Neuronal migration disorders (NMDs) are a group of birth defects caused by the abnormal migration of neurons in the developing brain and nervous system. In the developing brain, neurons must migrate from the areas where they are born to the areas where they will settle into their proper neural circuits. Neuronal migration, which occurs as early as the second month of gestation, is controlled by a complex assortment of chemical guides and signals. When these signals are absent or incorrect, neurons do not end up where they belong. This can result in structurally abnormal or missing areas of the brain in the cerebral hemispheres, cerebellum, brainstem, or hippocampus.
Causes of neuronal migration disorders
The majority of neuronal migration disorders seen in clinical practice are thought to be genetic in cause. Much of what is known about neuronal migration disorders to date has been discovered from intense research identifying the genes affected in individuals with these diseases. The widespread abnormal expression of defective genes leads to the global nature of the disorders, contrary to acquired developmental brain insults, which lead to more localized defects. Several genes have been implicated in causing the various disorders, and they continue to be identified. The most well characterized genes include DCX on the X chromosome, responsible for double cortex syndrome, and LIS1 on chromosome 17, the first gene identified for lissencephaly. Cobblestone lissencephaly is associated with abnormalities in fukutin, a gene responsible for Fukuyama muscular dystrophy, a syndrome consisting of muscle weakness and cobblestone lissencephaly.
Symptoms of neuronal migration disorders
Most neuronal migration disorders present with some combination of epilepsy, mental retardation, and abnormalities in head size, known as microcephaly. Some patients, such as those with small heterotopias, may have no symptoms at all since the severity of the defect is very mild. Patients may also have cerebral palsy or abnormalities in muscle tone. Depending on the severity of the malformation, the level of mental retardation may vary from mild to severe. Patients with lissencephaly are usually severely delayed, have failure to thrive, and are microcephalic. They may also have accompanying eye problems. Patients with double cortex syndrome or schizencephaly may have milder symptoms and may only present with seizures. Schizencephaly may have associated complications of increased fluid pressure in the brain, known as hydrocephalus.
Diagnosis of neuronal migration disorders
Diagnosis is usually made by Neuro-imaging. CT scan or MRI of the brain will show the characteristic abnormality. MRI has better resolution and may detect polymicrogyria or small heterotopias more easily than CT. Genetic testing is available for patients with lissencephaly to identify whether the DCX or LIS1gene is defective. Knowledge of the genes affected allows for counselling and family planning. Laboratory tests are not useful in diagnosis.
Medications for neuronal migration disorders
There are no known cures for the various neuronal migration disorders at this time. The majority of treatments are directed towards symptoms caused by the malformed brain. Seizures may be treated with anticonvulsant medications. Refractory seizures may respond to neurosurgical removal of abnormal brain tissue. Neurosurgery may be required to relieve hydrocephalus, by placement of a shunt. Increased muscle tone may respond to injections of botulinum toxin or muscle relaxants. Patients may require feeding through a tube due to inability to swallow normally.
Prevention of neuronal migration disorders
Management is only supportive and preventive. If seizures develop, they usually need to be treated with anticonvulsants. A few children require a neurosurgical procedure such as shunting of hydrocephalus or encephalocele operation. Physiotherapy can be offered to facilitate development or prevent worsening of contractures although its efficacy has not been established. Feeding needs to be monitored and supplemental nasogastric or gastric tube feeding provided in some cases. Detailed eye assessment is also needed.