual information from the left visual field
  - Plays a vital role in recognizing faces, objects, and locations in 3-dimensional space
  - Responsible for the sensory and motor functions of the left side of the body
- Left hemisphere
  - Plays a prominent role in verbal tasks such as speaking and writing, and processes visual information from the right visual field
  - Oversees computational and mathematical abilities, as well as logical reasoning
  - Responsible for sensory and motor functions of the right side of the body
Increased cognitive ability has been linked to increased callosal area and thickness, which reflects more fibers and thus increased connections between the 2 hemispheres
An example is that Albert Einstein’s corpus callosum was thicker than both younger and older controls¹
Early-life training in complex skills such as playing a musical instrument can lead to a thicker corpus callosum, likely due to the required coordination of bilateral sensory and motor functions²
ACC (agenesis of the corpus callosum) is a disorder of prosencephalic midline development
It is the most prevalent cerebral malformation and is characterized by the complete or partial absence of the brain’s most prominent white matter tract³
ACC can occur independently, as part of a syndrome encompassing various neurologic conditions, or rarely as a result of infection, ischemia, or teratogens⁴⁵⁶
Structural brain anomalies linked to ACC include Chiari malformation II, craniosynostosis, holoprosencephaly, Dandy-Walker syndrome, and schizencephaly
People with ACC may be asymptomatic or may experience a range of cognitive and neurologic deficits
- The symptoms of ACC depend on the complexity of sensory information⁷
- Thus, typically developing children with undiagnosed ACC may first exhibit symptoms during adolescence, because deficits may be more evident as the reliance on callosal connectivity increases⁷
- Severity varies by the degree of agenesis (partial versus complete) and whether the case of ACC is isolated or complex (ie, linked to other anomalies)⁸
- Evidence suggests that patients with ACC can integrate interhemispherically to transfer straightforward visual and tactile information; however, with more complicated or novel information, a decrease in interhemispheric transfer is observed
- Patients who have undergone surgical commissurotomy or corpus callosotomy for medication-resistant epilepsy experience more limitations in interhemispheric transfer than those with primary ACC⁷

Epidemiology

ACC was once believed to be extremely rare, but as neuroimaging has expanded, detection in people with typical functioning has increased
Reported prevalence of ACC varies between 1:5000 and 1:4000 (0.020% to 0.025%) in the general population, with some studies reporting a higher prevalence of 0.2% to 0.7%⁹¹⁰
Reported prevalence of ACC in people with developmental disabilities is between 1% and 3%⁸¹⁰
Actual prevalence of ACC may be higher than reported, as only symptomatic cases are typically reported
Males are more likely than females to develop ACC¹¹

What causes Agenesis of the Corpus Callosum?

Most published etiologies of ACC are attributed to genetic or metabolic factors, prenatal exposure to toxins, or infections; however, among patients treated in the clinical setting, the cause in most cases remains unknown (ie, in up to 70%)⁴⁵¹²
Genetic
- More than half of the 30% to 45% of ACC cases with a known genetic cause result from monogenic mutations; many of these mutations are de novo, and no specific pattern of inheritance has been found⁴¹²
- Chromosomal abnormalities are associated with 17% of ACC diagnosed in the first year of life¹³
- Examples of genes associated with ACC syndromes are listed in Table 1
- Examples of chromosomal abnormalities associated with ACC are listed in Table 2
- Selected copy number variants associated with ACC are listed in Table 3
- Other chromosomal abnormalities associated with ACC include:¹⁴
  - Trisomies (8, 13, 18)
  - dup(11)(q23qter)
  - del(4)(p16)
  - del(6)(q23)
  - dup(8)(p21p23)

Table 1. Genes associated with ACC syndromes.

Group	Syndrome	Gene(s)
Abnormal neuronal and/or glial proliferation	ACC with intellectual disability, ocular coloboma, and micrognathia	IGBP1
	Meckel syndrome	MKS1, MKS3, TMEM67, RPGRIP1L
	Mowat-Wilson syndrome	ZEB2
Abnormal midline patterning	Acrocallosal syndrome	GLI3, KIF7, HLS2
	Apert syndrome	FGFR2
	Donnai-Barrow syndrome	LRP2
	Joubert syndrome	KIF7, RPGRIP1L, TMEM67
Abnormal callosal neuron migration and/or specification	Muscular dystrophy-dystroglycanopathy type A	POMT1, POMGNT1, POMT2, GTDC2, ISPD, FKTN, FKRP
	Schizophrenia	DISC1
	Polymicrogyria, symmetric or asymmetric	TUBB2B
Abnormal postguidance development	Andermann syndrome (also known as ACCPN: agenesis of the corpus callosum with peripheral neuropathy)	KCC3
	Autosomal recessive spastic paraplegia type 11	SPG11
	Pontocerebellar hypoplasia type 9	AMPD2

Caption: ACC, agenesis of the corpus callosum.

Data from Edwards TJ et al. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain. 2014;137(pt 6):1579-1613, Table 3.

Table 2. Chromosomal abnormalities associated with complex syndromes of which ACC may be a part in which a causative gene remains unknown.

Inheritance pattern	Syndrome	ACC penetrance
Autosomal dominant	Pai syndrome	Moderate
Autosomal recessive	Lyon syndrome	Unclear
X-linked	Aicardi syndrome	High
X-linked	FG syndrome, also known as Opitz-Kaveggia syndrome	Low

Caption: ACC, agenesis of the corpus callosum.

Data from Edwards TJ et al. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain. 2014;137(pt 6):1579-1613.

Table 3. Selected copy number variants associated with ACC.

Syndrome	Candidate genes
1q42-q44 deletion (the most common copy number variant associated with ACC)	AKT3, DISP1, HNRNPU, FAM36A, ZBTB18
17p13.3 deletion (Miller-Dieker lissencephaly syndrome)	LIS1, YWHAE

Caption: ACC, agenesis of the corpus callosum.

Data from Edwards TJ et al. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain. 2014;137(pt 6):1579-1613, Table 4.

What are the Risk Factors?

Metabolic causes
- Pyruvate dehydrogenase deficiency
- Fumarase deficiency
- Smith-Lemli-Opitz syndrome
- Glutaric aciduria type II
- Neonatal adrenoleukodystrophy
- Nonketotic hyperglycinemia
Maternal age 40 years or older¹³
Maternal alcohol use or other substance use¹⁵
Prenatal infections such as rubella, cytomegalovirus, toxoplasmosis, or influenza¹⁵

How is Agenesis of the Corpus Callosum Diagnosed?

Approach to Diagnosis

Diagnosis is often suspected based on prenatal ultrasonographic findings
- During the second trimester of pregnancy, around 22 weeks of gestation, routine fetal anomaly screening via prenatal ultrasonography can detect ACC¹⁶
  - Absence of visualization of the corpus callosum during this period does not necessarily indicate a diagnosis of ACC, as this can be a common finding at this stage of gestation
- Presence of indirect signs may indicate the presence of ACC (eg, ventriculomegaly, the absence of the cavum septi pellucidi, widening of the interhemispheric fissure, cerebral ventricular abnormalities, changes in the pericallosal artery, radial arrangement of cerebral sulci near the third ventricle)
Obtain fetal MRI to confirm diagnosis when ACC is suspected on prenatal ultrasonography
- MRI may detect other associated anomalies not identifiable on fetal ultrasonography (eg, cortical and posterior fossa anomalies)
- Best to obtain fetal MRI in the third trimester, because diagnostic accuracy improves as the pregnancy progresses¹⁶
Prenatal postdiagnostic considerations
- Counseling
  - After prenatal ACC diagnosis, refer parents for counseling from a neurodevelopmental pediatrician and a geneticist to discuss possible causes and potential outcomes; counseling should include information about the risk of false-negative diagnoses, which may occur in at least 10% of patients with isolated ACC¹⁷¹⁸¹⁹
- Genetic testing
  - Prenatal genetic testing using chromosomal microarray on amniotic fluid sample is recommended because it facilitates parental discussion regarding prognosis and potential challenges²⁰
  - If the microarray results are normal, exome sequencing should be offered, because it is likely to be more informative
- Consider potential neurometabolic and infectious causes after confirmation of ACC diagnosis
  - Metabolic testing
    - Dysgenesis of the corpus callosum is more common than agenesis in cases associated with metabolic disorders, and metabolic testing is recommended to screen for common metabolic disorders linked to corpus callosum anomalies, such as nonketotic hyperglycinemia, pyruvate dehydrogenase deficiency, mitochondriopathies, and Smith-Lemli-Opitz syndrome
  - Congenital infection screening
    - Obtain congenital infection screening if the prenatal history suggests a prenatal infection or if there are suspected infection-related signs, such as microcephaly, congenital rash, intrauterine growth restriction, or hepatic involvement
Postnatal diagnostic evaluation
- Conduct a thorough screening physical examination for other possible neurologic and genetic problems
- Postnatal MRI is recommended to assess for any previously undetected neuroanatomical abnormalities, as there still remains a 15% chance of identifying additional anomalies after birth²¹
- Genetic testing in patients who did not undergo prenatal genetic testing
  - Chromosomal microarray is typically ordered first
  - Obtain whole-exome sequencing for patients with no abnormalities detected on chromosomal microarray

Staging or Classification

Table 4 shows the main classification
- Cases of ACC are further classified into isolated or complex ACC, with complex ACC being more prevalent than isolated ACC

Table 4. Classification of ACC.

Type	Description
Complete ACC (complete callosal agenesis)	Absence of all components More frequently associated with malformations of cortical development than partial ACC
Type 1	Axons are present Commissural fibers that develop by crossing the midline are absent Probst bundles are white matter fibers that normally cross the corpus callosum but in persons with ACC instead run along the superior and medial areas of the lateral ventricles
Type 2	Axons are absent Probst bundles are not seen
Partial ACC (partial callosal agenesis)	A short remnant of the corpus callosum is present More often associated with posterior fossa malformations than complete ACC
Hypogenesis	Incomplete formation: all segments of the corpus callosum are present but are diffusely thinned
Dysgenesis	Defective development: corpus callosum is present but has an abnormal shape

Caption: ACC, agenesis of the corpus callosum.

Data from Santo S et al. Counseling in fetal medicine: agenesis of the corpus callosum. Ultrasound Obstet Gynecol. 2012;40(5):513-521.

Workup

History

Early symptoms that may suggest ACC include:
- Feeding difficulties
- Delays in developmental milestones
  - May include difficulties maintaining a straight head posture, sitting, standing, and walking, are seen in 77% of cases²²
- Epilepsy has been reported in up to two-thirds of patients with complete or partial agenesis²³
  - Seizures can manifest as early as the first week after birth in persons with ACC, and the severity can vary
Later symptoms that may suggest ACC include:
- Speech and expressive language delays
- Sensory issues
  - Vision problems (eg, strabismus, nystagmus, optic atrophy, coloboma)
  - Hearing difficulty
  - Reduced pain perception
  - Increased tactile sensitivity
- Cognitive and psychosocial deficits
  - May suggest ACC and are likely attributable to dysfunction in processing complex or unfamiliar information, longer cognitive processing time, and reduced transmission of sensory-motor information between the 2 hemispheres
- Intellectual disability and learning disorders
  - A 2018 population-based prospective study of people with ACC found that 6% of participants had severe intellectual disability; 29% had borderline intellectual functioning, and 65% had an IQ greater than 85²⁴
  - Another study noted that among those with isolated ACC, 71.2% were of normal intelligence, 13.6% had a moderate disability, and 15.2% had a severe disability²⁵
- Attention-deficit/hyperactivity disorder
- Social anxiety disorder
- ASD (autism spectrum disorder)²⁶
  - Some studies have shown reduced corpus callosum volume and connectivity throughout the callosum in persons with ASD
  - One study noted that roughly 20% of adults and 35% to 50% of children and adolescents with ACC have symptoms consistent with ASD
- Severe social difficulties
  - Deficits in linguistic comprehension and syntax, including the ability to understand figurative language such as idioms, proverbs, and vocal prosody, as well as humor and other nonliteral language forms
  - Poor social and conversational skills, such as difficulty initiating and maintaining conversations, turn-taking, and understanding social cues
  - Limited ability to verbally express emotional experiences, similar to alexithymia
  - Reduced social self-awareness may make it challenging for affected persons to understand their own and others’ emotions and perspectives in social situations
  - Impairments in recognizing emotions in others’ facial expressions and imagining and inferring their mental, emotional, and social functioning can result in difficulty understanding and navigating social situations, leading to isolation and difficulty forming and maintaining relationships
- Cognitive functioning
  - Slow processing speeds
  - Trouble processing novel or complex information
  - Deficits in inhibition, adaptability, and cognitive control can manifest as difficulties with fluid intelligence, such as inattentiveness, impulsivity, impaired reasoning, and difficulty with novel problem-solving
  - Patients diagnosed with ACC usually do not have deficiencies in overlearned cognitive functions or crystallized intelligence⁷
- Neurologic symptoms may suggest ACC
  - A range of coordination and motor impairments have been associated with ACC
  - Cerebral palsy has also been linked to ACC

Physical Examination

No specific physical examination findings are associated with isolated agenesis of the corpus callosum
Physical manifestations of patients with complex ACC may include:
- Craniofacial abnormalities
  - May include cleft lip and/or palate, macrostomia, hypertelorism, broad and depressed nasal bridge, malocclusion of teeth, low-set ears, deep-set eyes, prominent forehead, microcephaly, or macrocephaly
- Skeletal abnormalities
  - May include dysplasias, brachydactyly, absent proximal and distal phalanges, clinodactyly of the fifth fingers, club foot, valgus foot, bilateral syndactyly of the second/third toes, or scoliosis
- Skin features
  - May include preauricular skin tags, excessive neck skin, cutis laxa, or ichthyosis
- Cardiovascular findings
  - Pansystolic murmur of ventricular septal defect (this cardiac defect has been linked to ACC)
- Neurologic findings
  - May include ocular pathologies (strabismus, nystagmus), ataxia, diminished coordination in general and specifically impaired hand-eye coordination and bimanual movements, fine motor skills deficits, hypotonia or spasticity, tremor, or muscle weakness

Laboratory Tests

Genetic testing¹⁵
- Indicated for patients with ACC confirmed by imaging in the pre- or postnatal period
- Obtain a chromosomal microarray on amniotic fluid in cases of prenatal diagnosis to look for microdeletions or microduplications
- Postnatal chromosomal microarray has been shown to detect up to 9.4% of pathogenic copy number variants
Neurometabolic screening
- Indicated to screen for potential neurometabolic causes when ACC is discovered through prenatal neuroimaging¹⁵
- Important in guiding recommended patient care and genetic counseling
- Dysgenesis of the corpus callosum is more common than agenesis in cases associated with metabolic disorders
- Screen for common metabolic disorders that are linked to corpus callosum anomalies, such as nonketotic hyperglycinemia, pyruvate dehydrogenase deficiency, mitochondriopathies, and Smith-Lemli-Opitz syndrome
- Obtain metabolic testing of blood, urine, and CSF (cerebrospinal fluid), including blood lactate and pyruvate levels, blood pH, plasma amino acid levels, urine organic acids and amino acids, 7-dehydrocholesterol, CSF lactate level (correlated with pyruvate dehydrogenase deficiency), and CSF-to-plasma glycine ratio
Congenital infection screening
- Indicated if the prenatal history is suggestive of a prenatal infection or if there are suspected infection-related signs (eg, microcephaly, congenital rash, intrauterine growth restriction, hepatic involvement)²⁷
- ELISA (enzyme-linked immunosorbent assay) is a frequently employed diagnostic tool for maternal infections that have been linked to the development of fetal ACC
- Screen for congenital infection on maternal blood and amniotic fluid, when available
  - Paired serology testing for virus-specific IgM and IgG antibodies can aid in the diagnosis and timing of infection in relation to gestational age
  - Amniocentesis is necessary for definitive diagnosis of fetal infection, and it should be delayed until after 18 to 20 weeks of gestation to avoid false-negative results
- Cytomegalovirus
  - There is no standard antenatal screening program for cytomegalovirus
  - Prenatal diagnosis is frequently made after the identification of an abnormal ultrasonographic finding suggestive of possible cytomegalovirus infection during a routine scan
  - Such findings should prompt serologic testing of the mother and/or amniocentesis with polymerase chain reaction
- Rubella
  - Fetal rubella can be diagnosed by detecting rubella DNA in the amniotic fluid
- Toxoplasmosis
  - Fetal toxoplasmosis can be diagnosed by detecting toxoplasma DNA in the amniotic fluid

Imaging Studies

Antenatal ultrasonography
- Can detect corpus callosum agenesis as early as the 16th week of gestation, though with up to 20% false-positive results²¹
- Findings on antenatal ultrasonography that suggest ACC include:
  - Enlarged and dilated third ventricle (solid arrow in panel A)
  - Widely separated lateral ventricles appear as parallel bodies with small frontal horns (asterisk in panel A and dotted arrows in panel B)
  - Colpocephaly (dilatation of the trigones and occipital horns)
  - Expanded interhemispheric fissure (panel B)
  - No septum pellucidum (dotted circle in panel C)
  - Color Doppler imaging may show the absence or distortion of the superior surface of the corpus callosum and the semicircular arterial loop (panel D)
MRI of the fetus is recommended to evaluate the corpus callosum directly and is essential to confirm the diagnosis and to detect any associated brain anomalies
Postnatally, MRI of the brain is the recommended diagnostic imaging modality for assessing the presence of ACC⁵
Additional radiologic signs suggestive of ACC include²⁹
- Sunray appearance: radial arrangement of gyri that originate from the ventricles in the absence of the corpus callosum
- Inverted Probst bundles along the superomedial surface of the lateral ventricles
- Nonconverging, parallel-appearing lateral ventricles
- A high-riding third ventricle

Differential Diagnosis

Table 5. Differential Diagnosis: Agenesis of the corpus callosum.

Condition	Description	Differentiated by
Holoprosencephaly	Genetic disorder that results in an incomplete separation of the hemispheres during fetal development	The presence of fused frontal horns, an abnormal anterior cerebral artery (azygos anterior cerebral artery), and absence of a normally developed interhemispheric fissure anteriorly
Septo-optic dysplasia (previously known as de Morsier syndrome)	A condition that affects the optic nerve, pituitary gland, and the middle part of the brainCharacterized by the underdevelopment of the optic nerve, abnormalities in the brain’s midline, and dysfunction of the pituitary gland which can cause hypopituitarism, hypothyroidism, hypogonadism, and adrenal insufficiencyThese hormonal imbalances can lead to severe health problems, such as hypoglycemia, adrenal crisis, seizures, and sudden death	The presence of fused or communicating frontal horns and the presence and/or thinning of the corpus callosum on brain MRI
Autism spectrum disorder	Neuropsychiatric disorder with a diagnosis based on a combination of factors, including deficits in communication and social interaction, as well as patterns of stereotyped, restricted, and repetitive behaviors	ACC can present with deficits in reciprocal social communication, interpreting social intentions, recognizing facial emotions, and processing emotions in the social context can present as social awkwardness with no stereotyped, restricted, or repetitive behaviorsBrain MRI imaging can be used to determine whether the corpus callosum is present or absent
Attention-deficit/hyperactivity disorder	Symptoms can be categorized into inattentiveness and hyperactivity/impulsiveness	Brain MRI imaging can be used to determine whether the corpus callosum is present or absent

Caption: ACC, agenesis of the corpus callosum.

Additional differential diagnoses to be considered include arachnoid cyst, porencephaly, social-pragmatic communication disorder, unrelated developmental delays, and language processing disorders. Brain MRI imaging is a useful tool in differentiating these conditions.

Data from Santo S et al. Counseling in fetal medicine: agenesis of the corpus callosum. Ultrasound Obstet Gynecol. 2012;40(5):513-521; and Hauptman AJ et al. Two sides to every story: growing up with agenesis of the corpus callosum. In: Pediatric Neuropsychiatry: A Case-Based Approach. Springer Nature; 2019:chap 11.

Treatment

Approach to Treatment

No specific management for ACC is available
Recommend symptomatic and supportive care to address symptoms
Adopting a multidisciplinary approach is optimal for monitoring and identifying underlying issues that may require further intervention

Nondrug and Supportive Care

Counseling for parents
- Recommend counseling for parents both prenatally and postnatally by a neuropediatrician and a geneticist³⁰
- Important to discuss possible causes and potential effects of the ACC
- Inform parents about the risk of false-negative diagnoses as well as the likelihood of recurrence in subsequent pregnancies³⁰
Neuropsychological assessment
- Obtain a baseline neuropsychological assessment, followed by regular follow-up assessments, to monitor progress and provide appropriate support and accommodations¹⁶
- Early assessment and follow-up beyond school age is recommended¹⁶
Dietary management for patients with ACC and metabolic diseases³¹³²³³
- Ketogenic diet is recommended for patients with pyruvate dehydrogenase deficiency
- Sodium benzoate is advised for nonketotic hyperglycinemia
- For Smith-Lemli-Opitz syndrome, dietary supplementation with cholesterol may prove beneficial
Occupational therapy, physical therapy, and/or speech therapy
- Assess for speech and language deficits and refer to appropriate specialists for indicated therapies¹⁶³⁴
- Refer for evaluation by an occupational therapist for any fine motor impairments³⁴
- Refer patients with coordination and balance problems for physical therapy evaluation³⁴
Additional ancillary resources³⁴
- Recommend other resources as needed, including visual rehabilitation, special education programs, social skills groups, and individual psychotherapy
- Parent training and coaching programs may help support caregiver emotional and mental well-being³⁴
Consulting medical specialists
- Manage in consultation with other specialists (eg, ophthalmologist, cardiologist, neurologist, psychiatrist) based on individualized clinical needs

Drug Therapy

Pharmacotherapy may be used for symptom management and may include:
- Antiseizure medications³⁵
- Medications for attention-deficit/hyperactivity disorder³⁶

Treatment Procedures

Ventriculoperitoneal shunt
- May be indicated for patients with ACC and hydrocephalus³⁵
Procedures to correct morphologic abnormalities
- Surgery may be indicated for concomitant anatomical abnormalities including cleft lip and/or palate, and congenital cardiac anomalies³⁷

Follow-Up

Monitoring

Asymptomatic ACC
- Assess and monitor at least annually for learning challenges given common association in patients with isolated ACC
- Follow up neuropsychiatric monitoring every 2 to 3 years is recommended³⁰

Prognosis

Prognosis is impacted by comorbidities; isolated ACC usually has a favorable prognosis²⁵
If ACC is isolated with no family history, the recurrence risk in subsequent pregnancies is about 2% to 3%¹⁵
Patients with the worst prognoses are those who have ACC accompanied by a neuronal migration disorder, with or without a Dandy-Walker deformity

Screening and Prevention

Screening

Prenatal ultrasonography is a regularly used screening tool for ACC

References

1.Men W et al. The corpus callosum of Albert Einstein’s brain: another clue to his high intelligence? Brain. 2014;137(pt 4):e268.

Agenesis of the Corpus Callosum – 6 Interesting Facts

Introduction

Epidemiology

What causes Agenesis of the Corpus Callosum?

What are the Risk Factors?

How is Agenesis of the Corpus Callosum Diagnosed?

Approach to Diagnosis

Staging or Classification

Workup

History

Physical Examination

Laboratory Tests

Imaging Studies

Differential Diagnosis

Treatment

Approach to Treatment

Nondrug and Supportive Care

Drug Therapy

Treatment Procedures

Follow-Up

Monitoring

Prognosis

Screening and Prevention

Screening

References

Share this:

Like this:

Related Posts

Related Posts:

Recent Post

features

Categories

Weekly Newsletter