Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy.

We report on clinical, histological and genetic findings in two patients carrying novel heteroplasmic mutations in the mitochondrial cytochrome c oxidase subunit genes COII and COIII. The first patient, a 35 year-old man had a multisystemic disease, with clinical symptoms of bilateral cataract, sensori-neural hearing loss, myopathy, ataxia, cardiac arrhythmia, depression and short stature and carried a 7970 G>T (E129X) nonsense mutation in COII. A sudden episode of metabolic encephalopathy caused by extremely high blood lactate lead to coma. The second patient developed exercise intolerance and rhabdomyolysis at age 22 years. A heteroplasmic missense mutation 9789 T>C (S195P) was found in skeletal muscle, but not in blood and myoblasts pointing to a sporadic mutation. Our report of two patients with isolated COX deficiency and new mutations in COX subunit genes may help to draw more attention to this type of mtDNA defects and provide new aspects for counselling affected families.

An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients.

Autosomal dominant spinocerebellar ataxias (SCA) form a group of clinically and genetically heterogeneous neurodegenerative disorders. The defect responsible for SCA3/Machado-Joseph disease (MJD) has been identified as an unstable and expanded (CAG)n trinucleotide repeat in the coding region of a novel gene of unknown function. The MJD1 gene product, ataxin-3, exists in several isoforms. We generated polyclonal antisera against an alternate carboxy terminus of ataxin-3. This isoform, ataxin-3c, is expressed as a protein of approximately 42 kDa in normal individuals but is significantly enlarged in affected patients confirming that the CAG repeat is part of the ataxin-3c isoform and is translated into a polyglutamine stretch, a feature common to all known CAG repeat disorders. Ataxin-3 like immunoreactivity was observed in all human brain regions and peripheral organs studied. In neuronal cells of control individuals, ataxin-3c was expressed cytoplasmatically and had a somatodendritic and axonal distribution. In SCA3 patients, however, C-terminal ataxin-3c antibodies as well as anti-ataxin-3 monoclonal antibodies (1 H9) and anti-ubiquitin antibodies detected intranuclear inclusions (NIs) in neuronal cells of affected brain regions. A monoclonal antibody, 2B6, directed against an internal part of the protein, barely detected these NIs implying proteolytic cleavage of ataxin-3 prior to its transport into the nucleus. These findings provide evidence that the alternate isoform of ataxin-3 is involved in the pathogenesis of SCA3/MJD. Intranuclear protein aggregates appear as a common feature of neurodegenerative polyglutamine disorders.

Onuf's nucleus is frequently involved in motor neuron disease/amyotrophic lateral sclerosis.

Involvement of Onuf's nucleus (ON) in 28 cases of amyotrophic lateral sclerosis/motor neuron disease (MND/ALS) with different clinical syndromes is reported. Although significant neuronal loss was absent, all cytoskeletal abnormalities typical of alpha-motor neurons in MND/ALS were found in ON. Spheroids were detected in 53.5% of cases; 0.6-4.5% of ON neurons contained Bunina bodies, which were present in 42.8% of cases. Ubiquitin-reactive inclusions (UBRI) of filamentous and hyaline type were found in 57.1% of cases and in 1.2-10.7% of ON neurons. Cases with pyramidal tract involvement (ALS) were involved by UBRI in 76.5%, whereas cases with progressive spinal muscular atrophy revealed the same inclusions in only 27.2%. No similar inclusions were present in sacral parasympathetic intermediolateral nucleus. It can be concluded, therefore, that ON belongs to the somatic motor system and is principally vulnerable to MND/ALS, albeit to a lower degree.

[Coma polyneuropathy after cardiopulmonary resuscitation]. / Komapolyneuropathie nach kardiopulmonaler Reanimation.

A 60 year old female patient developed an acute polyneuropathy a few days after a successful cardiopulmonary reanimation followed by coma for several days. Recovery was good as demonstrated at one year follow-up. Residual damage consisted in very mild myoclonic jerks (abortive Lance-Adams syndrome).

Ventricular meningiomas--report of 4 cases.

Four cases of rarely occurring meningiomas of the lateral ventricles are reported. These tumors are said to originate from meningeal cell clusters that have been mislocated during embryonal development. Patients of clinical history, diagnostic and surgical findings, and the postoperative course are described, with special emphasis on tumor growth aspects.

Cystic kidneys. Genetics, pathologic anatomy, clinical picture, and prenatal diagnosis.

According to the classification of Osathanondh and Potter of cystic kidneys we give an overview of the different types of cystic changes taking genetic aspects into account. Usually pathoanatomic types do not represent genetic entities: All type I kidneys are transmitted in an autosomal recessive way with varying clinical symptoms; in rare cases they even present in adults. The relationship to "congenital hepatic fibrosis", "cystic liver", and to the "Caroli syndrome" is discussed. Type II kidneys are usually not genetic in origin; but they may occur as part of several syndromes. Rarely genetic factors might contribute to type II kidneys that may present as familial cases of Potter syndrome ("renal non-function syndrome"). Type IV kidneys, although different in their pathoanatomic picture can be regarded according to a common pathogenetic theory as part of the spectrum of malformations as in type II. Therefore the genetic interpretation of type II kidneys also applies to type IV lesions. Type III kidneys include autosomal dominant polycystic kidney disease. This type may already present in childhood; the first prenatal diagnosis by ultrasonography is described in detail. Furthermore type III changes are part of syndromes or non-hereditary malformation complexes, and often present only as mild manifestations. Diseases with isolated involvement of the medulla (juvenile nephronophthisis/medullary cystic disease) or cortex are described as part of the differential diagnosis, they are heterogeneous and genetically only partly understood. Syndromes with cystic kidneys are reviewed as well as the possibilities of prenatal diagnosis of cystic diseases. Reliable prenatal diagnosis is only possible in type II, and possible in some of the other types. The nosology is improved if genetic information is taken into account.

Effects of dithiocarb and (+)-catechin against carbon tetrachloride-alcohol-induced liver fibrosis.

Treatment of male rats with carbon tetrachloride (CCl4, 2 x weekly 0.2 ml/kg p.o.) and a 5% alcohol solution, instead of drinking water, for 4 weeks led to marked increases in serum enzyme activities (GOT, GPT, SDH), hepatic triglyceride and hydroxyproline content. Diethyl dithiocarbamate (dithiocarb, 200 mg/kg p.o.) simultaneously applied with CCl4 totally suppressed the elevation in serum enzyme activities and hepatic hydroxyproline concentration, and partially suppressed that of the triglyceride content. (+)-Catechin (50-300 mg/kg p.o.) simultaneously applied with CCl4 had no influence on the enhanced serum enzymes, but depressed the augmented content of both hepatic triglyceride and hydroxyproline in a dose-dependent way. The most effective dose with respect to the reduction of the hydroxyproline concentration was 100 mg/kg (+)-catechin; the highest dose (300 mg/kg), however, enhanced the CCl4-alcohol-induced hydroxyproline augmentation.

Studies on the mechanism of paracetamol-induced protection against paracetamol hepatotoxicity.

In rats, 3 days treatment with paracetamol (1 oral dose of 1 g/kg daily) produced a complete protection against the hepatotoxic actions of a further dose of paracetamol as documented by determination of serum enzyme activities (glutamic-oxaloacetic transaminase, (GOT), glutamic-pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), bromsulphthalein retention and histological investigations. Subacute paracetamol treatment decreased liver glutathione levels by 46%, liver microsomal cytochrome P-450 content by 23%, hepatic hydroxylation of aniline by 29% and hepatic demethylation of aminopyrine by 46%. It afforded also some protection against the hepatotoxic actions of carbon tetrachloride, bromobenzene and thioacetamide, but did not influence the antiphlogistic activity of paracetamol (carrageenan paw edema test). Plasma and liver concentrations of free paracetamol after oral administration of 1 g/kg paracetamol were somewhat higher in the subacutely paracetamol-pretreated rats than in the non-pretreated control animals whereas no differences in the concentrations of conjugated paracetamol were found between the 2 groups. Pretreatment with paracetamol did not influence the urinary excretion of free paracetamol but caused some shift in the urinary excretion of paracetamol conjugates: pretreated rats excreted 23% less of the paracetamol glucuronide and sulfate and 33% more of the paracetamol mercapturate than the control animals. A depression of the microsomal mixed-function oxidase activity is presumed to be the main cause of the paracetamol-induced protection against paracetamol hepatotoxicity.