Evidence for the synthesis of an unusual high spin (S = 7/2) [Cu-3Fe-4S] cluster in the radical-SAM enzyme RSAD2 (viperin).

We demonstrate the synthesis and spectroscopic characterization of an unusual high spin (S = 7/2) [Cu-3Fe-4S] cluster in a member of the radical-SAM enzymes. This is the first step in using synthetic [Me-3Fe-4S] clusters for obtaining new insight into the mechanism of radical-SAM catalysis.

A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain.

BACKGROUND: More than 4 million children are exposed annually to sedatives and general anaesthetics (GAs) in the USA alone. Recent data suggest that common GAs can be detrimental to brain development causing neurodegeneration and long-term cognitive impairments. Challenged by a recent US Food and Drug Administration (FDA) warning about potentially neurotoxic effects of GAs in children, there is an urgent need to develop safer GAs. METHODS: Postnatal Day 7 (P7) rat pups of both sexes were exposed to six (repeated every 2 h) injections of equipotent hypnotic doses of ketamine or the neuroactive steroid (3ß,5ß,17ß)-3-hydroxyandrostane-17-carbonitrile (3ß-OH) for 12 h. Loss of righting reflex was used to assess hypnotic properties and therapeutic index; quantitative caspase-3 immunohistochemistry was used to assess developmental neuroapoptosis; patch-clamp recordings in acute brain slices were used to assess the effects of 3ß-OH on neuronal excitability and synaptic transmission. Cognitive abilities of rats exposed to ketamine, 3ß-OH, or vehicle at P7 were assessed in young adulthood using the radial arm maze. RESULTS: The neuroactive steroid 3ß-OH has a therapeutic index similar to ketamine, a commonly used clinical GA. We report that 3ß-OH is safe and, unlike ketamine, does not cause neuroapoptosis or impair cognitive development when administered to P7 rat pups. Interestingly, 3ß-OH blocks T-type calcium channels and presynaptically dampens synaptic transmission at hypnotically-relevant brain concentrations, but it lacks a direct effect on γ-aminobutyric acid A or glutamate-gated ion channels. CONCLUSIONS: The neurosteroid 3ß-OH is a relatively safe hypnotic that warrants further consideration for paediatric anaesthesia.

Painful Diabetic Neuropathy: Prevention or Suppression?

Pain-sensing sensory neurons (nociceptors) of the dorsal root ganglia (DRG) and dorsal horn (DH) can become sensitized (hyperexcitable) in response to pathological conditions such as diabetes, which in turn may lead to the development of painful peripheral diabetic neuropathy (PDN). Because of incomplete knowledge about the mechanisms underlying painful PDN, current treatment for painful PDN has been limited to somewhat nonspecific systemic drugs that have significant side effects or potential for abuse. Recent studies have established that several ion channels in DRG and DH neurons are dysregulated and make a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of nociceptors in animal models of type 1 and type 2 PDN. Furthermore, it has been reported that targeting posttranslational modification of nociceptive ion channels such as glycosylation and methylglyoxal metabolism can completely reverse mechanical and thermal hyperalgesia in diabetic animals with PDN in vivo. Understanding details of posttranslational regulation of nociceptive channel activity may facilitate development of novel therapies for treatment of painful PDN. We argue that pharmacological targeting of the specific pathogenic mechanism rather than of the channel per se may cause fewer side effects and reduce the potential for drug abuse in patients with diabetes.

Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations.

PURPOSE: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease characterized by impaired adrenal steroidogenesis and most often caused by CYP21A2 gene mutations. For the first time, we reported complete spectrum and frequency of CYP21A2 gene mutations in 61 unrelated patients with classical and non-classical CAH from Serbia. METHODS: Direct DNA sequencing of whole CYP21A2 gene and polymerase chain reaction with sequence-specific primers for detection of CYP21A1P/CYP21A2 chimeras were combined. RESULTS: We identified 18 different pathogenic alleles-two of them novel. Mutation detection rate was highest in patients with salt-wasting form of CAH (94.7%). The most prevalent mutation was intron 2 splice site mutation, c.290-13A/C>G (18.5%). Other mutation frequencies were: CYP21A1P/CYP21A2 chimeras (13%), p.P30L (13%), p.R356W (11.1%), p.G110fs (7.4%), p.Q318X (4.6%), p.V281L (4.6%), p.I172N (2.8%), p.L307fs (2.8%), p.P453S (1.9%), etc. Mainly, frequencies were similar to those in Slavic populations and bordering countries. However, we found 6.5% of alleles with multiple mutations, frequently including p.P453S. Effects of novel mutations, c.386T>C (p.Leu129Pro) and c.493T>C (p.Ser165Pro), were characterized in silico as deleterious. The effect of well-known mutations on Serbian patients' phenotype was as expected. CONCLUSIONS: The first comprehensive molecular genetic study of Serbian CAH patients revealed two novel CYP21A2 mutations. This study will enable genetic counseling in our population and contribute to better understanding of molecular landscape of CAH in Europe.

Intellectual ability in the duchenne muscular dystrophy and dystrophin gene mutation location.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70

Immunohistological demonstration of CaV3.2 T-type voltage-gated calcium channel expression in soma of dorsal root ganglion neurons and peripheral axons of rat and mouse.

Previous behavioral studies have revealed that CaV3.2 T-type calcium channels support peripheral nociceptive transmission and electrophysiological studies have established the presence of T-currents in putative nociceptive sensory neurons of dorsal root ganglion (DRG). To date, however, the localization pattern of this key nociceptive channel in the soma and peripheral axons of these cells has not been demonstrated due to lack of isoform-selective anti-CaV3.2 antibodies. In the present study a new polyclonal CaV3.2 antibody is used to localize CaV3.2 expression in rodent DRG neurons using different staining techniques including confocal and electron microscopy (EM). Confocal microscopy of both acutely dissociated cells and short-term cultures demonstrated strong immunofluorescence of anti-CaV3.2 antibody that was largely confined to smaller diameter DRG neurons where it co-localized with established immuno-markers of unmyelinated nociceptors, such as, CGRP, IB4 and peripherin. In contrast, a smaller proportion of these CaV3.2-labeled DRG cells also co-expressed neurofilament 200 (NF200), a marker of myelinated sensory neurons. In the rat sciatic nerve preparation, confocal microscopy demonstrated anti-CaV3.2 immunofluorescence which was co-localized with both peripherin and NF200. Further, EM revealed immuno-gold labeling of CaV3.2 preferentially in association with unmyelinated sensory fibers from mouse sciatic nerve. Finally, we demonstrated the expression of CaV3.2 channels in peripheral nerve endings of mouse hindpaw skin as shown by co-localization with Mrgpd-GFP-positive fibers. The CaV3.2 expression within the soma and peripheral axons of nociceptive sensory neurons further demonstrates the importance of this channel in peripheral pain transmission.

Unusual suicide with a chainsaw.

A 39-year-old male, with a history of multiple suicidal attempts and psychiatric pathology, a professional lumberjack, was found dead at the meadow with his throat cut and a chainsaw beside him. Autopsy revealed that all physical injuries were confined to the head, neck and left shoulder. Two major (long and wide) wounds were found and documented on both sides of the neck and head. A wound on the posterior and right lateral side of his neck and head was noted. Medical examiner noted an irregular rupture on the posterior-right side of the atlanto-occipital joint with impaired bone, but without any damage on the spinal cord. Another gaping cut was noted in the lower part on the left lateral side of his neck. Medical examiner noted that muscles of the left side of the neck, left common carotid artery, left internal jugular vein and left vagus nerve were completely cut off. The body of the C5 and C6 vertebra, with the spinal cord at that level, was completely cut. Also, there were multiple linear and striped parallel abrasions on the outer side of the left shoulder and one abrasion on the left lateral side of the neck. The conclusion of inquiries was "suicide by chainsaw".

Type 2 diabetes mellitus and impaired glucose regulation in overweight and obese children and adolescents living in Serbia.

An increase in the prevalence of pediatric type 2 diabetes mellitus (T2DM) has been reported by numerous studies in the United States during the past two decades. Available data from Europe are scarce, but also suggest the rising prevalence of this disease in overweight children. The aim of this study was to determine the prevalence of previously undiagnosed T2DM, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a clinic cohort of otherwise healthy overweight and obese Caucasian children and adolescents living in Serbia. The study group consisted of 301 subjects (176 girls, 125 boys) aged 5.2-18.9 years, with body mass index >90th percentile. Oral glucose tolerance test was performed in all subjects. Previously undiagnosed T2DM was discovered in 0.3% (n=1) and impaired glucose regulation in 15.9% (n=48) of the subjects. Isolated IFG was detected in 4.3% (n=13), isolated IGT in 8.3% (n=25) and combined IFG and IGT in 3.3% (n=10) of the subjects. Disturbances of glucose metabolism were present in a substantial number of the subjects, which emphasizes the need for prevention and treatment of childhood obesity.

Epidemiology of Charcot-Marie-Tooth disease in the population of Belgrade, Serbia.

BACKGROUND: The aim of this study was to determine prevalence and 15-year survival in Charcot-Marie-Tooth disease (CMT). METHODS: The study covers the period from 1 January 1988 to 31 December 2007 in the territory of Belgrade. Data on a number of CMT-affected persons and their basic demographic characteristics as well as data on the disease were collected from medical records. Data on the course and outcome of the disease were obtained through direct contact with patients, their families and their physicians. RESULTS: We registered 161 patients with CMT in the population of Belgrade. The most frequent type was CMT1. The crude prevalence of CMT disease in the Belgrade population on 31 December 2007 was 9.7/100,000 for all subtypes, 7.1/100,000 for CMT1, and 2.3/100,000 for CMT2. Gender-specific prevalence was 11.2/100,000 for males and 8.3/100,000 for females. The highest age-specific prevalence was registered in the oldest age group (75+ years; 19.1/100,000), and the lowest one in patients aged 5-14 years (5.0/100,000). The cumulative probability of 15-year survival for CMT patients in Belgrade was 85.6 ± 7.8% (44.9 ± 31.8% for males and 98.2 ± 1.8% for females). CONCLUSIONS: The prevalence of CMT found in Belgrade is similar to the prevalence registered in Southern European countries.

[What do we know about anesthetic mechanisms?: hypnosis, unresponsiveness to surgical incision and amnesia]. / Was wissen wir über Narkosemechanismen? : Bewusstlosigkeit, Bewegungslosigkeit und Amnesie.

Despite the increase of molecular knowledge in anesthesia research over the past decades there is still ongoing discussion about the mechanisms of anesthesia. This article focuses on presenting anesthetic sensitive ligand and voltage gated ion channels. The impact on anesthetic modulated ion channels is summarized for clinically commonly used anesthetics isoflurane, propofol and ketamine. Furthermore, the anesthetic features hypnosis, unresponsiveness to surgical incision and amnesia and their putative relevant anatomical sites in the central nervous system are briefly introduced.

Fragmentation of axillary fibrofatty tissue during dissection facilitates preservation of the intercostobrachial nerve and the lateral thoracic vein.

The preservation of neurovascular elements passing through the axillary fibrofatty tissue (the intercostobrachial nerve and the lateral thoracic vein) could be techniqually demanding if an en bloc axillary dissection is performed in the conventional way. In this paper we describe a surgical technique for more successful preservation of these elements, by which fragmentation of the axillary fibrofatty tissue is planned and performed "in advance". The techniques of axillary sampling biopsies, where lymphatic vessels are always divided, have shown that cutting of the lymph routes does not increase the risk of local regional recurrence. After adopting and applying this technique in a series of 22 consecutive dissections, the nerve was spared in 22 patients (100%) (compared to an earlier series where the nerve was spared in 53 of 65 patients (81.5%)), while the vein was spared in 21 patients (95%) (earlier 22 of 65 patients (34%)).

Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations.

OBJECTIVE: Congenital myasthenic syndromes (CMS) with underlying RAPSN mutations turned out to be of high clinical relevance due to their worldwide frequency. To date, all reported patients with CMS with sequence variations in the translated region of RAPSN carry the mutation N88K on at least one allele. The authors report two patients lacking the common N88K allele but harboring differing novel mutations of the RAPSN gene on both alleles: one patient is homozygous for a missense mutation (R164C); the second patient is compound heterozygous for a splice (IVS1-15C>A) and another missense mutation (L283P). METHODS: The authors analyzed the RAPSN gene for sequence variations and carried out in vitro studies in order to delineate the potential pathogenicity of the three novel RAPSN mutations. RESULTS: For the putative splice mutation (IVS1-15C>A), the authors constructed wild-type and mutated RAPSN minigenes for transfection and subsequent RNA analysis. The mutation generates a novel acceptor splice site leading to retention of 13 nucleotides of intron 1 in the mature mRNA and subsequently to a frameshift transcript. Cotransfection of wild-type AChR subunits with RAPSN-constructs carrying R164C and L283P indicate that both mutations diminish coclustering of AChR with rapsyn. CONCLUSIONS: Screening for the common mutation RAPSN N88K facilitates targeted genetic analysis in congenital myasthenic syndromes. However, absence of a N88K allele does not exclude underlying RAPSN mutations as cause of the congenital myasthenic syndromes. Sequencing of the entire gene may be considered in patients with joint contractures and respiratory problems even in the absence of the mutation N88K.

The role of T-type calcium channels in epilepsy and pain.

T-type calcium channels open in response to small depolarizations of the plasma membrane. The entry of two positive charges with every calcium ion leads to a further depolarization of the membrane, the low threshold spike, and opening of channels that have a higher threshold. In this manner, T-channels play an important pacemaker role in gating the activity of Na+ and Ca2+ channels. T-channels are preferentially expressed in dendrites, suggesting they play important roles in synaptic integration. Pharmacological evidence indicates that they are expressed in the receptive fields of sensory neurons, suggesting they play a primary role in nociception. Molecular cloning of the three T-channel genes has allowed detailed studies on their channel properties, pharmacology, distribution in the brain, up-regulation in animal models of disease, and provided the tools to screen for novel drugs. Studies on transgenic animals have provided the proof-of-concept that T-channels are important drug targets for the treatment of absence epilepsy and neuropathic pain. Mutations in ion channel genes, or channelopathies, have been found in many diseases. Similarly, T-channel gene mutations have been found in patients with childhood absence epilepsy. Considering the important role T-channels play in the thalamus, it is likely that T-channel mutations also contribute to a wider range of disorders characterized by thalamocortical dysrhythmia.

Survival and mortality of myotonic dystrophy type 1 (Steinert's disease) in the population of Belgrade.

The purpose of this investigation was to determine survival and mortality in patients with myotonic dystrophy type 1 (DM1) in the Belgrade population within the period from 1983 to 2002. Data of a number of diagnosed DM1 patients with their demographic, clinical and genetic characteristics were gathered from hospital records in all neurologic institutions in Belgrade for the period 1983-2002. Death certificates were reviewed to determine the cause of death. Survival analysis by life table method and Cox proportional hazard model was performed. Within the observed period, in the population of Belgrade, 15 fatal outcomes among 101 patients with DM1 were registered. Average DM1 mortality rate was 0.5/1,000,000 (95% CI 0.3-0.8), and standardized mortality ratio (SMR) was 5.3. A significant inverse correlation was found between age at onset of DM1 and CTG repeats (P=0.023). The cumulative probability of 15-year survival for DM1 patients in Belgrade was 49+/-5% (48+/-2% for males and 50+/-7% for females). Younger age at onset was a significant unfavorable prognostic factor (hazard ratio=4.2; P=0.012).

5alpha-reduced neuroactive steroids alleviate thermal and mechanical hyperalgesia in rats with neuropathic pain.

5alpha-reduced neuroactive steroids with selective modulatory action in vitro on T or combined modulatory action on T and GABA(A) currents present in peripheral sensory neurons have been shown to induce potent peripheral analgesia in vivo in intact animals. Although the role of T and GABA(A) currents in pathophysiology of neuropathic pain (NPP) is not established, it appears that blockade of T currents and/or potentiation of GABA(A) currents could be beneficial in the management of NPP. To study the potential usefulness of 5alpha-reduced neuroactive steroids in alleviating NPP, we selected two newly synthesized steroids-ECN and CDNC24-with a selective blocking effect on T currents and a selective potentiating effect on GABA(A) currents, respectively, and commercial analogs-alphaxalone and 3alpha5alphaP-with the effects on both ion channels. We used a sciatic nerve ligation model to induce thermal and mechanical hyperalgesia in adult rats and tested peripheral thermal and mechanical nociception following local injection of neuroactive steroids into the peripheral receptive fields of a ligated hind paw. We found that 5alpha-reduced neuroactive steroids alleviate thermal and mechanical hyperalgesia in NPP rats. ECN and CDNC24 were more selective in alleviating thermal nociception in NPP than in sham animals when compared to 3alpha5alphaP and alphaxalone although the anti-nociceptive effect induced by 3alpha5alphaP and alphaxalone was more profound. CDNC24 was most selective since it had very minimal anti-nociceptive effect in sham animals but a very profound anti-nociceptive effect in NPP animals suggesting that, under pathological conditions, peripheral GABA(A) receptors might be an attractive therapeutic target.

Haplotype analysis of the DM1 locus in the Serbian population.

OBJECTIVES: Analysis of the CTG-repeat number and three biallelic markers, Alu(+/-), HinfI(+/-), and TaqI(+/-), in the DMPK gene in healthy and myotonic dystrophy type 1 (DM1) Serbian individuals. Also, the consideration of haplotypes in the light of the proposed models of CTG-repeat evolution and origin of the DM1 mutation. MATERIALS AND METHODS: Markers were analyzed by PCR and haplotypes were obtained on 203 unrelated normal chromosomes and 24 unrelated DM1 chromosomes. RESULTS: A strong linkage disequilibrium was detected between the three biallelic markers alone (P <0.0001) and between distinct CTG-repeat size classes and reconstructed haplotypes. Greater than 98% of normal chromosomes contain (+++) and (- - -) haplotypes. The (+++) haplotype is the most common, while the (CTG)(9-17) are the most frequent alleles. We found a complete association of (+++) haplotype with (CTG)(> or =18) and mutated alleles. CONCLUSIONS: (CTG)(9-17)/(+++) haplotype is the ancestral haplotype and DM1 mutation occurred on (CTG)(18-35)/+++ chromosome.

Ca(v)3.2 channel is a molecular substrate for inhibition of T-type calcium currents in rat sensory neurons by nitrous oxide.

Although nitrous oxide (N(2)O; laughing gas) remains widely used as an anesthetic and analgesic in clinical practice, its cellular mechanisms of action remain inadequately understood. In this report, we examined the effects of N(2)O on voltage-gated Ca(2+) channels in acutely dissociated small sensory neurons of adult rat. At subanesthetic concentrations, N(2)O blocks low-voltage-activated, T-type Ca(2+) currents (T currents), but not high-voltage-activated (HVA) currents. This blockade of T currents was concentration dependent, with an IC(50) value of 45 +/- 13%, maximal block of 38 +/- 12%, and Hill coefficient of 2.6 +/- 1.0. No desensitization of the response or change in current kinetics was observed during N(2)O application. The magnitude of T current blockade by N(2)O does not seem to reflect any use- or voltage-dependent properties. In addition, T current blockade was not altered when intracellular GTP was replaced with guanosine 5'-(gamma-thio)triphosphate or guanosine 5'-0-(2-thiodiphosphate) suggesting a lack of involvement of G-proteins in the inhibition. N(2)O selectively blocked currents arising from the Ca(v)3.2 but not Ca(v)3.1 recombinant channels stably expressed in human embryonic kidney (HEK) cells in a concentration-dependent manner with an apparent affinity and potency similar to native dorsal root ganglion currents. Analogously, the block of Ca(v)3.2 T currents exhibited little voltage- or use-dependence. These data indicate that N(2)O selectively blocks T-type but not HVA Ca(2+) currents in small sensory neurons and Ca(v)3.2 currents in HEK cells at subanesthetic concentrations. Blockade of T currents may contribute to the anesthetic and/or analgesic effects of N(2)O.

Redox modulation of T-type calcium channels in rat peripheral nociceptors.

Although T-type calcium channels were first described in sensory neurons, their function in sensory processing remains unclear. In isolated rat sensory neurons, we show that redox agents modulate T currents but not other voltage- and ligand-gated channels thought to mediate pain sensitivity. Similarly, redox agents modulate currents through Ca(v)3.2 recombinant channels. When injected into peripheral receptive fields, reducing agents, including the endogenous amino acid L-cysteine, induce thermal hyperalgesia. This hyperalgesia is blocked by the oxidizing agent 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) and the T channel antagonist mibefradil. DTNB alone and in combination with mibefradil induces thermal analgesia. Likewise, L-cysteine induces mechanical DTNB-sensitive hyperalgesia in peripheral receptive fields. These data strongly suggest a role for T channels in peripheral nociception. Redox sites on T channels in peripheral nociceptors could be important targets for agents that modify pain perception.

[Deletions in the dystrophin gene and its phenotype expression]. / Delecije u genu za distrofin i njihova fenotipska ekspresija.

About 60% of both Duchenne's muscular dystrophy (DMD) and Becker's muscular dystrophy (BMD) is due to deletions of dystrophin gene. For cases with deletion mutations the "reading frame" hypothesis predicts that deletions which result in disruption of the translation reading frame prevent production of stable protein and are associated with DMD. In contrast, intragenic deletions that involve exons encoding an integral number of triplet codons maintain proper reading frame. The resulting abnormal proteins are stable and partially functional, resulting in a milder and more variable BMD phenotype. To test the validity of this theory,we analyzed 40 patients-19 independent deletions at the DMD/BMD locus. Clinical/molecular correlations based on the altera-tions of the reading frame were valid in 69.2% of cases. After exclusion of: --2 patients with del 3-6 (with no consistent clinical expression); --1 DMD patient with large in-frame deletion; --2 patients that were too young to be classified; --4 patients in whom it was impossible to identify the extent of deletion (del 47 and del 44-45), the correlation between deletion and clinical severity was as predicted in 92.4% of cases. The present data should be useful in establishing the prognosis in individual patients even in sporadic cases with no affected relatives.

Is the 31 CAG repeat allele of the spinocerebellar ataxia 1 (SCA1) gene locus non-specifically associated with trinucleotide expansion diseases?

A number of human hereditary neuromuscular and neurodegenerative disorders are caused by the expansion of trinucleotide repeats within certain genes. The molecular mechanisms that underlie these expansions are not yet known. We have analyzed six trinucleotide repeat-containing loci [spinocerebellar ataxias (SCA1, SCA3, SCA8), dentatorubral-pallidoluysian atrophy (DRPLA), Huntington chorea (HD) and fragile X syndrome (FRAXA)] in myotonic dystrophy type 1 (DM1) patients (n = 52). As controls, we analyzed two groups of subjects: healthy control subjects (n =133), and a group of patients with non-triplet neuromuscular diseases (n = 68) caused by point mutations, deletions or duplications (spinal muscular atrophy, Charcot-Marie-Tooth disease, type 1A, hereditary neuropathy with liability to pressure palsies, and Duchenne and Becker muscular dystrophy). Allele frequency distributions for all tested loci were similar in these three groups with the exception of the SCA1 locus. In DM1 patients, the SCA1 allele with 31 CAG repeats account for 40.4% of all chromosomes tested, which is significantly higher than in two other groups (11.3% in healthy controls and 6.6% in the group of non-triplet diseased patients; P < 0.001, Fisher's exact test). This is consistent with our previous findings in HD patients. The absence of this association in non-triplet diseases as well as in healthy controls could indicate a possible role of this SCA1 allele with 31 repeats in triplet diseases. Here we discuss a possible role of the SCA1 region in pathological trinucleotide repeat expansions.