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Objective: Thyroid peroxidase (TPO) deficiency is one of the causes of thyroid dyshormonogenesis, because TPO plays a key role in thyroid hormone biosynthesis. To determine the frequency and pattern of TPO abnormalities, we have been screening TPO genes of patients with congenital goitrous hypothyroidism. Subjects and methods: TPO genes of a patient with congenital goitrous hypothyroidism and her parents were directly sequenced, and two novel missense mutations (R665W and G771R) were found. The former was derived from her father and the latter from her mother. R665 and G771 were well conserved in the peroxidase superfamily. When mRNAs containing each of the mutations were transfected into CHO-K1 cells, each cell showed faint TPO enzyme activity. However, immunofluorescence and immunoelectron microscopic analyses revealed that neither of the mutated TPOs reached the plasma membrane. Conclusions: Two novel missense mutations in the TPO gene were found. TPO proteins encoded by these mutated alleles showed abnormal cellular localization; namely, localization on the plasma membrane was disturbed. The loss of plasma membrane localization in mutated TPOs brought about the iodide organification defect, which was diagnosed as congenital hypothyroidism.

Early initiation of enzyme replacement therapy (ERT) has demonstrated clinical benefit in patients with mucopolysaccharidosis type VI (MPS VI), a progressive, multisystem autosomal recessive lysosomal disorder caused by N-acetylgalactosamine-4-sulphatase (ASB) deficiency and the consequent accumulation of glycosaminoglycan. A previous case report highlighted that 3 years of ERT with recombinant human ASB (galsulfase) was well tolerated and effective in two Japanese siblings with MPS VI who initiated ERT at 5.6 years and 6 weeks of age, respectively. This report describes 10-year follow-up data from these two siblings who continued ERT with weekly infusions of galsulfase 1 mg/kg. Ten years of ERT was well tolerated, and the older sibling reached puberty. He had typical MPS VI phenotypic features, but exhibited significant improvement in shoulder range of motion and had largely unchanged hearing and cardiac function. His skeletal deformity remained unchanged. In contrast, in the younger sibling, typical symptoms of MPS VI, including progressive dysmorphic facial features, hepatosplenomegaly, and hearing impairment were largely absent. Her joint mobility was preserved, although skeletal deformity, including claw-hand deformity, was observed. Both siblings had progressive corneal clouding. The observations in these two patients suggest that early ERT initiated in newborns can be well tolerated and effective in preventing or slowing MPS VI disease progression, but is limited in terms of its effects on bone symptoms. For this, new approaches or bone-targeting treatments would be necessary.

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Dopamine (DA) is a neurotransmitter in the brain, playing a central role in several disease conditions, including tetrahydrobiopterin (BH4) metabolism disorders and Parkinson’s disease (PD). BH4 metabolism disorders present a variety of clinical manifestations including motor disturbance via altered DA metabolism, since BH4 is a cofactor for tyrosine hydroxylase (TH), a rate-limiting enzyme for DA synthesis. Genetically, BH4 metabolism disorders are, in an autosomal recessive pattern, caused by a variant in genes encoding enzymes for BH4 synthesis or recycling, including 6-pyruvoyltetrahydropterin synthase (PTPS) or dihydropteridine reductase (DHPR), respectively. Although BH4 metabolism disorders and its metabolisms have been studied, it is unclear how gene variants cause aberrant DA synthesis in patient neurons. Here, we generated induced pluripotent stem cells (iPSCs) from BH4 metabolism disorder patients with PTPS or DHPR variants, corrected the gene variant in the iPSCs using the CRISPR/Cas9 system, and differentiated the BH4 metabolism disorder patient- and isogenic control iPSCs into midbrain DA neurons. We found that by the gene correction, the BH4 amount, TH protein level and extracellular DA level were restored in DA neuronal culture using PTPS deficiency iPSCs. Furthermore, the pharmacological correction by BH4 precursor sepiapterin treatment also improved the phenotypes of PTPS deficiency. These results suggest that patient iPSCs with BH4 metabolism disorders provide an opportunity for screening substances for treating aberrant DA synthesis-related disorders.

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(i) For a Japanese woman, BMI in childhood is a good indicator of young adult BMI, and has the possibility of becoming an important parameter to monitor obesity progression. (ii) Therefore, attempts to control obesity in elementary school girls are necessary. (iii) Parents' weights may potentially influence obesity in adulthood; however, further examination of other confounding factors is necessary.