Alexander disease (ALX) is a rare neurological disorder characterized by white matter degeneration and cytoplasmic inclusions in astrocytes called Rosenthal fibers, labeled by antibodies against glial fibrillary acidic protein (GFAP). Three subtypes are distinguished according to age at onset: infantile (under age 2), juvenile (age 2 to 12) and adult (over age 12). Following the identification of heterozygous mutations in GFAP that cause this disease, cases of adult-onset ALX have been increasingly reported. We present a 60-year-old Japanese man with an unremarkable past and no family history of ALX. After head trauma in a traffic accident at the age of 46, his character changed, and dementia and dysarthria developed, but he remained independent. Spastic paresis and dysphagia were observed at age 57 and 59, respectively, and worsened progressively. Neurological examination at the age of 60 revealed dementia, pseudobulbar palsy, left-side predominant spastic tetraparesis, axial rigidity, bradykinesia and gaze-evoked nystagmus. Brain MRI showed tadpole-like atrophy of the brainstem, caused by marked atrophy of the medulla oblongata, cervical spinal cord and midbrain tegmentum, with an intact pontine base. Analysis of the GFAP gene revealed a heterozygous missense mutation, c.827G>T, p.R276L, which was already shown to be pathogenic in a case of pathologically proven hereditary adult-onset ALX. The typical tadpole-like appearance of the brainstem is strongly suggestive of adult-onset ALX, and should lead to a genetic investigation of the GFAP gene. The unusual feature of this patient is the symmetrical involvement of the basal ganglia, which is rarely observed in the adult form of the disease. More patients must be examined to confirm, clinically and neuroradiologically, extrapyramidal involvement of the basal ganglia in adult-onset ALX.

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by weakness and spasticity of the lower extremities. HSPs are heterogeneous disorders that involve over 80 causative genes. The frequency of HSPs is estimated to be 10–100/1,000,000. With this background, the Japanese research group “Japan Spastic Paraplegia Research Consortium: JASPAC” was organized in 2006 to elucidate the molecular epidemiologies of HSPs in Japan and the molecular pathologies of HSPs. To date, the JASPAC has collected 714 HSP families and analyzed 488 index patients. We found 279 pathogenic variants or probable pathogenic variants of causative genes in the 488 HSP patients. According to our results, we found 178 families with autosomal dominant patients (65%), and 101 with autosomal recessive and sporadic patients (48%). We found 119 patients with SPG4, 17 with SPG3A, 15 with SPG31, 13 with SPG11, and 11 with SPG10. Other HSP genes were the cause in less than five patients. On the other hand, we could not find causative genes in 35% of the autosomal dominant patients, or 52% of the autosomal recessive and sporadic patients. We are now trying to find new causative genes and elucidate the molecular mechanisms underlying HSPs.

Background: Alterations of vacuolar protein sorting‐associated protein 13 (VPS13) family members including VPS13A, VPS13B, and VPS13C lead to chorea acanthocytosis, Cohen syndrome, and parkinsonism, respectively. Recently, VPS13D mutations were identified as a cause of VPS13D‐related movement disorders, which show several phenotypes including chorea, dystonia, spastic ataxia, and spastic paraplegia.Methods: We applied whole‐exome analysis for a patient with a complicated form of hereditary spastic paraplegia (HSP) and her unaffected parents. Then, we screened the candidate genes in 664 Japanese families with HSP in Japan.Results: We first found a compound heterozygote VPS13D mutation and a heterozygote ABHD4 variation in a sporadic patient with spastic paraplegia. Then, we found three patients with VPS13D mutations in two Japanese HSP families. The three patients with homozygous mutations (p.Thr1118Met/p.Thr1118Met and p.Thr2945Ala/p.Thr2945Ala) in the VPS13D showed an adult onset pure form of HSP. Meanwhile, the patient with a compound heterozygous mutation (p.Ser405Arg/p.Arg3141Ter) in the VPS13D showed a childhood onset complicated form of HSP associated with cerebellar ataxia, cervical dystonia, cataracts, and chorioretinal dystrophy.Conclusion: In the present study, we found four patients in three Japanese families with novel VPS13D mutations, which may broaden the clinical and genetic findings for VPS13D‐related disorders.

Neuroferritinopathy is a neurodegenerative disease which demonstrates brain iron accumulation caused by the mutations in the ferritin light chain gene. On brain MRI in neuroferritinopathy, iron deposits are observed as low-intensity areas on T2WI and as signal loss on T2*WI. On T2WI, hyperintense abnormalities reflecting tissue edema and gliosis are also seen. Another characteristic finding is the presence of symmetrical cystic changes in the basal ganglia, which are seen in the advanced stages of this disorder. Atrophy is sometimes noted in the cerebellar and cerebral cortices. The variety in the MRI findings is specific to neuroferritinopathy. Based on observations of an excessive iron content in patients with chronic neurologic disorders, such as Parkinson disease and Alzheimer disease, the presence of excess iron is therefore recognized as a major risk factor for neurodegenerative diseases. The future development of multimodal and advanced MRI techniques is thus expected to play an important role in accurately measuring the brain iron content and thereby further elucidating the neurodegenerative process.