Shuji Wakai

Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy

In typical Fukuyama congenital muscular dystrophy (FCMD), peak motor function is usually only unassisted sitting or sliding on the buttocks, though a few patients are able to walk at some point. However, a few patients have a severe phenotype and never acquire head control. In addition, it is clinically difficult to differentiate this severe FCMD from Walker-Warburg syndrome (WWS) or from muscle-eye-brain disease (MEBD). In order to establish a genotype-phenotype correlation, we performed haplotype analysis using microsatellite markers closest to the FCMD gene (FCMD) in 56 Japanese FCMD families, including 35 families whose children were diagnosed as FCMD with the typical phenotype, 12 families with a mild phenotype, and 9 families with a severe phenotype. Of the 12 propositi with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder (A-F) haplotype whereas the other 2 were heterozygous for the haplotype. In the 9 severe cases, who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 required a shunt operation, and 7 had ophthalmological abnormalities. Haplotype analysis showed that 8 of the 9 cases of the severe phenotype are heterozygous for the A-F haplotype, and the other one homozygous for the haplotype. We confirmed that at least one chromosome in each of the 56 FCMD patients has the A-F haplotype. The rate of heterozygosity for the A-F haplotypes was significantly higher in severe cases than in typical or mild cases (P < 0.005). Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation. Thus, the present study yielded molecular genetic evidence of a broad clinical spectrum in FCMD.

Rett syndrome: findings suggesting axonopathy and mitochondrial abnormalities

We report the histopathologic findings of 3 sural nerve biopsies and 1 muscle biopsy from 3 patients with Rett syndrome. The 3 sural nerve biopsies demonstrated a few ultrastructural abnormalities, including the presence of many Pi-granules and mitochondrial changes in the cytoplasm of Schwann cells, occasional bands of Büngner and onion-bulb formations, and mitochondrial alterations in myelinated axons. Morphometric analysis disclosed reduction in the number of large myelinated fibers with normal densities in comparison to those of an age-matched normal control. Light microscopic examination of the biopsied muscle from a 6-year-old patient with Rett syndrome revealed the existence of many small, dark, angulated fibers with NADH-TR staining. Ultrastructural investigation of the muscle confirmed the presence of the dumbbell-shaped mitochondria. Peripheral nerve involvement and the possibility of mitochondrial abnormalities in Rett syndrome were suggested by the results.

Brain tumors associated with infantile spasms

Two patients with brain tumors associated with infantile spasms are reported. Both infants displayed typical clinical features of infantile spasms, comprising tonic spasms manifesting in series and hypsarrythmia. In Patient 1, magnetic resonance imaging revealed a tumor in the hypothalamic region, suggestive of hypothalamic hamartoma. In Patient 2, cranial computed tomography and magnetic resonance imaging indicated the existence of a primary brain tumor with calcification in the right temporal lobe. Adrenocorticotropic hormone therapy combined with clonazepam relieved seizures in both infants. In Patient 1, resection of the hypothalamic tumor is impossible because the tumor lacks a stalk. In Patient 2, pathologic investigation of removed tumor tissue demonstrated mixed-oligoastrocytoma. It is suggested that focal lesions, like those in our patients, are involved in the development of infantile spasms.

Classification of familial neonatal convulsions

in 2, and remained unchanged in the other 19. We compared the group of 9 improved patients to the other 21 according to age of starting lamotrigine, characteristics of spasms, aetiology, and co-medication. As shown in the table, the frequency of asymmetrical spasms was higher in the favourable group. Infantile spasms were more often due to symptomatic postnatal brain damage in the favourable group, and cryptogenic in the unfavourable group. Carbamazepine and vigabatrin were more frequently administered in the unfavourable group. All 5 seizure-free patients received valproate co-medication, whereas only a quarter of the unfavourable group did so. The favourable effect was maintained in the 5 seizure-free

A child case of haemophagocytic syndrome associated with cryptococcal meningoencephalitis

A previously healthy 12-year-old Japanese girl developed meningoencephalitis due to Cryptococcus neoformans. During the course of her illness she suffered persistent high fever, severe pancytopenia, hypercytokinemia and liver dysfunction. Laboratory findings, including results of a bone marrow examination, strongly indicated complication by haemophagocytic syndrome (HPS). The preceding cryptococcal infection was thought to be a cause of the HPS because no other viral or bacterial infection could be confirmed. The girl died of acute respiratory failure during the progressive course of HPS. This may be the first reported case of HPS due to cryptococcal infection in an otherwise healthy child.

Glycogen storage disease with normal acid maltase: Skeletal and cardiac muscles

We report a 5-year-old boy with lysosomal glycogen storage disease and normal acid maltase activity. This patient, the fourth reported in the literature, was referred to our hospital for evaluation of elevated serum GOT, GPT, and CK activities. He had neither muscle weakness nor atrophy. Echocardiography demonstrated marked thickening of the intraventricular septum and left ventricular wall which indicated hypertrophic cardiomyopathy. Biopsied skeletal muscle disclosed massive accumulation of glycogen and autophagic vacuoles. Electron microscopy of biopsied cardiac muscle revealed severe myofibrillar disruption with marked accumulation of free and intralysosomal glycogen. Activities of all major glycolytic enzymes in skeletal muscle, including acid maltase, were normal. It is unknown why muscle lysosomes appeared to be unable to digest the trapped glycogen despite the presence of acid maltase. Our findings illustrate the importance of performing skeletal muscle investigation during childhood in patients with hypertrophic cardiomyopathy.

Severe myoclonic epilepsy in infancy and carbamazepine

W135 and Y) meningococcal vaccine. Meningococcal strains can be separated into twelve serogroups, based on their capsular structure. Serogroup B is the most frequent isolated strain. Platonov has vaccinated 18 LCCD patients of whom 2 experienced a meningococi disease, 9 and 12 months after vaccination respectively. Unfortunately, the meningococcal strains of the 2 patients were not serogrouped and characterized further. Because it is very likely that the meningococcal involved had another serogroup than one of the four serogroups included in the vaccine (A, C, W135 or Y), we can not support the conclusion that these cases represent vaccine failures. In the same study, Platonov found a lower frequency of meningococcal disease in a period of 3 years after vaccination than before the vaccination, suggesting a beneficial effect. We have immunized 21 LCCD individuals with the tetravalent meningococcal vaccine and found that 2 patients developed meningococcal disease after vaccination [1]. One C8~-deficient 19-year-old female patient twice developed meningococcal disease with serogroup B (not included in the vaccine), 1 and 3 years after vaccination respectively. The first episode was due to meningococcus B:4:P1.4, and in the second episode a meningococcus B:4:P1.6 was isolated. The second 21-year-old C8~3-deficient male patient developed meningococcal disease with serogroup Y (included in the vaccine), but the onset of the disease was more than 3.5 years after vaccination. This patient had developed a significant antibody response to serogroup Y (measured by ELISA) determined 6 months after vaccination. Meningococcal capsular polysaccharides do not activate T-helper cells and induce relatively poor memory. After vaccination, a protective period of 4 years is assumed. Therefore, LCCD patients at risk for meningococcal disease require revaccination each 3-3.5 years with the tetravalent vaccine. The use of vaccine that also confers immunity to serogroup B should be investigated further. We agree entirely with Cremer and Wahn that LCCD patients should be informed about their risk to contract meningococcal disease in order to lower the threshold for early antibiotic treatment. However, for screening of complement deficiencies we strongly recommend to use also the more sensitive haemolysis-in-gelassay and not the traditional CH50 and AP50 test only [2]. 2. Fijen CAP, Kuijper EJ, Hannema AJ, Sjoholm AG, Putten JPM van (1989) Complement deficiencies in patients over ten years old with meningococcal disease due to uncommon serogroups. Lancet II :585-589 3. Mayer MM (1961) Complement and complement fixation. In: Kabat EA, Mayer M M (eds) Experimental immunochemistry, 2nd edn. Springfield, I1: Charles C. Thomas, pp 133-240 4. Nilsson UR, Nilsson B (1984) Simplified assays of hemolytic activity of the classical and alternative complement pathway. J Immunol Methods 72 : 49-59

Gelastic seizure with hypothalamic hamartoma: proton magnetic resonance spectrometry and ictal electroencephalographic findings in a 4-year-old girl.

Gelastic seizure is a rare symptom often associated with hypothalamic hamartoma. We present here a 4-year-old girl with gelastic epilepsy caused by hypothalamic hamartoma and report the magnetic resonance spectrometry and electroencephalographic (EEG) findings. At the age of 2½ years, she developed brief, repetitive laughing attacks or mixed attacks with laughing and crying, which were refractory to carbamazepine. An interictal EEG showed intermittent slow waves in the left frontocentral region and sporadic positive sharp waves in the left centroparietal area. Ictal EEG demonstrated dysrhythmic theta activity in the left central area 3 seconds after the onset of laughing. Brain magnetic resonance imaging demonstrated a large sessile mass, isointense to gray matter, in the region of the hypothalamus, suggesting hypothalamic hamartoma. Proton magnetic resonance spectrometry of the hypothalamic hamartoma revealed a significant reduction of the N-acetylaspartate/serum creatinine ratio. The altered chemical shift imaging with magnetic resonance spectrometry in our patient suggests a biochemical abnormality in the tissue of the hypothalamic hamartoma. Moreover, this abnormal function of the hamartoma tissue might be closely related to epileptogenesis because the time difference between the ictal laughter and the subsequent EEG changes in the ictal EEG does not support the idea that the activated cortex is the epileptogenic focus. (J Child Neurol 2002;17:44-46).

Congenital muscular dystrophy in Marinesco-Sjögren syndrome

The histochemical and immunocytochemical findings of biopsied muscle in a 2-year-old girl with Marinesco-Sjögren syndrome are reported. Muscle histology consisted of mild muscular dystrophy, such as that found in limb-girdle or non-Fukuyama congenital muscular dystrophy. By immunocytochemical stain using anti-dystrophin antibody, Duchenne and Becker muscular dystrophies were excluded. In addition to characteristic clinical features, including ataxia, congenital cataract, and psychomotor retardation, muscle involvement is essential to the diagnosis of Marinesco-Sjögren syndrome.

Electron microscopic study of the biopsied cardiac muscle in Duchenne muscular dystrophy

Cardiac muscular biopsies were performed on 4 patients with Duchenne muscular dystrophy (DMD). None of the patients had cardiac symptoms and all of them exhibited normal electro- and echocardiographic findings. Electron microscopic examination of cardiac muscles from 4 patients with DMD disclosed proliferation of the mitochondria, changes in the cristae, abnormalities of the Z-bands, dilatation of the sarcoplasmic reticulum, deposition of glycogen, and changes in the nuclei. The most striking finding in these patients was that the residual bodies were increased and were observed mainly in the perinuclear region. These ultrastructural features suggest that an extreme exhaustion had already been present in myocardial tissue of the patients prior to the onset of cardiac symptoms.