An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases.

We reported a 64-year-old autopsy case, showing a unique combination of disorders in visceral organs and brain. She had developmental delay, microencephaly, and facial dysmorphism. She developed sick sinus syndrome and liver cirrhosis. There were no abnormalities in laboratory tests for congenital metabolic errors or anomaly syndromes, including activities of lysosomal enzymes, isoelectric focusing of serum transferrin or array comparative genomic hybridization. She died of cardiorespiratory failure. At autopsy she showed liver cirrhosis and mesangial proliferation. The brain weighed 710 g. Bizarre putaminal changes were found, in which the size of area of putamen in coronal sections was small, aberrant fiber running was increased, and immunoreactivity for tyrosine hydroxylase was reduced. Loss of Purkinje cells was found throughout the cerebellar cortex. She had unreported combination of developmental delay, facial dysmorphism, small brain, bizarre putaminal lesion, cerebellar atrophy, cardiac disease, liver cirrhosis and renal disease. Although the exact cause of disease still remains to be investigated, it will be a clue for the establishment of new disease entity to accumulate subjects having the similar phenotype.

Melatonin alterations and brain acetylcholine lesions in sleep disorders in Cockayne syndrome.

BACKGROUND: Cockayne syndrome (CS) is a genetic disorder caused by deficient nucleotide excision repair. Patients with CS exhibit progeroid features, developmental delay, and various neurological disorders; they are also known to suffer from sleep problems, which have never been investigated in detail. OBJECTIVE: The aim of this study is to investigate the pathogenesis of sleep disorders in patients with CS. METHODS: We performed a questionnaire survey of the families of patients with CS, enzyme-linked immunosorbent analyses of the melatonin metabolite, 6-sulphatoxymelatonin (6-SM), in the patients' urine, and immunohistochemistry in the hypothalamus, the basal nucleus of Meynert (NbM), and the pedunculopontine tegmental nucleus (PPN) in four autopsy cases. RESULTS: Sleep-wakefulness rhythms were disturbed in patients with CS, and these disturbances seemed to be related to a reduced urinary excretion of 6-SM. In addition, although the hypothalamic nuclei were comparatively preserved, acetylcholine neurons (AchNs) were severely decreased in the NbM and PPN. CONCLUSIONS: AchNs modulate both arousal and rapid eye movement sleep, and selective lesions of AchNs in the PPN and/or NbM in combination with disturbed melatonin metabolism might be involved in the sleep disorders in CS.

[Efficacy of botulinum toxin type A against cervical dystonia and muscular hypertonia in persons with severe motor and intellectual disabilities with respiratory problems and/or dysphagia].

We administered intramuscular injections of botulinum toxin type A (BTX-A) in 11 persons with cervical dystonia (CD) and muscular hypertonia (MH). All patients had severe motor and intellectual disabilities (SMID). Furthermore, in 10 patients, SMID was accompanied by respiratory problems and/or dysphagia. Three patients received night nasal intermittent positive pressure ventilation and 3 had undergone tracheotomy; 5 patients had upper respiratory problems. Because of these complications, BTX-A dose was gradually increased in those patients until the desired effect was obtained (mean last dose, 6.8 u/kg/dose). All patients were clinically assessed with the Tsui scale before treatment with BTX-A. At 1, 2, 4, and 8 weeks after BTX-A injections, responses to the injections were assessed with the Tsui scale repetitively in all patients. Significant or mild improvements in the Tsui scale scores were observed in 8 patients without any severe adverse effects. In addition, some improvements in respiration and body weight gain were observed. We observed a reduction in the number of oral medications in 10 cases. Administration of BTX-A for the treatment of SMID has numerous benefits, not all of which can be explained by Tsui scale scores. BTX-A is safe and has potential for use in the treatment of CD and MH with respiratory problems and/or dysphagia.

De-novo balanced translocation between 7q31 and 10p14 in a girl with central precocious puberty, moderate mental retardation, and severe speech impairment.

No causative gene has been found for idiopathic central precocious puberty; and FOXP2, located in 7q31, is the only known gene for speech and language disturbances. We report a girl with central precocious puberty, moderate mental retardation, and severe speech impairment; accompanied by a de-novo balanced translocation between 7q31 and 10p14. Physical mapping through molecular cytogenetic investigations demonstrated the breakpoints of 7q31 and 10p14 within a bacterial artificial chromosome (BAC) clone RP11-124G5 and a cosmid clone derived from a BAC clone RP11-1122C18, respectively. FOXP2 was found to be localized approximately 500 kb distant from the centromeric end of the disrupted BAC RP11-124G5 at the 7q31 breakpoint. Speech impairment in the girl might be derived from dysfunction of FOXP2 by a position effect of the 7q31 translocation breakpoint.

Altered nestin expression in the cerebrum with periventricular leukomalacia.

Nestin is a cytoskeletal protein expressed by neural stem cells, and by immature neurons and glial cells. In an effort to explore the potential of the infant brain for repair and plasticity, we immunohistochemically studied nestin expression in the human cerebral cortex of control subjects and of patients with periventricular leukomalacia. During normal development, nestin immunoreactivity of the cortical gray and white matter was detectable throughout the fetal period, and disappeared around birth. In brain with periventricular leukomalacia, nestin expression was altered in a time- and space-dependent manner. In the cortical gray matter, neuronal immunoreactivity was often reduced in the subacute stage, but was increased in chronic and remote stages. In the white matter near a lesion of periventricular leukomalacia, glial immunoreactivity was increased in all stages. In many cases, neurons and axons far from a lesion also showed an altered expression of nestin. These findings indicate that in brain with periventricular leukomalacia, neurons and glial cells may recapitulate nestin expression in response to ischemic brain injury, suggesting functional relevance in repair and plasticity.

Myelin transcription factor 1 (MyT1) immunoreactivity in infants with periventricular leukomalacia.

Myelin transcription factor 1 (MyT1) is a zinc-dependent, DNA-binding protein, and is known to be expressed in early progenitors of oligodendrocytes. We examined the immunoreactivity of MyT1 in developing human brains and brains with periventricular leukomalacia (PVL) to understand the relationship between the expression of MyT1 and myelination in PVL brains. MyT1-positive glial cells were first detected at 19 gestational weeks (GWs) and then gradually increased until 26-29 GWs in the control group. Then they decreased and became very rare at 1 year of age. The expression of MyT1 immunoreactivity shifted from the nucleus to the cytoplasm of the glial cells in the developmental time course. In the chronic stage of PVL, MyT1-positive cells were significantly increased around necrotic foci and some of the regions were coincident with increasing MBP and PLP immunoreactivity. These results may reflect myelin repair on dysmyelination around PVL areas. Therefore, MyT1 may play an important role in the myelin repair in PVL regions.

[A case of FK 506-induced leukoencephalopathy].

We reported a 15-year-old boy with an acute myelomonocytic leukemia and FK 506-induced leukoencephalopathy. He was received FK 506 for graft versus host disease occurred after peripheral blood stem cell transplantation. He, four weeks later, had generalized seizures and consciousness disturbance. The serum level of FK 506 was high (27.5 ng/ml). His brain MRI showed abnormal high intensity areas in the frontal and parietal white matter lesions on T2-weighted images. Neuropathological studies revealed the destruction of myelin sheeths and axons in the cerebral white matter corresponded with abnormal lesions on MRI. There were calcification and mineralization in the small vessel walls of the cortex and white matter. Osteopontin immunoreactivity was detected in the endothelial cells of small vessels. These findings suggest that the vascular damage was involved in the FK 506-induced leukoencephalopathy.