Significance of Cortical Ribboning as a Biomarker in the Prodromal Phase of Sporadic Creutzfeldt-Jakob Disease.

A 63-year-old woman who presented for orofacial dystonia showed cortical ribboning, a typical MRI finding in sporadic Creutzfeldt-Jakob disease (sCJD). However, real-time quaking-induced conversion (RT-QuIC), the most sensitive method for an early diagnosis of sCJD, was negative. She developed sCJD six months later, at which time RT-QuIC became positive. The cerebral blood flow showed a decrease in the cerebral cortex (especially in the supramarginal gyrus) consistent with cortical ribboning, but an increase in the basal ganglia, probably involved in orofacial dystonia. Cortical ribboning on MRI might be a better biomarker than RT-QuIC in the prodromal phase of sCJD.

Familial congenital choanal atresia with GATA3 associated hypoparathyroidism-deafness-renal dysplasia syndrome unidentified on auditory brainstem response.

Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder primarily caused by GATA3 haploinsufficiency and is challenging to diagnose in early childhood. We report a Japanese family with HDR syndrome and congenital choanal atresia. The 6-year-old female proband was diagnosed with epilepsy at the age of three. Under carbamazepine monotherapy, the patient presented hypoparathyroidism accompanied by severe hypocalcemia. Subsequently, renal ultrasound analysis revealed bilateral multicystic dysplastic kidneys. Because she had difficulty hearing, we sequenced GATA3 and determined that she had a c.708_709insC (p.Ser237Glnfs*66) allelic variant in exon 3. As a result, we found a family of this disease. Each family member, including her grandfather, mother, and two siblings, had HDR syndrome of varying clinical penetrance. We found a craniofacial anomaly, congenital choanal atresia, which was inherited as an autosomal dominant trait. Hypocalcemia coupled with vitamin D deficiency, triggered by carbamazepine treatment, ultimately revealed the proband's childhood- onset HDR syndrome. Pure-tone audiometry revealed different severities of deafness as well as the progression of sensory hearing loss. However, auditory brainstem response for hearing screening is probably insufficient for ascertaining HDR syndrome in the early stages of life. We presented new clinical clues to diagnose the HDR syndrome.

False-positive TSH receptor antibody-a pitfall of third-generation TSH receptor antibody measurements in neonates.

Maternal Graves' disease (GD) during pregnancy may influence thyroid function in fetuses. Neonates born to mothers with high serum TSH receptor antibody (TRAb) levels have been reported to develop 'neonatal GD'. Therefore, evaluations of serum thyroid hormone and TRAb levels in neonates upon birth are crucial for a prompt diagnosis. At delivery, we measured TRAb with third-generation TRAb test using an M22 human monoclonal antibody in neonates by collecting umbilical cord blood in a blood collection tube with lithium-heparin, which provides a whole blood/plasma sample. In recent years, we have encountered positive TRAb levels (more than 2.0 IU/L) in nineteen neonates born to mothers with GD whose thyroid hormone levels were almost within the reference range and serum TRAb levels were less than 10 IU/L. All the neonates with positive TRAb levels did not exhibit thyrotoxicosis. However, when we measured TRAb levels with serum sample in six out of the nineteen cases, their serum TRAb levels were all negative, suggesting a discrepancy of TRAb levels between in lithium-heparin plasma from umbilical cord blood and serum. Moreover, this discrepancy was observed in neonates born to euthyroid mothers, adult active GD patients and healthy volunteers. Since lithium-heparin plasma from umbilical cord blood is widely used in laboratory tests at delivery, we may encounter 'false-positive' TRAb, which may, in turn, lead to a misdiagnosis of neonatal GD. This is a pitfall of third-generation TRAb measurements in neonates, particularly at delivery, and needs to be considered by obstetricians and neonatologists.

A Novel Truncation Mutation of the PRRT2 Gene Resulting in a 16-Amino-Acid Protein Causes Self-inducible Paroxysmal Kinesigenic Dyskinesia.

Paroxysmal kinesigenic dyskinesia (PKD) is a sporadic or autosomal-dominant, hereditary disorder characterized by brief, recurrent attacks of involuntary movements triggered by sudden, voluntary movement that generally develops during childhood and adolescence and is typically treated with carbamazepine. The proline-rich transmembrane protein 2 (PRRT2) gene contains 4 exons that encode 340 amino acids as the major isoform, and recent research has identified PRRT2 as the primary causative gene in PKD, benign familial infantile epilepsy (BFIE), and infantile convulsions with PKD (PKD/IC). Here, the authors report the phenotype of a family with a novel p.E16X (c.46G>T) nonsense mutation of the PRRT2 gene that lacked almost a full allele. In this family, none of the individuals in the pedigree exhibited evidence of cognitive impairment: the elder brother had PKD/IC with migraine; the younger brother had PKD with ataxia; the father had PKD; both siblings experienced a sensory aura; and all 3 had a history of febrile seizures. This is the first report of a short nonsense mutation in PRRT2 and indicates that the manifestations of the disease, including other mutations to date, can be explained by haploinsufficiency and that 1 intact PRRT2 allele can allow normal cognitive development.

Ring/marker chromosome derived from chromosome 7 in childhood acute megakaryoblastic leukemia with monosomy 7.

In some cases of childhood acute megakaryoblastic leukemia (AMKL), G-band analysis reveals supernumerary ring/marker chromosomes along with monosomy 7. However, their origin and relevance are poorly understood. We experienced three patients with AMKL, one of whom had Down's syndrome, whose blasts at the first visit exhibited both monosomy 7 and a ring/marker chromosome. For one case, precise molecular-cytogenetic techniques revealed that the ring chromosome was derived from a chromosome 7. It was strongly suggested that the ring chromosome was derived from a chromosome 7 in another case. The ring or one of the 2 marker chromosomes was derived from a chromosome 7 in the other case. All patients responded well to initial induction therapy. While it is not clear whether the ring/marker chromosome 7 affects the long-term prognosis of acute myeloid leukemia with monosomy 7, it may be of prognostic relevance to distinguish pure monosomy 7 from monosomy 7 with a ring/marker chromosome 7. For this purpose, conventional G-banding could be complemented with additional techniques such as spectral karyotyping or fluorescence in situ hybridization, which characterize the aberration in more detail. These methods may be useful for determining the optimal treatment and for elucidating the etiology of AMKL itself.

A case of Hirayama disease.

We report a male patient with Hirayama disease aged 13. The disease was insidiously progressive and he had severe disability of the right hand at presentation. He had muscular atrophy in the intrinsic muscles of the right hand and in the distal muscles of the right forearm. The atrophy was pronounced on the ulnar side. Cold paresis was also noticed. There was no sensory disturbance. On Electromyography, neurogenic changes were recorded in several atrophic muscles. Motor and sensory nerve conduction was normal. MR images of the spinal cord were normal when it was performed with a conventional method (i.e., without neck flexion). However, characteristic MR findings were obtained when the patient lay with maximum neck flexion. The posterior wall of the cervical dural canal was shifted anteriorly at the C3-7 vertebral level, which caused cord compression at the lower cervical spinal canal. The epidural space was crescent-shaped and showed high signal intensity on T2-weighted imaging. These clinical features are typical of Hirayama disease. Pediatrician should be aware of this disease and treat it as soon as possible in order to prevent progression of the atrophy.

Recent progress of vitamin B6 biosynthesis.

This review is the current summary of vitamin B6 (B6) biosynthesis in Escherichia coli and other microorganisms. The de novo biosynthesis of B6 has been studied extensively for last three decades. However, the de novo biosynthesis of B6 still remains unclear in spite of its simple structure. For the first two decades, B6 biosynthesis had been mainly studied with E. coli using genetic, nutritional, and isotopic labeling experiments. According to these studies, some compounds including glycolaldehyde were identified as the precursor. During the last decade, gene manipulate techniques were rapidly developed, and complete genome sequences of some microorganisms became available. Using these new tools, valuable information has been provided. The complete DNA sequence of pdx genes and other genes, which are possibly involved in B6 biosynthesis, were shown. The roles of some genes and precursors were proposed. Besides E. coli, B6 biosynthesis in other microorganisms has been also studied. In some microorganisms, snz/sno was reported to be involved in B6 biosynthesis. Intriguingly these genes show no similarity to any of the E. coli pdx genes, and are not found in E. coli. Microorganisms having snz/sno gene homologues lack homologues to pdxA/pdxJ genes, whereas those with homologues to pdxA/pdxJ lack snz/sno gene homologues. Therefore, it is most likely that there are at least two kinds of B6 biosynthetic pathways in microorganisms. These studies provided important clues of B6 biosynthesis, but the entire picture of the B6 biosynthetic pathway remains unclear.

Investigation of 1-deoxy-D-xylulose 5-phosphate synthase and transketolase of Bacillus subtilis in relation to vitamin B6 biosynthesis.

In Escherichia coli, 4-(phosphohydroxy)-L-threonine and 1-deoxy-D-xylulose 5-phosphate are believed to be direct precursors of vitamin B6 (B6), and 1-deoxy-D-xylulose 5-phosphate synthase (Dxs) and transketolase could catalyze the formation of each precursor. In this report, the possible involvement Dxs and transketolase (Tkt) in B6 biosynthesis in Bacillus subtilis was investigated. The gene disruptant of tkt and conditional mutants of dxs were constructed, and their ability of B6 biosynthesis was examined. It was found that the tkt disruptants retain the ability to synthesize B6. The conditional mutant of dxs synthesized the same amount of B6 per dry cell weight as the wild-type strain. Therefore, it is very likely that neither Dxs nor transketolase is involved in B6 biosynthesis in B. subtilis.

yaaD and yaaE are involved in vitamin B6 biosynthesis in Bacillus subtilis.

We show that yaaD and yaaE are involved in vitamin B6 (B6) biosynthesis in Bacillus subtilis. This is the first report which identifies genes involved in B(6) biosynthesis in B. subtilis. Based on homology, yaaD and yaaE belong to the highly conserved SNZ and SNO families, respectively. Disruptants of yaaD and yaaE required pyridoxal (PL) or pyridoxine (PN), and grew in the same way as the wild type in a minimal medium supplemented with 0.05 mM PL. The SNZ family is considered to be involved in singlet-oxygen resistance. Singlet-oxygen quenchers, L(+)-ascorbic acid and reduced glutathione, did not support the growth of these disruptants. Both yaaD and yaaE were transcribed at the highest level during the middle- to late-exponential phase and at a much lower level during the stationary phase. Neither PL nor PN affected the transcriptional rates of yaaD and yaaE. It is concluded that yaaD and yaaE are involved in B6 biosynthesis in B. subtilis, and are transcribed at the highest level during the middle- to late-exponential phase.

serC is involved in vitamin B6 biosynthesis in Escherichia coli but not in Bacillus subtilis.

The possible involvement of serC in vitamin B6 (B6) biosynthesis in Bacillus subtilis was investigated and compared with that in Escherichia coli. The genes of E. coli and B. subtilis were disrupted with pBEN66 and pMutin1-derived integration vectors, respectively. Nutrient requirement analyses showed that the serC-disrupted E. coli mutant required pyridoxine (PN) and L-serine, and lacked the ability to synthesize B6. Glycolaldehyde (GA), a confirmed precursor of B6, could replace PN and support the growth of the disruptant. However, the serC-disrupted E. coli mutant grown in a minimal medium supplemented with L-serine and GA synthesized B6 at a level less than 20% of that synthesized by the wild type. In contrast to E. coli, the serC-disrupted B. subtilis mutant required L-serine or glycine for growth, but did not require PN. The serC disruptant retained its ability for B6 biosynthesis and produced almost the same amount of PN as the wild type. GA had no effect on the growth and level of B6 biosynthesis of both the wild type and the serC disruptant. These results lead to the conclusion that serC is directly involved in B6 biosynthesis in E. coli, but not in B. subtilis.