A blinded, crossover study of the efficacy of the ketogenic diet.

Despite over 80 years of use, the ketogenic diet (KD) has never been tested in a blinded manner. Twenty children with intractable Lennox-Gastaut syndrome (LGS) were fasted 36 h and then randomized to receive the classic KD in conjunction with a solution containing either 60 g/day of glucose or saccharin. Parents and physicians were blinded to both the solution composition and level of ketosis. A crossover to the KD with the alternate solution occurred following the sixth day and a repeat fast. A 24-h electroencephalography (EEG) was obtained at baseline and after each arm. After administration of the solution, there was moderate evidence of a reduction in parent-reported seizures between the glucose and saccharin arms, with a median difference of 1.5 seizures per day (p = 0.07). There was no reduction in the number of EEG-identified events, with a median reduction of 7 events per day (p = 0.33). Ketosis was not completely eliminated in the glucose-added arm.

NMR-based urinalysis for rapid diagnosis of ß-ureidopropionase deficiency in a patient with Dravet syndrome.

BACKGROUND: Beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. To-date, about 30 genetically confirmed cases had been reported. The clinical phenotypes of this condition are variable; some patients were asymptomatic while some may present with developmental delay or autistic features. In severe cases, patients may present with profound neurological deficit including hypotonia, seizures and mental retardation. Using NMR-based urinalysis, this condition can be rapidly diagnosed within 15 min. CASE: An 11-month-old Chinese boy had dual molecular diagnoses, ß-ureidopropionase deficiency and Dravet syndrome. He presented with intractable and recurrent convulsions, global developmental delay and microcephaly. Urine organic acid analysis using GC-MS and NMR-based urinalysis showed excessive amount of ß-ureidopropionic acid and ß-ureidoisobutyric acid, the two disease-specific markers for ß-ureidopropionase deficiency. Genetic analysis confirmed homozygous known disease-causing mutation UPB1 NM_016327.2: c.977G>A; NP_057411.1:p.R326Q. In addition, genetic analysis for Dravet syndrome showed the presence of heterozygous disease-causing mutation SCN1A NM_001165963.1:c.4494delC; NP_001159435.1:p.F1499Lfs*2. CONCLUSIONS: The differentiation between Dravet syndrome and ß-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features. The detection of urine ß-ureidoisobutyric and ß-ureidopropionic acids using NMR or GC-MS is helpful in laboratory diagnosis of ß-ureidopropionase deficiency. The disease-causing mutation, c.977G>A of ß-ureidopropionase deficiency, is highly prevalent in Chinese population (allele frequency=1.7%); ß-ureidopropionase deficiency screening test should be performed for any patients with unexplained neurological deficit, developmental delay or autism.

Urinary glycosaminoglycans in patients with progressive myoclonus epilepsy.

Urinary GAGs analysis in Progressive Myoclonus Epilepsy (PME) showed an accumulation of uronic acid in the fraction eluted by 1 M NaCl and 3 M NaCl. As analogous changes were found in other myoclonic and epileptic patients receiving large doses of anticonvulsant drugs, these alterations in the GAG urinary pattern were not considered a primary disturbance of PME.

Urinary excretion of indican in progressive myoclonus epilepsy without Lafora bodies. The effect of sodium valproate.

Increased urinary excretion of indican was detected in earlier studies of patients with the form of progressive myoclonus epilepsy (PME) where no Lafora bodies are present in the brain and other tissues. Since then, all PME patients have been given sodium valproate and/or clonazepam. In a series of 10 patients now examined the mean excretion was on the same level as that of other epileptic and non-epileptic neurological patients (53 +/- 27 mg/g creatinine). Alternate reduction of the two drugs in one patient over a period of 24 days increased the excretion up to the high level measured earlier (96 mg/g creatinine) and caused marked worsening of the clinical condition while no remarkable changes were observed in another PME patient who received her normal medication. The highest values ever measured were found in one PME patient just before his death. In two patients who had no medication the excretion was also high but returned to the normal level during medication with sodium valproate. It is unknown at the moment whether this change is due to the improved clinical condition of the patients or to the compound itself.

Familial progressive myoclonic epilepsy. A clinical, genetical, biochemical and patho-anatomical study of a family with a 6-year follow-up.

Six siblings, including 4 cases of myoclonic epilepsy, their parents and 2 grandmothers were subjected to systematic investigation, and the patients were followed-up. The genetic studies revealed in the mother's family a patient with Lafora bodies demonstrated at autopsy. No chromosome abnormalities were found nor any linkage to the HLA system. The affected family members were characterized biochemically by an increased excretion of total glycosaminoglycans and/or an abnormal electrophoretic pattern of urinary glycosaminoglycans with an increased proportion of low-sulfated glycosaminoglycans. In the healthy family members this pattern of electrophoresis could also be demonstrated in the father and the paternal grandmother. Based on the biochemical results and the genetic studies it is suggested that the family members with progressive familial myoclonic epilepsy present a combination of at least 2 hereditary defects. The course of the disease has been relatively benign and treatment with sodium valproate, baclofen and clonazepam has shown quite satisfying results. In consequence of the biochemical findings combined treatment with A and E vitamins has been initiated.

Abnormal galactoside excretion in urine of a patient with early myoclonic epileptic encephalopathy.

An abnormal carbohydrate pattern was found in urine of a patient with early myoclonic epileptic encephalopathy. Three major oligosaccharides have been isolated from the urine; structural studies including sugar analyses, methylation procedure and enzymatic hydrolysis allow us to propose the following structures: beta-Gal-(1 leads to 3)-Gal beta-Gal-(1 leads to 3)-beta-Gal-(1 leads to 3)-Glc beta-Gal-(1 leads to 3)-beta-Gal-(1 leads to 3)-Gal Such oligosaccharide structures have not previously been described in any biological fluid. The origin of these compounds, and the possibility of a specific metabolic defect are discussed.

D-2-hydroxyglutaric aciduria in neonate with seizures and CNS dysfunction.

D-2-Hydroxyglutaric aciduria was documented in a newborn who presented with seizures, hypotonia, cortical blindness, a movement disorder, and developmental delay. Her clinical presentation differs from that of patients with L-2-hydroxyglutaric aciduria and a single previously reported patient with D-2-hydroxyglutaric aciduria. Cerebrospinal fluid levels of gamma-aminobutyric acid were elevated, while biogenic amine metabolites were normal. The movement disorder in our patient and in those with L-2-hydroxyglutaric aciduria suggests involvement of the basal ganglia in the disease process. Prenatal diagnosis of an affected fetus was accomplished during a subsequent pregnancy.

[Renal excretion of glycosaminoglycans under normal conditions and in several nervous system diseases in children]. / Pochechnaia ékskretsiia glikozaminoglikanov v norme i pri nekotorykh zabolevaniiakh nervoi sistemy u detei

The authors studied 101 children with diseases of the nervous system (with hereditary and acquired pathology) and 205 practically normal children. The urine excretion of specific components of the connective tissue (glycosaminoglycanes) was higher than in normals. Lesions of the connective tissue stroma in such forms of pathology is expressed not only in quantitative changes of glycosaminoglycane, but in their qualitative characteristics. Disturbances of the fractional compounds of glycosaminoglycane in the urine of patients differs from the parameters of chromatograms of normals by a high content of fractions of heparansulfate in a relatively low level of chondroethylsulfatolike fractions. In such states the severity of the clinical picture is accompanied by expressed metabolic disturbances.

Pyruvate metabolism in Lafora disease.

Lafora disease is an autosomal recessive and progressive degenerative disorder of the central nervous system (CNS). The pathogenic mechanism has been presumed to be an inborn error of carbohydrate metabolism, although this has never been proved. In a case of proven Lafora disease, pyruvate metabolism, which has a central position in carbohydrate metabolism, was studied in body fluids under various conditions and in brain biopsy material. No abnormalities in this metabolic pathway were found. This finding plus earlier reports in the literature exclude a defect in glycolysis; thus, a disturbance of carbohydrate metabolism as the pathogenic mechanism of Lafora disease is unlikely.

Normomorphic sialidosis in two female adults with severe neurologic disease and without sialyl oligosacchariduria.

Two female patients of German origin, aged 38 and 21 years, with myoclonus epilepsy and cerebellar ataxia, but without dysmorphic signs and dementia, were found to excrete normal amounts of sialyl oligosaccharides in their urine. The younger patient showed cherry red spots in her ocular fundi. The older patient had a brother with an autopsy-proven neuronal storage disease compatible with sialidosis, and in her rectal biopsy lamellar inclusion bodies were detected. Enzyme assays in cultured fibroblasts of both patients revealed a profound but incomplete deficiency of oligosaccharide sialidase activity and normal beta-galactosidase activity. Adult sialidosis was diagnosed in both patients. In their fibroblasts, moderate elevations of bound sialic acid could also be measured. The small residual sialidase activity, which in the older patient had a normal KM value, is considered responsible for the late onset and slow clinical course of the disease. It is concluded that in adult sialidosis the extraneural storage process can be difficult to demonstrate in terms of metabolite accumulation or excretion during the course of intraneuronal storage.

Content and composition of urinary glycosaminoglycans in the patients with myoclonus epilepsy with and without Lafora bodies.

Content, composition and molecular weight distribution of the urinary glycosaminoglycans (GAG) were determined in five patients with progressive myoclonus epilepsy (PME). In one patient (Family B) this syndrome was associated with cerebral Lafora bodies and in four siblings of Family A, no Lafora bodies were present in brain biopsy. Only one of the five patients had a moderate increase of urinary GAG excretion as expressed by 24-h output or creatinine. The heparan sulfate component of the GAG was moderately increased in two other patients. The molecular weight distribution of the urinary GAG was normal. The results do not support the contention that urinary GAG excretion is abnormal in PME. Among nine lysosomal enzymes in leucocytes, only the activity of alpha-mannosidase was increased 3-fold in the four siblings.