Escolar, Maria L.

Abstract Objective Biallelic pathogenic MBOAT7 variants are associated with neurodevelopmental disorders, intellectual disability (ID), epilepsy, and neuropsychiatric disorders such as attention‐deficit/hyperactivity disorder and autism spectrum disorders. We aimed to characterize the epilepsy phenotype in a cohort of patients affected by this syndrome. Methods We describe epilepsy features, electroencephalography, magnetic resonance imaging (MRI) findings, antiseizure treatment response, and neurodevelopment of 15 patients with biallelic MBOAT7 variants. Results All 15 patients had ID or developmental delay (DD). Twelve suffered from epilepsy, with mean age at seizure onset of 36 months (range = 2 months–6.5 years) and 10 of 12 showing signs of DD before seizure onset. Patients with epilepsy presented with focal motor seizures with impaired awareness ( n = 3), focal tonic–clonic seizures and epileptic spasms ( n = 1), focal to bilateral tonic–clonic seizures ( n = 1), unknown onset bilateral tonic–clonic seizures ( n = 2), myoclonic seizures ( n = 4), myoclonic–atonic seizures ( n = 1), atonic seizures ( n = 1), tonic seizures ( n = 1), and myoclonic absences ( n = 2). Seizure freedom was achieved in 66.7% (8/12), with variable antiseizure treatment regimes. We reviewed electroencephalograms of the patients with epilepsy. Background activity was normal in 64%, whereas 36% had either a generalized or a focal slowing. Interictal epileptiform discharges (IEDs) were reported in 83%. Generalized spikes/polyspikes were found in 53%, multifocal IEDs in 23%, and parasagittal focal IEDs in 26%. The most frequent abnormal brain MRI findings, reported in 58% of patients, included high‐intensity signal in T2 and fluid‐attenuated inversion recovery (FLAIR) sequences in dentate nuclei and globus pallidus. Biallelic missense variants seemed to be associated with better cognitive and motor outcomes compared to truncating variants and in‐frame deletions. Significance Biallelic MBOAT7 variants are associated with global developmental impairment in all affected patients and epilepsy in the majority. The seizure semiology is heterogenous. One third of our cohort had persistent seizures despite treatment. The most frequent MRI findings were hyperintensities in T2/FLAIR sequences in dentate nuclei and globus pallidus.

AbstractBackgroundNewborn screening (NBS) for Krabbe disease (KD) in New York and Missouri is conducted by measuring galactocerebrosidase (GALC) activity using tandem mass spectrometry (MS/MS). These NBS efforts have shown that the incidence of KD is unexpectedly low (1:400,000) while many individuals (ca. 1:6000) with reduced GALC activity and genotypes of uncertain significance are detected and subjected to follow up testing. Psychosine (PSY) is a putative marker of KD progression and can be measured in dried blood spots (DBS). We sought to determine the role that PSY levels play in NBS for KD, follow up, and treatment monitoring.MethodsPSY was eluted from DBS with methanol containing N,N‐dimethyl‐D‐erythro‐sphingosine as internal standard (IS). Liquid chromatography‐MS/MS was conducted over 17 minutes in the multiple reaction monitoring positive mode to follow the precursor to product species transitions for PSY and IS. Separation of the structural isomers PSY and glucosylsphingosine was accomplished by hydrophilic interaction liquid chromatography.ResultsPre‐analytical and analytical factors were studied and revealed satisfactory results. PSY was also measured in DBS collected from controls (range: <8 nmol/L, N = 220), KD patients at various disease stages (range: 8–112, N = 26), and GALC mutation carriers (range: <15 nmol/L, N = 18).ConclusionsPSY measurement in DBS could serve as a 2nd tier assay in NBS for KD, simplify and reduce the cost of follow up protocols, help determine disease progression, and be used to monitor KD patients following hematopoietic stem cell transplantation. However, additional chronological measurements of PSY in KD patients are required to confirm these possibilities.