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Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs due to pyramidal tract dysfunction. REEP2mutations have been identified as a cause of “pure” HSP, SPG72, with both autosomal dominant and autosomal recessive inheritance. We describe a rare Nepalese family with early-onset pure-type HSP harboring a heterozygous REEP2missense mutation (c.119T>G, p.Met40Arg). This is only the second SPG72 family with autosomal dominant inheritance. The proband presented slow and spastic gait at age 2 years and the symptoms progressed slowly. The proband’s father and uncle presented even milder symptoms of pure spastic paraplegia. Our study may provide an opportunity to further study the genotype–phenotype correlation of SPG72.

Recently, the expansion of an intronic AAGGG repeat in the replication factor C subunit 1 (RFC1) gene was reported to cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In Europeans, the expansion accounted for 22% of sporadic patients with late-onset ataxia. We genotyped 37 Japanese patients comprising 25 familial (autosomal recessive or undecided transmission) and 12 sporadic ones with late-onset ataxia. We found intronic repeat expansions in RFC1in three (12%) of the familial patients and one (8.5%) of the sporadic ones. Although our cohort study was small, the disease frequency in Japanese patients with CANVAS might be lower than that in European ones. In addition, we found biallelic ACAGG repeat expansion in one patient, indicating ACAGG repeat expansion might cause CANVAS. Clinically, we found one patient with sleep apnea syndrome, which has not been reported previously. Thus, this study might expand the clinical and genetic spectrum of CANVAS.

We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium (JASPAC). Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1gene. A mouse homolog of one UBAP1frameshift mutation carried by one of the patients was created as a disease model. Functional properties of the UBAP1 wild type and UBAP1-mutant in mouse hippocampus neurons were examined. We identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1gene as the genetic cause of a new type of HSP (SPG80). All the patients presented identical clinical features of a pure type of juvenile-onset HSP. Functional studies on mouse hippocampal neurons revealed that the C-terminal deletion UBAP1-mutant of our disease model had lost its ability to bind ubiquitin in vitro. Overexpression of the UBAP1 wild type interacts directly with ubiquitin on enlarged endosomes, while the UBAP1-mutant cannot be recruited to endosome membranes. Our study demonstrated that mutations in the UBAP1gene cause a new type of HSP and elucidated its pathogenesis. The full-length UBAP1 protein is involved in endosomal dynamics in neurons, while loss of UBAP1 function may perturb endosomal fusion and sorting of ubiquitinated cargos. These effects could be more prominent in neurons, thereby giving rise to the phenotype of a neurodegenerative disease such as HSP.

The tropomyosin-receptor kinase fused gene(TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFGgene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.

PLA2G6-associated neurodegeneration (PLAN) comprises heterogeneous neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation 2B, and Parkinson disease 14 (PARK14). In addition, very recently, PLA2G6mutations have been reported to represent a phenotype of hereditary spastic paraplegia (HSP). In this study, we screened 383 HSP families to clarify the frequency of PLA2G6mutations in the Japan Spastic Paraplegia Research Consortium, and revealed the clinical characteristics of HSP with PLA2G6mutations. We found three families with compound heterozygous mutations of the PLA2G6gene, c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, and c.1187-2 A > G/c.1933C > T, and one family with a homozygous mutation of the PLA2G6gene, c.1904G > A/c.1904G > A. All three families with compound heterozygous mutations presented a uniform phenotype of a complicated form of HSP with infantile/child-onset spastic paraplegia, cerebellar ataxia, and mental retardation. On the other hand, the family with a homozygous mutation presented a late-onset complicated form of HSP with parkinsonism. This study may extend the clinical and genetic findings for PLAN.

The originally published version of this article contained an error in Fig. 1 and Table 2. The correct figure and table of this article should have read as below. This has now been corrected in the PDF and HTML versions of the article. The authors apologize for any inconvenience caused.

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by pyramidal weakness and spasticity of the lower limbs. SPG46, one of autosomal recessive HSP, is clinically characterized by spasticity and pyramidal weakness of the lower limbs, mental retardation, congenital bilateral cataract, thin corpus callosum, and hypogonadism in males. Mutations in the nonlysosomal glucosylceramidase β2 (GBA2) gene have been identified in patients with SPG46. A Japanese woman was identified with bilateral cataracts when she was in an elementary school. She felt falling easily, speaking unclearness, and difficulty in walking and raising her left leg in her 30s. Her neurological examination at the age of 44 revealed dysarthria, spasticity in the upper and lower extremities, increased jaw jerk and tendon reflexes in the extremities, bilateral extensor plantar reflexes, ataxia, and pollakiuria. Magnetic resonance imaging showed thinning of the corpus callosum body as well as atrophy in the pons and cerebellum. A novel homozygous c.1838A > G (p.D613G) missense mutation was detected at exon 12 in GBA2. We diagnosed her illness as an autosomal-recessive form of hereditary SPG46. The clinical features matched previously reported phenotype of SPG46. This is the first report of a Japanese patient with SPG46 with a novel mutation in GBA2. We presume that the novel GBA2missense mutation found in our patient would cause loss of GBA2activity, resulting in the neurological manifestations of SPG46.