Krabbe disease is an autosomal recessive leukodystrophy. It is pathologically characterized by demyelination of the central and peripheral nervous systems and the accumulation of globoid cells in brain white matter. It is caused by a deficiency of galactocerebrosidase (GALC) activity. We investigated mutations of the GALC gene in 17 Japanese patients with Krabbe disease, the largest subject number of Japanese patients to date, and found 27 mutations. Of these mutations, six were novel, including two nonsense mutations, W115X and R204X, two missense mutations, S257F and L364R, a small deletion, 393delT, and a small insertion, 1719-1720insT. Our findings, taken with the reported mutations in Japanese patients, confirm several mutations common to Japanese patients, the two most frequent being 12Del3Ins and I66M+I289V, which account for 37% of all mutant alleles. With two additional mutations, G270D and T652P, these account for up to 57% of genetic mutations in Japanese patients. Distribution of the mutations within the GALC gene indicated some genotype-phenotype correlation. I66M+I289M, G270D, and L618S contributed to a mild phenotype. Screening for these mutations may provide an effective method with which to predict the clinical phenotype.

Mucolipidosis (ML) II alpha/beta and III alpha/beta are autosomal recessive diseases caused by a deficiency of α and/or β subunits of the enzyme N-acetylglucosamine-1-phosphotransferase, which is encoded by the GNPTAB gene. We analyzed the GNPTAB gene in 25 ML II and 15 ML III Japanese patients. In most ML II patients, the clinical conditions ‘stand alone’, ‘walk without support’ and ‘speak single words’ were impaired; however, the frequency of ‘heart murmur’, ‘inguinal hernia’ and ‘hepatomegaly and/or splenomegaly’ did not differ between ML II and III patients. We detected mutations in GNPTAB in 73 of 80 alleles. Fourteen new mutations were c.914_915insA, c.2089_2090insC, c.2427delC, c.2544delA, c.2693delA, c.3310delG, c.3388_3389insC+c.3392C>T, c.3428_3429insA, c.3741_3744delAGAA, p.R334L, p.F374L, p.H956Y, p.N1153S and duplication of exon 2. Previously reported mutations were p.Q104X, p.W894X, p.R1189X and c.2715+1G>A causing skipping of exon 13. Homozygotes or compound heterozygotes of nonsense and frameshift mutations contributed to the severe phenotype. p.F374L, p.N1153S and splicing mutations contributed to the attenuated phenotype, although coupled with nonsense mutation. These results show the effective molecular diagnosis of ML II and III and also provide phenotypic prediction. This is the first and comprehensive report of molecular analysis for ML patients of Japanese origin.

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficient arylsulfatase A (ASA) activity and characterized by neurological involvement that results in severe disability and premature death. We examined the safety and tolerability of intrathecally delivered recombinant human ASA (rhASA; SHP611, now TAK-611) in children with MLD (NCT01510028). Secondary endpoints included change in cerebrospinal fluid (CSF) sulfatide and lysosulfatide levels, and motor function (assessed by Gross Motor Function Measure-88 total score). Twenty-four children with MLD who experienced symptom onset aged ≤ 30 months were enrolled. Patients received rhASA every other week (EOW) for 38 weeks at 10, 30, or 100 mg (cohorts 1-3; n = 6 per cohort), or 100 mg manufactured using a revised process (cohort 4; n = 6). No rhASA-related serious adverse events (SAEs) were observed; 25% of patients experienced an SAE related to the intrathecal device or drug delivery method. Mean CSF sulfatide and lysosulfatide levels fell to within normal ranges in both 100 mg cohorts following treatment. Although there was a general decline in motor function over time, there was a tendency towards a less pronounced decline in patients receiving 100 mg. Intrathecal rhASA was generally well tolerated at doses up to 100 mg EOW. These preliminary data support further development of rhASA as a therapy for patients with MLD.

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.