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A PARK8 form of Parkinson's disease (PD) is caused by a novel gene, leucine-rich repeat kinase 2 (LRRK2), and a single mutation G2019S was found in a proportion of LRRK2-associated cases of diverse ethnic origins. We performed the LRRK2 G2019S mutation analysis in 304 Russian patients with PD, including 291 sporadic and 13 autosomal dominant cases. The frequency of the LRRK2 G2019S was 0.7% amongst the sporadic patients (2/291) and 7.7% amongst familial PD (1/13). The mutation was also found in three unaffected relatives and absent in 700 control chromosomes. One patient carrying the LRRK2 G2019S was found earlier to have an additional mutation, a heterozygous duplication of exon 5 of the parkin gene. All patients carrying the LRRK2 G2019S exhibited typical levodopa-responsive parkinsonism, and severe levodopa-induced dyskinesia was observed in the patient carrying the LRRK2 and parkin mutations. There was notable variability in ages of the disease onset in G2019S carriers not explained by APOE genotypes. Two subsets of G2019S-positive patients had different PARK8 haplotypes suggesting that the LRRK2 G2019S in Russian patients had arisen independently on different chromosomes. Identification of common LRRK2 mutations in some PD patients without an overt family history has notable implications for genetic counseling.

A recently described form of Parkinson's disease - PARK8 - is caused by mutations in the novel LRRK2 gene on chromosome 12q12. The most common mutation in this gene is the substitution G2019S and we studied it for the first time in a large group of Russian Slavonic patients (311 patients) with Parkinson's disease including 295 sporadic and 16 familial cases. The mutation LRRK2-G2019S was identified in 1% of patients examined (3 cases) and was not found in a group of population control. The clinical picture of all patients with the LRRK2-G2019S mutation was typical for levodopa-responsive parkinsonism and age of disease onset varied widely (from 39 to 71 years). Two different PARK8-linked haplotypes were found in carriers of the mutation that suggested the independent origin of the G2019S mutation on different chromosomes. The identification of mutations in the LRRK2 gene in patients with "ordinary" sporadic Parkinson's disease has serious implications for medical genetic counseling and prognosis in respective families.

Nikolai V. Konovalov (1900-1966) has left a significant imprint in the history of Russian neuroscience. He was among the coryphaei of international and national neurology. Along with the large number of fundamental scientific papers that have determined several aspects of the development of neuroscience, his contribution has been equally important to the establishment and development of one of the distinguished Russian scientific centers - the Institute of Neurology of the Russian Academy of Medical Sciences, which he headed from 1948 until 1966.

The results of mirapex (pramipexol) treatment of 402 patients with Parkinson's disease and juvenile parkinsonism during the period from 6 months to 7 years are summarized. Mirapex was used in monotherapy as well as in combination with levadopa and other antiparkinsonic drugs. The drug was well tolerated and effective in rest tremor, hypokinesia, muscle rigidity and depression, the more pronounced effect being seen at the early stage of the disease. The use of mirapex allows an effective control of motor fluctuations developing during long-term continuous levodopa therapy. The results obtained characterize mirapex as a drug of choice in the treatment of juvenile parkinsonism. In case of a break in mirapex treatment, the recommencement of treatment usually is not accompanied by reduced sensitivity to drug effect.

The review summarizes the results of a decade of molecular genetic studies of several high-incidence hereditary neurodegenerative diseases, including primary parkinsonism, various forms of hereditary dystonia and ataxia, polyglutamine disorders, hepatolenticular degeneration, essential tremor, etc. Various relevant mutations were studied. The character and frequencies of particular mutations and the corresponding genetic disorders were established for the Russian population. Particular genotypes were associated with various clinical variants of the diseases. Genetic loci were identified for several unique hereditary diseases of the nervous system (X-linked cerebellar hypoplasia, an atypical form of autosomal recessive muscular dystrophy, etc.). Nosological positions of the relevant clinical forms were clarified on the basis of the molecular genetic data. Protocols were developed for direct or indirect DNA diagnostics of the diseases under study to improve medical genetic counseling and prevention of new disease cases in affected families.

Using cytochemical computerized morphometric method, activity of the key enzymes of energetic metabolism (succinate dehydrogenase, alpha-glycerophosphate dehydrogenase, malate dehydrogenase, glutamate dehydrogenase and lactate dehydrogenase) was studied in blood lymphocytes of 75 patients with Parkinson's disease and 15 healthy controls. The signs of systemic mitochondrial insufficiency, which correlated with the disease duration and severity, were found in all the patients, including those with juvenile parkinsonism. These data may provide a basis for introducing cytochemical monitoring as well as for administration of modern "mitochondrial" drugs (yantavit, coenzyme Q10, L-carnitine, etc).

The study aimed at evaluation of possibility and features of voluntary postural control learning using biofeedback from a force platform in patients with spinocerebellar ataxias. Thirty-seven patients with different forms of spinocerebellar degenerations and 13 age-matched healthy subjects were trained to shift the center of pressure (CP) during several stabilographic computer games which tested an ability to learn 2 different types of voluntary postural control: general strategy and precise coordination of CP shifting. Despite the disturbances of static posture and ability for voluntary control of CP position, patients with spinocerebellar degenerations can learn to control a vertical posture using biofeedback on stabilogram. In contrast to healthy subjects, improvement of coordination in the training process does not exert a significant influence on the static posture characteristics, in particular on lateral CP oscillations. The results obtained suggest involvement of the cerebellum in both types of postural control that distinguishes them from pathology caused by motor cortex and nigro-striatal system involved only in one type of postural control.

Clinical and genetic analysis of juvenile parkinsonism was performed in 26 sibs from 20 families. Heterogeneity of the disorder was observed. Mutations in the parkin gene (locus PARK2, chromosome 6q25.2-27), with the prevalence of deletions over point mutations, have been identified in 41%. The comparative clinical analyses of patients examined confirmed the phenotypical polymorphism of "parkinopathy". We also showed the absence of asymmetric manifestation--an important and underestimated so far sign of the disease. The results of the study may be considered as a valuable clue to the clinical diagnosis of parkin-related juvenile parkinsonism in Russian population and implemented for mutation screening and medico-genetic counseling of affected families.

A disturbance of postural control is one of the most invalidating symptoms of Parkinson's disease (PD), and mechanisms underlying its development have not been so far elucidated. To specify the postural control features in different PD forms, clinico-neurophysiological analysis was conducted in 61 patients divided into 3 groups according to PD forms: tremor-rigid, rigid-tremor and akinetic-rigid. Dissociation between clinical expression of postural instability and its stabilometric reflection--the square of statokinesogram was found, indicating importance of differentiated approach in performance of stabilometric analysis in patients with different PD forms. The square of statokinesogram may be regarded as a neurophysiological marker of postural instability only in patients with rigid forms, in tremor parkinsonian phenotypes an increased square of stabilogram being mainly a stabilometric reflection of tremor. The importance of stabilometric test performance with cognitive loading, allowing switching out of voluntary posture control, is shown. Possible neuromediator mechanisms involved in postural instability in PD are discussed.

Autosomal recessive juvenile parkinsonism (AR-JP) is a form of hereditary parkinsonism characterized by variable clinical presentations and caused by mutations in a novel gene, parkin, on chromosome 6q25.2-27. Until now, no Russian cases of parkin-associated AR-JP have been reported on. We recruited 16 patients from 11 Russian families with dopa-responsive movement disorders according to the following criteria: 1) family history compatible with autosomal recessive inheritance; 2) onset of symptoms at A). The majority of our parkin-associated cases were characterized by early-onset dopa-responsive parkinsonism with benign course and slow progression (5 patients from two families have been followed for as long as 18-36 years), and 1 patient had a phenotype of dopa-responsive dystonia. This first description of Russian patients with AR-JP and molecularly proven parkin mutations confirms the widespread occurrence of this polymorphic hereditary extrapyramidal disorder., (Copyright 2003 Movement Disorder Society)

Essential tremor (ET) is the most common extrapyramidal disorder of the central nervous system with autosomal dominant transmission in the majority of cases and age-dependent penetrance of the mutant gene. In a number of cases, it shares some phenotypic features with autosomal dominant idiopathic torsion dystonia (locus DYT1 on chromosome 9q32-34) and is genetically heterogeneous: distinct variants of ET were mapped to chromosomes 3q13 (ETM1) and 2p22-25 (ETM2). We performed studies of candidate loci in a group of Slavonic (11 patients) and Tajik (19 patients) families with ET. Mutational analysis of the DYT gene in probands did not reveal the major deletion 946-948delGAG characteristic of idiopathic torsion dystonia, which allows one to genetically distinguish the studied hereditary forms of ET and torsion dystonia. Based on analysis of genetic linkage in informative Tajik pedigrees with ET, linkage to locus ETM1 on chromosome 3q13 was established in four families. Maximum pairwise Lod score was 2.46 at recombination fraction of theta = 0.00; maximum combined multipoint Lod score was 3.35 for marker D3S3720 and a common "mutant" haplotype for markers D3S3620, D3S3576, and D3S3720 allowed us to locate a mutant gene in a relatively narrow chromosome region spanning 2 cM. In one informative pedigree with ET, both candidate loci ETM1 and ETM2 were definitely excluded on the basis of negative Lod scores obtained by linkage estimations, which testifies to the existence of another distinct gene for autosomal dominant ET.

Kuhns' indirect immunofluorescent test was used to study fixation of serum brain antibodies (Ab) of patients with bulbar, cervicothoracic, lumbosacral lateral amyotropic sclerosis (LAS) on brain sections of rabbits. The disease is characterized by formation of brain Ab complementary to various structures of nervous and glial cells, myelin of fibers from different conducting systems, vessels which exhibit both common and individual antigenic properties. It was found that fixation of antineuronal, antimyelin brain Ab of patients with bulbar, cervicothoracic and lumbosacral LAS in different CNS structures varies.

The article describes a case of homocarnosinemia with increased liquor and plasma content of homocarnosine, increased urinary excretion of homocarnosine, and low activity of serum carnosinase. These metabolic disturbances were accompanied by moderate neurological disorders. Changes in carnosine metabolism in family members were less pronounced and not accompanied by neuropathological symptoms.

Hepatolenticular degeneration (HLD) is a severe autosomal-recessive disorder of the copper metabolism. It is characterized by excessive accumulation of copper in the brain and in viscera and is conditioned by the damage in the gene of copper ATP-ase (ATP7B). The paper presents the results of screening of ATP7B gene mutation in 42 patients with HLD from Russian population. The regions of ATP7B gene that are the most frequently exposed to the mutation have been studied (the exzones 14, 15, 16, 18). It is demonstrated that A-->C mutation in the 14-th exzone that led to the change of histidine1069 amino acid for glutamine, was found in more than 60% of patients--Slavs from the European Russia. This mutation was observed in both homo- and heterozygous states. The deletion of (CCC-->CC) nucleotide in the 15-th exzone of the gene was observed in 2 cases. The detailed analysis of the clinical-genetic correlations was performed in patients with the determined damages of ATP7B gene. In Russia the experience of the direct DNA-diagnosis of HLD is described for the first time. It is significant for early evaluation of the patients in preclinical state and for prescription of the preventive copper-eliminating therapy.

Two novel protein antigens-Hbmp-1 and Hbmp-2 have been isolated from human brain tissue. Test-systems for determining auto-antibodies (a-Ab) to above mentioned proteins, as well as to basic myelin protein, S-100 beta and glial fibrillary acid protein have been developed. Sixty-three HLD patients have been examined. Increased a-Ab levels to the novel proteins has been shown in HLD patients; no difference between HLD patients and control groups being found for a-Ab levels to other proteins. Correlation has been observed between a type and course of the disease, on the one hand, and a-Ab levels to Hbmp-1 and to Hbmp-2, on the other hand.

Limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM) are autosomal recessive disorders caused by mutations in the dysferlin gene on chromosome 2p13. The authors studied a large Russian family with both LGMD2B and MM. All affected individuals, as well as one preclinical boy with dystrophic changes on muscle biopsy, were found to be homozygous for a novel dysferlin mutation, TG573/574AT (Val67Asp). This finding supports the view that additional factors (e.g., modifier genes) contribute to the phenotypic expression of causative mutations in dysferlinopathies.

We examined a large Turkmen family with 'pseudo-dominant' inheritance of Friedreich's ataxia resulting from consanguineous marriage of a Friedreich's ataxia patient to a heterozygote carrying an ancestral mutated allele. Two distinct phenotypes of the disease co-segregated within this genealogy. Two brothers from the younger generation exhibited 'classical' Friedreich's ataxia with onset of symptoms before 10 years and a rapidly progressive course. In contrast, three patients (two sisters from the younger generation and their father) had a more benign phenotype of late-onset Friedreich's ataxia with the onset at 26, 45 and 48 years and slow progression over decades. The patients with 'classical' Friedreich's ataxia were homozygous for a common ancestral expanded allele of the X25 gene containing 700-800 GAA repeats, while the patients with late-onset Friedreich's ataxia had two different mutated alleles, the shorter 250-repeat expansion of paternal origin and the longer 700-repeat expansion of maternal origin. One may conclude that clinical variability of Friedreich's ataxia in our patients is accounted for predominantly by a modifying effect of one of the two (shorter or longer) expanded alleles inherited from their affected father. Our observation clearly demonstrates the significance of variable-sized alleles for the phenotypic expression of the disease.

For the first time in Russia, analysis of the GCH-I and DYT1 genes was carried out for the purpose of direct DNA diagnostics in families with various forms of hereditary torsion dystonia (TD). Four new missense mutations (Met102Lys, Thr94Lys, Cys141Trp, and Ser176Thr) in the GCH-I gene were found in patients with dopa-responsive dystonia (DRD), testifying to a genetic heterogeneity of this clinical form of TD. The distribution of the major del GAG mutation in exon 5 of the DYT1 gene was studied in patients with non-dopa-responsive dystonia (NDRD). In total, the mutation was found in 68% of the patients. The frequency of this mutation in Ashkenazi Jews with NDRD was 100% (twice higher than in Slavonic families), suggesting the founder effect reported for NDRD in this ethnic group. Mutations of the GCH-I and DYT1 genes were also found in patients with atypical and questionable cases of TD, which are difficult to diagnose with methods other than DNA analysis. The data obtained made it possible to extend the spectrum of clinical signs of DRD and NDRD and to revise the views on true penetrance of the corresponding mutant genes, which is important for medical genetic counseling in affected families.

18 patients with hepatolenticular degeneration (Wilson's disease, WD) aged 15-38 years were subjected to an overall clinical and neurophysiologic examinations. As a result, the data obtained enable to evaluate functional reserves of CNS of the WD patients in correlation with the illness duration and severity of neurologic symptoms. Correlation between an increase of interpeak I-V and the degree of neurological deficit and, also, level of ceruloplasmin was established (r = -0.45; p < 0.05). Correlation between an increase of latency P300 and the degree of manifestation of neurologic symptoms was identified as well (r = 0.63; p < 0.05). Positive dynamics of evoked potentials was followed in 4 WD patients during copper-eliminative drugs treatment.

A gene for X-linked congenital cerebellar hypoplasia was recently localized to chromosome Xp11.21-q24. This region comprises several brain-specific genes responsible for various neurological disorders, including the proteolipid protein (PLP), doublecortin, and PAK3 genes. We screened these genes for mutations in patients with X-linked congenital cerebellar hypoplasia and found no pathogenic nucleotide changes or gene dose alterations. These findings allow the ruling out of PLP, doublecortin, and PAK3 as the disease-causing genes in this hereditary neurological syndrome.

Hereditary torsion dystonia represent a clinically and genetically heterogeneous group of movement disorders. The most severe and frequent form of hereditary torsion dystonia is early-onset generalized dystonia, DYT1. The DYT1 gene (Ozelius et al., 1997) encodes an ATP-binding protein torsin A. A unique 3-bp deletion (GAG) was found in the heterozygous state in almost all patients with early-onset dystonia from different populations. We observed 39 patients with early-onset generalized torsion dystonia belonging to 22 families from Russia. Seven families were of Ashkenazi Jewish (AJ) ethnic background, and other patients originated from the Slavonic population of Russia. The GAG deletion was identified in 24 affected persons from 15 families (68.2% of the families studied). In all the 7 families of AJ origin the disease was found to be caused by the deletion. In Slavs, the deletion was identified in 8 of 15 families (53%). In two deletion-positive families we observed the co-occurrence of typical early-onset generalized dystonia and atypical phenotypes-either isolated postural hand tremor or stutter., (Copyright 1999 Wiley-Liss, Inc.)

We examined a large family of Ashkenazi Jewish origin with autosomal dominant dopa-responsive dystonia (DRD). Mutation analysis of the GTP cyclohydrolase I gene revealed in affected members a novel point mutation (a C/A change in exon 1) resulting in a threonine-to-lysine substitution at residue 94. The mutation was characterized by variable expressivity and was associated with either a 'classical' DRD phenotype or various atypical phenotypes, such as subtle transitory equinovarus postures of the feet or isolated hand tremor. This observation demonstrates the significance of the molecular testing in establishing the clinical diagnosis of DRD., (Copyright Lippincott Williams & Wilkins)