Mutation of the CLN6 Gene in Teenage-Onset Progressive Myoclonus Epilepsy

Progressive myoclonus epilepsies are severe, intractable, and neurodegenerative. They afflict patients of all ages, but more commonly adolescents, and comprise the main differential diagnosis of common juvenile myoclonic epilepsy. Genetic or minimally invasive pathologic diagnoses are available for many but not all teenage-onset progressive myoclonus epilepsies. We describe a multiplex family with autosomal recessive teenage-onset progressive myoclonus epilepsy that had remained undiagnosed despite extensive genetic and pathologic testing. We describe whole exome sequencing combined with homozygosity mapping to identify the disease gene directly and diagnose the family. The affected gene is CLN6, previously known to underlie variant late-infantile and adult-onset neuronal ceroid lipofuscinoses. Combined with other recent work, our results add CLN6 to the genetic mutations causing teenage-onset progressive myoclonus epilepsy, expand the group of teenage-onset progressive myoclonus epilepsy patients who can be diagnosed by genetic testing, and extend the clinical spectrum of CLN6 mutations to include teenage-onset progressive myoclonus epilepsy. This work also exemplifies the potentiality of next-generation sequencing in the genetic identification and diagnosis of patients with neurologic diseases of unknown cause.     

Successful Treatment of Progressive Myoclonus Epilepsy With TRH

Thyrotropin-releasing hormone (TRH) is sometimes used for the treatment of neurologic disorders such as intractable epilepsy and spinocerebellar degeneration. A 14-year-old girl with progressive myoclonus epilepsy was treated with intravenous TRH for 12 months. Clinical symptoms, such as cortical myoclonus and cerebellar signs, were improved, and P25-N33 amplitudes of somatosensory-evoked potentials decreased after TRH therapy. P100 amplitudes on flash visual- evoked potentials and photosensitivity on electroencephalograms also decreased but only temporarily. Changes in neurophysiologic findings after TRH therapy indicate that TRH inhibits hyperexcitability in the sensorimotor cortex and the visual cortex. Therefore, intravenous TRH therapy is recommended as an alternative therapy in the treatment of progressive myoclonus epilepsy.     

Neonatal Sleep Myoclonus Followed by Myoclonic-Astatic Epilepsy: A Case Report

Neonatal sleep myoclonus documented polygraphically during the second month of life and subsequent development of a seizure disorder are reported in a 3-year-old boy. Several generalized tonic-clonic seizures associated with febrile illnesses occurred during the first year of life; astatic and myoclonic attacks began at age 13 months. A complex partial seizure occurred for the first time at age 3 years. Differential diagnosis of age-related generalized myoclonic epileptic syndromes and various forms of neonatal myoclonus were considered in this unusual case.     

Neuropharmacology of Progressive Myoclonus Epilepsy: Response to 5-Hydroxy-L-Tryptophan

Summary: Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of patients with progressive myoclonus epilepsy (PME) suggest hypofunctional serotonergic neurotransmission. To study this hypothesis, we enrolled 6 patients with PME [Unverricht-Lundborg disease (U-L), mitochondria1 encephalomyopathy, or Lafora disease] in a controlled, double-blinded, dose-ranging, cross-over add-on pilot clinical trial of 5-hydroxy-L-tryptophan (L- 5-HTP) plus carbidopa after 2 other patients had received open-label L-5-HTP for compassionate use. Prestudy CSF 5-HIAA concentrations were low (<20 ng/ml) in 6 patients regardless of the etiology of PME. One patient with U-L disease showed clinical improvement and a fivefold increase in CSF 5-HIAA, and 1 with Lafora disease showed a twofold increase in CSF 5-HIAA without improvement. A patient with Lafora disease reported enough improvement in myoclonus-evoked convulsions to continue chronic use of the drug. One patient with mitochondria1 encephalomyopathy developed status epilepticus during treatment with L-5-HTP.As a group, patients had no statistically significant changes in myoclonus evaluation scale scores, subjective and objective measures of ataxia, seizure frequency, antiepileptic drug (AED) levels, or routine blood tests. These data suggest a serotonergic abnormality regardless of the underlying etiology of PME, but one that seldom responds to acute treatment with L-5-HTP.     

Reduced Serotonin and 3-Hydroxyanthranilic Acid Levels in Serum of Cystatin B-Deficient Mice, a Model System for Progressive Myoclonus Epilepsy

Summary:  Purpose: To evaluate the levels of tryptophan and its metabolites along serotonin (5-HT) and kynurenine (KYN) pathways in serum of progressive myoclonus epilepsy (EPM1) patients and cystatin B (CSTB)-deficient mice, a model system for EPM1.
Methods: Tryptophan and its metabolites along serotonin (5-HT) and KYN pathways were determined in serum of EPM1 patients and CSTB-deficient mice by reverse-phase high-pressure liquid chromatography (HPLC) with electrochemical detection.
Results: Reduced levels of 5-HT and KYN intermediate metabolite 3-hydroxyanthranilic acid were found in serum of CSTB-deficient mice. A similar trend was found in EPM1 patients. Although tryptophan concentration was reduced in serum of EPM1 patients, no such decrease was observed in CSTB-deficient mice.
Conclusions: The present study demonstrates that tryptophan metabolism along 5-HT and KYN pathways are disrupted in EPM1. Further studies are needed to elucidate the role of KYN pathway in pathogenesis of EPM1.     

A Neuropathological Case-Study of Myoclonus Epilepsy

A 28–year-old male of progressive my-oclonus epilepsy was reported, who had showed a gradual progression in myoclonus, mental retardation and cerebellar symptoms, and had been treated with a large dosage of diphenylhydantoin. Neuropathologically, slight degenerative changes of the cerebral cortex, especially in the IV layer, the external pallidum, and the dentate and olivary nuclei were observed. The most obvious change was diffuse reduction of Purkinje's and granular cells in the cerebellum. A congenital cyst was found with surrounding gliosis in the central teg-mental tract of the pons. A significant relationship between myoclonus and the cyst was proposed, and furthermore, influences of diphenylhydantoin intoxication on the clinicopathological development of myoclonus epilepsy were emphasized.     

Uptake of Taurine, GAB A, 5-HT, and Dopamine by Blood Platelets in Progressive Myoclonus Epilepsy

The uptakes of four neurotransmitters (taurine, GABA, 5-HT, and dopamine) by blood platelets from patients with degenerative-type progressive myoclonus epilepsy (PME) and from controls were studied using different incubation times and different concentrations. Only the uptakes of taurine differed significantly between patients and controls: patients' uptakes were 70% to 80% of control values at 10, 30, 60, and 120 min of incubation time. Km values were approximately the same, but Vmax values in PME patients were lower, showing quantitative but not qualitative differences in taurine uptake by platelets in PME. These results suggest that a defect or an inhibitory mechanism of some factor needed in the transport or binding of taurine (but not of GABA, 5-HT, and dopamine) is present in PME.     

A Case of Cluster Headache Accompanied by Myoclonus and Hemiparesis

Background

Cluster headache is a primary headache disorder characterized by periodic episodes of intense headache accompanied by autonomic symptoms. We report an unusual clinical presentation of cluster headache that was preceded by myoclonus and accompanied by hemiparesis.

Case Report

A 26-year-old man visited hospital due to recurrent jerky movements on the left side of his face and neck area lasting 3 days. These jerky movements had disappeared spontaneously without specific treatment. On the 10th day after onset of the jerky movements, the patient developed a series of unilateral severe headaches that were accompanied by autonomic symptoms lasting 1-2 hours. According to the second edition of The International Classification of Headache Disorders, he was diagnosed as having cluster headache. Two of the 16 severe headache attacks this patient suffered were accompanied by dysarthria and hemiparesis. Electroencephalography performed during hemiparesis revealed diffuse lateralized slow activity on the ipsilateral hemisphere of the headache side. The headache and accompanying hemiparesis disappeared after medical treatment for cluster headache.

Conclusions

We describe a case of cluster headache accompanied by hemiparesis, which was preceded by myoclonus. We also outline the possible mechanisms underlying this case.     

A Sporadic Case of Benign Myoclonus Epilepsy of Adult Onset: Its Clinical Aspects and Electroencephalographic, Polygraphic Study

Abstract: sporadic case of myoclonus epilepsy of adult onset with a benign course is presented. Its clinical implications were discussed symptomatologically and nosologi-cally. EEG findings consisted of the slowing of basic activity, characteristic polyspike and wave discharges or other paroxysmal patterns and photomyoclonic response (PMR). The PMR was well evoked by flashes of 6-21 Hz and of yellow or red color. Clinical similarities of this case to those of hereditary myoclonus epilepsy without progressive dementia and cerebellar ataxia, and pathognomonic characteristics of electrophysiological findings indicated that the myoclonic epilepsy syndrome might share basic properties, which are state-dependent, but independent of underlying neuropathology or heredity.
During sleep, paroxysmal discharges with spike(s) significantly decreased in slow-wave sleep and almost recovered in REM sleep. This finding suggests that the brain stem may be responsible for the epileptogeneity in this case.     

A Case of Osteogenesis Imperfecta Type II Caused by a Novel COL1A2 Gene Mutation: Endoscopic Third Ventriculostomy to Prevent Hydrocephalus

Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder caused by defects in type I collagen synthesis. OI is generally classified into four types (I to IV), and the clinical prognosis varies from a lethal outcome for type II and varying deformities for type III to a normal lifespan for the other types. We describe a female patient with biochemically confirmed OI caused by a novel mutation in the COL1A2 gene. Persistence of blue sclerae supported the diagnosis of OI type II. The case was complicated with obstructive hydrocephalus, for which endoscopic third ventriculostomy (ETV) was performed. The ETV was transiently effective for the obstructive hydrocephalus. The patient subsequently developed brain atrophy, partly through ischemic events after the ETV, which appeared to contribute to maintenance of smooth circulation of the cerebrospinal fluid. We conclude that continuous and adequate medical care including ETV can facilitate long-term survival even in lethal OI type II.     

A Case of Musicogenic Epilepsy

• 1. ) A case of musicogenic epilepsy or psychomotor seizures supervening whenever the patient hears a certain tune has been presented.
• 2. ) The EEG features of the seizure are such as are often seen in psychomotor seizures.
• 3. ) Auditory evoked response may be left out of consideration.
• 4. ) There is no appreciable relationship between the disease and the life history of the patient. The attempt of our patient to cure herself by making use of conditioned reflex proved to be a failure. The patient is more liable to the disease when she is on the strain while hearing a tune.
• 5. ) Our consideration of the mechanism of the disease has led to the presumptive conclusion that hyperacusis, conditioned reflexes and the impact of life history may be involved, and the fragility of the memory function of the temporal lobe underlie the genesis of the disease.

     

同型半胱氨酸代谢基因突变的致死性青年椎动脉夹层1例

正头颈动脉夹层年发病率为2.5～3/10万,椎动脉夹层为1.0～1.5/10万,头颈动脉夹层引起的缺血性卒中约占全部缺血性卒中的2%[1],占青年缺血性卒中的8%～25%[2-3]。血管壁受到外力及血流动力学因素引起动脉内膜撕裂是动脉夹层的重要病因[4]。本文报道一例同型半胱氨酸代谢基因突变的致死性青年椎动脉夹层。