Hiroaki Ehara

The carbohydrate deficient glycoprotein syndrome in three Japanese children

We describe 3 children (from two families) with a multisystemic disorder characterized by mental retardation, nonprogressive ataxia, polyneuropathy, hepatopathy during infancy and growth retardation. Due to the clinical similarities to a recently recognized disorder associated with carbohydrate-deficient transferrin, we examined serum transferrin by means of isoelectric focusing, and found increases in disialo transferrin and asialotransferrin. Removal of sialic acid with neuraminidase revealed the same transferrin phenotypes as in their parents. Similarly, carbohydrate-deficient fractions of serum alpha 1-antitrypsin were also detected. Therefore, the diagnosis was made of the recently identified carbohydrate-deficient glycoprotein syndrome. This is a genetic disorder with distinctive clinical features and multiple carbohydrate-deficient glycoproteins. These seem to be the first reported Japanese patients with this syndrome.

Live birth prevalence of Down syndrome in Tottori, Japan, 1980–1999

One hundred sixty‐four patients with Down syndrome (DS) were confirmed in Tottori Prefecture, Japan, from 1980 to 1999. The sex ratio of 1.52 (99 males and 65 females) was comparable to that reported in previous studies. The live birth prevalence per 1,000 was 1.52 (95% CI: 1.29–1.75) from 1980 to 1999, with a prevalence of 1.34 (95% CI: 1.05–1.63) recorded between 1980 and 1989, and 1.74 (95% CI: 1.37–2.11) between 1990 and 1999. There was no statistically significant change between these two decades (χ2‐test). Live birth prevalence in these two decades showed a significant increase (χ2‐test, P < 0.005) compared with that recorded in 1969–1978 in Tottori Prefecture (0.803, 95% CI: 0.677–0.929). Mean ages of mothers at the birth of a DS patient were 31.0 years in 1980–1989 and 32.4 years in 1990–1999 (t‐test, no significant difference). Dispersion analysis on the mean age of mothers at birth for patients born between 1969–1978, 1980–1989, and 1990–1999 showed a significant difference (t‐test, P < 0.005), while comparing the mean age of mothers in 1969–1978 to those in 1990–1999 also revealed a significant difference (t‐test, P < 0.001). Live birth prevalence has increased due to the rise in fertility rates among older women, although maternal age‐specific risk rates remain unchanged. The widespread introduction of induced abortion following prenatal diagnosis decreased live birth prevalence of DS largely in European (and a few Asian) countries after 1990, or kept prevalence steady, despite increasing fertility rates among women aged 30 and over. In contrast, all published studies have reported an increase in live birth prevalence of this syndrome in Japan, probably resulting from the fact that prenatal diagnoses are used only exceptionally in this country (due to the negative attitude toward selection of life in Japanese culture).

Neuroleptic malignant syndrome and methylphenidate

A 1-year-old female presented with neuroleptic malignant syndrome probably caused by methylphenidate. She had defects in the supratentorial brain including the basal ganglia and the striatum (multicystic encephalomalacia) due to severe perinatal hypoxic-ischemic encephalopathy, which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, methylphenidate is a dopamine agonist via the inhibition of uptake of dopamine, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative gamma-aminobutyric acid-ergic deficiency might occur because diazepam, a gamma-aminobutyric acid-mimetic agent, was strikingly effective. This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate.

New autosomal-recessive syndrome of leber congenital amaurosis, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction, and metabolic acidosis

We report on a new autosomal-recessive syndrome in 4 Japanese children in 2 families. The key manifestations are Leber congenital amaurosis, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction, metabolic acidosis, and autosomal-recessive inheritance. There were no consanguineous marriages. Abnormal eye movements were noticed neonatally, and ophthalmological examinations showed no visual acuity, pigmentary retinal degeneration, and nonrecordable electroretinograms in all cases. Inadequate weight gain and short stature gradually became apparent after birth, and at present the height range is -4.6 - -7.2 SD (standard deviations). Developmental delay was noted at age 4 months, and the developmental quotient is 50-70 at present. Deterioration of development and convulsions were not recognized. Elevated serum aminotransferase levels and metabolic acidosis were also found at age 4 months. Proximal renal tubular acidosis was clarified by bicarbonate tolerance tests in 1 case, and may have caused metabolic acidosis. Growth hormone secretion was insufficient by insulin tolerance test in 3 cases. One year of growth hormone therapy in 2 cases did not affect growth velocity. Hepatic dysfunction and metabolic acidosis ameliorated later. No renal cysts were found. A cranial computed tomographic scan and magnetic resonance imaging showed normal findings. Amino acids, organic acids, and very long chain fatty acid levels in plasma were all normal in the 3 cases examined. Histopathological and mitochondrial DNA analyses showed no evidence of mitochondrial disorders.

Martsolf syndrome in Japanese siblings

We describe a Japanese brother and sister with Martsolf syndrome. They had short stature, severe mental retardation, cataract, hypogonadism, craniofacial dysmorphism, and bone and joint symptoms including scoliosis, lax finger joints, and talipes valgus. Previously undescribed findings included proximal femoral epiphyseal dysplasia reminiscent of Legg–Calve–Perthes disease in both patients, and Klippel–Feil malformation and osteopathia striata in one patient. Brain MRI showed mild frontal and temporal lobe atrophy, and mild ventricular enlargement. Severe GH deficiency was demonstrated after insulin tolerance and glucagon/propranolol tolerance tests. No responses to serum LH and FSH after a gonadotropin‐releasing hormone (GnRH) test suggested secondary hypogonadism, that is, hypogonadotropic hypogonadism, due to hypothalamus‐pituitary axis insufficiency in both patients.

Schizencephaly in triple-X syndrome

The patient, a Japanese woman aged 25 years (TN #1136), was born at term with breech presentation and a weight of 2250 g. Her parents were not consanguineous and an elder brother was healthy. Her Apgar score was 6 at 1 min and oxygen was administered. She smiled at 6 months of age. She was admitted to hospital for further examination of psychomotor retardation at 10 months of age. On admission, she had spastic diplegia, psychomotor retardation (she could not control her head), growth retardation (length 66.5 cm (–2.0 SD), weight 5770 g (–2.9 SD), occipitofrontal circumference (OFC) 40.0 cm (–3.7 SD)). Minor anomalies were not recognized. Complete blood cell counts and blood chemistry data were normal. Titers of toxoplasma antibody were not increased and antibodies against cytomegalovirus and rubella virus were not tested. An electroencephalogram (EEG) revealed right hemispheric low-voltage, left central 3 Hz spike and wave and right occipital spikes. Because infantile spasms were noticed on admission, she was treated with adrenocorticotropic hormone (5 units/day) and then with phenobarbital (30 mg/day) and nitrazepam (3 mg/day). Paroxysmal discharges disappeared after 2 years treatment with antiepileptics. Her menarch was seen at 15 years of age. At 25 years of age, her height was 125.0 cm (–6.6 SD), her weight was 23.2 kg (– 4.2 SD) and the OFC was 45.6 cm (–8.5 SD). She had severe mental retardation, spastic diplegia, optic atrophy, scoliosis and bilateral dislocation of the hip joints. Magnetic resonance imaging (MRI) demonstrated right hemispheric closed-lip schizencephaly with arachnoid cyst, left abnormal gyral formation, reduction of the white matter around enlarged lateral ventricles and a complete defect of the septum pellucidum (Fig. 1) No other focal changes were observed on MRI. An EEG showed no paroxysmal discharges. A conventional chromosomal analysis (G-banding) confirmed 47,XXX.

Epidemiology of spina bifida in Tottori Prefecture, Japan, 1976-1995

The authors studied the epidemiology of spina bifida in Tottori Prefecture, Japan, from 1976 to 1995. Thirty-four patients (16 men and 18 women) were registered in this study. Consanguineous marriages, familial occurrence, and abnormalities in prenatal history were not observed. The incidence rate in the entire prefecture and in the eastern, central, and western regions was 0.234, 0.148, 0.425, and 0.230 per 1,000 live births, respectively. The incidence rate in the central region was greater than that in the eastern region with statistical significance (P < 0.05), but the cause of the cluster is unknown. The incidence rate of 0.234 per 1,000 live births for 20 years is compatible with the previous two studies of 1922-1940 and 1948-1954 in Japan. Such apparently stable trends suggest that environmental factors have affected the Japanese less than genetic factors. Seasonal variations are not demonstrated.

New Syndrome With the Sakoda Complex, Bilateral Anophthalmia, and Cortical Dysgenesis

An 8-year-old Japanese boy had Sakoda complex (basal encephalomeningocele, agenesis of the corpus callosum, and cleft lip and/or palate) associated with bilateral anophthalmia, dysgenesis of the cerebral cortex, severe mental retardation, and intractable epilepsy as core symptoms and hemiparesis, microcephalus, short stature, and hemivertebra. Tada and Nakamura described the first case of the Sakoda complex associated with bilateral anophthalmia, cortical dysgenesis, neonatal-onset seizures, and severe mental retardation. Fourteen patients with the Sakoda complex with or without ocular dysplasia were reviewed. It is proposed that these cases belong to a clinical entity that is distinguishable from the remaining 12 patients because of bilateral anophthalmia, cortical dysgenesis, and its resulting severe mental retardation and intractable epilepsy. There is a possibility that these two cases are one severe end of certain spectrum disorders in which certain common gene(s) might be implicated.

Reply to correspondence to the editor by de Wit et al.—“Re: Polymicrogyria versus pachygyria in 22q11 deletion”

We are pleased to respond to the comments of de Wit et al. [2005] regarding our article in which we described a case with chromosome 22q11 deletion syndrome associated with pachygyria and polymicrogyria [Ehara et al., 2003]. In contrast to the mutations in genes including LIS1, DCX, and RELN, whose mechanism and resulting type of brain malformation were clarified, precise etiology of cortical dysplasia in this syndrome remains obscure. The association of polymicrogyria with pachygyria is important in such a case. We add an axial T2-weighted image of our patient (Fig. 1). The reduced number of gyri with thick gray matter of the posterior portion of the left hemisphere shows pachygyria. Cases with this association confirmed neuropathologically have been reported [van Allen and Clarren, 1983; Sakuta et al., 1991; Graf et al., 1998]. We also recognize that it is often difficult to differentiate polymicrogyria from pachygyria and that pachygyria on magnetic resonance imaging (MRI) is sometimes diagnosed as polymicrogyria histologically [Byrd et al., 1991]. Our description is based on MRI but the final diagnosis requires neuropathological findings.

A case in the spectrum of the oculo-encephalo-hepato-renal syndrome

An 18-year-old male is presented with unprecedented central nervous system findings (cerebral dysplasia and sacral meningocele) possibly in the spectrum of the oculo-encephalo-hepato-renal syndrome. He had severe mental retardation, triplegia, epilepsy, retinitis pigmentosa, and chronic renal failure. Magnetic resonance imaging demonstrated cerebral dysplasia (left dominant abnormal gyri, hypoplastic white matter, basal ganglia, and thalamus, and absence of the septum pellucidum) and the hypoplastic cerebellum and brainstem. A sacral meningocele was observed first at 16 years of age. His renal function gradually worsened after 11 years of age. His liver function was normal. The previously reported 72 cases with the oculo-encephalo-hepato-renal syndrome are reviewed.