WDR45 variants cause ferrous iron loss due to impaired ferritinophagy associated with nuclear receptor coactivator 4 and WD repeat domain phosphoinositide interacting protein 4 reduction.

Static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration is a neurodegenerative disorder with brain iron accumulation caused by the variants of WDR45, a core autophagy-related gene that encodes WD repeat domain phosphoinositide interacting protein 4. However, the pathophysiology of the disease, particularly the function of WDR45/WD repeat domain phosphoinositide interacting protein 4 in iron metabolism, is largely unknown. As no other variants of core autophagy-related genes show abnormalities in iron metabolism, the relation between autophagy and iron metabolism remains to be elucidated. Since iron deposition in the brain is the hallmark of static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration, iron chelation therapy has been attempted, but it was found to worsen the symptoms; thus, the establishment of a curative treatment is essential. Here, we evaluated autophagy and iron metabolism in patient-derived cells. The expression of ferritin and ferric iron increased and that of ferrous iron decreased in the patient cells with WDR45 variants. In addition, the expression of nuclear receptor coactivator 4 was markedly reduced in patient-derived cells. Furthermore, divalent metal transporter 1, which takes in ferrous iron, was upregulated, while ferroportin, which exports ferrous iron, was downregulated in patient-derived cells. The transfer of WDR45 via an adeno-associated virus vector restored WD repeat domain phosphoinositide interacting protein 4 and nuclear receptor coactivator 4 expression, reduced ferritin levels, and improved other phenotypes observed in patient-derived cells. As nuclear receptor coactivator 4 mediates the ferritin-specific autophagy, i.e. ferritinophagy, its deficiency impaired ferritinophagy, leading to the accumulation of ferric iron-containing ferritin and insufficiency of ferrous iron. Because ferrous iron is required for various essential biochemical reactions, the changes in divalent metal transporter 1 and ferroportin levels may indicate a compensatory response for maintaining the intracellular levels of ferrous iron. Our study revealed that the pathophysiology of static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration involves ferrous iron insufficiency via impaired ferritinophagy through nuclear receptor coactivator 4 expression reduction. Our findings could aid in developing a treatment strategy involving WDR45 manipulation, which may have clinical applications.

Miglustat therapy in a case of early-infantile Niemann-Pick type C.

Niemann-Pick disease type C (NPC) is a rare, progressive autosomal recessive disease. It is caused by mutations in either the NPC1 or NPC2 genes, resulting in defective regulation of intracellular lipid trafficking. Miglustat, which reversibly inhibits glucosylceramide synthase, reportedly has beneficial effects on the progressive neurological symptoms of NPC and was approved in Japan in 2012. Some reports suggested that miglustat therapy delayed the onset or progression of NPC when treatment was initiated before the onset of neurological manifestation or at an early stage. We report here a patient with the early-infantile form of NPC who started on miglustat at 4months of ages. To our knowledge, this patient is the youngest reported patient with NPC in which miglustat therapy was initiated. Our patient, who had hypotonia and developmental delay before treatment, remained stable and showed no new neurological symptoms. In addition, pulmonary involvement was improved during miglustat therapy. Our case and previous reports underscore the importance of early initiation of miglustat therapy for NPC.

Seizure recurrence following pyridoxine withdrawal in a patient with pyridoxine-dependent epilepsy.

Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive disorder characterized by early onset and recurrent seizures that can be controlled by a high dose of pyridoxine. PDE is caused by mutations in ALDH7A1, which encodes antiquitin. Antiquitin converts α-aminoadipic semialdehyde to α-aminoadipic acid. Seizure recurrence after pyridoxine withdrawal is a criterion for diagnosis, but PDE can be diagnosed conclusively by genetic testing for mutations in the ALDH7A1 gene. In this case study, we report the long-term follow-up of a patient suspected with PDE. She experienced prolonged generalized tonic seizures and was hospitalized in an intensive care unit following pyridoxine withdrawal. Later, we identified a compound heterozygous mutation, c.1216G>A, p.Gly406Arg, and a novel splice donor site mutation, IVS9+5G>A. Confirmation of these mutations would have prevented an unsafe withdrawal test. This case suggests the importance of the genetic determination of PDE to avoid the diagnostic withdrawal of pyridoxine.

Discrepancy between auditory brainstem responses, auditory steady-state responses, and auditory behavior in two patients with Pelizaeus-Merzbacher disease.

We reported two cases of Pelizaeus-Merzbacher disease. Both cases visited our hospital manifesting horizontal nystagmoid movements present from birth, and delayed motor development. Magnetic resonance imaging of the brain showed diffuse dysmyelination of the cerebral white matter, and auditory brainstem response showed waves I and II but absence of all subsequent components. Conditioned orientation reflex (COR) audiometry showed poor reactions in an infantile case whose development was severely retarded, and who spoke no meaningful words. Auditory steady-state response (ASSR) was a helpful tool for identifying her auditory ability; thereafter, her communication skills improved naturally. The other case was mildly developmentally retarded, and the results of COR audiometry and ASSR were considered the same level. The discrepancy between results of these hearing tests may arise under the influence of developmental level of the case.