Two Siblings Showing a Mild Phenotype of Joubert Syndrome with a Specific CEP290 Variant.

Joubert syndrome (JS) is a genetic neurodevelopmental disorder characterized by lower brainstem dysplasia and cerebellar vermis agenesis termed molar tooth sign (MTS), psychomotor retardation, abnormal respiratory pattern in infancy, and oculomotor abnormalities. Arima syndrome (AS), which is a severe form of JS, is characterized by severe psychomotor retardation, congenital visual impairment, progressive renal dysfunction, and lower brainstem dysplasia from early infancy. Numerous patients with AS expire in early childhood. Recently, c.6012-12T> A in the CEP290 gene was reported as a specific variant of AS. Herein, we report the cases of two siblings showing a phenotype of JS with compound heterozygous mutations (c.6012-12T > A / c.5924delT) in the CEP290 gene. The older sister (aged 19 years) had hypotonia, hypertelorism, and anteverted nares since birth. As a neonate, she developed a transient abnormal respiratory pattern and nystagmus, and brain magnetic resonance imaging (MRI) showed MTS. The younger sister (aged 13 years) exhibited mild hypotonia and pendular nystagmus as a neonate; MRI revealed MTS. Both sisters had psychomotor retardation, oculomotor dysfunction, and bilateral renal cysts with normal renal function. They can walk and have simple conversation. They do not meet the diagnostic criteria for AS, and their symptoms were milder than those of previously reported cases with this specific mutation. This report indicates the expanding spectrum of the CEP290 variant.

Diffusion Restriction in the Optic Radiation of Term Neonates With Hypoxic-Ischemic Encephalopathy Demonstrated by Magnetic Resonance Imaging (MRI).

OBJECTIVE: There has been no previous report of diffusion restriction in the optic radiation of term neonates with hypoxic-ischemic encephalopathy. Here, using diffusion-weighted magnetic resonance imaging (MRI), we assessed diffusion restriction in the optic radiation within the first 2 weeks of life and estimated signal changes and the apparent diffusion coefficient in the optic radiation and lateral geniculate body using T1-weighted MRI. MATERIALS AND METHODS: Forty-five term neonates with hypoxic-ischemic encephalopathy underwent MRI twice during the first 2 weeks of life. Diffusion-weighted imaging and apparent diffusion coefficient were used to evaluate the presence of diffusion restriction in the optic radiation and lateral geniculate body. Apparent diffusion coefficient and T1 signal changes in the optic radiation and lateral geniculate body were also compared with those in 11 control neonates showing a normal pattern on MRI. RESULTS: Diffusion restriction in the optic radiation was observed in 29% (13/45) of the hypoxic-ischemic encephalopathy neonates at a median age of 3.5 days (range: 1-9 days). The apparent diffusion coefficient in the optic radiation of affected neonates was significantly reduced in comparison with the controls. In all neonates with optic radiation involvement, increased T1 signal intensity was observed in the optic radiation in the second week, and was also evident in in lateral geniculate body in 8 of those neonates. CONCLUSION: Diffusion restriction in the optic radiation is not rare among term neonates with hypoxic-ischemic encephalopathy, being visualized by diffusion-weighted imaging in the first week of life and also high-intensity T1 signal changes in the second week. This diffusion restriction in the optic radiation might be due to transsynaptic neuronal degeneration.

SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

Leigh syndrome with Fukuyama congenital muscular dystrophy: a case report.

We report the first case of Leigh syndrome (LS) with Fukuyama congenital muscular dystrophy (FCMD). A neonate suffered from lactic acidosis and subsequently presented with poor feeding, muscle weakness, hypotonia, cardiopulmonary dysfunction, and hydrocephalus. He died at 17 months. The findings of brain magnetic resonance imaging indicated some specific features of both LS and FCMD, and FCMD gene mutation was detected. Decreased mitochondrial respiratory complex I and II activity was noted. Mitochondrial DNA sequencing showed no pathogenic mutation. A case with complex I+II deficiency has rarely been reported, suggesting a nuclear gene mutation.

Hematopoietic contribution to skeletal muscle regeneration in acid alpha-glucosidase knockout mice.

Recent studies have shown that cells from bone marrow (BM) can give rise to differentiated skeletal muscle fibers. However, the mechanisms and identities of the cell types involved remain unknown. We performed BM transplantation in acid alpha-glucosidase (GAA) knockout mice, a model of glycogen storage disease type II, and our observations suggested that the BM cells contribute to skeletal muscle fiber formation. Furthermore, we showed that most CD45+:Sca1+ cells have a donor character in regenerating muscle of recipient mice. Based on these findings, CD45+:Sca1+ cells were sorted from regenerating muscles. The cell number was increased with granulocyte colony-stimulating factor after cardiotoxin injury, and the cells were transplanted directly into the tibialis anterior (TA) muscles of GAA knockout mice. Sections of the TA muscles stained with anti-laminin-alpha2 antibody showed that the number of CD45+:Sca1+ cells contributing to muscle fiber formation and glycogen levels were decreased in transplanted muscles. Our results indicated that hematopoietic stem cells, such as CD45+:Sca1+ cells, are involved in skeletal muscle regeneration.