A Case of Anorexia Nervosa with Focal Cortical Dysplasia.

Anorexia nervosa (AN) is a fatal condition associated with extreme underweight and undernutrition. It is more common in young females, with a female-to-male ratio of 10 : 1. Focal cortical dysplasia (FCD) is characterized by dysplasia of the cerebral cortex and is a common cause of pharmacoresistant epilepsy. However, FCD associated with AN has never been reported. We report the first case of AN in a 12-year-old male diagnosed with FCD-type 2 on head magnetic resonance imaging (MRI). He became concerned about lower abdominal distention and began reducing his food intake. He was admitted to our hospital after weight loss of 10 kg in a 1 year. Head MRI showed a localized high-signal area from the cortex to the white matter of the fusiform gyrus near the left hippocampus, with no associated decreased blood flow or electroencephalography (EEG) abnormalities. These findings were characteristic of FCD type II. In males with AN, the search for underlying disease is particularly important. The pathophysiology of the association between AN and FCD is unclear. However, both conditions are reportedly associated with autism spectrum disorder. Further cases are needed to clarify whether FCD is associated with eating disorders.

Identification of a novel splice-site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy.

WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug-resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice-site mutation with uniparental isodisomy. A 1-year and 7-month-old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities, such as swelling of both cheeks, folded fingers, rocking feet, and scoliosis. Brain imaging revealed slight hypoplasia of the cerebrum. Electroencephalogram showed focal paroxysmal discharges during the interictal phase of seizures. Vitamin B6 and zonisamide were administered for early infantile epileptic encephalopathy; however, the seizures were not relieved. Despite altering the type and dosage of antiepileptic drugs and ACTH therapy, the seizures were intractable. Whole-exome analysis revealed the homozygosity of WWOX(NM_016373.4):c.516+1G>A. The WWOX mRNA sequencing using peripheral blood RNA confirmed that exon 5 was homozygously deleted. Based on these results, the patient was diagnosed with WOREE syndrome at 5 months. The WWOX variant found in this study is novel and has never been reported before. WOREE syndrome being extremely rare, further case series and analyses of its pathophysiology are warranted.

De novo non-synonymous CTR9 variants are associated with motor delay and macrocephaly: human genetic and zebrafish experimental evidence.

CTR9 is one of five genes that form the PAF1 complex, which binds to RNA polymerase II and plays critical roles in transcriptional elongation and transcription-coupled histone modifications including histones H3K4me3 and H3K36me3. In this study, de novo CTR9 non-synonymous variants (p.(Glu15Asp) and p.(Pro25Arg)) were detected in two unrelated patients with macrocephaly, motor delay, and intellectual disability. A pull-down assay showed that the mutant CTR9 proteins had stronger affinities to the PAF1 protein than the wild-type protein. Functional analyses using zebrafish showed that the knockout of the ctr9 gene caused motor defects and enlargement of the telencephalon, which is homologous to the mammalian cerebrum. The rescue experiment, in which the human CTR9 mutants were introduced into ctr9-knockout zebrafish, failed to maintain the swimming posture of the ctr9-knockout fish, suggesting that the human CTR9 mutant proteins do not function normally in vivo. In addition, the overexpression of human CTR9 mutant mRNA caused telencephalon enlargement in zebrafish larvae, suggesting that the human CTR9 mutant proteins interfered with normal endogenous CTR9 function. We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.

Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy.

KARS encodes lysyl-tRNA synthetase, which is essential for protein translation. KARS mutations sometimes cause impairment of cytoplasmic and mitochondrial protein synthesis, and sometimes lead to progressive leukodystrophies with mitochondrial signature and psychomotor regression, and follow a rapid regressive course to premature death. There has been no disease-modifying therapy beyond supportive treatment. We present a 5-year-old male patient with an asymmetrical leukodystrophy who showed overt evidence of mitochondrial dysfunction, including elevation of lactate on brain MR spectroscopy and low oxygen consumption rate in fibroblasts. We diagnosed this patient's condition as KARS-related leukodystrophy with cerebral calcification, congenital deafness, and evidence of mitochondrial dysfunction. We employed a ketogenic diet as well as multiple vitamin supplementation with the intention to alleviate mitochondrial dysfunction. The patient showed alleviation of his psychomotor regression and even partial restoration of his abilities within 4 months. This is an early report of a potential disease-modifying therapy for KARS-related progressive leukodystrophy without appreciable adverse effects.

Boys with attention-deficit/hyperactivity disorder perform wider and fewer finger tapping than typically developing boys - Peer comparisons and the effects of methylphenidate from an exploratory perspective.

AIM: This study aimed to investigate the differences in fine motor and coordination skills between boys with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) boys and the effect of methylphenidate (MPH) in boys with ADHD. METHODS: Fourteen boys aged 7-12 years who were diagnosed with ADHD and previously treated with MPH were instructed to tap their thumbs and index fingers together repetitively for 10 s after attaching magnetic sensors. The participants executed "in-phase" and "anti-phase" tapping. A two-way analysis of variance for comparing boys with ADHD and TD boys and the paired t-test to investigate the effect of MPH between sessions with and without MPH were performed. RESULTS: Boys with ADHD showed a significantly lower "number of taps" and a significantly higher "average of local maximum distance" than TD boys. "Energy balance" was significantly lower in ADHD boys than in TD boys. MPH caused a significant difference in the "standard deviation (SD) of phase difference" in "anti-phase tapping." CONCLUSION: Our studies indicated that finger-tapping movements in boys with ADHD tended to be significantly wider and fewer than those in TD boys, and MPH may improve the phase difference of bimanual fine motor coordination skills in boys with ADHD who are above 1.0 SD. The results should be interpreted with caution because we conducted statistical tests for many outcomes and groups without considering the multiplicity factor from an exploratory perspective.

Siblings with MAN1B1-CDG Showing Novel Biochemical Profiles.

Congenital disorders of glycosylation (CDG), inherited metabolic diseases caused by defects in glycosylation, are characterized by a high frequency of intellectual disability (ID) and various clinical manifestations. Two siblings with ID, dysmorphic features, and epilepsy were examined using mass spectrometry of serum transferrin, which revealed a CDG type 2 pattern. Whole-exome sequencing showed that both patients were homozygous for a novel pathogenic variant of MAN1B1 (NM_016219.4:c.1837del) inherited from their healthy parents. We conducted a HPLC analysis of sialylated N-linked glycans released from total plasma proteins and characterized the α1,2-mannosidase I activity of the lymphocyte microsome fraction. The accumulation of monosialoglycans was observed in MAN1B1-deficient patients, indicating N-glycan-processing defects. The enzymatic activity of MAN1B1 was compromised in patient-derived lymphocytes. The present patients exhibited unique manifestations including early-onset epileptic encephalopathy and cerebral infarction. They also showed coagulation abnormalities and hypertransaminasemia. Neither sibling had truncal obesity, which is one of the characteristic features of MAN1B1-CDG.

Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3.

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.

Association of Kabuki syndrome and tethered cord syndrome: a report of three cases and literature review.

Kabuki syndrome (KS) is a congenital disorder characterized by distinctive facial features, skeletal and dermatoglyphic abnormalities, mild-to-moderate intellectual disability, and postnatal growth deficiency. Recently, mutations in the KMT2D and KDM6A genes have been identified as the causative factors in most KS cases. In this study, we present three cases of KS associated with tethered cord syndrome. All cases had a sacral dimple, which is a skin stigmata, and radiological abnormalities, including fatty or thickened filum terminale. Untethering surgery was performed and clinical improvement was achieved. Although in the association between KS and closed neural tube defect (NTD) has rarely been discussed, we emphasize that sacral dimples in KS and tethered cord syndrome are not uncommon. The KS patients with sacral dimple must be carefully investigated by radiological examination and urological study if there is abnormality. Further understanding of the genetic mechanism underlying KS might provide a novel insight on the correlation between the genetics and development of closed NTDs.

Novel ACOX1 mutations in two siblings with peroxisomal acyl-CoA oxidase deficiency.

Peroxisomal acyl-CoA oxidase (ACOX1) deficiency is a rare autosomal recessive single enzyme deficiency characterized by hypotonia, seizures, failure to thrive, developmental delay, and neurological regression starting from approximately 3 years of age. Here, we report two siblings with ACOX1 deficiency born to non-consanguineous Japanese parents. They showed mild global developmental delay from infancy and began to regress at 5 years 10 months and 5 years 6 months of age respectively. They gradually manifested with cerebellar ataxia, dysarthria, pyramidal signs, and dysphasia. Brain MRI revealed T2 high-intensity areas in the cerebellar white matter, bilateral middle cerebellar peduncle, and transverse tracts of the pons, followed by progressive atrophy of these areas. Intriguingly, the ratios of C24:0, C25:0, and C26:0 to C22:0 in plasma, which usually increase in ACOX1 deficiency were within normal ranges in both patients. On the other hand, whole exome sequencing revealed novel compound heterozygous variants in ACOX1: a frameshift variant (c.160delC:p.Leu54Serfs*18) and a missense variant (c.1259 T > C:p.Phe420Ser). The plasma concentration of individual very long chain fatty acids (C24:0, C25:0, and C26:0) was elevated, and we found that peroxisomes in fibroblasts of the patients were larger in size and fewer in number as previously reported in patients with ACOX1 deficiency. Furthermore, the C24:0 ß-oxidation activity was dramatically reduced. Our findings suggest that the elevation of individual plasma very long chain fatty acids concentration, genetic analysis including whole exome analysis, and biochemical studies on the patient's fibroblasts should be considered for the correct diagnosis of ACOX1 deficiency.

Novel ARX mutation identified in infantile spasm syndrome patient.

We report a 7-year-old boy with infantile spasms caused by a novel mutation in the Aristaless-related homeobox (ARX) gene. He showed infantile spasms and hypsarrhythmia on electroencephalogram from early infancy. Brain MRI did not reveal severe malformation of the brain except mild hypoplasia of the corpus callosum. Two-fold adrenocorticotropic hormone (ACTH) therapy failed to control the seizures, and ketogenic diet therapy and multi-antiepileptic drug therapy were required as he showed intractable daily tonic-clonic seizures. Exome sequencing identified a hemizygous mutation in the ARX gene, NG_008281.1(ARX_v001):c.1448 + 1 G > A, chrX: 25025227 C > T (GRCh37). To our knowledge, this mutation has not been reported previously.

Quantitative assessment of fine motor skills in children using magnetic sensors.

AIM: We aimed to establish objective and quantitative data on fine motor development in typically developing children using magnetic sensors. METHODS: The study included 110 Japanese elementary school children volunteers (57 boys, 53 girls). The participants were instructed to tap their thumbs and index fingers together repetitively for 10 s. After attaching coils to the participants' right and left thumbs and index fingers, participants executed "in-phase" and "anti-phase" tapping. We used two-way analysis of variance to analyze the influences of age and sex on fine motor development. RESULTS: The "number of taps" significantly increased with age, while the "standard deviation (SD) of tapping interval" significantly decreased. More than half of the "acceleration" parameters significantly increased with age. Boys performed significantly faster than girls in some parameters of "velocity" and "acceleration," while girls had significantly lower "SD of local maximum velocity in opening motion" and "SD of local minimum velocity in closing motion." DISCUSSION: We established both objective and quantitative reference data on fine motor development in typically developing Japanese children aged between 7 and 12 years using magnetic sensors. We revealed that this system can monitor real-time details of the parameters involved in the finger-tapping movement in children without complications. This device could be useful for obtaining objective and quantitative data on fine motor skills in the clinical assessment of developmental coordination disorder, assessments of educational intervention, or rehabilitation and discovery of new therapeutic agents.

A case of autism spectrum disorder with cleft lip and palate carrying a mutation in exon 8 of AUTS2.

We report a patient with autism and cleft lip and palate carrying a de novo heterozygous AUTS2 mutation, c.1464_1467del ACTC (p.Tyr488*). Although the causal relationship between cleft lip and palate and this mutation is unclear, this case report may expand the clinical phenotype of AUTS2 syndrome.

Feasibility and safety of Robot Suit HAL treatment for adolescents and adults with cerebral palsy.

To investigate whether Robot Suit HAL treatment (HAL-T) is safe and feasible for gait disorders in adolescents and adults with cerebral palsy (CP). We tested HAL-T in adolescents and adults with bilateral spastic CP (four men, four women; mean age: 18.2 years). Three participants were classified as level III under the Gross Motor Function Classification System (GMFCS), and five were classified as level IV. The participants underwent HAL-T twice per week for 4 weeks. The outcome measures, which were assessed before and after HAL-T, included comfortable gait speed (CGS), step length (SL), cadence, and GMFCS level. Adverse events were noted. All participants completed the HAL-T sessions despite some mild adverse events occurring. The mean increases in CGS, SL, and cadence were 0.19 ±â€¯0.14 m/s (p = 0.006), 0.09 ±â€¯0.08 m (p = 0.020), and 18.0 ±â€¯15.9 steps/min (p = 0.015), respectively. HAL-T is safe and feasible for gait disorders in patients with CP. HAL-T can significantly improve CGS, SL, and cadence and may be effective for improving walking ability in adolescents and adults with CP.

A novel missense PTEN mutation identified in a patient with macrocephaly and developmental delay.

Phosphatase and tensin homolog (PTEN) plays an important role in tumor suppression. A germline mutation in the PTEN gene induces not only PTEN hamartoma tumor syndrome, including Cowden syndrome, but also macrocephaly/autism syndrome. Here, we describe a boy with macrocephaly/autism syndrome harboring a novel missense heterozygous PTEN mutation, c.959T>C (p.Leu320Ser). Interestingly, a previously reported nonsense mutation resulting in p.Leu320X was found in Cowden syndrome patients. Our case may be suggestive of a genotype-phenotype correlation.

Development of the Japanese version of the State Behavioral Scale for critically ill children.

AIMS: The State Behavioral Scale (SBS) was developed to assess sedation states, including agitation, in pediatric patients on mechanical ventilation. The purpose of this study was to determine the reliability and validity of a back-translated Japanese version of the SBS. METHODS: Translation was done by the back-translation method followed by a prospective study in a Japanese intensive care unit. For reliability, a nurse/researcher pair evaluated SBS along eight dimensions (respiratory drive, response to ventilation, coughing, best response to stimulation, attentiveness to care provider, tolerance to care, consolability, and movement after consoled). For validity, SBS scores were compared to the Richmond Agitation-Sedation Scale and a visual analog scale (VAS). RESULTS: The original author approved the back-translated SBS. Thirty-one patients aged 0 weeks to 8 years were evaluated from 59 total critical pediatric patient encounters. The researcher and nurse SBS scores demonstrated excellent inter-rater reliability (weighted κ = 0.96, 95% CI 0.92-0.99). In addition, there was a very strong correlation between the researcher and nurse VAS scores (ρ = 0.80, P < 0.001). Weighted kappa coefficients for the eight dimensions ranged from 0.71 (95% confidence interval, 0.55-0.88; consolability) to 0.89 (95% confidence interval, 0.80-0.98; best response to stimulation). In validity testing, nurse SBS and nurse VAS scores were strongly correlated (ρ = 0.80, P < 0.001) with the researcher SBS and researcher Richmond Agitation-Sedation Scale scores (ρ = 0.91, P < 0.001). CONCLUSION: This study suggests that our Japanese version of the SBS is valid and reliable for evaluating sedation for critically ill children.

A patient with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and severe hypoganglionosis associated with a novel SOX10 mutation.

In this report, we present the case of a female infant with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) associated with a novel frameshift mutation (c.842dupT) in exon 5, the last exon of SOX10. She had severe hypoganglionosis in the small intestine and entire colon, and suffered from frequent enterocolitis. The persistence of ganglion cells made both the diagnosis and treatment difficult in the neonatal period. She also showed hypopigmentation of the irises, hair and skin, bilateral sensorineural deafness with hypoplastic inner year, severe demyelinating neuropathy with hypotonia, and diffuse brain hypomyelination. The p.Ser282GlnfsTer12 mutation presumably escapes from nonsense-mediated decay and may generate a dominant-negative effect. We suggest that hypoganglionosis can be a variant intestinal manifestation associated with PCWH and that hypoganglionosis and aganglionosis may share the same pathoetiological mechanism mediated by SOX10 mutations.

Desulfation of Heparan Sulfate by Sulf1 and Sulf2 Is Required for Corticospinal Tract Formation.

Heparan sulfate (HS) has been implicated in a wide range of cell signaling. Here we report a novel mechanism in which extracellular removal of 6-O-sulfate groups from HS by the endosulfatases, Sulf1 and Sulf2, is essential for axon guidance during development. In Sulf1/2 double knockout (DKO) mice, the corticospinal tract (CST) was dorsally displaced on the midbrain surface. In utero electroporation of Sulf1/2 into radial glial cells along the third ventricle, where Sulf1/2 mRNAs are normally expressed, rescued the CST defects in the DKO mice. Proteomic analysis and functional testing identified Slit2 as the key molecule associated with the DKO phenotype. In the DKO brain, 6-O-sulfated HS was increased, leading to abnormal accumulation of Slit2 protein on the pial surface of the cerebral peduncle and hypothalamus, which caused dorsal repulsion of CST axons. Our findings indicate that postbiosynthetic desulfation of HS by Sulfs controls CST axon guidance through fine-tuning of Slit2 presentation.

Preaxial polydactyly in an individual with Wiedemann-Steiner syndrome caused by a novel nonsense mutation in KMT2A.

Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down-slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co-workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12-year-old Japanese boy with a novel nonsense mutation in KMT2A. He had right preaxial polydactyly, which has not been previously reported in WDSTS. We could not identify a causal relationship between the KMT2A mutation and preaxial polydactyly, and cannot exclude the preaxial polydactyly is a simple coincidence. We summarized the clinical features of WDSTS associated with KMT2A mutation and discussed the cardinal symptoms in detail.

A novel BBS10 mutation identified in a patient with Bardet-Biedl syndrome with a violent emotional outbreak.

We report a 10-year-old girl with Bardet-Biedl syndrome caused by a novel mutation in the Bardet-Biedl syndrome 10 (BBS10) gene. She had multiple malformations, including a dysmorphic face, postaxial polydactyly, polycystic kidney and amblyopia. She presented with typical BBS features, including intellectual disability with emotional outbursts and mild obesity. Whole-exome sequencing identified compound heterozygous mutations with NM_024685.3:c.1677C>A [p.(Tyr559*)] and c.1974T>G [p.(Tyr658*)]. To our knowledge, the latter mutation has never been reported previously.