Familial Cerebellar Ataxia and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia with DAB1 and C9ORF72 Repeat Expansions: An 18-Year Study.

BACKGROUND: Coding and noncoding repeat expansions are an important cause of neurodegenerative diseases. OBJECTIVE: This study determined the clinical and genetic features of a large German family that has been followed for almost 2 decades with an autosomal dominantly inherited spinocerebellar ataxia (SCA) and independent co-occurrence of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We carried out clinical examinations and telephone interviews, reviewed medical records, and performed magnetic resonance imaging and positron emission tomography scans of all available family members. Comprehensive genetic investigations included linkage analysis, short-read genome sequencing, long-read sequencing, repeat-primed polymerase chain reaction, and Southern blotting. RESULTS: The family comprises 118 members across seven generations, 30 of whom were definitely and five possibly affected. In this family, two different pathogenic mutations were found, a heterozygous repeat expansion in C9ORF72 in four patients with ALS/FTD and a heterozygous repeat expansion in DAB1 in at least nine patients with SCA, leading to a diagnosis of DAB1-related ataxia (ATX-DAB1; SCA37). One patient was affected by ALS and SCA and carried both repeat expansions. The repeat in DAB1 had the same configuration but was larger than those previously described ([ATTTT]≈75 [ATTTC]≈40-100 [ATTTT]≈415 ). Clinical features in patients with SCA included spinocerebellar symptoms, sometimes accompanied by additional ophthalmoplegia, vertical nystagmus, tremor, sensory deficits, and dystonia. After several decades, some of these patients suffered from cognitive decline and one from additional nonprogressive lower motor neuron affection. CONCLUSION: We demonstrate genetic and clinical findings during an 18-year period in a unique family carrying two different pathogenic repeat expansions, providing novel insights into their genotypic and phenotypic spectrums. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spectrin mutations cause spinocerebellar ataxia type 5.

We have discovered that beta-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincoln's grandparents and two additional families. Two families have separate in-frame deletions of 39 and 15 bp, and a third family has a mutation in the actin/ARP1 binding region. Beta-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane. We found marked differences in EAAT4 and GluRdelta2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant beta-III spectrin stabilizes EAAT4 at the plasma membrane. Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling.

Clinical and neurophysiological profile of four German families with spinocerebellar ataxia type 14.

Spinocerebellar ataxia type 14 (SCA14) is an autosomal-dominant ataxia caused by point mutations of the Protein Kinase C Gamma gene. In addition to slowly progressive cerebellar ataxia, it is characterised by dystonia and myoclonus. With scant neuropathological data and no detailed neurophysiological examinations little is known on extracerebellar consequences of SCA14 related cerebellar pathology. To this end, we here delineate clinical phenomenology and neurophysiology of four German SCA14 families. Detailed clinical examination including ataxia severity evaluation by means of the Scale for the Assessment and Rating of Ataxia (SARA) was carried out in 9 affected family members (mean age 49.8 years ± 14.4 SD). Motor thresholds (MT), the contralateral silent period (CSP), short interval intracortical inhibition (SICI) and intracortical facilitation (ICF), interhemispheric inhibition (IHI) and short afferent inhibition (SAI) were determined using transcranial magnetic stimulation (TMS). Somatosensory evoked potentials (SEP) of the median nerve, and acoustic and visual evoked potentials (AEP, VEP) were also performed. Most patients reported symptoms since early childhood. There was a positive correlation between age and SARA scores (r = .721, P < 0.05). Patients had cerebellar ataxia, mild dystonia (focal, task-specific or segmental), subtle pyramidal signs and myoclonus. SICI increased with increasing conditioning pulse intensities in healthy controls but not in patients. Other neurophysiological parameters did not differ between groups. SCA14 is a slowly progressive ataxia associated with mild dystonia and myoclonus. Reduced SICI reflects abnormalities of intracortical inhibitory circuits.

Repeat length in spinocerebellar ataxia type 4 (SCA4) predicts age at onset and disease severity.

BACKGROUND: Recently, an exonic GGC repeat expansion (RE) was identified by long-read genome sequencing in the ZFHX3 gen, causing spinocerebellar ataxia type 4 (SCA4), a dominant form of ataxia with sensory neuropathy. However, the analysis of larger cohorts of patients remained demanding, resulting in a challenge to diagnose patients and leaving the question of anticipation in SCA4 unanswered. OBJECTIVES: We aimed to develop a GGC repeat test for clinical SCA4 screening and to apply this test to screen two large German SCA pedigrees and samples of unrelated patients collected over the last 25 years. METHODS: We modulated a commercial GGC-RE kit (Bio-Techne AmplideX® Asuragen® PCR/CE FMR1 Reagents) with ZFHX3-specific primers and adapted PCR conditions. The test was applied to patients and 50 healthy controls to determine the exact repeat number. Clinical data were revised and correlated with the expanded allele sizes and an exploratory analysis of structural MRI was performed. RESULTS: Repeat size, determined by our protocol for (GGC)n RE analysis shows a strong inverse correlation between repeat length and age at onset and anticipation in subsequent generations. The phenotype also appears to be more strongly expressed in carriers of longer RE. Clinical red flags were slowed saccades, sensory neuropathy and autonomic dysfunction. CONCLUSION: Our protocol enables cost-effective and robust screening for the causative SCA4 RE within ZFHX3. Furthermore, detailed clinical data of our patients gives a more precise view on SCA4, which seems to be more common among patients with ataxia than expected.

A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.

Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees. Ultrarare DNA variants near the repeat expansion indicate a common distant founder event in Sweden. Intranuclear ZFHX3-p62-ubiquitin aggregates were abundant in SCA4 basis pontis neurons. In fibroblasts and induced pluripotent stem cells, the GGC expansion led to increased ZFHX3 protein levels and abnormal autophagy, which were normalized with small interfering RNA-mediated ZFHX3 knockdown in both cell types. Improving autophagy points to a therapeutic avenue for this novel polyG disease. The coding GGC-repeat expansion in an extremely G+C-rich region was not detectable by short-read whole-exome sequencing, which demonstrates the power of LR-GS for variant discovery.

Mesial temporal lobe epilepsy in a patient with spinocerebellar ataxia type 13 (SCA13).

We report a female patient of German descent with a molecular diagnosis of SCA13 who presented with a history of cerebellar ataxia and epilepsy. The underlying mutation R420H had been shown to cause a dominant negative effect on the functional properties of the voltage-gated potassium channel KCNC3. Despite widespread KCNC3 expression in the central nervous system, the patient presented with a left mesiotemporal electroencephalogram focus and left hippocampal sclerosis. This is the first case, which reports an association between mesial temporal lobe epilepsy and spinocerebellar ataxia type 13. This demonstrates that epilepsy of structural-metabolic cause may be contingent upon genetically defined channelopathies.

A case of Huntington's disease with two reduced penetrance alleles.

We present a case of Huntington's Disease (HD) with two reduced penetrance alleles and show that age of onset and motor symptoms are comparable to heterozygous patients with the same number of CAG triplet repeats. We performed a review of the literature on clinical presentation of homozygous HD cases and highlight that, so far, evidence exists that HD is a truly dominant disorder. This has important implications for pathophysiology concepts of the disease.

Possible genetic heterogeneity of spinocerebellar ataxia linked to chromosome 15.

Autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. We investigated an SCA family from Serbia of Roma ethnic origin; four affected and nine unaffected family members underwent a detailed neurological examination. The presenting symptom in all patients was gait unsteadiness in early adulthood. Additional features included pyramidal signs, depression, and cognitive impairment. The condition follows an autosomal dominant pattern of inheritance. After excluding repeat expansions in nine known SCA genes, a genome-wide linkage analysis with 412 microsatellite markers localized the putative disease gene to a 40.7 cM (42.5 Mb) region on chromosome 15q between markers D15S1006 and D15S116. The maximum model-based multipoint LOD score was 1.75. This region is only 4.3 Mb away from the SCA11 (TTBK2) gene. Accordingly, mutations in TTBK2 were not found, suggesting a second SCA gene on chromosome 15q as cause of this novel form of SCA. In addition, we excluded alterations in two candidate genes in the linked region, namely expansion of a polyglutamine-coding CAG repeat in ARID3B and mutations in SEMA6D.

Structural changes associated with progression of motor deficits in spinocerebellar ataxia 17.

Spinocerebellar ataxia (SCA17) is a rare genetic disorder characterized by a variety of neuropsychiatric symptoms. Recently, using magnetic resonance imaging (MRI) voxel-based morphometry (VBM), several specific functional-structural correlations comprising differential degeneration related to motor and psychiatric symptoms were reported in patients with SCA17. To investigate gray matter volume (GMV) changes over time and its association to clinical neuropsychiatric symptomatology, nine SCA17 mutation carriers and nine matched healthy individuals underwent a detailed neuropsychiatric clinical examination and a high-resolution T1-weighted volume MRI scan, both at baseline and follow-up after 18 months. Follow-up images revealed a progressive GMV reduction in specific degeneration patterns. In contrast to healthy controls, SCA17 patients showed a greater atrophy not only in cerebellar regions but also in cortical structures such as the limbic system (parahippocampus, cingulate) and parietal precuneus. Clinically, progression of motor symptoms was more pronounced than that of psychiatric symptoms. Correlation with the clinical motor scores revealed a progressive reduction of GMV in cerebellar and cerebral motor networks, whereas correlation with psychiatric scores displayed a more widespread GMV impairment in frontal, limbic, parietal, and also cerebellar structures. Interestingly, changes in global functioning were correlated with bilateral atrophy within the para-/hippocampus. While there was a good temporal association between worsening of motor symptoms and progression in cerebral and cortical neurodegeneration, the progression in psychiatric related neurodegeneration seemed to be more widespread and complex, showing progressive atrophy that preceded the further development of clinical psychiatric symptoms.

Clinical spectrum of the pentanucleotide repeat expansion in the RFC1 gene in ataxia syndromes.

OBJECTIVE: To determine the clinical significance of an intronic biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) in patients with late-onset cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), in patients with other ataxias, and in healthy controls by comprehensive genetic analyses. METHODS: In this case-control study, we included 457 individuals comprising 26 patients with complete or incomplete CANVAS, 70 patients with late-onset cerebellar ataxia, 208 healthy controls, and 153 individuals from 39 multigenerational families without ataxia to determine repeat stability. All 96 patients were screened for the repeat expansion by duplex PCR. To further characterize the repeat type and lengths, we used fragment length analysis, repeat-primed PCR, Sanger sequencing, and Southern blotting. Expression of RFC1 and the neighboring gene WDR19 were determined by quantitative PCR. RESULTS: Massive biallelic pentanucleotide expansions were found in 15/17 patients with complete CANVAS (88%), in 2/9 patients with incomplete CANVAS (22%), in 4/70 patients with unspecified, late-onset cerebellar ataxia (6%), but not in controls. In patients, the expansion comprised 800-1,000 mostly AAGGG repeats. Nonmassively expanded repeat numbers were in the range of 7-137 repeats and relatively stable during transmission. Expression of RFC1 and WDR19 were unchanged and RFC1 intron retention was not found. CONCLUSIONS: A biallelic pentanucleotide repeat expansion is a frequent cause of CANVAS and found in a considerable number of patients with an incomplete clinical presentation or other forms of cerebellar ataxia. The mechanism by which the repeat expansions are causing disease remains unclear and warrants further investigations.

Exon deletions and intragenic insertions are not rare in ataxia with oculomotor apraxia 2.

BACKGROUND: The autosomal recessively inherited ataxia with oculomotor apraxia 2 (AOA2) is a neurodegenerative disorder characterized by juvenile or adolescent age of onset, gait ataxia, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum AFP levels. AOA2 is caused by mutations within the senataxin gene (SETX). The majority of known mutations are nonsense, missense, and splice site mutations, as well as small deletions and insertions. METHODS: To detect mutations in patients showing a clinical phenotype consistent with AOA2, the coding region including splice sites of the SETX gene was sequenced and dosage analyses for all exons were performed on genomic DNA. The sequence of cDNA fragments of alternative transcripts isolated after RT-PCR was determined. RESULTS: Sequence analyses of the SETX gene in four patients revealed a heterozygous nonsense mutation or a 4 bp deletion in three cases. In another patient, PCR amplification of exon 11 to 15 dropped out. Dosage analyses and breakpoint localisation yielded a 1.3 kb LINE1 insertion in exon 12 (patient P1) and a 6.1 kb deletion between intron 11 and intron 14 (patient P2) in addition to the heterozygous nonsense mutation R1606X. Patient P3 was compound heterozygous for a 4 bp deletion in exon 10 and a 20.7 kb deletion between intron 10 and 15. This deletion was present in a homozygous state in patient P4. CONCLUSION: Our findings indicate that gross mutations seem to be a frequent cause of AOA2 and reveal the importance of additional copy number analysis for routine diagnostics.

Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17.

Trinucleotide repeat expansions are dynamic mutations causing many neurological disorders, and their instability is influenced by multiple factors. Repeat configuration seems particularly important, and pure repeats are thought to be more unstable than interrupted repeats. But direct evidence is still lacking. Here, we presented strong support for this hypothesis from our studies on spinocerebellar ataxia type 17 (SCA17). SCA17 is a typical polyglutamine disease caused by CAG repeat expansion in TBP (TATA binding protein), and is unique in that the pure expanded polyglutamine tract is coded by either a simple configuration with long stretches of pure CAGs or a complex configuration containing CAA interruptions. By small pool PCR (SP-PCR) analysis of blood DNA from SCA17 patients of distinct racial backgrounds, we quantitatively assessed the instability of these two types of expanded alleles coding similar length of polyglutamine expansion. Mutation frequency in patients harboring pure CAG repeats is 2-3 folds of those with CAA interruptions. Interestingly, the pure CAG repeats showed both expansion and deletion while the interrupted repeats exhibited mostly deletion at a significantly lower frequency. These data strongly suggest that repeat configuration is a critical determinant for instability, and CAA interruptions might serve as a limiting element for further expansion of CAG repeats in SCA17 locus, suggesting a molecular basis for lack of anticipation in SCA17 families with interrupted CAG expansion.

Spinocerebellar ataxia type 17 is caused by mutations in the TATA-box binding protein.

The spinocerebellar ataxia type 17 (SCA17) is characterized by cerebellar ataxia, dementia, and involuntary movements, including chorea and dystonia. In addition, psychiatric symptoms, pyramidal signs, and rigidity are common. MRI shows variable atrophy of the cerebrum, brainstem, and cerebellum. The autosomal dominantly inherited progressive neurodegenerative disorder is caused by an expanded CAA/CAG repeat coding for glutamine. Alleles of the normal range carry 25 to 42 glutamine residues, disease causing alleles 43 to 63. Alleles with 43 to 48 glutamine codons may be associated with incomplete penetrance. The mean age of onset is about 30 years for individuals with full-penetrance alleles, but ranges from three to 55 years.

Mutation analysis in the fibroblast growth factor 14 gene: frameshift mutation and polymorphisms in patients with inherited ataxias.

The spinocerebellar ataxias (SCAs) with autosomal dominant inheritance are a group of neurodegenerative disorders with overlapping as well as highly variable phenotypes. Genetically, at least 25 different loci have been identified. Seven SCAs are caused by CAG trinucleotide repeat expansions, for 13 the chromosomal localization is known solely. Recently, a missense mutation in the fibroblast growth factor 14 gene (FGF14) has been reported in a Dutch family with a new dominantly inherited form of SCA. To evaluate the frequency of mutations in the FGF14 gene, we performed molecular genetic analyses for the five exons in 208 nonrelated familial ataxia cases and 208 control samples. In one patient, we detected a novel single base pair deletion in exon 4 (c.487delA) creating a frameshift mutation. In addition, we found DNA polymorphisms in exon 1a, 4, and 5, an amino-acid exchange at position 124, as well as a single-nucleotide polymorphism in the 3'-untranslated region of exon 5.

Clinical and magnetic resonance imaging characteristics of sporadic cerebellar ataxia.

BACKGROUND: It is unknown whether multiple system atrophy of the cerebellar type (MSA-C) and idiopathic cerebellar ataxia with extracerebellar presentation (IDCA-P) represent distinct entities. OBJECTIVE: To investigate the discriminative validity of magnetic resonance imaging in sporadic cerebellar ataxia. DESIGN: Basal ganglia and infratentorial structures were screened for signal abnormalities and atrophic changes. Magnetic resonance imaging raters were masked to the clinical diagnosis. SETTING: Outpatient clinic of a university hospital. PATIENTS: Forty-one individuals were diagnosed as having MSA-C (n = 30) or IDCA-P (n = 11) based on their clinical features. RESULTS: Shrinkage of the cerebellar vermis and hemispheres was found in both groups. Atrophy of the brainstem and middle cerebellar peduncles was significantly more frequent in patients with MSA-C (P<.001). Hyperintensities of infratentorial structures were common in patients with MSA-C (middle cerebellar peduncles: 87%; pons: 97%) but were absent in patients with IDCA-P. Hypointensities or hyperintensities of basal ganglia structures did not reliably differentiate the groups. CONCLUSIONS: Patients with MSA-C were characterized by a higher frequency and severity of magnetic resonance imaging abnormalities (atrophic changes and additional hyperintense signal changes) of the middle cerebellar peduncles and pons. The presence of these magnetic resonance imaging features points to the diagnosis of MSA-C and helps differentiate MSA-C from other types of sporadic cerebellar ataxia with extracerebellar features.

Spinocerebellar ataxia type 17: report of a family with reduced penetrance of an unstable Gln49 TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes.

BACKGROUND: Spinocerebellar ataxia type 17 (SCA17), a neurodegenerative disorder in man, is caused by an expanded polymorphic polyglutamine-encoding trinucleotide repeat in the gene for TATA-box binding protein (TBP), a main transcription factor. Observed pathogenic expansions ranged from 43-63 glutamine (Gln) codons (Gln43-63). Reduced penetrance is known for Gln43-48 alleles. In the vast majority of families with SCA17 an expanded CAG repeat interrupted by a CAA CAG CAA element is inherited stably. RESULTS: Here, we report the first pedigree with a Gln49 allele that is a) not interrupted, b) unstable upon transmission, and c) associated with reduced penetrance or very late age of onset. The 76-year-old father of two SCA17 patients carries the Gln49 TBP allele but presents without obvious neurological symptoms. His children with Gln53 and Gln52 developed ataxia at the age of 41 and 50. Haplotype analysis of this and a second family both with uninterrupted expanded and unstable pathological SCA17 alleles revealed a common core genotype not present in the interrupted expansion of an unrelated SCA17 patient. Review of the literature did not present instability in SCA17 families with expanded alleles interrupted by the CAA CAG CAA element. CONCLUSION: The presence of a Gln49 SCA17 allele in an asymptomatic 76-year-old male reams the discussion of reduced penetrance and genotypes producing very late disease onset. In SCA17, uninterrupted expanded alleles of TBP are associated with repeat instability and a common founder haplotype. This suggests for uninterrupted expanded alleles a mutation mechanism and some clinical genetic features distinct from those alleles interrupted by a CAA CAG CAA element.

Spinocerebellar ataxia 28: a novel AFG3L2 mutation in a German family with young onset, slow progression and saccadic slowing.

BACKGROUND: Spinocerebellar ataxia type 28 (SCA28) is related to mutations of the ATPase family gene 3-like 2 gene (AFG3L2). To date, 13 private missense mutations have been identified in families of French, Italian, and German ancestry, but overall, the disorder seems to be rare in Europe. Here, we report a kindred of German ancestry with four affected family members presenting with slowly progressive ataxia, mild pyramidal tract signs and slow saccades. METHODS: After excluding repeat expansions in the genes for SCA1-3, 6-8, 10, 12, and 17, Sanger sequencing of the coding regions of TTBK2 (SCA11), KCNC3 (SCA13), PRKCG (SCA14), FGF14 (SCA27) and AFG3L2 (SCA28) was performed. The 17 coding exons of AFG3L2 with flanking intronic sequences were amplified by PCR and sequenced on both strands. RESULTS: Sequencing detected a novel potential missense mutation (p.Y689N) in the C-terminal proteolytic domain, the mutational hotspot of AFG3L2. The online programme "PolyPhen-2" classifies this amino acid exchange as probably damaging (score 0.990). Similarly to most of the published SCA28 mutations, the novel mutation is located within exon 16. Mutations in exon 16 alter the proteolytic activity of the protease AFG3L2 that is highly expressed in Purkinje cells. CONCLUSIONS: Genetic testing should be considered in dominant ataxia with pyramidal tract signs and saccadic slowing.

Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4.

Oculocutaneous albinism (OCA) is caused by a deficiency of melanin synthesis and characterized by generalized hypopigmentation of skin, hair, and eyes. Due to the hypopigmentation of the retinal pigment epithelium, OCA is usually associated with congenital visual impairment, in addition to an increased risk of skin cancer. OCA is a genetically heterogeneous disease with distinct types resulting from mutations in different genes involved in the pathway which results in pigmentation. OCA1 is associated with mutations in the TYR gene encoding tyrosinase. OCA2 results from mutations in the P gene encoding the P protein and is the most common form of OCA. OCA3, also known as rufous/red albinism, is caused by mutations in the TYRP1 gene, which encodes the tyrosinase-related protein 1. Recently, OCA4 was described as a new form of OCA in a single patient with a splice site mutation in the MATP gene (or AIM1), the human ortholog of the murine underwhite gene. The similarity of MATP to transporter proteins suggests its involvement in transport functions, although its actual substrate is still unclear. We screened 176 German patients with albinism for mutations within the MATP gene and identified five individuals with OCA4. In this first report on West European patients, we describe 10 so far unpublished mutations, as well as two intronic variations, in addition to two known polymorphisms.

Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism.

Oculocutaneous albinism (OCA) in man may be caused by mutations within the tyrosinase gene (TYR) resulting in OCA1. Analysing patients with recessively inherited albinism we found DNA variations in 82 unrelated individuals. 53 out of 78 mutations and polymorphisms revealed by this study are not published previously. The changes include 68 nucleotide substitutions resulting in amino acid changes, stop mutations and polymorphisms as well as four nucleotide insertions and six deletions. Furthermore, we found an accumulation of three to five mutations in 17 patients with OCA1.

Spinocerebellar ataxia type 1 (SCA1): phenotype-genotype correlation studies in intermediate alleles.

CAG repeat expansions with loss of CAT interruptions in the coding region of the ataxin-1 gene are associated with spinocerebellar ataxia type 1 (SCA1). For molecular genetic diagnosis it is necessary to define the limits of normal and pathological size ranges. In most studies, normal alleles as measured by PCR range from 6-39 units with interruptions of 1-3 CAT trinucleotides that are thought to be involved in the stability of the trinucleotide stretch during DNA replication. Expanded alleles have been reported to carry 39-81 CAG trinucleotides without stabilising CAT interruptions. To evaluate the limits between normal and disease size ranges we analysed the repeat length and composition of the SCA1 gene in 15 individuals with alleles ranging from 36 and 41 triplets for genotype-phenotype correlation studies. We found the 39 trinucleotide-allele to be either interrupted by CAT repeats or formed by a pure CAG stretch. The clinical features of individuals carrying 39 uninterrupted CAG repeats did not differ from the SCA1 phenotype in general with dysphagia, pale discs, pyramidal signs and cerebellar tremor being more frequent as compared to other SCA genotypes. In contrast, the interrupted 39 trinucleotide-allele is not correlated with the SCA1 phenotype.