Article summary with Genetic control of postnatal human brain growth by Van Dyck & Morrow - 2017

How does the human brain develop after birth?

The human brain changes dramatically in size and connectivity after birth. At age six, the brain will have reached about 90% of the adult volume. The growth of head circumference is largely driven by the growth of the underlying brain tissue.

What is occipitofrontal circumference?

Occipitofrontal circumference (OFC) refers to the largest circumference of the head (measure over the most prominent part on the back of the head and just above the eyebrows). OFC is a reliable predictor of brain volume in children younger than six. Clinicians can use OFC to detect brain growth abnormalities. Abnormal brain size in early postnatal years is often indicative of disorders of neurodevelopment.

What is microcephaly?

Microcephaly is a medical condition involving a shorter-than-normal head. Infants with primary microcephaly show small head circumference at birth and are often caused by genetic insults that disrupt neurogenesis. This is associated with intellectual disability at age seven. Infants with postnatal microcephaly show normal head circumference at birth, but then show subsequent attenuations in head circumference growth. This is often the result of defects in later-stage developmental mechanisms (for example with connectivity or gliogenesis). Postnatal microcephaly is associated with abnormal/absent language, social impairment, and epilepsy.

What is macrocephaly?

Macrocephaly is a condition in which head circumference is abnormally large. Postnatal macrocephaly refers to exaggerated head growth after birth, whereby infants are born with a normal head circumference, but then show abnormal head enlargement, often due to increased brain growth. This is associated with developmental delays of motor, language, and cognitive functions.

What are the potential biological mechanisms that cause postnatal brain growth?

Three biological mechanisms that underlie postnatal brain development are identified:

• Axonal and dendritic outgrowth increase during the second half of gestation. They form connections/synapses with other cells and give rise to early neural circuits. Dendrite elaboration accelerates during early childhood, followed by a gradual decline during late childhood and adolescence. Research indicates that altered axonal and dendrite formation are associated with intellectual and developmental disabilities.
• Synaptogenesis and experience-dependent synapse remodeling. Synapse formation begins prenatally, but the majority of synaptogenesis occurs in early childhood. It increases from birth until late childhood and is then followed by a gradual period of pruning that continues until early adulthood.
• Gliogenesis and myelination. The increase in number and size of glial cells are in large part responsible for early rapid and head growth. Myelination rapidly increases from six months to twenty-four months and gradually continues until late adolescence.

Which disorders are associated with abnormal postnatal brain growth?

Disorders may arise from an attenuation or an exaggeration of growth, and from monogenic of complex etiologies. Disorders with monogenic postnatal microcephalies are Angelman Syndrome, Rett Syndrome, and Christianson Syndrome. Disorders with monogenic postnatal macrocephalies are PTEN-related disorders, Tuberous Sclerosis Complex, and neurogenerative disorders.

What is the Angelman Syndrome?

The Angelman Syndrome is a postnatal microcephaly disorder that mainly affects the nervous system. Symptoms include a small head circumference, severe intellectual disability, developmental disability, speech problems, balance and movement problems, seizures, and sleep problems. Symptoms usually show after one year. The Angelman Syndrome arises from loss of expression of the maternally inherited allele of the imprinted ubiquitin protein ligase E3A gene.

What is the Rett Syndrome?

The Rett Syndrome is a progressive neurodevelopmental disorder characterized by impairments in language and coordination, repetitive movements, slower growth, difficulty walking, and a small head circumference. Other symptoms may be seizures, scoliosis, and sleeping problems. This disorder mainly affects females. Symptoms start to show after six to eighteen months. The majority of cases are the result from loss-of-function mutations in the X-linked gene MECP2. Loss of MECP2 leads to repression of several genes involved in brain development.

What is the Christianson Syndrome?

Christianson Syndrome is an X linked syndrome associated with intellectual disability, microcephaly, seizures, ataxia, and absent speech. There are also often common facial abnormalities, such as a long narrow face, large ears, open mouth, thick eyebrows, uncontrolled drooling, and abnormal eye movements. Christianson Syndrome is caused by a loss-of-function mutation in SLC9A&, which encodes for NHE6. NHE6 regulates endosomal lumen pH by allowing for electroneutral exchange of proton ions out of the endosome for monovalent cations into the endosome. Over-acidification of endosomal pH in absence of functional NHE6 may disrupt endosomal trafficking which is necessary for growth and neuronal development.

What are PTEN-related disorders?

Mutations in phosphatase and tensin homolog are implicated in various disorders with macrocephaly, including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus syndrome. These disorders have a predisposition of tumors and are collectively referred to as PHTS (meaning PTEN Hamartoma Tumor Syndrome). The brain overgrowth is likely due to abnormalities in proliferation and connectivity. The loss of PTEN protein or function disrupts neurodevelopmental events that occur prenatally (for example neurogenesis) and postnatally (for example dendritic growth and myelination).

What is Tuberous Sclerosis Complex?

Tuberous Sclerosis Complex causes non-cancerous tumors to grow in the brain and on other vital organs. Other symptoms may include seizures, intellectual disability, behavioral problems, skin abnormalities, kidney disease, and lung disease. It is caused by mutations in either TSC1 or TSC2. Tumors develop because of a disruption to the functional allele or other TSC protein that leads to uncontrolled cell growth.

What are neurodegenerative disorders?

Neurodegeneration refers to the progressive loss of structure or function of neurons. Many neurodegenerative disorders are due to neurometabolic disease related to synthesis, metabolism, transport, or storage of biochemical compounds. Many patients show microcephaly as a result of brain atrophy and cerebral white matter reduction.

What are Autism Spectrum Disorders?

Autism Spectrum Disorders refer to genetically and clinically heterogeneous disorders of atypical neurodevelopment characterized by impaired communication and social interactions and stereotyped behaviors. Some of the Autism Spectrum Disorders are associated with larger head circumference and brain volume. There are associations with defects in postnatal pruning, hyperactivated mTOR, and impaired autophagy.

What is schizophrenia and how is it related to brain development?

Schizophrenia is characterized by continuous or relapsing episodes of psychosis. It may arise in part from abnormal brain growth that begins years before symptom onset. MRI studies show reduced brain and gray matter volume, increased extracerebral spinal fluid, exaggerated typical back-to-front gray matter loss (predominantly in the prefrontal and temporal cortices).