Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12–24, 36–48, and 60–72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.

Tetrahydrobiopterin (BH4) deficiencies are disorders affecting phenylalanine metabolism in liver and neurotransmitters biosynthesis in brain. BH4 is the essential cofactor in the enzymatic hydroxylation of 3 aromatic amino acids (phenylalanine, tyrosine, and tryptophan). BH4 is synthesized from guanosine triphosphate (GTP) catalyzed by GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase, and sepiapterin reductase (SPR), and in aromatic amino acids hydoxylating system is regenerated by pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR). To date, 4 enzyme deficiencies (GTPCH, PTPS, DHPR, PCD) have been reported and they all follow an autosomal recessive mode of inheritance. The incidence of BH4 deficiency is at 1 in 1,000,000, except that in Taiwanese (much higher than in Japanese and Caucasians). BH4 deficiency has been diagnosed in patients with hyperphenylalaninemia (HPA) by neonatal mass-screening based on BH4 oral loading tests, analysis of urinary or se rum pteridines, and measurement of dihydropterindine reductase (DHPR) activity in blood from a Guthrie card. BH4 deficiency without treatment causes combined symptoms of HPA and neurotransmitter (dopamine, norepinephrine, epinephrine, and serotonin) deficiency, such as red hair, psychomotor retardation, and progressive neurological deterioration. Treatment of BH4 deficiencies consists of BH4 supplementation (2-20 mg / kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitters precausers (L-dopa / CarbiDOPA and 5-hydroxytryptophan), and supplements of folinic acid in DHPR deficiency.

This open-label, phase 1/2 study (JMACCT CTR JMA-IIA00350) evaluated the efficacy and safety of intracerebroventricular idursulfase beta in patients with mucopolysaccharidosis II (MPS II). Herein, we report the 100-week results. Six patients with severe MPS II aged 23–65 months were enrolled. Idursulfase beta (increasing from 1 to 30 mg between weeks 0 and 24, followed by a 30-mg final dose) was administered intracerebroventricularly once every 4 weeks using an implanted cerebrospinal fluid (CSF) reservoir; intravenous administration of idursulfase was also continued throughout the study. Efficacy endpoints included developmental age by the Kyoto Scale of Psychological Development 2001 and heparan sulfate (HS) concentration in CSF (primary outcome). In all six patients, HS concentrations decreased (40%–80%) from baseline to week 100. For overall developmental age, the difference in change from baseline to week 100 in each patient compared with patients treated by intravenous idursulfase administration (n = 13) was +8.0, +14.5, +4.5, +3.7, +8.2, and –8.3 months (mean, +5.1 months). Idursulfase beta was well tolerated. The most common adverse events were pyrexia, upper respiratory tract infection, and vomiting. The results suggest that intracerebroventricular idursulfase beta is well tolerated and can be effective at preventing and stabilizing developmental decline in patients with neuronopathic MPS II.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that causes degeneration of anterior horn cells in the human spinal cord and subsequent loss of motor neurons. The severe form of SMA is among the genetic diseases with the highest infant mortality. Although SMA has been considered incurable, newly developed drugs—nusinersen and onasemnogene abeparvovec—improve the life prognoses and motor functions of affected infants. To maximize the efficacy of these drugs, treatments should be started at the pre-symptomatic stage of SMA. Thus, newborn screening for SMA is now strongly recommended. Herein, we provide some data based on our experience of SMA diagnosis by genetic testing in Japan. A total of 515 patients suspected of having SMA or another lower motor neuron disease were tested. Among these patients, 228 were diagnosed as having SMA with survival motor neuron 1 (SMN1) deletion. We analyzed the distribution of clinical subtypes and ages at genetic testing in the SMN1-deleted patients, and estimated the SMA incidence based on data from Osaka and Hyogo prefectures, Japan. Our data showed that confirmed diagnosis by genetic testing was notably delayed, and the estimated incidence was 1 in 30,000–40,000 live births, which seemed notably lower than in other countries. These findings suggest that many diagnosis-delayed or undiagnosed cases may be present in Japan. To prevent this, newborn screening programs for SMA (SMA-NBS) need to be implemented in all Japanese prefectures. In this article, we also introduce our pilot study for SMA-NBS in Osaka Prefecture.