Lissencephaly type 1 due to doublecortin gene mutation (ORPHA:2148)
Type 1 lissencephaly due to doublecortin (DCX) gene mutations is a semi-dominant X-linked disease characterised by intellectual deficiency and seizures that are more severe in male patients.
Epidemiology
The prevalence is unknown.
Clinical description
Boys presenting with lissencephaly show an abnormally thick cortex with very few gyri (pachygyria) or even none (agyria). Clinical manifestations include swallowing and feeding difficulties, abnormal muscular tone, seizures and severe to profound psychomotor retardation. Female patients display a less severe malformation referred to as ''doublecortex'' or subcortical laminar heterotopia (SCLH) and present with clinical signs of variable severity ranging from mild epilepsy, beginning in childhood or adolescence with difficulties at school, to refractory epileptic seizures and severe intellectual deficiency.
Etiology
The condition is caused by doublecortin (DCX, located at Xq22.3-q23) gene mutations. These mutations lead to a specific defect of neuronal migration during embryogenesis, affecting all the neurons in males (lissencephaly) or only a population of neurons in heterozygous females, explaining why affected females display the less severe SCLH malformation. The DCX gene is linked to 50% of the cases of agyria, 33% of frontal pachygyria cases and 75% of SCLH cases. There is no correlation between the type of mutation and the severity of the disease. The group of type I lissencephalies includes Miller-Dieker syndrome and isolated lissencephalies linked to a deletion or point mutation in the LIS1 gene located on chromosome 17 (see these terms). In contrast to lissencephaly resulting from mutations in DCX, these types of lissencephaly are never familial.
Diagnostic methods
The diagnosis of subcortical laminar heterotopia and lissencephaly relies on magnetic resonance imaging (MRI). There seems to be a correlation between the degree of pachygyria of the cortex, widening of the ventricles, and thickness of laminar heterotopia on the one hand, and early onset of attacks and severity of intellectual deficiency on the other hand.
Differential diagnosis
SCLH should be distinguished from periventricular nodular heterotopia (see this term), which is also observed in girls, and is caused by a mutation in the filamin A gene, also located on the X chromosome. The clinical picture is milder with later onset and moderate epilepsy occurring in the young adult.
Genetic counseling
The molecular diagnosis of SCLH and lissencephaly is useful for genetic counselling and potential early antenal diagnosis of this very severe epileptogenic encephalopathy, before the stage when gyri normally appear (15 weeks of amenorrhea). If the mother carries the mutation, her risk of having a child with the mutation is 50%. Even when the mutation fails to be detected in the mother's blood, a risk nevertheless exists for future pregnancies, due to germinal mosaicism (5% to 10% of the cases).
Management and treatment
Antiepileptic medication generally succeeds in controlling epilepsy, although in some cases seizures do not completely resolve despite the use of several drugs. A gastric catheter or even a gastrotomy may be necessary to prevent complications linked to swallowing and feeding difficulties (malnutrition, regurgitation-induced pneumopathy). Orthopaedic problems (hip luxation, progressive scoliosis) can be prevented by posture correction and use of a surgical corset, which allow surgery to be delayed or avoided.
Prognosis
The prognosis depends on the degree of cerebral involvement. Lissencephaly is a severe disease, potentially associated with multiple impairments. The prognosis of SCLH is more variable, and depends on the severity of learning difficulties and epilepsy.

                            Last update: 
                            January 2007


                            - Expert reviewer(s): 
                            Pr Vincent DES PORTES