PTG protein depletion rescues malin-deficient Lafora disease in mouse.

Ubiquitin ligases regulate quantities and activities of target proteins, often pleiotropically. The malin ubiquitin E3 ligase is reported to regulate autophagy, the misfolded protein response, microRNA silencing, Wnt signaling, neuronatin-mediated endoplasmic reticulum stress, and the laforin glycogen phosphatase. Malin deficiency causes Lafora disease, pathologically characterized by neurodegeneration and accumulations of malformed glycogen (Lafora bodies). We show that reducing glycogen production in malin-deficient mice by genetically removing PTG, a glycogen synthesis activator protein, nearly completely eliminates Lafora bodies and rescues the neurodegeneration, myoclonus, seizure susceptibility, and behavioral abnormality. Glycogen synthesis downregulation is a potential therapy for the fatal adolescence onset epilepsy Lafora disease.

A longitudinal study of Taiwanese sialidosis type 1: an insight into the concept of cherry-red spot myoclonus syndrome.

BACKGROUND AND PURPOSE: Sialidosis type 1 (ST-1) is a neurodegenerative disorder with limited long-term follow-up report. This study is to document the chronological profile of ST-1. METHODS: We perform serial analysis of 17 Taiwanese patients with ST-1 focusing on evolution of clinical features, electrophysiological findings, genetic studies, and neuroimage examinations. RESULTS: All patients had a mutation at 554A-->G in exon 3 of the NEU1 gene causing Ser182Gly substitution. Fifteen patients were homozygous. Two patients were heterozygous with novel mutations, 956C-->T causing Ala319Val in one and 163C-->T causing Gln55stop codon in the other. The neuraminidase activity was markedly decreased in all 11 available patients. Only three patients (17.6%) manifested the macular cherry-red spot. The majority of patients (82.3%) developed full-blown manifestation of myoclonus, ataxia, and seizures within 5 years. Abnormal somatosensory evoked potentials with giant cortical waves were found in all patients. Prolonged P100 peak latency of the visual evoked potentials (VEPs) were found in 16 patients (94.1%) in the early stage even without visual symptoms. CONCLUSION: ST-1 in Taiwanese population illustrates distinct characteristics of phenotype with infrequent cherry-red spot. We suggest to screen the NEU1 mutations in patients presenting action myoclonus with abnormal VEPs, even without macular cherry-red spots.

Phenotypic variations in 3 children with POLG1 mutations.

Autosomal inherited mitochondrial diseases have been of increasing interest among clinicians and mitochondrial research groups because these diseases are caused through a secondary effect on the mitochondrial DNA. It was thought that the genetic stability of mitochondrial DNA relies on the accuracy of DNA polymerase gamma. Mutations of DNA polymerase gamma 1 gene (MIM# 174763) have been shown to be a cause of mitochondrial disorders associated with Mendelian disorders characterized by multiple mitochondrial DNA deletions or depletions. To date, several clinical phenotypes associated with polymerase gamma mutation have been reported presenting in both adults and children. We present 3 children in whom were found to have reported pathogenic DNA polymerase gamma 1 mutations: heterozygous p.G517V in 2 half siblings and heterozygous p.T251I and p.P587L in the other. The aim of this communication is to report 3 pediatric cases associated with DNA polymerase gamma 1 mutations to augment the expanding clinical phenotype that has been previously reported.

Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome.

The authors report a kindred in which GTP-CH deficiency resulted in a myoclonus-dystonia syndrome. The proband, a 17-year-old boy, presented with early-onset myoclonus and later, dystonia and bradykinesia. Blood prolactin was increased and CSF homovanillic acid, 5-hydroxyindoleacetic acid, and biopterin were all reduced. L-Dopa/carbidopa administration resulted in clinical improvement. In the paternal branch, the grandfather and three relatives had myoclonus-dystonia and resting or postural tremor of limbs. The authors found a missense mutation in the exon 6 of GCH-1 gene (K224R).

Dancing eye syndrome and hyperphosphatasemia.

An 11-month-old boy with a relapsing dancing eye syndrome associated with elevation of serum alkaline phosphatase, lactate dehydrogenase, and aminotransferase activities is reported. During two clinical episodes the serum alkaline phosphatase activity increased up to four times the upper reference limit, remained elevated for a few weeks and normalized gradually in parallel with clinical improvement under steroid therapy. We found no evidence of liver or bone pathology nor of a neural crest tumor. The association between dancing eye syndrome and hyperphosphatasemia has not yet been described. The beneficial effect of the steroid therapy strengthens the hypothesis of an autoimmune origin.

Seizures and myoclonus associated with antidepressant treatment: assessment of potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment with CYP2D6 inhibitors.

All adverse drug reaction reports labelled seizures or myoclonus during treatment with antidepressants and stored in the Swedish national database for spontaneous reporting of adverse drug reactions were reviewed in order to evaluate possible risk factors. The reporting physicians were contacted and asked for complementary information, and blood samples for determination of the CYP2D6 and CYP2C19 genotypes were obtained from patients available. In total, 25 cases of seizures and 7 cases of myoclonus were studied. The drugs included were maprotiline (n=8), mianserin (n=7), fluvoxamine (n=6), amitriptyline (n=3), clomipramine (n=3), citalopram (n=2), paroxetine (n=2) and lofepramine (n=1). Previously suggested predisposing factors were identified in all but four cases (87%). None of the 11 patients genotyped were found to be poor metabolizers with respect to the enzymes CYP2D6 or CYP2C19. Thus, neither the CYP2D6 nor the CYP2C19 genotype were found to be associated with the occurrence of seizures/myoclonus during treatment with antidepressants. However, 15 patients (47%) were concomitantly treated with drugs with potential inhibitory effects on CYP2D6, such as neuroleptics and dextropropoxyphene, and the patients might thus have been converted from the extensive metabolizer to the poor metabolizer phenotype during this treatment. Concomitant treatment with drugs decreasing the seizure threshold and/or inhibiting the metabolism of antidepressants appeared to be an important risk factor for the occurrence of seizures/myoclonus.

Activated sialidase activity in transformed lymphocytes by Epstein-Barr (EB) virus of sialidosis type I (cherry-red spot-myoclonus syndrome).

We report a new Japanese family of sialidosis type I. The sialidase activity was deficient in the lymphocytes of 2 patients (6.8% (sister) and 12.5% (brother) of control mean). However, surprisingly, using the transformed lymphocytes by EB virus, this activity was activated to 51.7% (sister) and 49.5% (brother) of control mean, respectively. Although the mechanism for this activation was not known, we discussed the possible mechanisms for this phenomenon.

Autoantibodies to glutamic acid decarboxylase in palatal myoclonus and epilepsy.

We report the presence of serum autoantibodies directed against glutamic acid decarboxylase in a patient with epilepsy and palatal myoclonus not associated with brain lesions. Glutamic acid decarboxylase antibody reactivity was dependent on the presence of carboxy-terminal amino acids, similar to that reported in patients with stiff-man syndrome. Marked reduction in the frequency of epileptic attacks and improvement in palatal myoclonus occurred when benzodiazepine was administered and phenytoin was gradually tapered. Testing for anti-glutamic acid decarboxylase antibodies may be indicated in patients with palatal myoclonus and with convulsive disorders refractory to therapy.

Mitochondrial encephalo-neuro-myopathy with myoclonus epilepsy, basal nuclei calcification and hyperlactacidemia.

We report a new case of MERRF (myoclonus epilepsy with ragged red fibers) syndrome with basal nuclei calcification on the brain CT scan, without hormonal abnormalities, with high CSF protein and hyperlactacidemia, juvenile onset and death at 18 years. Biochemical study of mitochondrial muscle enzymes showed decreased NADH-cytochrome-C-reductase and Succinate-cytochrome C-reductase activity, suggesting a Complex III defect of the respiratory chain. Similar reported cases are reviewed.

Biotin-reversible neurodegenerative disease in infancy.

Two siblings with consanguineous parents began having myoclonic jerks at age 5 months after introduction of mixed feeding. There was later developmental regression. The elder girl died without diagnosis aged 1 year, after prolonged continuous hyperventilation. The younger sibling did not have metabolic acidosis when first investigated for myoclonus and hypotonia aged 5 months. At 9.5 months, when intermittently decerebrate and hyperventilating, she had a metabolic acidosis with elevated blood lactic, pyruvic and beta-hydroxybutyric acids, and beta-hydroxyisovaleric aciduria. On the assumption that she had beta-methylcrotonyl-CoA carboxylase deficiency she was started on biotin, 10 mg daily. Within 36 h there was dramatic clinical and biochemical improvement. Previously defective eye movement control and gaze became normal, hyperventilation ceased, and excessive organic acid excretion in urine was abolished. She remains on long-term biotin and at age 2 years her development appears normal in all respects. Fibroblast culture however revealed normal quantities of the enzymes beta-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase and pyruvate carboxylase. Irrespective of niceties of enzyme and organic acid biochemistry, the clinician must be aware of biotin-reversible regressive brain disease which may present before manifest metabolic acidosis.

Friedreich's disease: IV. Reduced mitochondrial malic enzyme activity in heterozygotes.

Friedreich's disease (FD) obligate heterozygotes have reduced mitochondrial malic enzyme (MEm) activity in cultured fibroblasts. This indicates that the MEm deficiency in homozygous affected patients is genetically determined. Heterozygote MEm activity was only 20% of the control mean activity, lower than the 50% expected in an autosomal-recessive disorder. This may result from negative interactions between mutant and normal subunits in the tetrameric enzyme. These data support the idea that MEm deficiency causes FD, but further studies are required to prove this hypothesis.

Neuraminidase activities in sialidosis and mucolipidosis.

Defects of neuraminidase activities towards sialyloligosaccharides in fibroblasts and leucocytes and enhanced excretion of sialyloligosaccharides in urine were shown in patients with adult type sialidosis with partial deficiency of beta-galactosidase and cherry red spot-myoclonus syndrome. No differences in their neuraminidase residual levels and urinary excretion patterns on thin-layer chromatography were found between these two disorders. In mucolipidosis II and III patients, the neuraminidase activities towards sialyloligosaccharides were almost normal in leucocytes, although decreased in fibroblasts. The discrepancy of neuraminidase activities towards 2 leads to 3 and 2 leads to 6 sialyloligosaccharide isomers was not noticed in all cases.

Propionyl coenzyme A carboxylase deficiency presenting as non-ketotic hyperglycinaemia.

A 4-month-old girl presented with myoclonic seizures and an electroencephalogram showing hypsarrhythmia. Hyperglycinuria and a cerebrospinal fluid to plasma glycine ratio of 0.2 suggested the diagnosis of non-ketotic hyperglycinaemia. Propionic acid and methyl citric acid were present in the urine, and propionyl coenzyme A carboxylase was deficient in leucocytes and fibroblasts. The ketotic and non-ketotic hyperglycinaemias cannot be differentiated by CSF: plasma glycine ratios.

Cherry-red spot myoclonus syndrome and alpha-neuraminidase deficiency: neurophysiological, pharmacological and biochemical study in an adult.

A 22 year old patient with non-familial progressive myoclonus, macular cherry-red spot, moderate cerebellar syndrome and normal intelligence is described. The myoclonus began at the age of 18 years. Focal myoclonus could easily be elicited by voluntary and passive movements, and by touch and electrical stimulation of median nerve. Somatosensory evoked potentials showed a high voltage early component. Jerk-locked averaging of the EEG preceding action myoclonus detected an otherwise hidden, time-related, EEG spike. The myoclonus responded partially but clearly to L-5 hydroxytryptophan plus carbidopa treatment. Biochemical study showed an alpha-neuraminidase deficiency in cultured fibroblasts: the decrease in this enzyme activity was compared to that found in a patient affected by mucolipidosis III.

Platelet enzyme abnormalities in neuropsychiatric disease.

Blood platelets accumulate, store and release a variety of biogenic amines including norepinephrine, serotonin and dopamine (DA) which are known to act as neurotransmitter substances. Platelet monoamine oxidase (MAO) shares many biochemical properties with the mitochondrial MAO present in brain tissue. For these reasons it has been suggested that platelets might serve as a diagnostic and research model for nerve cells in a variety of neuropsychiatric diseases. In some patients with schizophrenia and manic depressive phychoses, platelet MAO activity is significantly decreased. Central nervous system inhibition of MAO could lead to excess accumulation of monoamines in the brain; this would be consistent with the DA hypothesis of schizophrenia. Disturbances of monoamines and enzyme kinetics in the hereditary ataxias and in Huntington disease have been described, but these findings are unproven and controversal. If platelet models for human neuropsychiatric disease can be established, they will be immensely important in preclinical diagnosis, therapy and genetic counseling.

Neuraminidase activity in the mucolipidoses (types I, II and III) and the cherry-red spot myoclonus syndrome.

Two neuraminidase (EC 3.2.1.18) comonents, A and B, were distinguished in cultured skin fibroblasts on the basis of thermolability at 37 degrees C. The more labile component (A) t1/2 = 4.7--5.3 min at 37 degrees C, comprises 66--90% of total neuraminidase activity when determined using sodium (4-methylumbelliferyl-alpha-D-N-acetylneuraminate) (MU-alpha-N) as substrate. Activity was assayed at 0 degrees C for 18 h instead of 37 degrees C to fully determine both thermolabile and thermostable components. Diminished activity was noted in cultured fibroblasts from mucolipidoses I, II and III (MLI, MLII, MLIII) and the cherry-red spot myoclonus syndrome (CRSM) patients when assayed at both 0 and 37 degrees C with either MU-alpha-N or each of a series alpha (2 leads to 3)- and alpha (2 leads to 6)-linked N-acetylneuraminyloligosaccharides. Increased sensitivity and rapidity of analyses were achieved using MJ-alpha-N as substrate in determining neuraminidase activity. Results from two obligate heterozygote MLI cell lines (14.5 and 8.0% of control activity) indicate that the MU-alpha-N substrate could be useful for heterozygote detection.

Cherry-red spot-myoclonus syndrome.

A 21-year-old woman had typical clinical and biochemical findings of the cherry-red spot-myoclonus syndrome. She had 20/50 acuity in each eye, flutter-like ocular oscillations, rebound nystagmus, and transient vertical dissociation. Cherry-red maculas and optic atrophy were present. Although electroretinographic signals were normal, visual evoked potentials were almost absent. Levels of neuraminidase were significantly reduced in cultured ebroblasts from the patient and her parents, while lysosomal inclusions probably containing oligosaccharides were found in her conjunctival fibroblasts.

Sialidosis type 1: cherry red spot-myoclonus syndrome with sialidase deficiency and altered electrophoretic mobilities of some enzymes known to be glycoproteins. 1. Clinical findings.

A family is described with three affected brothers, two of whom were examined, born to consanguineous parent, who in early adult life began to experience ataxia, intention myoclonus, and progressive visual failure. The brothers examined had cherry red spots at the maculae and cataracts. They were of normal intelligence. The intention myoclonus responded partially to treatment with clonazepam and pheneturide, but not to 5-hydroxytryptophan in combination with carbidopa or to sodium valproate. Studies in one patient showed the excretion of large quantities of sialylated oligosaccharides in the urine. Both patients showed deficient sialidase activity in their cultured fibroblasts. Further studies on cultured skin fibroblasts revealed increased electrophoretic mobility of six glycoprotein enzymes that was returned approximately to normal by treatment with sialidase. The clinical and biochemical findings indicate that these patients are further cases of the newly described condition sialidosis type 1.