Clinical Guidance

AQP4. Two sibs with biallelic AQP4 pathogenic variants have been reported with improving MLC similar to heterozygous HEPACAM-related improving MLC . GPRC5B. Three unrelated individuals with de novo heterozygous pathogenic variants in GPRC5B have been described . For these individuals, brain MRI presentation and clinical course are indistinguishable from MLC1-related classic MLC and biallelic HEPACAM-related classic MLC. HEPACAM. Most known biallelic and heterozygous HEPACAM pathogenic variants affect the extracellular or transmembrane domains of the protein .

Source: GeneReviews — "Megalencephalic Leukoencephalopathy with Subcortical Cysts"

Penetrance

Classic MLC. The penetrance of biallelic pathogenic variants in MLC1 or HEPACAM and heterozygous pathogenic variants in GPRC5B is expected to be complete. Improving MLC. The penetrance of heterozygous pathogenic variants in HEPACAM is reduced . The proportion of individuals with a heterozygous HEPACAM variant who exhibit or have exhibited clinical manifestations of improving MLC is unknown. The penetrance of biallelic pathogenic AQP4 variants is unknown.

Source: GeneReviews — "Megalencephalic Leukoencephalopathy with Subcortical Cysts"

Diagnostic Criteria

Suggestive Findings

Two phenotypes are observed in megalencephalic leukoencephalopathy with subcortical cysts (MLC): classic MLC and improving MLC.

Classic MLC

Classic MLC should be suspected in individuals with the following clinical and brain imaging findings and family history.

Clinical findings

• Macrocephaly with onset that is either congenital or within the first year of life

• Normal or mildly delayed early development

• Slow deterioration of motor functions with cerebellar ataxia and mild spasticity

• Seizures

• Dysarthria

• Decline in cognitive function (occurs later and is typically milder than motor decline)

• Behavioral problems in some individuals

• Temporary exacerbation of signs and symptoms after minor head trauma

Imaging findings. Brain MRI features include the following abnormalities :

Source: GeneReviews — "Megalencephalic Leukoencephalopathy with Subcortical Cysts"

Differential Diagnosis

The differential diagnosis of macrocephaly and diffuse leukoencephalopathy is limited. Other disorders with white matter disease and swelling of the abnormal white matter are listed in . The clinical features and course of these disorders are usually different from those of megalencephalic leukoencephalopathy with subcortical cysts (MLC), and none of these disorders shares all the MRI features characteristic of MLC. Note: If the head circumference of an infant is well within the normal limits at age one year, it is highly unlikely that the infant has MLC.

Table 3.

Disorders of Interest in the Differential Diagnosis of Megalencephalic Leukoencephalopathy with Subcortical Cysts

Gene | Disorder | MOI | MRI Features

ASPA | Canavan disease | AR | In Canavan disease:

Source: GeneReviews — "Megalencephalic Leukoencephalopathy with Subcortical Cysts"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Megalencephalic Leukoencephalopathy with Subcortical Cysts: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Megalencephalic Leukoencephalopathy with Subcortical Cysts"

Clinical Guidance

In individuals with classic MLC, minor head trauma may lead to temporary motor deterioration, seizures, or (rarely) coma. For this reason, contact sports and other activities with a high risk of head trauma should be avoided in affected individuals. Wearing a helmet should also be considered for situations associated with increased risk of head trauma.

Source: GeneReviews — "Megalencephalic Leukoencephalopathy with Subcortical Cysts"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Megalencephalic Leukoencephalopathy with Subcortical Cysts"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. Megalencephalic Leukoencephalopathy with Subcortical Cysts: Recommended Surveillance

Source: GeneReviews — "Megalencephalic Leukoencephalopathy with Subcortical Cysts"