Kiyotaka Suwa

Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells

Previous studies have demonstrated that mutation in the forkhead domain of the forkhead box P2 (FOXP2) protein (R553H) causes speech-language disorders. To further analyze FOXP2 function in speech learning, we generated a knockin (KI) mouse for Foxp2 (R552H) [Foxp2 (R552H)-KI], corresponding to the human FOXP2 (R553H) mutation, by homologous recombination. Homozygous Foxp2 (R552H)-KI mice showed reduced weight, immature development of the cerebellum with incompletely folded folia, Purkinje cells with poor dendritic arbors and less synaptophysin immunoreactivity, and achieved crisis stage for survival 3 weeks after birth. At postnatal day 10, these mice also showed severe ultrasonic vocalization (USV) and motor impairment, whereas the heterozygous Foxp2 (R552H)-KI mice exhibited modest impairments. Similar to the wild-type protein, Foxp2 (R552H) localized in the nuclei of the Purkinje cells and the thalamus, striatum, cortex, and hippocampus (CA1) neurons of the homozygous Foxp2 (R552H)-KI mice (postnatal day 10), and some of the neurons showed nuclear aggregates of Foxp2 (R552H). In addition to the immature development of the cerebellum, Foxp2 (R552H) nuclear aggregates may further compromise the function of the Purkinje cells and cerebral neurons of the homozygous mice, resulting in their death. In contrast, heterozygous Foxp2 (R552H)-KI mice, which showed modest impairment of USVs with different USV qualities and which did not exhibit nuclear aggregates, should provide insights into the common molecular mechanisms between the mouse USV and human speech learning and the relationship between the USV and motor neural systems.

Panipenem-betamipron and decreases in serum valproic acid concentration.

Serum concentrations of valproic acid (VPA) were reduced to 0% to 40% of the original levels by concomitant use with panipenem-betamipron (PAM-BP) in three patients. The serum VPA level began to decrease 2 days after the administration of PAPM-BP, and it began to increase within 24 hours of the last dose. The rapid change in the serum VPA level suggests the existence of unique and as yet unknown mechanisms of interaction between VPA and PAPM-BP. Epileptic seizures developed in two of the three patients during PAPM-BP use, which signaled the dangers of PAPM-BP administration to patients concomitantly administered VPA. PAPM-BP should not be used in patients administered VPA.

Expression analysis and mutation detection of DLX5 and DLX6 in autism

Linkage analysis has reported the chromosomal region 7q21 to be related with autism. This region contains an imprinting region with MECP2-binding sites, and DLX5 is reported to be modulated by MECP2. DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis. From these points, DLX5 and DLX6 are candidate genes for autism. Therefore, we analyzed the expression of DLX5 and DLX6, and also PEG10 as a control in the lymphoblasts of autistic spectrum disorder (ASD) patients by real-time PCR to identify potential abnormality of expression. And we also analyzed DLX5 and DLX6 on ASD patients for mutation by direct sequence. The expression level of DLX5 was not different between ASD and controls but was higher in four ASD patients compared to controls. Clinical features of these four patients were variable. DLX5 expression was biallelic in two ASD patients and two controls, indicating that DLX5 was not imprinted. There was no mutation in DLX5 in ASD. Although DLX5 was not likely to play major role in ASD, genes relating to DLX5 expression and downstream of DLX5 are considered to be candidate genes for some of the ASD patients. In DLX6, we detected a G656A base change (R219H) in two ASD patients who were male siblings. DLX6 may contribute to the pathogenesis of ASD.

Acute relapsing encephalopathy mimicking acute necrotizing encephalopathy in a 4-year-old boy

A 4-year-old boy showed two episodes of encephalitis/encephalopathy involving disturbed consciousness, convulsion, and paresis associated with the elevated levels of protein and myelin basic protein of the cerebrospinal fluid. MRI studies of the brain revealed symmetrical lesions in the brain stem and thalami at the first episode, and additional lesions were found in the cerebellum involving both the gray and white matter in the second episode. The intensities of MRI lesions were low in T I and high in T2. These episodes were followed by an elevation of the anti-viral antibody titers, for influenza A virus during the first episode and for adenovirus during the second. In the second episode, intravenous methylprednisolone therapy resulted in rapid improvement of his neurological signs.

Interstitial deletion of the long arm of chromosome 4 [del(4)(q21.22q23)] and a liver tumor

We report on a boy with proximal interstitial deletion of chromosome 4, del(4)(q21.22q23). The patient was born at term with a low birth weight, flat nasal bridge, micrognathia, wide-spaced nipples, clinodactyly of fifth fingers, overlapping fingers, post-axial polydactyly of the right foot, micropenis, hypospadias, a dermal sinus, and cardiac malformations. He developed psychomotor retardation, seizures, and a liver tumor with an increased serum alpha-fetoprotein level and rapid growth. The patient carried a deletion of chromosome 4 involving the 4q21-q22 region that was reported to form a unique syndrome. The absence of central nervous system overgrowth and the presence of a malignant liver tumor are unique to our patient, compared to others with the 4q21-q22 deletion syndrome. The clinical manifestations and relationship between the liver tumor and chromosomal anomaly are discussed.

Co-existence of nemaline and cytoplasmic bodies in muscle of an infant with nemaline myopathy

A sporadic case of congenital myopathy had severe muscle weakness of neonatal onset. Nemaline and cytoplasmic bodies were detected in muscle biopsies taken at 4 months of age. These findings were consistent with a diagnosis of nemaline myopathy (severe neonatal form). The simultaneous and abundant presence of these two types of sarcoplasmic inclusion has been found in only a few cases. However, these cases suggest that the sarcoplasmic inclusions may be formed, at least partially, by common mechanisms.

Non-invasive screening of fragile X syndrome A using urine and hair roots

The diagnosis of fragile X A syndrome (FRAXA) during childhood depends largely on DNA-based diagnostic tests due to the lack of the specific clinical features. To determine a non-invasive screening method for fragile X syndrome, we studied the method of DNA-based diagnosis using urine or hair roots instead of routinely used peripheral blood cells. The amplification of repeat-containing alleles of FMR-1 by PCR using Pfu polymerase was applied on DNA extracted from urine sediments or hair roots of 50 and 28 normal individuals, respectively. Consistent amplification of repeat-containing DNA fragments of normal size to ethidium-visible quantities were obtained in 92% (46/50) of urine samples and 100% (28/28) of hair roots. No bands of normal size or abnormal or artificial smears were detected in two male FRAXA patients. No female samples were examined in the present study because the separation of two alleles was unsatisfactory on agarose gels with DNA from blood samples. Our results indicate that the use of hair roots in a DNA-based test constitutes a rapid, simple and less-invasive screen to diagnose males with FRAXA.

Febrile convulsions in patients with Down syndrome

A clinical and electroencephalographic study on multiple febrile convulsions in comparison with simple febrile convulsions Takashi Kajitani, Takafumi Kimura, Motonori Kaneko and Yoko Takeda (Department of Pediatrics, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan) Multiple FC in which repeated seizures occur within 24 hours comprise one type of complex FC together with prolonged FC of longer than 15 minutes and focal FC, and have been regarded as one of the risk factors for the development of epilepsy. The object of this study was to clarify the clinical and EEG features of multiple FC compared with those of simple FC. Patients and methods. We conducted clinical and EEG studies on 117 children (68 males, 49 females) who had visited our department with the complaint of multiple FC from 1978 to 1993. We compared the results with those for 117 children (71 males. 46 females) with simple FC who were selected at random during the same period. Children with developmental retardation, neurological abnormalities, prolonged FC or focal FC were excluded. Results. The first seizures in the multiple FC and simple FC groups occurred at from 1 year to 2 years of age in more than half the cases, respectively. The age at onset of multiple FC ranged from 1 year to 2 years of age in 49 cases (42%), 2 to 3 years in 27 cases (23%), and 3 to 4 years in 20 cases (17%). In 15 children with multiple FC (13%), repeated seizures recurred in a single day. In children with multiple features of the first or subsequent FC, epilepsy or non-febrile seizures developed in 12 cases (lO%), whereas in those whose seizures occurred with fever and were not complex, epilepsy or non-febrile seizures developed in 7 cases (6%). The difference between these two groups was not statistically significant. In children who could be followed-up to over 6 years of age, the total number of FC was more than 5 times in 53 (68%) of 78 cases with multiple FC, and in 19 (21%) of 92 cases with simple FC. The difference was significant (P < 0.001). In multiple FC children whose EEG records could been obtained for over 3 years of age, diffuse irregular spike and wave (SW) bursts, focal spikes and diffuse SW associated with focal spikes were observed in 37%, 22% and 17%, respectively, whereas in simple FC children they were observed in 34%, 15% and 18%, respectively. Conclusion. Multiple features (clustering seizures in a day or two) of FC were not a risk factor for the development of epilepsy or non-febrile seizures, if children with developmental retardation and/or neurological abnormalities were excluded.