Lissencephaly Type 2

Lissencephaly type 2 is a very rare brain problem that starts before birth. In this condition, the baby’s brain surface does not form normal folds and grooves. Instead, the outer surface looks thick, uneven, and “bumpy,” like small round stones, so doctors call it a “cobblestone” brain. In lissencephaly type 2, brain cells (neurons) do not stop in the right place while the baby is in the womb. They “over-migrate” and move past the normal outer border of the brain into the space just under the coverings of the brain. This wrong movement of neurons damages the normal brain layers and makes the cortex thick and disorganized.

Lissencephaly type 2, also called cobblestone lissencephaly, is a very rare brain development problem where the surface of the brain looks bumpy instead of smooth and layered. This happens because brain cells (neurons) migrate too far and “spill over” beyond the normal outer boundary of the brain during early pregnancy. Children often have severe developmental delay, weak muscles, feeding problems, seizures, vision problems and sometimes eye or muscle disease as part of a wider syndrome such as Walker–Warburg syndrome or other congenital muscular dystrophies. There is no cure today, so treatment focuses on helping the child be as safe, comfortable, and active as possible and on supporting the family over time.

This condition is usually part of a group of genetic diseases called “dystroglycanopathies.” These diseases affect a protein called alpha-dystroglycan, which is important for brain, muscle, and eye development. Because of this, children often have brain problems, muscle weakness, and eye abnormalities together.

Lissencephaly type 2 is severe. Many babies have strong developmental delay, trouble feeding, seizures, and vision problems. Life expectancy is often short, but this depends on the exact gene change and how severe the brain and body problems are.

Other names

Doctors use several other names for lissencephaly type 2. These names are helpful to recognize in reports and articles:

• Cobblestone lissencephaly

• Cobblestone cortical malformation

• Cobblestone dysplasia

• Type II lissencephaly

• LIS2 (lissencephaly 2)

• Lissencephaly 5 (for some LAMB1-related cobblestone cases)

• Dystroglycanopathy with cobblestone lissencephaly

• “Cobblestone brain” (descriptive term sometimes used in reports)

Some modern experts prefer the term “cobblestone malformation” instead of “type II lissencephaly,” because the way the brain is damaged is different from classic type I lissencephaly. However, in practice many doctors still use “lissencephaly type 2” and “cobblestone lissencephaly” as the same condition.

Types

Researchers describe several ways to group lissencephaly type 2. One useful way is by neuropathology (how the brain looks under the microscope).

1. Cobblestone lissencephaly A (severe form)
   This type shows very severe brain malformation, almost no normal folds, and a very thick, disorganized cortex. It is often linked to mutations in genes like POMT1, POMT2 or FKRP, and is usually seen in the most severe dystroglycanopathy syndromes, such as Walker-Warburg syndrome.

2. Cobblestone lissencephaly B (intermediate form)
   This type is of medium severity. There are some abnormal folds and bumpy areas but not as extreme as type A. It is sometimes connected to changes in the LARGE1 gene and other glycosylation genes.

3. Cobblestone lissencephaly C (milder form)
   This type is less severe. Some folds may be present, but they are abnormal and uneven. It is often linked to POMGNT1 gene mutations and can be seen in milder dystroglycanopathies such as Fukuyama congenital muscular dystrophy.

4. Syndromic cobblestone lissencephaly
   Here the brain problem is part of a wider syndrome, such as Walker-Warburg syndrome, muscle-eye-brain (MEB) disease, or Fukuyama congenital muscular dystrophy (FCMD). These children usually have severe muscle weakness and serious eye defects along with the brain changes.

5. Non-syndromic (isolated) cobblestone lissencephaly
   In some families, the brain shows cobblestone lissencephaly, but muscles and eyes are less affected or appear normal. For example, changes in the LAMB1 gene can cause cobblestone lissencephaly with mainly brain involvement.

6. Gene-based subtypes
   Doctors also classify lissencephaly type 2 by the main gene involved, such as POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE1, TMEM5, ISPD, LAMB1, and others in the alpha-dystroglycanopathy pathway. Each gene has slightly different patterns of brain, eye, and muscle disease, but all share the cobblestone cortex feature.

Causes

All known causes of lissencephaly type 2 relate to problems in genes that control sugar (glycan) chains attached to alpha-dystroglycan, a protein important for brain and muscle cell attachment. These gene changes are usually inherited in an autosomal recessive way, meaning both parents carry one faulty copy.

1. POMT1 gene mutations
   Changes in the POMT1 gene disturb an enzyme needed to add sugar units (O-mannosylation) to alpha-dystroglycan. Without proper sugar chains, neurons cannot anchor correctly, causing over-migration and cobblestone cortex. POMT1 mutations are a common cause in severe syndromes like Walker-Warburg.

2. POMT2 gene mutations
   POMT2 works together with POMT1 in the same glycosylation pathway. Mutations reduce enzyme activity, so alpha-dystroglycan is under-glycosylated, leading to brain, muscle, and eye malformations with cobblestone lissencephaly.

3. POMGNT1 gene mutations
   POMGNT1 adds other sugar pieces to alpha-dystroglycan. When this gene is faulty, the glycan chains are incomplete, disturbing neuron migration and especially causing the milder cobblestone C form and Fukuyama muscular dystrophy.

4. FKTN (fukutin) gene mutations
   FKTN mutations cause disorders such as Fukuyama congenital muscular dystrophy, which almost always shows cobblestone lissencephaly. The protein is part of the dystroglycan glycosylation steps, so defects disrupt brain and muscle structure.

5. FKRP gene mutations
   Mutations in FKRP (fukutin-related protein) cause a range from limb-girdle muscular dystrophy to severe congenital muscular dystrophy with cobblestone brain changes. Again, the main problem is incomplete glycosylation of alpha-dystroglycan.

6. LARGE1 gene mutations
   LARGE1 is a glycosyltransferase that elongates the sugar chains on alpha-dystroglycan. Mutations lead to the intermediate cobblestone B subtype in some series, with an uneven brain surface and white matter changes.

7. TMEM5 gene mutations
   TMEM5 mutations have been identified as a cause of cobblestone lissencephaly and related dystroglycanopathies. The gene product is involved in adding special sugars; when defective, neuronal migration and brain layering are disturbed.

8. ISPD gene mutations
   ISPD mutations also cause cobblestone-type brain malformations. The protein is involved in making sugar precursors for glycosylation, and defective ISPD leads to loss of normal alpha-dystroglycan function.

9. LAMB1 gene mutations
   Biallelic LAMB1 variants can cause lissencephaly 5, a cobblestone-type malformation often without marked muscle or eye disease. LAMB1 encodes a laminin protein in the brain’s basement membrane, and defects weaken the outer barrier, allowing neurons to over-migrate.

10. Other alpha-dystroglycanopathy genes
    Additional genes in the same pathway (such as POMGNT2 and POMK) have been linked to the broader dystroglycanopathy spectrum, including cobblestone malformations in some patients.

11. Walker-Warburg syndrome (WWS)
    WWS is a severe congenital muscular dystrophy with eye and brain malformations. Most affected children show cobblestone lissencephaly due to underlying glycosylation gene defects such as POMT1 and POMT2.

12. Muscle-eye-brain (MEB) disease
    MEB is another dystroglycanopathy in which cobblestone lissencephaly is a typical brain finding, caused by mutations in genes involved in alpha-dystroglycan glycosylation.

13. Fukuyama congenital muscular dystrophy (FCMD)
    FCMD often shows a mild form of cobblestone lissencephaly and is strongly associated with FKTN mutations. The combination of muscle weakness and cortical malformation reflects the shared glycosylation defect.

14. Autosomal recessive inheritance in consanguineous families
    In families where parents are closely related (such as cousins), recessive mutations in these genes are more likely to be passed in two copies to the baby, increasing the risk of cobblestone lissencephaly.

15. New (de novo) gene mutations
    Sometimes the disease occurs even when parents are not carriers, due to a new mutation that happens in the egg, sperm, or early embryo. These de novo changes can affect the same glycosylation genes.

16. Lissencephaly-5 (LIS5) spectrum
    Some children with Lissencephaly-5, a related condition with cobblestone cortex, have changes in LAMB1 and other basement-membrane genes, showing that different but related pathways can produce the same brain pattern.

17. Combined gene variants in glycosylation pathways
    In rare cases, more than one gene in the glycosylation pathway may carry variants, together lowering glycosylation enough to cause cobblestone lissencephaly. This “combined effect” is still being studied.

18. Unknown genetic cause with cobblestone pattern
    Even with modern genetic panels, a significant number of patients with clear cobblestone lissencephaly on MRI still have no identified mutation, showing that there are still unknown genes involved.

19. Disruption of glia limitans (outer brain barrier)
    Many causes finally act by damaging the glia limitans (the thin barrier at the surface of the brain). When this barrier is weak, neurons can over-migrate into the coverings of the brain and form the bumpy cobblestone surface.

20. Alpha-dystroglycan hypoglycosylation as the final pathway
    All these gene changes share one main final pathway: alpha-dystroglycan has too few or wrong sugar chains (“hypoglycosylation”). This single biochemical problem explains why muscles, eyes, and brain can all be affected at the same time.

Symptoms

Symptoms usually appear at birth or in early infancy and reflect both the brain malformation and associated muscle and eye problems.

1. Severe developmental delay
   Babies learn skills very slowly. They may not learn to sit, stand, or walk independently, or they reach these milestones much later than other children.

2. Low muscle tone (hypotonia)
   The baby may feel “floppy” when lifted. Poor muscle tone makes it hard to control the head and body and contributes to feeding and movement problems.

3. Muscle weakness
   Children may have trouble moving their arms and legs against gravity, and they tire easily. This is partly from the muscular dystrophy component of dystroglycanopathies.

4. Seizures
   Many children develop seizures early in life due to the severe disruption of brain structure. Seizures can be hard to control and may take different forms (staring spells, jerking, stiffness).

5. Feeding difficulty
   Poor sucking, swallowing problems, and easy choking are common. Some babies need feeding tubes to get enough nutrition and avoid aspiration.

6. Failure to thrive and poor weight gain
   Because of feeding problems and high energy needs, the child may not gain enough weight and may look small and thin for age despite proper care.

7. Breathing problems
   Weak respiratory muscles and brainstem involvement can cause shallow breathing, pauses in breathing, or frequent chest infections, especially during sleep or illness.

8. Eye abnormalities and poor vision
   Many children have structural eye problems (such as retinal changes, optic nerve hypoplasia, or persistent fetal vessels) and severe vision loss.

9. Nystagmus or abnormal eye movements
   Because of brain and eye involvement, the eyes may move in quick, uncontrolled movements (nystagmus) or may not fix steadily on faces and objects.

10. Abnormal head size (microcephaly or macrocephaly)
    Some babies have a small head (microcephaly) if brain growth is reduced; others may have an enlarged head if hydrocephalus (extra fluid) is present.

11. Hydrocephalus signs
    Vomiting, a bulging soft spot (fontanelle), rapidly increasing head size, and irritability can happen when fluid builds up in the brain because of structural malformations.

12. Spasticity or abnormal stiffness over time
    As the child grows, muscles may become stiff and tight (spasticity), causing difficulty in moving joints and sometimes painful contractures.

13. Intellectual disability
    Because the cortex is severely disorganized, thinking, language, and learning are strongly affected. Most children have severe to profound intellectual disability.

14. Poor coordination and posture
    Problems with the cerebellum and brainstem can cause poor balance, difficulty holding a stable sitting or standing posture, and abnormal body positions.

15. Frequent infections and medical complications
    Because of feeding, breathing, and movement difficulties, children may have frequent lung infections, hospital stays, and other complications that affect overall health.

Diagnostic tests

Diagnosis of lissencephaly type 2 uses a combination of clinical exam, specialized tests, and imaging. Brain MRI and genetic testing are central, and other tests help understand muscle and eye involvement and manage complications.

Physical exam tests

1. General physical and neurologic examination
   The doctor looks at head size, body growth, muscle tone, reflexes, and basic movements. The strong combination of low muscle tone, developmental delay, and abnormal reflexes raises suspicion of a major brain and muscle disorder.

2. Developmental assessment
   Simple bedside tests and standardized checklists are used to see how the child is doing in motor, language, and social skills. Very delayed or missing milestones in several areas point toward a severe brain malformation such as lissencephaly type 2.

3. Eye examination in the clinic
   Using a light and simple tools, the doctor checks how the eyes move and whether the child can fix and follow. Obvious eye problems together with neurologic signs suggest a dystroglycanopathy with cobblestone lissencephaly.

4. Muscle tone and posture evaluation
   By gently moving the arms and legs, the doctor checks if muscles are floppy or stiff and whether joints move freely or are tight. A mix of low tone early and later stiffness fits with congenital muscular dystrophy plus brain involvement.

Manual tests

5. Manual muscle testing
   Clinicians grade muscle strength on a simple scale by asking the child (when older) to push or pull against their hands, or by observing resistance to movement in infants. Marked weakness in many muscles supports the diagnosis of muscular dystrophy.

6. Range-of-motion examination
   The doctor manually moves each joint to see if it bends and straightens fully. Limited movement and fixed positions show contractures, a common consequence of long-standing weakness and abnormal muscle tone.

7. Primitive reflex and posture testing
   Checking primitive reflexes (such as Moro or grasp) helps to understand how the brainstem and cortex are working. Abnormal or persistent primitive reflexes beyond the normal age support serious brain dysfunction.

8. Balance and coordination observation
   For older children, therapists observe sitting, standing, and reaching tasks. Very poor balance and coordination, far below age expectations, are consistent with cerebellar and brainstem abnormalities seen on imaging in cobblestone lissencephaly.

Lab and pathological tests

9. Serum creatine kinase (CK) level
   A blood test for CK helps detect muscle damage. High CK levels are typical in congenital muscular dystrophies and support the idea of a dystroglycanopathy when combined with brain MRI findings.

10. Basic blood tests (full blood count, electrolytes, metabolic screen)
    These tests help rule out other causes of seizures, failure to thrive, or metabolic disorders. While usually non-specific, they are part of the initial evaluation for any infant with severe neurologic symptoms.

11. Genetic panel testing for lissencephaly / dystroglycanopathy genes
    Next-generation sequencing panels examine many genes at once, including POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE1, TMEM5, ISPD, LAMB1, and others. Finding two disease-causing variants confirms the molecular diagnosis of lissencephaly type 2.

12. Chromosomal microarray (CMA)
    CMA looks for larger deletions or duplications in chromosomes. While most cobblestone cases are single-gene disorders, CMA can detect rare structural changes or rule out other syndromic conditions.

13. Targeted single-gene sequencing
    If MRI and clinical findings strongly suggest a specific gene (for example, POMT1 in a classic Walker-Warburg picture), focused sequencing of that gene can be used as a first, quicker test.

14. Muscle biopsy with immunostaining
    In some centers, a small sample of muscle is taken and stained to see if alpha-dystroglycan is properly glycosylated. Reduced or absent staining supports a dystroglycanopathy and fits with cobblestone lissencephaly on brain imaging.

Electrodiagnostic tests

15. Electroencephalogram (EEG)
    EEG records the brain’s electrical activity using scalp electrodes. In lissencephaly type 2, EEG often shows abnormal background rhythms and frequent epileptic discharges, helping to classify and manage seizures.

16. Electromyography (EMG) and nerve conduction studies
    These tests measure how muscles and nerves respond to electrical signals. Patterns typical of muscular dystrophy, together with brain imaging, support the diagnosis of a dystroglycanopathy with cobblestone cortex.

17. Visual evoked potentials (VEPs)
    VEPs check how well signals travel from the eyes to the visual cortex. Abnormal results in a child with structural eye defects and cobblestone lissencephaly confirm severe visual pathway involvement.

Imaging tests

18. Brain MRI (postnatal)
    MRI is the key test. It shows the cobblestone appearance with a thick, irregular cortex, abnormal white matter, underdeveloped corpus callosum, small cerebellum, and a “Z-shaped” or kinked brainstem in many cases. These features clearly distinguish type 2 lissencephaly from classic type 1.

19. Prenatal ultrasound (second and third trimester)
    High-resolution ultrasound during pregnancy can detect abnormal brain shape, lack of normal grooves, ventriculomegaly, and sometimes posterior fossa anomalies. When these findings appear together with muscle or eye signs, doctors may suspect cobblestone lissencephaly.

20. Fetal or neonatal brain MRI
    Fetal MRI is more sensitive than ultrasound for brain details. It can show the irregular cortical surface, abnormal white matter, hypoplastic brainstem, and cerebellar changes, allowing earlier and more precise diagnosis before or shortly after birth.

Non-pharmacological treatments (therapies and others)

1. Physiotherapy (physical therapy)
   Physiotherapy uses guided movement and stretches to keep joints flexible, maintain posture and reduce muscle shortening in a child who cannot move normally. The therapist teaches parents daily exercises, safe positioning and ways to handle the child without causing pain. Regular physiotherapy helps slow contractures, supports breathing by improving chest movement and can reduce discomfort from stiff hips, knees and spine. Even when a child cannot walk, gentle range-of-motion exercises and supported sitting or standing can improve comfort and help circulation and digestion.

2. Occupational therapy
   Occupational therapy focuses on helping the child participate in daily activities such as sitting, playing, reaching, and basic self-care at whatever level is possible. The therapist may suggest special seating systems, hand splints, adapted toys and switches to make interaction easier. The goal is not to make the child “normal” but to support the highest possible independence and comfort in everyday routines. This therapy also teaches families safer handling, energy conservation and ways to adapt the home environment so caregiving is physically easier.

3. Speech, feeding and swallowing therapy
   Speech-language therapists help with communication and swallowing. In lissencephaly type 2, speech may be very limited, so the focus is often on safe feeding and alternative communication. Therapists assess risk of aspiration, suggest food textures and fluid thickness, and teach positioning during feeds. They may introduce communication systems such as pictures, eye-gaze boards or simple switches. The purpose is to reduce pneumonia risk, improve nutrition, and give the child a way to express comfort, pain or choices.

4. Vision therapy and low-vision support
   Many children have eye or vision problems, so eye doctors and vision specialists can help. They may prescribe glasses, patching, or visual stimulation activities adapted to the child’s level. Even if the child has severe visual impairment, simple high-contrast toys, lights and positioning can encourage tracking and eye movement. Vision support aims to improve interaction with the environment and reduce frustration by using senses that work better, such as touch and hearing.

5. Early developmental and play therapy
   Early intervention programs offer structured play-based sessions tailored to the child’s abilities. Simple activities like music, touch, movement games and sensory play stimulate the brain and help the child learn cause-and-effect. Therapists coach parents to build therapy into daily routines like bathing and feeding. Even when progress is slow, regular stimulation can improve alertness, social interaction and quality of life, and it gives families positive ways to connect with their child.

6. Positioning and postural management
   Because children may not sit or stand independently, careful positioning is essential. Special cushions, wedges and molded seating systems help keep the spine aligned and reduce pressure sores. Night splints and positioning pillows can prevent joints from becoming locked in bent positions. Good postural care also supports breathing by allowing the chest to expand more freely and can lessen reflux by keeping the head and upper body elevated during and after feeds.

7. Respiratory physiotherapy
   Weak muscles and poor cough can lead to chest infections. Respiratory physiotherapy uses gentle chest percussion, vibration and positioning to loosen mucus, along with techniques to help the child cough more effectively. Devices such as suction machines or mechanical cough assist may be used in advanced cases. The goal is to keep airways clear, reduce hospital admissions for pneumonia and make breathing more comfortable, especially during colds or after surgery.

8. Assistive communication devices (AAC)
   Augmentative and alternative communication tools include simple picture boards, eye-gaze systems, switches that play recorded messages, and, in some cases, tablet-based communication apps. Even if speech is absent, these tools allow the child to express basic needs, preferences and feelings. Teams choose the simplest system that matches vision and motor skills. Over time, consistent use can improve social connection, reduce frustration and help caregivers understand pain or distress earlier.

9. Orthopedic aids and mobility supports
   Braces, ankle–foot orthoses, standing frames and custom seating systems help maintain joint alignment, reduce contractures and support weight-bearing where possible. For some children, supported standing in a frame improves bone strength and digestion and offers a different view of the world. Orthopedic teams may also recommend specially adapted wheelchairs or strollers to improve comfort and safety during transport. These aids aim to prevent secondary deformities and make daily care easier.

10. Special education and individualized learning plans
    Most children with lissencephaly type 2 have severe learning difficulties, but they can still benefit from a structured educational plan. Special education services focus on sensory experiences, communication, and simple routines rather than academic goals. Teachers and therapists collaborate to set realistic targets and use multi-sensory methods. The purpose is to enhance awareness, interaction and joy, not to push unrealistic expectations, which can be stressful for families.

11. Psychological and emotional support for families
    Parents and siblings carry a heavy emotional load, facing grief, uncertainty and ongoing caregiving. Access to counseling, parent support groups, and psychological care can reduce anxiety and depression. Talking with other families who have children with similar conditions can lessen isolation and provide practical tips. Emotional support is an essential part of care, because caregiver well-being strongly affects the child’s quality of life and the family’s ability to continue home care.

12. Social work, respite and palliative care services
    Social workers help families access financial benefits, home nursing, equipment funding and respite care. Palliative care teams do not mean “giving up”; they focus on comfort, symptom relief and planning ahead for serious complications. They can support decisions about hospitalizations, intensive care and advanced directives. Early involvement of palliative care often improves symptom management and helps families feel more in control of difficult choices.

13. Seizure first-aid training for caregivers
    Because seizures are common, families should learn what to do during a seizure and when to call emergency services. Training covers safe positioning, protecting the head, timing the seizure, and not putting anything in the mouth. Caregivers also learn how to use prescribed rescue medicines when needed. This knowledge reduces panic, prevents injuries during seizures and ensures that prolonged seizures are treated quickly, which can lower the risk of brain damage and hospital admission.

14. Feeding strategies and safe swallowing techniques
    Dietitians and therapists suggest food textures, pacing, and positions that lower the risk of choking or aspiration. Techniques may include thickening liquids, using slow-flow nipples or special spoons, and offering small bites. Families are shown early signs of swallowing problems so they can seek help before repeated chest infections occur. These strategies aim to maintain good nutrition and hydration while protecting the lungs from food and fluid going down the wrong way.

15. Sleep hygiene and nighttime care routines
    Many children have disturbed sleep from seizures, reflux or discomfort. Simple measures such as a calm bedtime routine, consistent schedule, gentle stretches or massage before sleep, and safe positioning can improve rest. Families may use baby monitors or seizure alarms if recommended. Better sleep helps the child’s daytime alertness and reduces caregiver exhaustion, making daily care more manageable and lowering stress levels at home.

16. Environmental seizure precautions
    To reduce injury during seizures, caregivers can pad sharp corners, avoid high surfaces without protection, and use safe seating systems with harnesses when needed. Bathing may be done in shallow water with constant supervision or with special supports. These precautions do not reduce seizure frequency, but they help prevent falls, head injuries and drowning, making the home environment safer for a child at high seizure risk.

17. Infection-prevention practices
    Because many children have weak cough and aspiration risk, preventing infections is vital. Non-drug measures include regular hand-washing, avoiding cigarette smoke, limiting contact with sick visitors, good oral care, and proper suctioning or chest physiotherapy when recommended. Seasonal measures, like extra caution during flu or RSV season, can also help. These steps aim to cut down on pneumonia and hospital stays, which strongly affect survival and quality of life.

18. Genetic counseling for family planning
    Genetic counselors explain the cause, inheritance pattern, and recurrence risk of lissencephaly type 2 to parents and extended family. They discuss options such as carrier testing of family members, prenatal diagnosis and assisted reproductive techniques with pre-implantation genetic testing. This non-pharmacological service does not change the affected child’s condition but helps families make informed decisions about future pregnancies and reduces guilt and confusion about the origin of the disease.

19. Home modifications and equipment
    Simple changes like ramps, wider doorways, hoists, and bathroom adaptations can make moving and caring for the child safer and less physically demanding. Adjustable beds, pressure-relieving mattresses, and mobile hoists protect both the child and caregivers from injuries. These modifications are often arranged with help from social workers, therapists and equipment services and can allow families to keep the child at home longer instead of moving to an institution.

20. Long-term care planning and advanced care discussions
    Because lissencephaly type 2 is often life-limiting, it is kind to discuss long-term plans early, in a calm period rather than during crisis. This may include thinking about preferred place of care, resuscitation decisions, and what level of hospital intervention feels right for the child and family. These conversations are revisited over time as the situation changes. Planning ahead can reduce distress in emergencies and ensure care matches the family’s values.

---

Drug treatments

Important note: Doses for these medicines must always be set and adjusted by the child’s own doctors. The information below is educational, not personal medical advice.

1. Levetiracetam (for seizures)
   Levetiracetam is a modern anti-seizure medicine often used as a first-line drug in children with severe brain disorders. It belongs to the “antiepileptic drug” class and is approved for partial-onset, myoclonic and generalized tonic–clonic seizures. Doctors usually start with a low mg/kg/day dose, divided twice daily, and slowly increase based on seizure control and side effects such as tiredness, irritability or mood changes. It can be given by mouth or infusion if the child cannot swallow.

2. Valproic acid / sodium valproate
   Valproate is a broad-spectrum anti-seizure drug used when seizures are frequent, mixed-type or difficult to control. It increases levels of the calming brain chemical GABA and stabilizes electrical activity. Typical dosing is weight-based and divided two or three times daily. Doctors monitor liver function and blood counts because rare but serious side effects include liver damage, pancreatitis and low platelets, along with hair loss, weight gain and tremor. It is usually avoided in older girls and women who could become pregnant because of strong risks to unborn babies.

3. Topiramate
   Topiramate is another broad-spectrum antiepileptic that helps control focal and generalized seizures. It modulates sodium channels, enhances GABA activity and reduces excitatory glutamate signals. Dosing begins very low and is slowly increased to limit side effects such as sleepiness, reduced appetite, tingling in fingers, and problems with concentration or kidney stones. In children with lissencephaly type 2, it is often combined with other antiseizure drugs when one medicine alone is not enough.

4. Lamotrigine
   Lamotrigine blocks certain sodium channels and reduces release of excitatory neurotransmitters, helping prevent seizures. It is added carefully because starting too fast can cause serious skin rashes, including Stevens–Johnson syndrome. Doctors begin at a very low dose and increase slowly over weeks, especially when used with valproate. Common side effects include dizziness, headache and nausea. It is useful in mixed seizure types and sometimes improves mood, which can help in older children with severe disability.

5. Clobazam
   Clobazam is a benzodiazepine used as an add-on drug for difficult-to-control seizures or seizure clusters. It enhances the calming effect of GABA. It is usually given once or twice daily, with the dose adjusted for weight and response. Side effects include sleepiness, drooling, behavior changes and tolerance over time, meaning higher doses may be needed or the effect may lessen. Doctors try to balance seizure control with maintaining alertness for interaction and therapy.

6. Diazepam (rescue medicine)
   Diazepam is a fast-acting benzodiazepine used as an emergency “rescue” drug for prolonged seizures or clusters. It may be given rectally or intravenously, depending on the setting and product. It quickly enhances GABA activity to stop abnormal electrical discharges. Because it can cause breathing slowing and deep sleep, caregivers are taught precise dosing and when to call emergency services. It is not used regularly every day, only for seizure emergencies.

7. Midazolam (buccal or intranasal rescue)
   Midazolam is another short-acting benzodiazepine used as out-of-hospital rescue medicine. Liquid or spray forms can be placed in the cheek or nose when a seizure lasts longer than the plan allows. It is absorbed quickly through mucous membranes, often stopping seizures in minutes. Side effects include sleepiness and possible breathing or airway problems, so families receive clear written plans from their neurologist on exactly when and how to use it.

8. Phenobarbital
   Phenobarbital is an older barbiturate antiepileptic sometimes used in infants or when newer drugs fail. It increases GABA activity and reduces brain excitability. Dosing is weight-based and monitored with blood levels. Side effects may include sedation, hyperactivity in some children, breathing suppression at high levels and effects on bone health with long-term use. Because of these issues, many teams prefer newer medicines when available, but phenobarbital remains an option in severe neonatal or early-life epilepsy.

9. Baclofen (for spasticity and stiffness)
   Some children develop spasticity, where muscles become stiff and tight. Baclofen is a muscle relaxant and antispastic agent that acts on GABA-B receptors in the spinal cord to reduce muscle tone. It can be given by mouth or, in selected older children, via an implanted pump into the spinal fluid. The daily dose is increased slowly to avoid side effects such as sleepiness, weakness, nausea and low blood pressure. Stopping suddenly can cause dangerous withdrawal with seizures and high fever, so it must be tapered under medical supervision.

10. Tizanidine
    Tizanidine is another muscle relaxant used for spasticity. It works on alpha-2 adrenergic receptors to reduce the nerve signals that cause muscles to tighten. It is usually given several times a day, starting at a low dose. Side effects can include sleepiness, low blood pressure and liver enzyme changes, so monitoring is important. In lissencephaly type 2 it may be used when baclofen alone does not control spasticity or causes too many side effects.

11. Botulinum toxin type A injections
    Botulinum toxin injections are used in specific tight muscles (such as calf or hip muscles) to reduce spasticity and improve comfort or ease of care. The drug blocks acetylcholine release at the neuromuscular junction, temporarily weakening the muscle for about three months. Dosing is based on weight and muscle size and must be done by trained specialists. Side effects are generally local weakness, pain at the injection site, and very rarely more generalized weakness or swallowing problems.

12. Glycopyrrolate (for drooling)
    Glycopyrrolate reduces saliva production by blocking muscarinic receptors in salivary glands. It can be useful when drooling is heavy and causes skin breakdown or aspiration risk. The medicine is given by mouth in small weight-based doses, often two or three times daily. Common side effects include dry mouth, constipation, urinary retention and blurred vision, so benefits must be carefully balanced against discomfort and the child’s ability to tolerate decreased secretions.

13. Proton pump inhibitors (for reflux, for example omeprazole)
    Proton pump inhibitors reduce acid production in the stomach. In lissencephaly type 2, they are used when severe gastro-esophageal reflux causes pain, vomiting or aspiration. The dose depends on weight and is usually given once or twice a day before feeds. Side effects may include diarrhea, headache and, with long-term use, possible effects on mineral absorption and infection risk. Doctors regularly review whether the medicine is still needed or if non-drug measures alone are enough.

14. H2-receptor antagonists (for reflux)
    Medicines like famotidine lower stomach acid by blocking histamine H2 receptors. They may be used short-term or when proton pump inhibitors are not suitable. Dosing is weight-based and usually divided twice daily. Side effects can include headache, diarrhea or constipation, and rarely confusion at high doses. They help relieve heartburn and feeding discomfort, which can improve tolerance of feeds and overall comfort.

15. Osmotic laxatives (for constipation, for example polyethylene glycol)
    Constipation is common because of low muscle tone, immobility and some medicines. Polyethylene glycol and similar osmotic laxatives draw water into the bowel to soften stools. The powder is mixed with fluid and given once or more per day according to medical advice. Side effects are mainly bloating, cramping or loose stools if the dose is too high. Good constipation control reduces discomfort, reflux and behavioral distress.

16. Bronchodilators (for wheeze, for example salbutamol/albuterol)
    When children have reactive airways or chronic lung disease, inhaled bronchodilators open the breathing tubes by relaxing smooth muscle around them. Metered-dose inhalers or nebulizers are used, often with a spacer and mask. Doses are set by the child’s doctor and may be given during infections or regularly. Side effects can include fast heartbeat, tremor and restlessness. These medicines can ease wheeze and shortness of breath, helping children tolerate feeds and activity better.

17. Inhaled corticosteroids
    Inhaled steroids reduce inflammation in the airways and are sometimes used when a child has recurrent wheeze or asthma-like symptoms. They are given through an inhaler with spacer or a nebulizer at doses tailored to the child’s age and severity. Possible side effects include oral thrush and, with long-term high doses, effects on growth, so doctors use the lowest effective dose and monitor regularly. By calming airway inflammation, they may decrease hospital visits for respiratory problems.

18. Antibiotics for respiratory and other infections
    Children with lissencephaly type 2 are prone to pneumonia, urinary infections and skin infections. Antibiotics such as amoxicillin or broader-spectrum agents are chosen based on the likely organism and local guidelines. Dosing is strictly weight- and age-based and must be prescribed by a doctor. Overuse can cause resistance, diarrhea and allergic reactions, so antibiotics are reserved for clear signs of bacterial infection, not routine viral illnesses.

19. Vitamin D supplementation (medicine form)
    Many children with severe disability have low vitamin D because of limited sun exposure and poor intake. Vitamin D drops or tablets in medical doses can be prescribed to maintain healthy levels, support bone strength and reduce fracture risk. Doses vary by age, baseline level and local guidelines. Too much vitamin D can cause high calcium, so supplementation should follow blood tests and medical advice rather than over-the-counter self-dosing.

20. Routine vaccines and special immunizations
    Vaccines are biological drugs that train the immune system to fight serious infections. Children with lissencephaly type 2 should receive routine childhood vaccinations unless doctors advise otherwise, and often benefit from extra vaccines such as influenza and, where available, RSV or pneumococcal boosters. Doses and schedules follow national programs. Vaccination helps prevent illnesses that could be life-threatening in a medically fragile child and is one of the most effective “treatments” we have.

---

Dietary molecular supplements (supportive only)

Important note: Supplements should only be started after discussion with the child’s doctors and dietitian, because they can interact with medicines or cause side effects.

1. High-energy pediatric formulas
   Many children with lissencephaly type 2 struggle to gain weight. Special high-calorie feeds provide more energy and protein in small volumes. These formulas often contain balanced carbohydrates, fats (including medium-chain triglycerides) and proteins, plus vitamins and minerals. Typical dosing is calculated by a dietitian based on weight, growth and tolerance and may be given orally or through a feeding tube. The mechanism is simply improved energy intake, which supports growth, immunity and wound healing.

2. Thickening agents for fluids
   Thickeners are powders or gels added to liquids to slow down flow and make swallowing safer in children with aspiration risk. The “dose” is usually a measured scoop per volume of liquid to reach nectar- or honey-like thickness as recommended by the speech therapist. Thicker fluids move more slowly, giving the child more time to coordinate breathing and swallowing, which can reduce coughing, choking and pneumonia.

3. Omega-3 fatty acid supplements
   Omega-3 fats (from fish oil or algae oil) are often used to support general brain and heart health. They may have mild anti-inflammatory and membrane-stabilizing effects. Typical pediatric doses are weight-based and must avoid high vitamin A content in some fish oils. Evidence for direct benefit in lissencephaly is limited, but they may support overall health, especially in children with restricted diets. Side effects can include fishy taste, reflux and, at high doses, effects on bleeding risk.

4. Multivitamin preparations
   A daily pediatric multivitamin can help cover gaps when intake of fruits, vegetables and varied foods is limited. Doses usually follow age-appropriate recommendations, and liquid forms are often easier for tube-fed or orally fed children with swallowing difficulties. Vitamins act as cofactors in many metabolic processes, supporting energy production, immunity and tissue repair. Over-supplementation, especially of fat-soluble vitamins, should be avoided by sticking to recommended doses.

5. Calcium and vitamin D combinations
   Childhood immobility and anti-seizure medicines can weaken bones. Calcium plus vitamin D combinations help support bone mineralization when dietary intake is low. Doctors base doses on blood tests, weight and local guidelines. These supplements work together: vitamin D improves calcium absorption from the gut, and calcium provides the raw material for strong bones. Monitoring is important to prevent kidney stones or high calcium levels.

6. Probiotic preparations
   Probiotics are live beneficial bacteria given as drops, powders or capsules. They may help balance gut flora, improve stool consistency and reduce antibiotic-associated diarrhea in some children. The strain and dose matter, and evidence varies. In medically fragile children, they should only be used under medical guidance, especially in those with central lines or severe immune compromise. Their mechanism is modulation of gut microbiota and barrier function rather than directly treating the brain condition.

7. Fiber supplements
   When dietary fiber is low and constipation is persistent, soluble fiber supplements such as partially hydrolyzed guar gum or inulin can be added. Doses start low to avoid bloating and are increased slowly with plenty of fluid if allowed. Fiber holds water in the stool and feeds beneficial gut bacteria, helping bowel movements become softer and more regular. These products are often used together with or instead of laxative medicines depending on the child’s response.

8. Medium-chain triglyceride (MCT) oil
   MCT oil is a specialized fat that is easier to absorb and use for energy than long-chain fats. It can be added in measured milliliter doses to feeds to increase calories without raising volume too much. Dietitians calculate the amount to avoid diarrhea or cramping. MCTs are absorbed directly into the portal circulation and do not require bile salts, which helps children with certain digestive issues, though they do not specifically treat lissencephaly itself.

9. Electrolyte solutions for sick days
   During vomiting or diarrhea, doctors may recommend oral rehydration solutions with specific amounts of sodium, potassium and glucose to prevent dehydration. The “dose” depends on weight and fluid loss and must follow healthcare guidance. These solutions use the sodium-glucose transport mechanism in the gut to enhance water absorption. They are safer than plain water or sugary drinks and support circulation and kidney function during acute illness.

10. Special amino-acid or semi-elemental formulas
    If the child has severe feeding intolerance or malabsorption, special formulas with partially broken-down proteins, fats and carbohydrates may be used. Doses and rates are set by dietitians and gastroenterologists. These products reduce the digestive work needed and may decrease reflux, bloating or diarrhea. They do not change the brain malformation but can improve comfort and nutritional status, which in turn supports immunity and healing.

---

Immune-booster, regenerative and stem-cell drugs

At present, there are no approved immune-booster, regenerative or stem-cell drugs that can repair the brain changes in lissencephaly type 2. Research is ongoing in areas like gene therapy, protein replacement, and cell-based treatments for related muscular dystrophies, but these approaches are experimental and available only in clinical trials, usually for adults or carefully selected patients. Families may read about “stem cell cures” on the internet, but many such claims are unproven or unsafe. The safest strategy today is to use evidence-based supportive care, good nutrition, vaccination, and prompt treatment of infections to support the child’s natural immune system. Any participation in research should be through reputable, ethics-approved clinical trials, discussed with the child’s neuromuscular and neurology team.

---

Surgeries (procedures and why they are done)

1. Gastrostomy tube (G-tube) placement
   A G-tube is a feeding tube placed directly into the stomach through the abdominal wall. Surgeons perform it when a child cannot safely take enough food by mouth because of swallowing problems, aspiration risk or very poor intake. The tube allows direct delivery of liquid feeds, water and medicines, improving nutrition and reducing chest infections from food going into the lungs. It can be done endoscopically or surgically and often greatly eases daily care.

2. Fundoplication (anti-reflux surgery)
   Fundoplication is an operation where the upper part of the stomach is wrapped around the lower esophagus to strengthen the valve and reduce reflux. It may be offered when severe reflux causes pain, repeated aspiration pneumonia or failure to gain weight despite medicines and feeding changes. The goal is to stop acid and food from flowing back up, which protects lungs and teeth and can make feeding more comfortable. It is often done at the same time as G-tube placement.

3. Ventriculo-peritoneal (VP) shunt for hydrocephalus
   If a child with lissencephaly type 2 develops hydrocephalus (excess fluid in the brain), surgeons may insert a VP shunt. This thin tube drains cerebrospinal fluid from the brain’s ventricles down to the abdomen, where it is absorbed. The aim is to reduce pressure, relieve symptoms like vomiting, irritability or apnea, and prevent further stretching of brain tissues. Shunts need monitoring because they can block or become infected, requiring urgent care.

4. Orthopedic surgeries for contractures or scoliosis
   Some children develop severe joint contractures or spinal curvature that cause pain or interfere with sitting and care. Orthopedic surgeons may perform procedures such as tendon lengthening, hip reduction or spinal fusion. These surgeries aim to improve comfort, sitting balance and ease of care, rather than to restore walking. Decisions are individualized and must consider the child’s overall health, respiratory status and expected benefits versus recovery burden.

5. Tracheostomy (windpipe opening) in selected cases
   When long-term airway support is needed, a tracheostomy tube may be placed through the neck directly into the windpipe. This can make suctioning easier, allow certain ventilator supports and sometimes reduce the work of breathing. It is considered only in carefully selected children after extensive discussions, because it changes daily care and may not extend life in every case. The main aim is to improve comfort and manage severe, ongoing respiratory problems.

---

Prevention strategies (mainly for complications)

1. Genetic counseling before future pregnancies – to reduce the chance of another affected child through informed reproductive choices.

2. Routine vaccinations and infection control – to prevent pneumonia, flu and other serious infections in a medically fragile child.

3. Early seizure diagnosis and treatment – to lower the risk of status epilepticus and related brain injury.

4. Safe feeding and swallowing management – to prevent aspiration and recurrent chest infections.

5. Regular physiotherapy and splinting – to prevent or slow contractures and painful deformities.

6. Bone health monitoring and supplementation – to prevent fractures due to immobility and certain medicines.

7. Respiratory physiotherapy and positioning – to prevent mucus build-up and pneumonia.

8. Constipation prevention with diet and bowel plans – to avoid discomfort, reflux worsening and hospital admissions.

9. Pressure sore prevention with regular turning and cushions – to protect skin and avoid infections and pain.

10. Advanced care planning – to prevent unwanted, burdensome interventions and ensure that care matches family values as the disease progresses.

---

When to see doctors

Parents or caregivers should contact a doctor urgently if a child with lissencephaly type 2 has a first seizure, a seizure that lasts longer than the rescue plan allows, repeated vomiting, fever with breathing difficulties, bluish color, or a big change in alertness. New feeding problems, choking or weight loss also need prompt review. Regular planned visits with a child neurologist, pediatrician, neuromuscular specialist and therapists help adjust treatment and equipment as the child grows. Families should also ask for urgent review if they feel something is “not right,” even if they cannot describe it exactly, because small changes can signal serious infections or shunt problems in this fragile population.

---

Things to eat and things to avoid

Always follow advice from your own doctors and dietitian. This is general information, not a personal diet plan.

Helpful to include (as tolerated):

1. Energy-dense pediatric formulas to support growth when oral intake is low.

2. Well-cooked, soft cereals and porridges that are easy to swallow and can be thickened.

3. Pureed fruits and vegetables for vitamins, blended to a safe texture.

4. Healthy fats such as small amounts of oils added to purees, if tolerated, for extra calories.

5. Protein sources like pureed beans, lentils or smooth yogurt if dairy is tolerated.

6. Thickened fluids such as thickened water or juice according to swallowing plan.

7. Fiber-containing purees such as blended prunes or vegetables to help bowel function.

8. Electrolyte solutions during illness when recommended, to prevent dehydration.

9. Small, frequent meals rather than large feeds to reduce reflux and discomfort.

10. Vitamin- and mineral-fortified products prescribed or approved by the care team to fill nutritional gaps.

Best to avoid or limit (unless doctors say otherwise):

1. Thin liquids like plain water or juice in children with aspiration risk, unless thickened as advised.

2. Hard, crumbly, or sticky foods (nuts, raw carrots, dry biscuits, chewy candies) that are choking hazards.

3. Very large meals or rapid feeding, which can worsen reflux and aspiration.

4. Highly salted or very sugary processed foods, which add calories without needed nutrients and may upset the stomach.

5. Caffeinated drinks, which can disturb sleep and sometimes affect seizures.

6. Unpasteurized dairy or raw eggs, which increase infection risk.

7. Herbal or “miracle” supplements sold online that claim to cure brain disorders without scientific proof.

8. Very high-dose vitamins or minerals started without blood tests or medical guidance.

9. Fast changes in formula type or feeding regime without checking with the health team, as this can cause diarrhea or constipation.

10. Any diet that restricts major food groups (for example, extreme ketogenic diets) unless prescribed and closely monitored by specialists.

---

Frequently asked questions (FAQs)

1. Can lissencephaly type 2 be cured?
   No. At present there is no cure that can reverse the brain malformation. Treatment focuses on controlling seizures, managing complications, supporting development and improving quality of life for the child and family. Research into gene-based and protein-based therapies is ongoing, but these are not yet available as standard treatment.

2. Is lissencephaly type 2 always part of a syndrome like Walker–Warburg?
   Often, but not always. Many children with type 2 lissencephaly have it as part of syndromes such as Walker–Warburg syndrome or other congenital muscular dystrophies, but some have “isolated” cobblestone lissencephaly without obvious muscle or eye disease. Genetic testing helps clarify the exact diagnosis and guide counseling.

3. What is the life expectancy?
   Life expectancy is often shortened, especially in severe syndromic forms like Walker–Warburg syndrome, where many children die in early childhood because of infections, breathing problems or brain complications. However, milder forms exist, and some individuals live longer. It is hard to predict for one child, so doctors discuss prognosis based on that child’s specific findings.

4. Will my child ever walk or talk?
   Most children with lissencephaly type 2 have severe motor and intellectual disability and do not walk or use spoken language. However, therapies can still help them gain skills such as improved head control, better sitting with support, and ways to communicate using eye-gaze, facial expressions or devices. The focus is on comfort and connection rather than on reaching typical milestones.

5. Why does my child have so many seizures?
   The abnormal brain structure disrupts the normal balance between excitatory and inhibitory signals, making seizures much more likely. Many children have multiple seizure types and require combinations of medicines. Even with good care, seizures may not be fully controlled, but treatment aims to reduce their number, length and severity as much as possible while keeping the child comfortable and alert.

6. Can anything prevent the condition in a future pregnancy?
   If a genetic cause is identified, options such as carrier testing, prenatal diagnosis and pre-implantation genetic testing can reduce the chance of another affected child. These options are personal and depend on local laws and resources, so families should meet with a genetic counselor and specialists to discuss them.

7. Is intensive therapy worth it if progress is slow?
   Yes, when it is realistic and family-centered. Physiotherapy, occupational therapy and speech therapy may not change the underlying brain structure but can prevent complications, improve comfort, support communication and strengthen family bonds. Therapy plans should be practical and sustainable, not overwhelming for caregivers.

8. Should we consider a feeding tube?
   A feeding tube is usually considered when a child cannot safely take enough nutrition by mouth. It can improve weight gain, reduce aspiration and lessen the stress of long, exhausting feeds. Decisions are made together with the care team after careful discussion of benefits, risks and family preferences. Many parents later report that tube feeding made life easier for everyone.

9. How can we manage frequent chest infections?
   Key steps include good swallowing management, appropriate vaccinations, chest physiotherapy, positioning, prompt treatment of reflux and constipation, and early medical review when breathing changes. Some children need home suction or respiratory devices. A personalized respiratory plan from the medical team can guide day-to-day care and actions during illness.

10. Is it safe to travel with a child who has lissencephaly type 2?
    Travel can be possible with careful planning. Families should carry medicines, feeding supplies, equipment and a summary letter from the care team. They should choose destinations with access to medical care and avoid extreme temperatures or infection outbreaks. Before major trips, it is wise to discuss plans with the child’s doctors to adjust medications or ensure needed vaccines.

11. Do special diets, like ketogenic diets, help?
    Ketogenic or similar diets can help seizures in some epilepsy types but require strict medical and dietetic supervision and can have side effects. In complex conditions like lissencephaly type 2, the benefits and risks must be carefully weighed. Families should never start such diets on their own; they should discuss them with an experienced epilepsy and nutrition team.

12. What support is available for parents and siblings?
    Support may include counseling, peer support groups, respite care, home nursing, educational support for siblings and social services for financial help. Palliative care teams often coordinate emotional and spiritual support as well. Families should be encouraged to ask for and accept help; caring for themselves is part of caring for the child.

13. How often should my child see specialists?
    Most children benefit from regular follow-up with a neurologist, pediatrician and therapy team, often every three to six months or more frequently during unstable periods. Eye, orthopedic, respiratory and gastroenterology reviews are scheduled based on individual needs. Regular visits allow early detection of problems and adjustment of treatment plans.

14. Should we enroll in research studies?
    Clinical trials and registries can help advance understanding and may offer access to new interventions, but they also carry burdens and possible risks. Families considering research should review information carefully, ask many questions and ensure the study is approved by an ethics committee. Participation is voluntary, and declining does not affect routine care.

15. Where can we find reliable information?
    Reliable information usually comes from university hospitals, recognized children’s hospitals, national rare-disease organizations and peer-reviewed medical articles. Doctors can suggest trusted websites and printed resources. Families should be cautious with sites that promise cures, sell expensive unproven treatments or discourage standard medical care.

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: February 01, 2025.