Alcohol Induces Sensitization to Gluten in Genetically Susceptible Individuals: A Case Control Study

Background

The mechanisms of cerebellar degeneration attributed to prolonged and excessive alcohol intake remain unclear. Additional or even alternative causes of cerebellar degeneration are often overlooked in suspected cases of alcohol-related ataxia. The objectives of this study were two fold: (1) to investigate the prevalence of gluten-related serological markers in patients with alcohol-related ataxia and; (2) to compare the pattern of brain involvement on magnetic resonance imaging between patients with alcohol and gluten ataxias.

Materials & Methods

Patients diagnosed with alcohol and gluten ataxias were identified from a retrospective review of patients attending a tertiary clinic. HLA genotype and serological markers of gluten-related disorders were recorded. Cerebellar volumetry, MR spectroscopy and voxel-based morphometric analyses were performed on patients and compared with matched control data.

Results

Of 904 registered patients, 104 had alcohol ataxia and 159 had gluten ataxia. 61% of the alcohol ataxia group and 70% of the gluten ataxia group had HLA DQ2/DQ8 genotype compared to 30% in healthy local blood donors. 44% of patients with alcohol ataxia had antigliadin antibodies compared to 12% in the healthy local population and 10% in patients with genetically confirmed ataxias. None of the patients with alcohol ataxia and antigliadin antibodies had celiac disease compared to 40% in patients with gluten ataxia. The pattern of structural brain abnormality in patients with alcohol ataxia who had antigliadin antibodies differed from gluten ataxia and was identical to that of alcohol ataxia.

Conclusions

Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten. Such sensitization may result from a primary cerebellar insult, but a more systemic effect is also possible. The duration and amount of exposure to alcohol may not be the only factors responsible for the cerebellar insult.     

Inferior Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation in Purebred Eurasier Dogs with Familial Non-Progressive Ataxia: A Retrospective and Prospective Clinical Cohort Study

Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5 – 6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance.     

Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation

We examined a large French family with autosomal dominant cerebellar ataxia (ADCA) that was excluded from all previously identified spinocerebellar ataxia genes and loci. The patients-seven women and a 4-year-old boy-exhibited slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate mental retardation (IQ 62-76), and mild developmental delays in motor acquisition. Nystagmus and pyramidal signs were also observed in some cases. This unique association of clinical features clearly distinguishes this new entity from other previously described ADCA. Cerebral magnetic-resonance imaging showed moderate cerebellar and pontine atrophy in two patients. We performed a genomewide search and found significant evidence for linkage to chromosome 19q13.3-q13.4, in an approximately 8-cM interval between markers D19S219 and D19S553.     

Changes of ataxia, spontaneous movement and the cerebellar noradrenaline system with aging in ataxic mice

Changes of cerebellar weight, spontaneous movement and ataxia with aging were investigated in Weaver and cytosine arabinoside-injected mice (Ara-C). In addition, changes of cerebellar NA and MHPG concentrations in both mice were measured by high performance liquid chromatography. Cerebellar weight increased with aging in both mice. Spontaneous movements in Weaver mice were not significantly changed, but Ara-C mice showed a decreasing tendency with aging. Ataxic gait improved with aging in Weaver mice, but not in Ara-C mice. With aging, cerebellar NA and MHPG concentrations were decreased in controls, but not in Ara-C mice. In Weaver mice, cerebellar MHPG concentration was decreased. These results suggest that NA turnover in ataxic mice is different from that in controls, but is not correlated closely with ataxia.     

A linkage study of hereditary ataxias and related disorders

Genetic markers controlled by 21 genetic systems were studied in 13 families containing members suffering from various hereditary disorders involving ataxia. Classical cerebellar ataxia was present in four, Friedreich ataxia in two, hereditary spastic paraplegia in four, and the Charcot-Marie-Tooth syndrome in three families. In each family, every available member above the lowest age at onset observed in that family, was subjected to a thorough clinical investigation and blood was sampled for investigation of genetic markers.The families with cerebellar ataxia and with Charcot-Marie-Tooth syndrome contained enough informative relatives to allow a formal linkage study using the lodscore method. Three of the pedigress with cerebellar ataxia gave evidence of linkage between the disease and the HLA system with a combined lodscore of 2.128 at a recombination fraction of 0.05 for both sexes combined. The recombination fraction was considerably higher in females than in males, although the difference between the two sexes was not statistically significant.Negative lodscores were obtained for the remaining family with cerebellar ataxia, which might be due to the fact that this family only provided information on recombination in females. However, the clinical features in this family differed from those in the other three families by a significantly higher frequency of dementia and pyramidal tract lesions. Based on these observations and on contradictory results in the literature concerning linkage between cerebellar ataxia and HLA, we suggest that there are two forms of cerebellar ataxia: One (CA¹) linked to HLA with symptoms restricted to lesions in the cerebellum and spinocerebellar system and another (CA²) not linked to HLA with symptoms from more wide-spread lesions of the CNS.None of the other genetic markers (except perhaps GLO) showed linkage to the cerebellar ataxias. Negative lodscores throughout with all 21 genetic markers were found in the families with Charcot-Marie-Tooth syndrome.There was no evidence for linkage between HLA on the one hand and Friedreich ataxia or hereditary spastic paraplegia on the other.List of Abbreviations HA Hereditary ataxias - HLA Major histocompatibility system - CA Cerebellar ataxia - FA Friedreich ataxia - HSP Hereditary spastic paraplegia - CMT Charcot-Marie-Tooth syndrome - MS Multiple sclerosis - Hp Haptoglobin - Gc Group-specific component - PGM Phosphoglucomutase, locus 1 - SP (AcP) Acid phosphatase - AK Adenylatekinase - PGD 6-phosphogluconatedehydrogenase - ADA Adenosinedeaminase - GPT Glutamate pyruvat transaminase - GT Galaktose-1-phosphat uridylyltransferase - EsP Carboxylesterase D - GLO Glyoxylase I This study was aided by grants from Warwara Larsen's Foundation, the Danish Multiple Sclerosis Society and the Medical Research Council     

Delayed cerebellar ataxia: a new complication of falciparum malaria?

Twelve cases of an unusual phenomenon of ataxia were investigated in otherwise well, conscious patients recovering from a febrile attack of presumed falciparum malaria. The ataxia occurred as the fever was subsiding, usually after an afebrile period of two to four days. The delay between onset of fever and the ataxia was three to four weeks. Peripheral blood of all the patients contained gametocytes of Plasmodium falciparum, and in some cases ring stages. The ataxia was most noticeable in the legs and the clinical picture suggested selective impairment of the cerebellar system. Signs of improvement appeared in a few weeks but complete recovery took one to four months. The most likely pathogenic mechanism of the ataxia in these cases was an immune reaction triggered by the malaria parasite and affecting the cerebellum or its connections, or both.     

Genetic background of apparently idiopathic sporadic cerebellar ataxia

Disease-causing mutations have been identified in various entities of autosomal dominant ataxia and in Friedreich's ataxia. However, no molecular pathogenic factor is known to cause idiopathic cerebellar ataxias. We investigated the CAG/CTG trinucleotide repeats causing spinocerebellar ataxia types 1, 2, 3, 6, 7, 8 and 12, and the GAA repeat of the frataxin gene in 124 patients apparently suffering from idiopathic sporadic ataxia, including 20 patients with the clinical diagnosis of multiple system atrophy. Patients with a positive family history, a typical Friedreich phenotype, or symptomatic ataxia were excluded. Genetic analyses uncovered the most common Friedreich mutation in 10 patients with an age at onset between 13 and 36 years. The SCA6 mutation was present in nine patients with disease onset between 47 and 68 years of age. The CTG repeat associated with SCA8 was expanded in three patients. One patient had SCA2 attributable to a de novo mutation from a paternally transmitted, intermediate allele. We did not identify the SCA1, SCA3, SCA7 or SCA12 mutation in idiopathic sporadic ataxia patients. No trinucleotide repeat expansion was detected in the MSA subgroup. This study has revealed the genetic basis in 19% of apparently idiopathic ataxia patients. SCA6 is the most frequent mutation in late onset cerebellar ataxia. The frataxin trinucleotide expansion should be investigated in all sporadic ataxia patients with onset before age 40, even when the phenotype is atypical for Friedreich's ataxia.     

Protective effect of IL-18 on kainate- and IL-1 beta-induced cerebellar ataxia in mice

The pathogenesis of sporadic cerebellar ataxia remains unknown. In this study, we demonstrate that proinflammatory cytokines, IL-18 and IL-1beta, reciprocally regulate kainate-induced cerebellar ataxia in mice. We show that systemic administration of kainate activated IL-1beta and IL-18 predominantly in the cerebellum of mice, which was accompanied with ataxia. Mice deficient in caspase-1, IL-1R type I, or MyD88 were resistant to kainate-induced ataxia, while IL-18- or IL-18R alpha-deficient mice displayed significant delay of recovery from ataxia. A direct intracerebellar injection of IL-1beta-induced ataxia and intracerebellar coinjection of IL-18 counteracted the effect of IL-1beta. Our data firstly show that IL-18 and IL-1beta display differential direct regulation in kainate-induced ataxia in mice. Our results might contribute toward the development of a new therapeutic strategy for cerebellar ataxia in humans.     

Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.     

A Deletion in the VLDLR Gene in Eurasier Dogs with Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation (DWLM)

Dandy-Walker-like malformation (DWLM) is the result of aberrant brain development and mainly characterized by cerebellar hypoplasia. DWLM affected dogs display a non-progressive cerebellar ataxia. Several DWLM cases were recently observed in the Eurasier dog breed, which strongly suggested a monogenic autosomal recessive inheritance in this breed. We performed a genome-wide association study (GWAS) with 9 cases and 11 controls and found the best association of DWLM with markers on chromosome 1. Subsequent homozygosity mapping confirmed that all 9 cases were homozygous for a shared haplotype in this region, which delineated a critical interval of 3.35 Mb. We sequenced the genome of an affected Eurasier and compared it with the Boxer reference genome and 47 control genomes of dogs from other breeds. This analysis revealed 4 private non-synonymous variants in the critical interval of the affected Eurasier. We genotyped these variants in additional dogs and found perfect association for only one of these variants, a single base deletion in the VLDLR gene encoding the very low density lipoprotein receptor. This variant, VLDLR:c.1713delC is predicted to cause a frameshift and premature stop codon (p.W572Gfs*10). Variants in the VLDLR gene have been shown to cause congenital cerebellar ataxia and mental retardation in human patients and Vldlr knockout mice also display an ataxia phenotype. Our combined genetic data together with the functional knowledge on the VLDLR gene from other species thus strongly suggest that VLDLR:c.1713delC is indeed causing DWLM in Eurasier dogs.     

Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice.

SV40 T antigen (Tag) expression directed to cerebellar Purkinje cells resulted in the generation of three transgenic mouse lines that displayed ataxia, a neurological phenotype characteristic of cerebellar dysfunction. Onset of symptoms and cerebellar pathology, characterized by specific Purkinje cell degeneration, appeared to be directly dependent upon transgene copy number. The SV5 line (containing > 30 transgene copies), exhibited embryonic transgene expression that caused selective death of immature Purkinje cells and a subsequent block in cerebellar development and ataxia at 2 weeks. The developmental effect of the disruption of Purkinje cells in SV5 mice suggests that a normal complement of these cells is required for early development of the cerebellar cortex, especially granule cell proliferation and migration from external to internal layers. Transgene expression in a second line, SV4 (10 copies), was detectable during the second postnatal week. Death of mature Purkinje cells in the SV4 line resulted in onset of ataxia at 9 weeks. Ataxia in a third line, SV6 (2 copies), was detected after 15 weeks. The distinct cerebellar phenotypes of the SV4-6 lines correlate with specific Tag-induced Purkinje cell ablation as opposed to tumorigenesis.     

Autosomal recessive cerebellar ataxias

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.     

Identification of CHIP as a Novel Causative Gene for Autosomal Recessive Cerebellar Ataxia

Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia.     

An essential function for NBS1 in the prevention of ataxia and cerebellar defects

Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia-like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Here we show that inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD.     

Familial periodic cerebellar ataxia without myokymia maps to a 19-cM region on 19p13.

Familial periodic cerebellar ataxia (FPCA) is a heterogeneous group of rare autosomal dominant disorders characterized by episodic cerebellar disturbance. A potassium-channel gene (KCNA1) has been found to be responsible for one of its subgroups, familial periodic cerebellar ataxia with myokymia (FPCA/+M; MIM 160120). A different subgroup that is not associated with myokymia (FPCA/-M; MIM 108500) was recently mapped to chromosome 19p. Here we have performed linkage analysis in two large families with FPCA/-M that also demonstrated neurodegenerative pathology of the cerebellum. Three markers in 19p13 gave significant lod scores (> 3.0), while linkage to KCNA1 and three known loci for spinocerebellar ataxia (SCA1, SCA2, and SCA3) was excluded. The highest lod score was obtained with the marker D19S413 (4.4 at recombination fraction 0), and identification of meiotic recombinants in affected individuals placed the locus between the flanking markers D19S406 and D19S226, narrowing the interval to 19 cM. A CAG trinucleotide-repeat expansion was detected in one family but did not cosegregate with the disease.     

Hemodynamic vertebrobasilar insufficiency demonstrated by chronic oligemic cerebral flow and cerebellar ataxia: two new concepts

We propose in the paper of the concept of nuclear hemodynamic vertebrobasilar insufficiency, defined as an oligemic blood flow lower than 35 ml/100 g/min. in the brain stem-cerebellum zone, when using the method of inhalation of 133Xe. In 15 patients, the neurophysiologic manifestations included intermittent symptoms. We describe here permanent neurophysiologic motor disturbances: extrapyramidal Dopa sensitive syndrome (2/15), chronic cerebellar ataxia (12/15), often associated with cerebellar atrophy (8/12). The concept of chronic oligemic cerebellar ataxia, corresponding to selective neuronal death and/or neurochemical failure, is proposed.     

Cholestanol induces apoptosis of cerebellar neuronal cells

Cerebrotendinous xanthomatosis (CTX) is a hereditary lipid storage disease characterized by hyper-cholestanolemia, cerebellar ataxia, xanthoma, and cataract. We hypothesized that cholestanol in serum of CTX patients might induce neuronal cell death in the cerebellum and eventually lead to cerebellar ataxia. To gain support for this hypothesis we developed hyper-cholestanolemia rats by feeding cholestanol. Neuronal cells, especially Purkinje cells in the cerebellum were stained by Sudan black B only in the cholestanol-fed rats, indicating the deposit of cholestanol in cerebellum. To examine effects of cholestanol in vitro, cerebellar neuronal cells were cultured with cholestanol. The cholestanol concentration increased and the viability decreased in cells cultured with cholestanol. Apoptosis was evident in cells cultured with cholestanol more frequently than in control cells, determined using the terminal deoxynucleotidyl transferase (TdT) dUTP nick end-labeling (TUNEL) method. As activities of interleukin-1beta-converting enzyme (ICE) and CPP32 protease were increased in cells cultured with cholestanol, all these data taken together suggest that cholestanol induced apoptosis of cerebellar neuronal cells. Our observations may explain the mechanism of cerebellar ataxia of CTX patients.     

Cerebellar ataxia and functional genomics: Identifying the routes to cerebellar neurodegeneration

Cerebellar ataxias are progressive neurodegenerative disorders characterized by atrophy of the cerebellum leading to motor dysfunction, balance problems, and limb and gait ataxia. These include among others, the dominantly inherited spinocerebellar ataxias, recessive cerebellar ataxias such as Friedreich's ataxia, and X-linked cerebellar ataxias. Since all cerebellar ataxias display considerable overlap in their disease phenotypes, common pathological pathways must underlie the selective cerebellar neurodegeneration. Therefore, it is important to identify the molecular mechanisms and routes to neurodegeneration that cause cerebellar ataxia. In this review, we discuss the use of functional genomic approaches including whole-exome sequencing, genome-wide gene expression profiling, miRNA profiling, epigenetic profiling, and genetic modifier screens to reveal the underlying pathogenesis of various cerebellar ataxias. These approaches have resulted in the identification of many disease genes, modifier genes, and biomarkers correlating with specific stages of the disease. This article is part of a Special Issue entitled: From Genome to Function.     

Genetic Heterogeneity of Familial Hemiplegic Migraine

Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped a gene responsible for this disorder to the short arm of chromosome 19, within a 30-cM interval bracketed by D19S216 and D19S215. Linkage analysis conducted on two large pedigrees did not show any evidence of heterogeneity, despite their clinical differences due to the presence, in one family, of cerebellar ataxia and nystagmus. Herein we report linkage data on seven additional FHM families including another one with cerebellar ataxia. Analysis was conducted with a set of seven markers spanning the D19S216-D19S215 interval. Two-point and multipoint lod score analyses as well as HOMOG testing provided strong evidence for genetic heterogeneity. Strong evidence of linkage was obtained in two families and of absence of linkage in four families. The posterior probability of being of the linked type was >.95 in the first two families and <.01 in four other ones. It was not possible to draw any firm conclusion for the last family. Thus, within the nine families so far tested, four were linked, including those with associated cerebellar ataxia. We could not find any clinical difference between the pure FHM families regardless of whether they were linked. In addition to the demonstration of genetic heterogeneity of FHM, this study also allowed us to establish that the most likely location of the gene was within an interval of 12 cM between D19S413 and D19S226.     

Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1.

Autosomal dominant cerebellar ataxia is a group of clinically and genetically heterogeneous disorders. We carried out genomewide linkage analysis in 15 families with autosomal dominant pure cerebellar ataxia (ADPCA). Evidence for linkage to chromosome 19p markers was found in nine families, and combined multipoint analysis refined the candidate region to a 13.3-cM interval in 19p13.1-p13.2. The remaining six families were excluded for this region. Analysis of CAG-repeat expansion in the alpha1A-voltage-dependent calcium channel (CACNL1A4) gene lying in 19p13.1, recently identified among 8 small American kindreds with ADPCA (spinocerebellar ataxia type 6 [SCA6]), revealed that 8 of the 15 families studied had similar, very small expansion in this gene: all affected individuals had larger alleles (range of CAG repeats 21-25), compared with alleles observed in neurologically normal Japanese (range 5-20 repeats). Inverse correlation between the CAG-repeat number and the age at onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in the SCA6 families that we studied. We conclude that more than half of Japanese cases of ADPCA map to 19p13.1-p13.2 and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene.