97

Benign Familial Neonatal Convulsions Noboru Kumagai, MD, Hideto Iwai, MD, Yukio Yama­shita, MD, Satoshi Iwata, MD, Shoichi Kusano, MD, Takasumi Asaishi, MD and Hidenori Yamawaki, MD Department of Pediatrics, Ashikaga Red Cross Hospital, Ashikaga, Tochigi (NK, HI, YY, SI, SK, TA); Mito Red Cross Hospital, Mito, Ibaragi (HY)

Since Bjerre et al first reported benign familial neonatal convulsions in 1968, cases in more than ten families have been reported, mainly in Europe and the United States, but only three cases have been reported in Japan. We report three siblings who seem to have this nosologic condition.

Results The first child, a female born in 1979, exhibited short and frequent generalized tonic-clonic convulsions from the 3rd day of life. She had been left without treatment. Three months after birth, a neighbor pointed out her convul­sions to her mother, which prompted her admission to Ashikaga Red Cross Hospital. The results of physical and neurological examinations in the interictal period were negative. Laboratory data and EEG were within normal limits. But subdural effusion in the frontal region was observed on CAT-scanning. Chloral hydrate was then administered and the convulsions disappeared the next day. Thereafter, phenobarbital, valproate and phenytoin were administered for two years, and no convulsion recur­red. The subdural effusion gradually disappeared. Mental retardation has not been observed so far. The second child, a female born in 1981, exhibited generalized con­vulsions from the 3rd day of life. Because she was ob­served in another hospital, the details of her symptoms are not known. She has been given valproate, and since 3 months of age she has remained convulsion-free. The third child, a male born in 1984, was found to have generalized convulsions from the 3rd day of life. He was admitted to Ashikaga Red Cross Hospital on the 21 st day after birth. The results of physical and neurological examinations were negative. Laboratory data, EEG and CAT-scanning were within normal limits. With the administration of phenobarbital, the convulsions had disappeared the next day, but recurred 3 months after birth. Combined treat­ment with phenobarbital and valproate was started, and the convulsions were disappeared after several days. No recurrence or maldevelopment has been seen.

Conclusion There have been a few reports of benign familial neonatal convulsions in Japan. The desease was not observed in the neonatal period but in infancy. In this point, the authors' cases are the same. Whereas in the foreign reports, many cases were found only in the neonatal period. It is con­sidered that the therapy should be continued for at least one year, in Japan.

Key words: Benign familial neonatal convulsions, neo­natal convulsions, infantile convulsions.

138 Brain & Development, Vol 9, No 2,1987

98

Tuberous Sclerosis: Ornithine, Proline and Glutamate Metabolism in Cultured Fibroblasts Harumi Tanaka, MD, Kazuharu Nakazawa, MSc and Masa­taka Arima, MD Division of Mental Retardation and Birth Defect Re­search, National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo

We previously described the high contents of hydroxypro­line in several affected tissues and urine [11, and the elevation of serum free proline [21 in patients with tube­rous sclerosis (TS). Ornithine is an important precursor of endogenous proline in mammalian cells, therefore, the pathophysiological regulation of proline and· glutamate metabolism by ornithine was investigated in cultured fibroblasts from patients with TS.

Materials and Methods Seven strains derived from normal-appearing skin and 5 from tumorous skin (tumor) of 9 patients with TS, and 6 strains derived from normal skin of 6 controls were CUl­tured in Eagle's MEM containing dialyzed fetal bovine serum with or without 0.1 mM ornithine. Measurement of ornithine aminotransferase (OAT, EC 2.6.1.13) was carried out by the method of Ohura·et al [31. Determina­tion of proline, glutamate and glutamine was performed by the post-labeling method with o-phthalaldehyde and sodium hypochlorite as previously described [2, 41 .

Results OAT activity was decreased in TS, especially in TS (tu­mor) after mild sonication treatment. The yield of the OAT protein source was inhibited in TS (tumor) on culturing without ornithine. Free glutamate in the me­dium was significantly increased in TS (tumor). Free pro­line in cells was significantly decreased in TS (tumor) on culturing with ornithine, but protein-bound proline was not. The relative ratio of free glutamate to glutamine in the medium and that of free glutamate to proline in cells cultured with ornithine were increased in TS (tumor). These results suggest that the requirement for ornithine, increased turnover of proline to glutamate and increased elimination of glutamate into the medium occur in TS (tumor).

Conclusion Aberrant regulation or turnover of proline and glutamate metabolism may occur in TS, especially in tumor cells.

References 1. TanakaH, ArimaM. BrainDev (Tokyo) 1981;3:81-5. 2. Tanaka H, Nakazawa K, Arima M, et al. Brain Dev (To­

kyo) 1983;5:450-6. 3. Ohura T, Kominami E, Katunuma N. J Nutr Sci Vita­

minol (Tokyo) 1983;29: 123-8. 4. Nakazawa K, Tanaka H, Arima M. J Chromatogr 1982;

233:313-6.

Key words: Tuberous sclerosis, ornithine aminotrans­ferase, proline, glutamate, fibroblast.

99

Incontinentia Pigmenti Achromians (Ito) with Severe Developmental Retardation and Intractable Seizures -An Autopsy Case Report-Osamu FUjino, MD, Toshikazu Igarashi, MD, Masanobu Furuya, MD, Hisashi Enokido, MD, Kiyoshi Hashimoto, MD, Takehisa Fujita, MD, Iunichi Sato, MD and Yoshio Morimatsu, MD Department of Pediatrics, Nippon Medical School, the 1st Hospital, Tokyo (OF, TI, MF, HE); the 2nd Hospital, Kawasaki, Kanagawa (KH, TF); Department of Neuro­pathology, Tokyo Metropolitan Institute for Neurosci­ence, Fuchu, Tokyo (IS, YM).

The neuropathology of incontinentia pigmenti achromians has not been reported previously except by DL Ross in 1982. Here we report a cliniconeuropathological study of a girl with this disorder. This girl was born after a non­eventful pregnancy, labor and delivery. Her birth weight was 2,810 g. The parents were healthy and nonconsangui­neous. At birth, macular or irregular shaped hypopigmen­tation on the left trunk and a hypopigmented streak on the left thigh and leg were noted, and they subsequently became more evident.

At 2 months of age, left hemi- or gem:ralized clonic convulsions and myoclonic convulsions of the face occur­red, and she was admitted to our hospital. Routine blood chemistry, urinalysis and CSF were normal. Analysis of amino acids in urine and serum and chromosomes were normal. EEG showed sharp waves on right frontal deriva­tion, hypsarrhythmia and multifocal sharp wave activity. CT scan showed dilation of Sylvian fissures and inter­hemispheric fissure and asymmetry of latenl ventricles. Seizures were intractable to treatment with anticonvulsant drugs, ACTH, high dose pyridoxine, intravenous high dose gammaglobulin or ketogenic diet. Her psychomotor devel­opment was severely retarded, and she died of pneumonia at 13 months.

Autopsy findings: The brain weighed 930 g. Macro­scopically, brachycephalic and micropolygyria were noted, especially on the frontal and parietal lobes. Lateral ventricles were dilated and the anterior horn of the right ventricle was hypoplastic. Microscopically, gray matter heterotopia was the most significant finding. Fibrillary gliosis of the centrum semiovale and deposition of pseudo­calc were noted.

In development of the human brain, neural cells migrate most actively between 3 and 6 months of gesta­tion. By 3 and half months of gestation, melanoblasts migrate from the neural crest to the skin, where they mature to melanocytes. A second trimestt~r disorder of migrational events in both brain and neural crest cells could account for the coexistence of brain and skin pig­mentary pathology.

Key words: Incontinentia pigmenti achromians (Ito), micropolygyria, gray matter heterotopia, intractable sei­zure.

100

A Case of Naevus Leiomyomatosus Associated with Central Nervous System Disorder Masanobu Tayama, MD, Toshiaki Hashimoto, MD and Masuhide Miyao, MD Department of Pediatrics, National Sanatorium Higashi Tokushima Hospital, Itano, Tokushima (MT); Depart­ment of Pediatrics, Tokushima University School of Medicine, Tokushima (TH, MH)

The patient was an II-year-old girl whose chief complaint was nausea and an exanthema on her forehead. Psycho­moter development in infancy was normal. The exan­thema on her forehead was not observed at birth. From about 8 years of age, the exanthema was visible, but she did not consult a doctor. At 10 years of age, she com­plained of nausea with a few minutes' loss of conscious­ness. Follwoing this, she complained of repeated similar attacks. As a result, she visited a doctor, was found to have an abnormal EEG, and was administered an anticon­vulsant. However, attacks of nausea continued, and her body weight decreased. She was admitted to Tokushima University Hospital.

Physical examination revealed a brown exanthema on her right forehead and some minor anomalies (high arched palate, Dubois sign, abnormal arrangement of the teeth and hypertelorism). Cranial nerve findings were normal, deep tendon reflex was normal and disdiadochokinesis was seen.

Laboratory findings revealed normal routine examina­tion results. IQ was 78, and on EEG, spike or spike and wave complex was found frequently in the right hemi­sphere, and sleep spindle was found to be poor during the sleep record. The CT scan demonstrated agenesis of the corpus callosum, right ventricular hypoplasia and un­balanced distribution of white matter and gray matter in the right hemispehere. An exanthema biopsy revealed many smooth muscle bundles running from the upper to lower zone in various directions in the dermis and resem­bled arrectores pilorum muscle in a well-demarcated state. Therefore, we diagnosed this exanthema as naevus of leiomyomatosus.

Naevus of leiomyomatosus on the forehead is rare, and that associated with the central nervous system has not been reported. We suggest that this case was one of a new neurocutaneous syndrome.

Key words: Naevus leiomyomatosus, smooth muscle, neurocutaneous syndrome.

Brain & Development, Vol 9, No 2, 1987 139

101

A Study of the Spinal Neurons in Tuberous Sclerosis Kozaburo Hiramatsu, MD, Kazuya Goto, MD, Teruyuki Ogawa, MD and Hiroto Yamashita, MD Departments of Pediatrics (KH, KG, TO) and Pathology (HY), Medical College of Oita, Oita

Mental retardation is one of the most outstanding neuro­logical symptoms of tuberous sclerosis. This symptom results from the immaturity of the neuronal circuit as in other disorders characterized by mental retardation. The purposes of this study were to clarify the spinal cord le­sion and to demonstrate the immaturity of the neuropils of the spinal cord in tuberous sclerosis.

Patient and Methods The patient was a I-month-old male with a cardiac tumor. After head CT scanning, he was diagnosed as having tuberous sclerosis. He died of heart failure at 1 month of age. His spinal cord was removed at autopsy. After fixation, the cord was sectioned at 10 pm intervals for staining with HE, LFB, cresyl violet and PTAH. In addi­tion to these stainings, the Golgi-Valverde method was applied to secions in three planes; transverse, sagittal and frontal. Morphometric analysis of Golgi-impregnated motoneurons and propriospinal neurons was performed as reported by Ulfhake and Kellerth (1983) in the cat.

Results In the whole segments of the spinal cord the neurons were not affected and the cellular arrangement showed a nor­mal appearance. In the thoracic 'segments two eosinophilic giant cells were observed in the white matter. Their con­figuration was similar to that of the giant cells in brain nodules.

Golgi-irnpregnated motoneurons in the lumbar seg­ments were large and they exhibited radial and multipolar dendritic trees. The ratio of the combined diameter of the first order dendrites and the mean diameter of the cell body may be an indicator of the maturity of the entire dendritic trees. The ratio in this study was 0.97, which was not significantly different from that of the control case. Golgi-impregnated propriospinal neurons in the in­termediate gray matter of the lumbar segments were of medium size. Their dendrites extended in the directions of the ventro-dorsal and rostro-caudal axes. The ratio of the combined diameter of the first order dendrites and the mean diameter of the cell body was 0.58, which was sig­nificantly different from that of the control case (P < 0.01).

Conclusion The findings obtained in the present study suggest that there is spinal cord involvement already at an early stage of tuberous sclerosis. Also, morphometric analysis of Golgi impregnation revealed that the dendrites of pro­priospinal neurons in the intermediate gray matter showed the immaturity of the neuronal circuit.

Key words: Tuberous sclerosis, spinal cord, Golgi­Valverde method.

140 Brain & Development, Vol 9, No 2,1987

102

Findings for Biopsied Sural Nerves in 4 Cases of Xero­derma Pigmentosum Group A Nobutada Tachi, MD, Takashi Kusano, MD, Masato Naga­oka, MD, Shinsuke Fujibayashi, MD, Ryoji Minami, MD and Shigetaka Imamura, MD Department of Pediatrics, Sapporo Meidcal College, Sap­poro (NT, TK); National Sanatorium Yakumo Hospital, Yakumo (MN, SF, RM); Hokkaido Prefectural Institute for Physically Disabled Children, Sapporo (SI)

We described the clinical features and findings for biop­sied sural nerves in 4 cases of xeroderma pigmentosum (XP).

Eight genetic forms of XP have been reported on the basis of the results of complementation studies. Four cases were diagnosed as having XP group A from the results of complementation studies using cultured skin fibroblasts. All cases showed delayed mental and motor development, such as head control over 4 months of age and walking without support over 18 months of age. Three cases showed gradual gait disturbance from 6 to 9 years of age. MCV and SCV of the ulnar nerve showed slight to moderate delay.

As to sural nerve pathology, there was a normal density of myelinated fibers with a selective reduction of large diameter fibers in a slightly neurologically impaired case. In severely neurologically impaired cases, there were great reductions in the densities of myelinated and unmyeli­nated fibers. Ultrastructural observation disclosed many denervated Schwann cell bands and collagen pockets in severely neurologically impaired cases, while onion-bulb formation and a myelin figure in Schwann cell cytoplasma were seen in a slightly neurologically impaired case. These findings indicated that the degeneration process in the peripheral nerves in XP is axonal degeneration. The peripheral neuropathy in XP resembles that in ataxia­telangiectasia and Friedreich ataxia, which are known to involve a DNA repair defect in cultured skin fibroblasts.

Key words: Xeroderma pigmentosum, group A, sural nerve, axonal degeneration.

103

Clinico-Pathological Study on Hypomelanosis of Ito - A Neurocutaneous Syndrome Michiko Hara, MD, Kayoko Saito, MD, Kunio Yajima, MD and Yukio Fukuyama, MD Department of Pediatrics, Tokyo Women's Medical Col­lege, Tokyo

Hypomelanosis of Ito, which is characterized by bizarre cutaneous hypopigmented patterns, is frequently as­sociated with non cutaneous anomalies and neurological abnormalities, so it is now regarded as a neurocutaneous syndrome.

We studied 5 children with this disease from both cliniconeurological and cutaneous pathological aspects. Cutaneous hypopigmentation was seen diffusely in one, unilaterally in two and partially in the other two cases. All had mental retardation with slight or moderate brain atrophy detected on CT, hypotonia and growth retarda­tion. Four had intractable epilepsies such as infantile spasms, myoclonic seizures and complex partial seizures. All cases had two or more minor anomalies, and the two had peculiar coarse faces and hypertelorism.

Skin punch biopsy specimens taken from the hypo­pigmented areas showed a decrease in the amount of melanin granules in melanocytes, and a decrease in, and coarseness and unevenness of elastic fibers. S-IOO protein positive cells were almost completely absent in the basal cell layers of the epidermis in the hypopigmented cuta­neous regions.

These findings indicate that hypo melanosis of Ito is a neurocutaneous syndrome consisting of characteristic cutaneous findings, various congenital anomalies and some organic brain abnormalities.

Key words: Neurocutaneous syndrome, hypomelanosis, epilepsy, infantile spasms, skin punch biopsy.

104

Early Diagnosis of the Prader-Willi Syndrome Shouko Enomoto, MD, Kazuo Kodama, MD, Eiji Kita­zumi, MD, Satoshi Shimabukuro, MD, Akiko Miyata, MD and Tomoko Hasegawa, MD Department of Pediatrics, National Rehabilitation Center for Disabled Children (Seishi-Ryougoen), Tokyo (SE, KK, KK, SS); Fuchu Metropolitan Hospital, Tokyo (AM); Shizuoka Children's Hospital, Shizuoka (TH)

It is desirable that diagnosis of the Prader-Willi syndrome (PWS) be made as early as possible in order to avoid un­necessary examination, to take appropriate care and to prevent extreme obesity. So we attempted to delineate clinical characteristics of PWS in early infancy.

Materials and Methods Eighteen cases of PWS seen by us during their first year of life are reviewed. Their clinical records, photographs and videorecordings were analyzed.

Results The clinical findings of these cases in early infancy were as follows:

1) Severe muscle hypotonia was observed at the neo­natal period accompanied by perinatal asphyxia, neonatal respiratory distress, and feeding difficulty. Voluntary movement was very poor. The supine frog posture was common.

All had abduction contracture of the hip joint. Be­tween five and six months muscle tone increased gradually in the lower extremities but marked hypotonia of the neck, shoulder girdle and trunk remained. Full extension of the trunk was aquired later than the standing reaction.

2) The variety of facial appearances we classified into the following three types: (a) Scaphocephalic type, characterized by a rather scaphocephalic head, narrow forehead, and almondshaped palpebrel fissures. The ap­pearance was similar to that described in the published reports; (b) Brachicephalic type with a wide face and downward slanting palpebrel fissure. This group's ap­pearance gave us a very different impression from the descriptions in published reports; (c) Atypical type.

3) Soft, glossy white skin was common and very strik­ing. This characteristic has not been pointed out in the published literature. In Japanese children particularly, this seems to be an important diagnostic clue.

4) Low birth weight was noted in more than half. Body weight gain was rather poor initially but after five to six months of age the weight gain curve became steeper than standard.

S) Thirteen cases were studied by chromosome analy­sis and a deletion of chromosome 15 was identified in six.

Conclusion It is possible to diagnose or strongly suspect PWS in early infancy by considering the above-described features in addition to those in the published literature.

Key words: Prader-Willi syndrome, floppy infant, early diagnosis.

Brain & Development, Vol 9, No 2,1987 141