JAMA Neurology: Ataxia Topic Collection

Fragile X–Associated Tremor/Ataxia Syndrome Influence of the FMR1 Gene on Motor Fiber Tracts in Males With Normal and Premutation Alleles Fragile X–Associated Tremor/Ataxia Syndrome

Wang J, Hessl D, Schneider A, et al. — Mon, 10 Jun 2013 00:00:00 GMT

Importance

Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile X–associated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS.

Objective

To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles.

Design and Setting

A case-control study conducted at the University of California, Davis, from April 1, 2008, through August 31, 2009. All data were collected masked to the carrier status of the FMR1 gene.

Participants

Thirty-six male premutation carriers with FXTAS and 26 male premutation carriers without FXTAS were recruited through their family relationships with children affected by fragile X syndrome. The controls were 34 unaffected family members and healthy volunteers from the local community.

Main Outcomes and Measures

The CGG repeat lengths and FMR1 mRNA expression levels in peripheral blood lymphocytes, motor functioning, and white matter structural integrity that were estimated using diffusion tensor imaging. After data collection, we selected 4 motor tracts to reconstruct using diffusion tensor tractography, namely, the middle and superior cerebellar peduncles, descending motor tracts (containing the corticospinal, corticobulbar, and corticopontine tracts), and the anterior body of the corpus callosum.

Results

All fiber tracts exhibited weaker structural connectivity in the FXTAS group (decreased 5%-53% from controls, P ≤ .02). Genetic imaging correlation analysis revealed negative associations of CGG repeat length and FMR1 mRNA with connectivity strength of the superior cerebellar peduncles in both premutation groups (partial r² = 0.23-0.33, P ≤ .004). In addition, the measurements from the corpus callosum and superior cerebellar peduncles revealed a high correlation with motor functioning in all 3 groups (r between partial least square predicted and actual test scores = 0.41-0.56, P ≤ .04).

Conclusions and Relevance

Distinct pathophysiologic processes may underlie the structural impairment of the motor tracts in FXTAS. Although both the corpus callosum and superior cerebellar peduncles were of great importance to motor functioning, only the superior cerebellar peduncles exhibited an association with the elevated RNA levels in the blood of fragile X premutation carriers.

Hereditary Ataxia and Spastic Paraplegia in Portugal A Population-Based Prevalence Study Hereditary Ataxia and Spastic Paraplegia

Coutinho P, Ruano L, Loureiro JL, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are scarce.

Objective

To present the prevalence and distribution of HCA and HSP in Portugal.

Design and Setting

Population-based, nationwide, systematic survey, from January 1, 1994, through April 15, 2004, in Portugal.

Participants

Multiple sources of information were used (review of clinical files, active collaboration of neurologists and geneticists, and investigation of affected families), but the main source was active collaboration of general practitioners. Patients were examined by the same team of neurologists, using homogeneous inclusion criteria. The clinical data were registered, and all families were genetically tested.

Results

Overall, 1336 patients from a population of 10 322 million were diagnosed as having HCA or HSP, a prevalence of 12.9 per 100 000 population. Hereditary cerebellar ataxia was more prevalent (prevalence, 8.9 per 100 000 population; 5.6 for dominant and 3.3 for recessive ataxias) than HSP (prevalence, 4.1 per 100 000 population; 2.4 for dominant and 1.6 for recessive). Machado-Joseph disease (spinocerebellar ataxia type 3) (prevalence, 3.1 per 100 000 population), Friedreich ataxia (prevalence, 1.0 per 100 000 population), and ataxia with oculomotor apraxia (prevalence, 0.4 per 100 000 population) were the most frequent HCAs. Spastic paraplegia types 4 (prevalence, 0.91 per 100 000 population), 3 (prevalence, 0.14 per 100 000 population), and 11 (prevalence, 0.26 per 100 000 population) were the most prevalent HSPs.

Conclusions and Relevance

This population-based survey covered all the Portuguese territory and mobilized most general practitioners and health centers. To our best knowledge, this survey was the largest ever performed for HCA and HSP. Prevalence of autosomal dominant ataxias was high, particularly for Machado-Joseph disease (spinocerebellar ataxia type 3). The genetic cause has not been identified in 39.7% of the patients studied.

New Subtype of Spinocerebellar Ataxia With Altered Vertical Eye Movements Mapping to Chromosome 1p32 Subtype of SCA With Altered Vertical Eye Movements

Serrano-Munuera C, Corral-Juan M, Stevanin G, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

To provide clinical and genetic diagnoses for patients' conditions, it is important to identify and characterize the different subtypes of spinocerebellar ataxia (SCA).

Objective

To clinically and genetically characterize a Spanish kindred with pure SCA presenting with altered vertical eye movements.

Design

Family study of ambulatory patients. Electro-oculographic and genetics studies were performed in 2 referral university centers.

Setting

Primary care institutional center in Spain.

Participants

Thirty-six participants from a large Spanish kindred were clinically examined, and 33 family members were genetically examined. Detailed clinical data were obtained from 9 affected relatives. Two ataxic siblings and 2 asymptomatic family members were examined using an enhanced clinical protocol for a follow-up period of 7 years.

Main Outcomes and Measures

High-density genome-wide single-nucleotide polymorphism arrays, along with microsatellite analysis, and genetic linkage studies were performed. Whole-exome sequencing was used for 2 affected relatives. For most patients, the initial symptoms included falls, dysarthria, or clumsiness followed by a complete cerebellar syndrome. For all 9 affected relatives, we observed altered vertical eye movements, as initial ocular signs for 3 of them and for the 2 asymptomatic family members, all having inherited the risk haplotype. Neuroimaging showed isolated cerebellar atrophy.

Results

Initial genome-wide linkage analysis revealed suggestive linkage to chromosome 1p32. Multipoint analysis and haplotype reconstruction further traced this SCA locus to a 0.66-cM interval flanked by D1S200 and D1S2742 (z_max = 6.539; P < .0001). The causative mutation was unidentified by exome sequencing.

Conclusions and Relevance

We report a new subtype of SCA presenting in patients as slow progressing ataxia with altered vertical eye movements linked to a 11-megabase interval on 1p32. The Human Genome Nomenclature Committee has assigned this subtype of ataxia the designation SCA37.

Clinical Application of Whole-Exome Sequencing A Novel Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Sequence Variation in a Child With Ataxia Whole-Exome Sequencing

Liew WM, Ben-Omran T, Darras BT, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

Ataxia in children is a diagnostic challenge. Besides the more common acquired causes of ataxia, there are more than 50 inherited disorders associated with ataxia. Our objective was to highlight whole-exome sequencing as a rapidly evolving clinical tool for diagnosis of mendelian disorders, and we illustrate this in the report of a single case of a novel sequence variation in the SACS gene.

Observations

A 4-year-old girl presented with delayed gross motor development, ataxia, and polyneuropathy. Results of initial testing for the common causes of inherited and acquired ataxia were unrevealing. Whole-exome sequencing showed a novel frameshift homozygous sequence variation in the SACS gene, consistent with the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Conclusions

Whole-exome sequencing is a powerful clinical tool that has been increasingly used to assist in the diagnosis of mendelian disorders. It provides a cost-effective, efficient, and expedited approach to making a clinical diagnosis and, in some cases, may be the only way to make a diagnosis.