Creatine transporter deficiency: Novel mutations and functional studies.

X-linked cerebral creatine deficiency (MIM 300036) is caused by deficiency of the creatine transporter encoded by the SLC6A8 gene. Here we report three patients with this condition from Israel. These unrelated patients were evaluated for global developmental delays and language apraxia. Borderline microcephaly was noted in one of them. Diagnosis was prompted by brain magnetic resonance imaging and spectroscopy which revealed normal white matter distribution, but absence of the creatine peak in all three patients. Biochemical testing indicated normal plasma levels of creatine and guanidinoacetate, but an increased urine creatine/creatinine ratio. The diagnosis was confirmed by demonstrating absent ([14])C-creatine transport in fibroblasts. Molecular studies indicated that the first patient is hemizygous for a single nucleotide change substituting a single amino acid (c.619 C > T, p.R207W). Expression studies in HeLa cells confirmed the causative role of the R207W substitution. The second patient had a three base pair deletion in the SLC6A8 gene (c.1222_1224delTTC, p.F408del) as well as a single base change (c.1254 + 1G > A) at a splicing site in the intron-exon junction of exon 8, the latter occurring de novo. The third patient, had a three base pair deletion (c.1006_1008delAAC, p.N336del) previously reported in other patients with creatine transporter deficiency. These three patients are the first reported cases of creatine transporter deficiency in Israel.

In vivo 1H magnetic resonance spectroscopic measurement of brain glycine levels in nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder of glycine metabolism. Defective glycine cleavage causes elevated concentrations of glycine in plasma, urine, and cerebrospinal fluid. A longitudinal study using magnetic resonance imaging (MRI) and single-voxel 1H magnetic resonance spectroscopy (MRS) was performed on an infant with the typical clinical picture of NKH. He was examined twice during the course of treatment with sodium benzoate and dextromethorphan. At the age of 10 months, MRI showed normal brain structure, while MRS detected a prominent glycine peak in the brain. Repeat MRS at the age of 13 months showed a small increase in glycine peak and a prominent glutamate/glutamine peak not previously detected. The MRS measurements were consistent with the slight increase in blood glycine level and the elevation in glutamine level, indicating that 1HMRS can be a valuable tool in the diagnosis and monitoring of treatment effects in patients with NKH.

["CHARGE" association].

CHARGE association represents a group of congenital anomalies with no clear etiology. The broad array of abnormalities, which involves several systems, has been the basis for the acronym CHARGE: coloboma, heart anomaly, choanal atresia, retarded growth and development, hypoplastic genitalia and ear malformation. We present 3 children with CHARGE association to illustrate the phenotypic variability and note the multidisciplinary treatment they received. It is recommended that this entity be approached in an interdisciplinary, integrated way to allow for faster diagnosis and better prognosis.

[Endometrial measurement by transvaginal sonography in postmenopausal bleeding].

We evaluated the role of transvaginal sonography (TVS) in the investigation of postmenopausal bleeding (PMB) in 50 women with PMB and 25 asymptomatic postmenopausal women presenting for periodic check-up, who served as controls. All those with PMB had a diagnostic curettage or hysterectomy within a week of TVS examination. Measurement of endometrial thickness was compared with the histopathological diagnosis of the endometrium. Of the 32 patients whose endometrial thickness was more than 5 mm, 22 had pathological changes in the endometrium. These included 6 cases of endometrial cancer and 16 with benign changes. All 18 patients of the PMB group with endometrial thickness less than 5 mm had normal endometrial histology. Endometrial thickness in all asymptomatic controls was less than 5 mm. Our results showed endometrial thickness greater than 5 mm to be 100% sensitive and 64% specific in identifying endometrial pathology. TVS follow-up without curettage may be considered for PMB patients with uniform endometrium less than 5 mm thick.

Prediction of participation and sensory modulation of late preterm infants at 12 months: a prospective study.

The aim of the study was to prospectively assess the differences in participation and sensory modulation between late preterm infants (LPI) and term babies, and to predict it by LPI characteristics. The study population includes 124 late preterm infants at gestational age between 34 and 35 6/7 weeks who were born at the same medical center. The control group comprised of 33 term babies (18 boys, 15 girls), born during the same period and location (mean age 12.47, SD = 0.73). Sensory modulation was assessed by the test of sensory functions in infants and the infant/toddler sensory profile and for assessment of participation and parents' satisfaction we used questionnaires. Term infants had better sensory modulation than LPI. Approximately 10% of the sensory modulation of participants in the study was explained by gestational age and head circumference. LPI participation and parental satisfaction decreased in the LPI group. Among all the explanatory variables only multiple gestations and head circumference contributed to the explained variance of participation (16%), and parents' satisfaction (13%). At age of 1 year, children born as late preterm are at increased risk of developing sensory modulation disorder, showing less participation, and resulting in less parental satisfaction.

Rotation of the vermis as a cause of enlarged cisterna magna on prenatal imaging.

OBJECTIVES: Dandy-Walker complex is a continuum of developmental anomalies of the posterior fossa which includes vermian rotation. However, vermian rotation alone may be benign. The aim of this study was to describe our experience with sagittal-plane prenatal ultrasound in the diagnosis of rotation of the vermis in cases of suspected enlarged cisterna magna on routine antenatal imaging, and to describe the follow-up of these patients. METHODS: Seven women, who were referred to our ultrasound unit for evaluation of an enlarged fetal cisterna magna and suspected agenesis of the vermis on axial-plane imaging, underwent further multiplanar studies of the posterior fossa and measurements of the vermis. RESULTS: The mean maternal age was 27 (range, 20-33) years and the mean gestational age at diagnosis was 19.5 (range, 18-31) weeks. The standard axial plane image showed a 'direct communication' between the cisterna magna and the fourth ventricle. In the mid-sagittal plane, the vermis was clearly delineated, with posterosuperior rotation. Vermis size was within normal limits for gestational age in all cases. Findings were confirmed by prenatal magnetic resonance imaging (MRI) in two cases and postnatal MRI and/or sonography in five. During a mean follow-up of 4.5 (range, 1-7.5) years, all children developed normally, with no neurological complications. CONCLUSION: The finding of an enlarged cisterna magna on standard- (axial-)plane ultrasound should be evaluated further in the sagittal plane to determine whether the cause is rotation of a normal vermis. This may spare patients unnecessary tests, anxiety and, in some cases, pregnancy termination.

Microcephaly due to fetal brain disruption sequence. Case report.

A case of microcephaly that developed intrauterine is described. Since it began three weeks after a car accident during second trimester of pregnancy, we attribute it to "brain disruption sequence" resulting in an arrest of brain development after the injury.