Toshiyuki Kumagai

Epilepsy in Angelman syndrome associated with chromosome 15q deletion

Summary: We report eight sporadic cases of typical Angelman syndrome (AS) associated with chromosome 15q12 deletion. Age at first visit was 3–35 months (average 18 months), and follow‐up period was 4‐20 years (average 14.1 years). The characteristic features of epilepsy in AS are (a) seizure onset in early childhood (8 of 8); (b) evolution of seizure type with age (8 of 8); (c) EEG abnormality changes from high‐voltage slow bursts (HVS) in infancy to diffuse spike and waves in middle childhood (4 of 5); (d) atypical absence seizures (8 of 8), often occurring as atypical absence status (4 of 8); and (e) diminution of seizure discharges and clinical seizures after puberty (7 of 7). We believe that AS may frequently exist in the intractable epilepsies of childhood with severe mental retardation. We stress the importance of AS as one of the main etiologic background diseases of the intractable epilepsies with infantile onset such as West syndrome, Lennox‐Gastaut syndrome, and others.

Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22–q24.1

Hirschsprung disease (HSCR), a clinically complex syndrome often associated with a combination of mental retardation, microcephaly, and characteristic facial features, is genetically heterogeneous.1–10 Recently, mutations in ZFHX1B , which encodes Smad-interacting protein 1 (SIP1), were identified by our group11 and Cacheux et al 12 in patients with t(2;13)(q22;q22) and t(2;11)(q22.2;q21), respectively. These patients had clinical profiles consistent with a dominant form of the disease (Mowat-Wilson syndrome: MIM 235730).9,13 These and subsequent articles have demonstrated a link between patients with nonsense and frameshift mutations of the gene and the presence in these patients of the following clinical findings: profound mental retardation, delayed motor development, and specific facial features, including hypertelorism, a broad nasal bridge, strabismus, a pointed chin, prognathism, a nose with a prominent columella, and posteriorly rotated ears. Often associated with these features were microcephaly, epilepsy, congenital heart disease, HSCR, and midline defects such as agenesis or hypoplasia of the corpus callosum and hypospadias.13–19 This variety of clinical features is observed not only in patients with nonsense and frameshift mutations but also in patients harbouring deletions involving ZFHX1B at 2q22,9,11,15,20 including a previously reported isolated case.6 Thus, ZFHX1B clearly plays a critical role in the manifestation of clinical features of Mowat-Wilson syndrome. However, several points remain to be elucidated: (1) How broad are the clinical features in patients with ZFHX1B mutations and deletions? (2) What are the underlying molecular mechanisms by which the deletion of ZFHX1B at 2q22 affects the clinical phenotype? (3) What kind of clinical features might appear if the deletions were extended to include 2q23–q24.1? To address these questions, we have characterized the clinical features and underlying molecular basis of 27 cases with mutations or deletions in ZFHX1B , including 12 previously reported cases comprising …

A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations

BackgroundSLC19A3 (solute carrier family 19, member 3) is a thiamin transporter with 12 transmembrane domains. Homozygous or compound heterozygous mutations in SLC19A3 cause two distinct clinical phenotypes, biotin-responsive basal ganglia disease and Wernickes-like encephalopathy. Biotin and/or thiamin are effective therapies for both diseases.MethodsWe conducted on the detailed clinical, brain MRI and molecular genetic analysis of four Japanese patients in a Japanese pedigree who presented with epileptic spasms in early infancy, severe psychomotor retardation, and characteristic brain MRI findings of progressive brain atrophy and bilateral thalami and basal ganglia lesions.ResultsGenome-wide linkage analysis revealed a disease locus at chromosome 2q35-37, which enabled identification of the causative mutation in the gene SLC19A3. A pathogenic homozygous mutation (c.958G > C, [p.E320Q]) in SLC19A3 was identified in all four patients and their parents were heterozygous for the mutation. Administration of a high dose of biotin for one year improved neither the neurological symptoms nor the brain MRI findings in one patient.ConclusionOur cases broaden the phenotypic spectrum of disorders associated with SLC19A3 mutations and highlight the potential benefit of biotin and/or thiamin treatments and the need to assess the clinical efficacy of these treatments.

Magnetic resonance imaging and positron emission tomography of band heterotopia

A case of band heterotopia was reported with findings of positron emission tomography (PET). The patient was an 8-year-old girl who had mild mental retardation and intractable partial epilepsy. Her MRI showed another diffuse layer of gray matter underlying the normal-looking cortex and separated from it by an apparently normal layer of white matter. PET scan with [18F]fluorodeoxyglucose revealed that band heterotopia had the same degree of glucose metabolism as that of the overlying cortex.

Founder-haplotype analysis in Fukuyama-type congenital muscular dystrophy (FCMD)

Abstract Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive, severe muscular dystrophy associated with brain anomalies. After our initial mapping of the FCMD locus to 9q31–33, we performed linkage disequilibrium analysis, which led us to suspect that the FCMD gene lay within a region of less than 100 kb containing D9S2107. In the present study, we developed two new microsatellites (D9S2170 and D9S2171) in close vicinity to D9S2107 and examined haplotypes of FCMD chromosomes by using four markers (cen-D9S2105-D9S2170-D9S2171-D9S2107-tel). As 82% of the FCMD chromosomes that we examined shared the founder haplotype (138–192–147–183) and 94% of the FCMD patients in our panel carried founder haplotypes on one or both chromosomes, the data supported the hypothesis of a single founder of this disease in the Japanese population. Eight haplotypes different from the founder’s were observed in FCMD chromosomes, indicating that eight different FCMD mutations in addition to the founder’s have occurred in Japan. Moreover, we have detected several historical recombinations that have disrupted the founder haplotype at D9S2105 or D9S2170 and conclude that the FCMD gene is probably located just centromeric to D9S2170.

Long-term prognosis of tuberous sclerosis with epilepsy in children

A follow-up study was performed on 40 children with tuberous sclerosis and epilepsy. In 68% of the patients with infantile spasms and 73% of those without them, complex partial seizures were observed. Thus, patients with tuberous sclerosis are subject to not only infantile spasms but also complex partial seizures. Patients with infantile spasms showed mental retardation more often than those without. Seizures which had evolved from infantile spasms were more difficult to control than those which had not. The prognosis of infantile spasms associated with tuberous sclerosis was better than that of prenatal group other than tuberous sclerosis. Forty percent of the 40 cases showed asymmetry on EEG, and the asymmetry tended to disappear as the patients grew up.

Williams syndrome and deficiency in visuospatial recognition

This study aimed to assess the visuospatial abilities of five children with Williams syndrome (four males aged 9 years 3 months, 7 years 11 months, 8 years 1 month, and 10 years 8 months respectively, and one female aged 6 years 3 months). First, the childrens visuospatial abilities were examined by asking them to copy a figure. Second, their cognitive processing abilities were assessed using the Japanese Kaufman Assessment Battery for Children. This test was used because it is an objective one, standardized in Japan, and is a measure of fluid ability including spatial localization. Participants scored significantly low on the spatial memory subtest indicating that there was a deficit in spatial localization. Childrens performance in line copying tasks improved when the dots were in colour. Results suggest a deficit in the dorsal stream of visual cognition, with a relatively preserved ventral stream.

SIL1, a causative cochaperone gene of Marinesco‐Sjögren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex

Marinesco‐Sjögren syndrome (MSS) is a rare autosomal recessively inherited disorder with mental retardation (MR). Recently, mutations in the SIL1 gene, encoding a co‐chaperone which regulates the chaperone HSPA5, were identified as a major cause of MSS. We here examined the pathophysiological significance of SIL1 mutations in abnormal corticogenesis of MSS. SIL1‐silencing caused neuronal migration delay during corticogenesis ex vivo. While RNAi‐resistant SIL1 rescued the defects, three MSS‐causing SIL1 mutants tested did not. These mutants had lower affinities to HSPA5 in vitro, and SIL1‐HSPA5 interaction as well as HSPA5 function was found to be crucial for neuronal migration ex vivo. Furthermore time‐lapse imaging revealed morphological disorganization associated with abnormal migration of SIL1‐deficient neurons. These results suggest that the mutations prevent SIL1 from interacting with and regulating HSPA5, leading to abnormal neuronal morphology and migration. Consistent with this, when SIL1 was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed. Taken together, abnormal neuronal migration and interhemispheric axon development may contribute to MR in MSS.

Factors influencing effectiveness of thyrotropin-releasing hormone therapy for severe epilepsy in childhood: significance of serum prolactin levels.

Summary: Various factors possibly influencing responsiveness to thyrotropin‐releasing hormone (TRH) therapy were studied in 38 children (20 M, 18 F) with severe epilepsy. Mean age at treatment was 4.7 years (range; 0–18 years). Seizure type was infantile spasms (IS) in 16, generalized tonic seizures in 8, secondarily generalized partial seizures in 4, generalized tonic‐clonic seizures in 2, atypical absence in 5, myoclonic seizures in 1, and atonic seizures in 2 cases. All seizure types were classified by ictal EEGs documented by simultaneous EEG‐VTR according to the International Classification of seizures, except for two with atonic seizures and one with IS. Factors analyzed were sex, age, etiology, neurologic abnormality, seizure types, seizure frequency, EEGs, duration of TRH therapy, and serum hormone [human growth hormone (HGH), prolactin (PRL), thyroid‐stimulating hormone (TSH)] levels before and after TRH therapy. We showed that: (a) serum PRL level was significantly correlated to effectiveness of TRH therapy (the higher the PRL, the greater the response rate); (b) serum basal PRL decreased significantly, especially in good responders; and (c) serum basal PRL was elevated especially in patients with IS, which responded more to TRH therapy. These interesting findings seen in severe epilepsy of childhood deserve fürther neuroendocrinologic study.

Mutations in HADHB, which encodes the β-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy

Mitochondrial trifunctional protein (MTP) is a hetero‐octamer composed of four α‐ and four β‐subunits that catalyzes the final three steps of mitochondrial β‐oxidation of long chain fatty acids. HADHA and HADHB encode the α‐subunit and the β‐subunit of MTP, respectively. To date, only two cases with MTP deficiency have been reported to be associated with hypoparathyroidism and peripheral polyneuropathy. Here, we report on two siblings with autosomal recessive infantile onset hypoparathyroidism, peripheral polyneuropathy, and rhabdomyolysis. Sequence analysis of HADHA and HADHB in both siblings shows that they were homozygous for a mutation in exon 14 of HADHB (c.1175C>T, [p.A392V]) and the parents were heterozygous for the mutation. Biochemical analysis revealed that the patients had MTP deficiency. Structural analysis indicated that the A392V mutation identified in this study and the N389D mutation previously reported to be associated with hypoparathyroidism are both located near the active site of MTP and affect the conformation of the β‐subunit. Thus, the present patients are the second and third cases of MTP deficiency associated with missense HADHB mutation and infantile onset hypoparathyroidism. Since MTP deficiency is a treatable disease, MTP deficiency should be considered when patients have hypoparathyroidism as the initial presenting feature in infancy.