Megalencephalic leukoencephalopathy with subcortical cysts (MLC) causes early-onset, slowly progressive central nervous system white matter disease, macrocephaly, and later cognitive and motor decline. We describe brain structure in a patient with MLC and proven MLC1 mutations. A male, normal at birth, had macrocephaly at 6 months followed by developmental delay. Magnetic resonance imaging showed extensive signal abnormality in cerebral white matter and subcortical progressive cystic changes in the bilateral temporal and right frontal areas. Biopsy of frontal gyrus at age 15 months showed normal gray matter. The subcortical white matter was pale due to prominent fine uniform 2- to 4-μ-thick vacuoles with a few interspersed myelinated axons and rare microglia. The vacuoles had a single-, double-, or, rarely, triple-unit membrane (resembling myelin) and contained occasional organelles but no intermediate filaments. Both normal myelinated and thinly myelinated axons were observed. The outer and occasionally the inner layers of myelin surrounding intact axons formed blebs that may represent a source for vacuoles. Genetic analysis identified 2 heterozygous mutations of intron 3 (c.322–1 G>A) and intron 7 (c.597+1G>A), the 1st leading to deletion of amino acids 60 to 89 and the 2nd to deletion of amino acids 194 to 199. Fine uniform vacuolation of white matter with wide separation of myelinated axons is the hallmark of MLC in early childhood.

CACNA1A-related disorders are rare and progressive; to date, there is no approved treatment. Trials with N-acetyl-leucine (NAL) demonstrated efficacy in disorders featuring ataxia, cognitive impairment, and epilepsy. Accordingly, we hypothesized that NAL may be effective in CACNA1A-associated disorders. Four patients (1 boy, age 15 years, 3 girls, age 5, 9, and 14) received NAL as individualized off-label treatment and were assessed using the SARA Score, SCAFI and CGI-I. In all children NAL resulted in rapid improvement of ataxia, (gait, balance, fine motor and speech - mean SARA improvement at first follow-up: 3.25 points). Improvement was sustained up to 3 years (mean long-term SARA improvement: 5.13 points). SCAFI and CGI-I showed similar improvement. NAL was well-tolerated, without adverse reactions. N-acetyl-leucine is a novel potential treatment for a so far untreatable rare disease spectrum of CACNA1A-disorders. The sustained benefit may reflect neuroprotective effects seen in other populations. Clinical trials are needed to control the results.

The high prevalence of antiphospholipid antibodies (aPL) and antinuclear antibodies (ANA) in patients with epilepsy may be associated with either the disease itself or the antiepileptic treatment. The purpose of this prospective study was to determine the prevalence of aPL and ANA in children with idiopathic epilepsy before and during treatment with antiepileptic drugs. aPL, including both anticardiolipin and anti-β2-glycoprotein I antibodies, and ANA statuses were determined in 40 healthy children, 30 children treated with sodium valproate (VPA) monotherapy, and 20 children treated with carbamazepine (CBZ) monotherapy before and at 6, 12, and 24 months after treatment initiation. Fifteen children (50%) in the VPA-treated group and 7 (35%) in the CBZ-treated group showed positivity for aPL before treatment initiation, compared with only 4 of the 40 controls. Nine children (30%) in the VPA-treated group and 4 (20%) in the CBZ-treated group showed positivity for ANA before treatment initiation, compared with only 2 of the 40 controls. The subgroup analysis found nonsignificant associations at the different time points regarding the positivity of all of the autoantibodies. Only patients treated with VPA had a significantly decreased risk of aPL positivity after 6 months of treatment. The increased prevalence of autoantibodies in children with idiopathic epilepsy is strongly associated with the disease itself.