Pre-movement gating of somatosensory evoked potentials in Segawa disease.

INTRODUCTION: Segawa disease (SD), an autosomal dominant dopa-responsive dystonia with marked diurnal fluctuation, can be clinically classified into the postural dystonia type (SD-P) and action dystonia type (SD-A). Compared to SD-A, SD-P has an earlier onset and is characterized by postural dystonia. In SD-A, along with postural dystonia, dystonic movements appear in late childhood. To evaluate the differences between these two types of SD, we studied the gating of SEPs, which is useful to investigate sensory-motor integration and might be one of the methods to detect the thalamo-cortical involvement. METHODS: Fourteen patients with SD (11-63 years) and 18 age-matched normal subjects (11-51 years) were studied. Among the 14 patients with SD, 8 patients had SD-P and 6 had SD-A. Using median nerve stimulation at the wrist, the amplitude of the frontal N30 (FrN30) was compared between pre-movement and rest conditions. RESULTS: We found that the amplitude of the contralateral FrN30 was attenuated before movement in normal controls and in the majority of both SD types. On the other hand, the pre-movement-rest amplitude ratio in patients with SD-A was significantly larger than in patients with SD-P (P=0.0025). No significant differences were observed in the pre-movement-rest ratio between SD-P and normal subjects. CONCLUSION: The preservation or impairment of pre-movement gating shown here suggests a physiological difference between the two types of SD. More specifically, sensorimotor integration of the basal ganglia-thalamo-cortical circuits may be intact in SD-P, but are affected in SD-A. We discuss the different pathophysiology seen in the different phenotype of SD based on the different developmental involvement in the basal ganglia.

Epilepsy in autism: A pathophysiological consideration.

Eighty cases of idiopathic autism with epilepsy and 97 cases without epilepsy were studied to evaluate the pathophysiology of epilepsy in autism. The initial visit to this clinic ranged 8months-30years 3months of age, and the current ages are 5years 8months-42years 3months, 60% reaching to over 30years of age. The average follow up duration is 22.2years±9.4years. The ages of onset of epilepsy were from 7months to 30years of age, with the two peaks at 3.2years and 16.7years. EEG central focus appeared earlier than frontal focus. Abnormality of locomotion and atonic NREM were observed more frequently in epileptic group. These suggest the neuronal system related to abnormality of locomotion and atonic NREM, which are the hypofunction of the brainstem monoaminergic system, is the pathomechanism underling the epilepsy in autism. By showing the abnormal sleep-wake rhythm and locomotion being the very initial symptoms in autism, we had shown the hypofunction of the brainstem monoaminergic system is the initial pathomechanism of autism. Thus, epilepsy in autism is not the secondary manifestation, but one of the pathognomonic symptoms of autism. The brainstem monoaminergic system project to the wider cortical area, and the initial monoaminergic hypofunction may lead to the central focus which appears earlier. The failure of the monoaminergic (serotonergic) system causes dysfunction of the pedunculo-pontine nucleus (PPN) and induces dysfunction of the dopamine (DA) system, and with development of the DA receptor supersensitivity consequently disinhibits the thalamo-frontal pathway, which after maturation of this pathway in teens cause the epileptogenesis in the frontal cortex.

[Case of DYT1 dystonia (early-onset torsion dystonia) showing long-term focal dystonia in the arm].

DYTI dystonia (DYT1-D, early-onset torsion dystonia) is caused by a GAG deletion in the DYTI gene. Here we report a girl with child-onset familial DYT1-D showing localized arm involvement. The patient developed postural and action dystonia in the right and left arms at 7 and 9 years, respectively. She was misdiagnosed as hysteria due to lack of abnormalities on laboratory tests. At 11 years of age she was introduced to our clinic. Increased muscle tonus and dystonic discharges seen on surface electromyogram in the right arm and the sternocleidomastoid muscle led to the diagnosis of dystonia. A GAG deletion in the DYTI gene was confirmed in the patient, her healthy father and paternal grandfather with torsion dystonia. Titration of levodopa resulted in the fluctuation of her arm dystonia. Combined therapy by levodopa and trihexyphenidyl relieved postural dystonia in the right arm but not action dystonia in the left. Both types of dystonia in the right and left arms were well ameliorated by the additional increase of levodopa. Somatosensory evoked potentials demonstrated abnormal premovement gating. The latency and accuracy of the amplitude were disturbed in visually guided saccadic eye movement. Now at more than 11 years after onset, the patient has not shown torsion or involvement of the lower extremities. Most DYT1-D patients are refractory to medication and early surgical intervention is recommended. However, the presence of DYT1-D patients showing a milder disease course should also be considered.

A missense mutation in SCN1A in brothers with severe myoclonic epilepsy in infancy (SMEI) inherited from a father with febrile seizures.

Severe myoclonic epilepsy in infancy (SMEI) is an age-dependent epileptic encephalopathy occurring in the first year of life and is one of the intractable epilepsies. Heterozygous mutations in the voltage-gated sodium channel alpha subunit type1 gene (SCN1A) are frequently identified in patients with SMEI; two-thirds of these mutations are truncation mutations (non-sense and frameshift), and one-third are missense mutations. Although most reported SMEI cases arise as sporadic mutations, close relatives of SMEI patients have also been shown to manifest other types of epilepsies at a higher rate than that in the general population. Here, we report a familial case of SMEI, in which two brothers were affected with SMEI while their father had previously experienced simple febrile seizures. A gene-based analysis identified a novel missense mutation in the SCN1A gene (c.5138G>A, S1713N) in both brothers and in their father. Clinically, both siblings showed failure in locomotion, an impairment of the sleep-wake cycle after late infancy, and the subsequent appearance of frontal foci. The similarity in clinical manifestations in both brothers suggests that the impairment of elements of the brainstem, particularly aminergic neurons, develops after late infancy in SMEI. However, the siblings differed in age at onset of SMEI and of myoclonic seizures, as well as in the severity of speech delay. Our molecular and clinical findings suggest that different genetic backgrounds and/or environmental factors may critically affect the clinical features of patients with SCN1A mutations, consistent with the heterogeneity prevalent in this disorder.