Hypophosphatasia (HPP), caused by mutations in the gene ALPL encoding tissue-nonspecific alkaline phosphatase (TNALP), is an inherited systemic skeletal disease characterized by mineralization defects of bones and teeth. The clinical severity of HPP varies widely, from a lethal perinatal form to mild odontohypophosphatasia showing only dental manifestations. HPP model mice (Akp2 -/ -) phenotypically mimic the severe infantile form of human HPP; they appear normal at birth but die by 2 weeks of age because of growth failure, hypomineralization, and epileptic seizures. In the present study, we investigated the feasibility of fetal gene therapy using the lethal HPP model mice. On day 15 of gestation, the fetuses of HPP model mice underwent transuterine intraperitoneal injection of adeno-associated virus serotype 9 (AAV9) expressing bone-targeted TNALP. Treated and delivered mice showed normal weight gain and seizure-free survival for at least 8 weeks. Vector sequence was detected in systemic organs including bone at 14 days of age. ALP activities in plasma and bone were consistently high. Enhanced mineralization was demonstrated on X-ray images of the chest and forepaw. Our data clearly demonstrate that systemic injection of AAV9 in utero is an effective strategy for the treatment of lethal HPP mice. Fetal gene therapy may be an important choice after prenatal diagnosis of life-threatening HPP.

Neurocutaneous melanosis (NCM) is a rare congenital disease characterized by the presence of large or multiple congenital melanocytic nevi and benign or malignant melanocytic tumors of the leptomeninges [2] with high risk of melanoma development [1]. Acute disseminated encephalomyelitis (ADEM) is an uncommon monophasic inflammatory demyelinating disease that usually presents in children and young adults [3]. Here, we report a boy aged 10 years and 7 months with NCM complicated by ADEM. Case reportA boy aged 10 years 7 months was admitted to our hospital with consciousness disturbance and involuntary movement. He had been followed at our hospital due to NCM after birth. At age 10 years 3 months, he underwent ventricleperitoneal shunt surgery due to the development of gait disturbance, vomiting and headache with intracranial invasion of melanocytes on MRI. At age 10 years and 7 months, he collapsed at his elementary school without tonic-clonic convulsion or cyanosis. On arrival to our hospital, he was able to open his eyes, but could not speak. Body temperature was 36.1°C, pulse and respiratory rate was 126/min and 28/min. Physical examination revealed a sluggish reaction of light reflex in the right pupil with papilloedema and chorea-like involuntary movement predominantly in the right extremities. The hematological and biochemical examination and electrocardiogram were normal. Cerebrospinal fluid showed an increased number of cells (23/mm 3 ; lymphocytes 89% and neutrophils 11%; no melanoma cells), 432 mg/dl protein, 102 mg/dl sugar and 112 mEq/l chloride. Despite anti-convulsive treatment, his muscle tonus, particularly in the lower legs, increased with involuntary movement and right ocular adduction. The next day, his temperature rose to 39°C and he remained in a deep coma. The Babinski reflex was positive on both sides. On T2-weighed and fluid-attenuated inversion recovery (FLAIR) MRI, a high-intensity area was observed in the sub-cortical area of the left anterior lobe (Fig. 1a,b). The diagnosis of ADEM was made because of increased CSF protein and abnormal MRI findings, and the patient was treated with methyl-predonisolone pulse therapy (30 mg/kg× 3 days). On the 3rd day of admission, the high-grade fever, anisocoria and Babinski reflex were diminished. Light reflex returned to normal. On the 4th day of admission, reactions to verbal orders re-appeared, and his consciousness returned to normal. At 4 weeks after admission, CSF findings showed numerous melanoma cells (Fig. 1c) with increased levels of 5-S-cysteinyldopa (114.1 nmol/l: basal CSF level=0), and the day after CSF examination, he became drowsy again. Brain CT revealed a high-density area in the left anterior lobe, suggesting cerebral bleeding by tumor invasion (Fig. 1c). He died of multiple intracranial metastases with cerebral bleeding. Autopsy was not allowed. DiscussionWe reported here the first case of NCM with ADEM. The cause of ADEM in this case is uncertain, but elevated 5-SEur

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