Utility and limitations of EEG in the diagnosis and management of ALDH7A1-related pyridoxine-dependent epilepsy. A retrospective observational study.

Purpose: Pyridoxine-dependent epilepsy due to ALDH7A1 variants (PDE-ALDH7A1) is a rare disorder, presenting typically with severe neonatal, epileptic encephalopathy. Early diagnosis is imperative to prevent uncontrolled seizures. We have explored the role of EEG in the diagnosis and management of PDE. Methods: A total of 13 Norwegian patients with PDE-ALDH7A1 were identified, of whom five had reached adult age. Altogether 163 EEG recordings were assessed, 101 from the 1st year of life. Results: Median age at seizure onset was 9 h (IQR 41), range 1 h-6 days. Median delay from first seizure to first pyridoxine injection was 2 days (IQR 5.5). An EEG burst suppression pattern was seen in eight patients (62%) during the first 5 days of life. Eleven patients had recordings during pyridoxine injections: in three, immediate EEG improvement correlated with seizure control, whereas in six, no change of epileptiform activity occurred. Of these six, one had prompt clinical effect, one had delayed effect (< 1 day), one had no effect, one had uncertain effect, and another had more seizures. A patient without seizures at time of pyridoxine trial remained seizure free for 6 days. Two patients with prompt clinical effect had increased paroxysmal activity, one as a conversion to burst suppression. Autonomic seizures in the form of apnoea appeared to promote respiratory distress and were documented by EEG in one patient. EEG follow-up in adult age did not show signs of progressing encephalopathy. Conclusion: A neonatal burst suppression EEG pattern should raise the suspicion of PDE-ALDH7A1. Respiratory distress is common; isolated apnoeic seizures may contribute. EEG responses during pyridoxine trials are diverse, often with poor correlation to immediate clinical effect. Reliance on single trials may lead to under-recognition of this treatable condition. Pyridoxine should be continued until results from biomarkers and genetic testing are available.

The spectrum of pyridoxine dependent epilepsy across the age span: A nationwide retrospective observational study.

BACKGROUND: Pyridoxine-dependent epilepsy (PDE) is a rare seizure disorder usually presenting with neonatal seizures. Most cases are caused by biallelic pathogenic ALDH7A1variants. While anti-seizure medications are ineffective, pyridoxine provides seizure control, and dietary interventions may be of benefit. As the natural history beyond adolescence is insufficiently explored, our study aimed to assess the spectrum of PDE at various ages in Norway. METHODS: Patients were ascertained by contacting all Norwegian paediatric, neurological, and neurohabilitation departments and relevant professional societies. Medical records were collected and reviewed. RESULTS: We identified 15 patients treated for PDE; 13 had ALDH7A1 variants (PDE-ALDH7A1), one had PNPO deficiency, and in one, aetiology remained obscure. Of those with PDE-ALDH7A1, 12 were alive at time of study; five were > 18 years old and six were < 4 years. Median age was 10 years (range 2 months-53 years). Estimated minimum prevalence was 6.3/million among children and 1.2/million among adults. Ten had seizure onset on the first day of life. Perinatal complications and neuroradiological abnormalities suggested additional seizure aetiologies in several patients. Pyridoxine had immediate effect in six, while six had delayed (>1 h) or uncertain effect. Median delay from first seizure to continuous treatment was 11 days (range 0-42). Nine experienced breakthrough seizures with intercurrent disease or due to pyridoxine discontinuation. Cognitive outcomes ranged from normal to severe intellectual disability. The condition appeared to remain stable in adult life. SIGNIFICANCE: We found a much higher prevalence of PDE-ALDH7A1 in children relative to adults, suggesting previous underdiagnosis and early mortality. Perinatal complications are common and can delay diagnosis and initiation of pyridoxine treatment. Lifelong and continuous treatment with pyridoxine is imperative. Due to better diagnostics and survival, the number of adult patients is expected to rise.

Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome.

Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/intellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. We identified biallelic loss-of-function (LOF) variants in CBY1, segregating with the clinical features of Joubert syndrome in the families. CBY1 localizes to the distal end of the mother centriole, contributing to the formation and function of cilia. In accordance with the clinical and mutational findings in the affected individuals, we demonstrated that depletion of Cby1 in zebrafish causes ciliopathy-related phenotypes. Levels of CBY1 transcript were found reduced in the patients compared with controls, suggesting degradation of the mutated transcript through nonsense-mediated messenger RNA decay. Accordingly, we could detect CBY1 protein in fibroblasts from controls, but not from patients by immunofluorescence. Furthermore, we observed reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B in patient fibroblasts. Our data show that CBY1 LOF-variants cause a ciliopathy with features of Joubert syndrome.

Biochemical and genetic characterization of an unusual mild PEX3-related Zellweger spectrum disorder.

Patients with PEX3 mutations usually present with a severe form of Zellweger spectrum disorder with death in the first year of life. Whole exome sequencing in adult siblings with intellectual disability revealed a homozygous variant in PEX3 that abolishes the normal splice site. A cryptic acceptor splice site is activated and an in-frame transcript with a deletion is produced. This transcript translates into a protein with residual activity explaining the relatively mild peroxisomal abnormalities and clinical phenotype.

Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction.

In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.