Molecular genetic testing for hereditary ataxia

Wallace, Stephanie E; Bird, Thomas D.

doi:10.1212/cpj.0000000000000421

Cited by 21 publications

(20 citation statements)

References 9 publications

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“…[1][2][3][4] The most common genetic ataxias, as well as several rarer forms, are caused by nucleotide repeat expansions, which typically require targeted non-sequencebased testing to identify. [5][6][7][8] Recent studies identified a recessive intronic (AAGGG) repeat expansion in replication factor C subunit 1 (RFC1) related to cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) in Australia and the United Kingdom. 9,10 In addition, this expansion may be responsible for up to 22% (33/150) of sporadic cerebellar ataxia and 63% (32/51) of ataxia associated with sensory neuropathy.…”

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confidence: 99%

Prevalence of RFC1 -mediated spinocerebellar ataxia in a North American ataxia cohort

et al. 2020

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ObjectiveWe evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America.MethodsA cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for RFC1, resulting in a combined 911 subjects tested.ResultsIn the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in RFC1 (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the DAB1 gene (spinocerebellar ataxia type 37).ConclusionsIn a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.

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confidence: 99%

Prevalence of RFC1 -mediated spinocerebellar ataxia in a North American ataxia cohort

et al. 2020

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“…Friedrich's ataxia is diagnosed with genetic testing for trinucleotide repeat, 58 suspected in children and adolescents with profound gait abnormalities and possible family history.…”

Section: Chronic Pure Sensory Neuropathy/neuronopathymentioning

confidence: 99%

“…The most common etiologies overlap with those for DSP, specifically diabetes mellitus, vitamin abnormalities, and monoclonal gammopathy of unknown significance. An important comprehensive review 58 suggests the following tiered testing: an initial screen may include tests for diabetes mellitus or prediabetes with hemoglobin A1c, fasting glucose and 2-hour GTT, vitamin abnormalities with vitamin B12 level, and MMA and paraproteinemia with SPEP and IFE. Other initial tests may include triglyceride levels, thyroid-stimulating hormone, and vitamin B6, B1, and E. A second-line evaluation may include tests for SS-A and SS-B, Lyme's disease (ELISA or Western blot), sarcoidosis (serum ACE), heavy metals, and HIV, while a third-line evaluation may include amyloidosis (genetic testing or fat aspirate), Fabry's disease (α-galactosidase A assay), hepatitis C (virus antibody screening, ribonucleic acid confirmation if screen positive), leprosy (biopsy of the lesion), paraneoplastic disease (anti-Hu, anti-CV2/ collapsing response mediator protein 5, ANNA-3, anti-leucine-rich glioma inactive protein 1), acute intermittent porphyria (porphobilinogen in urine and erythrocytes), celiac disease (antigliadin antibodies), and other hereditary neuropathies (genetic testing).…”

Section: Small Fiber and Autonomic Neuropathymentioning

confidence: 99%

Laboratory Evaluation of Peripheral Neuropathy

Lau

2019

Semin Neurol

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Peripheral neuropathy is a common neurological disorder, with high prevalence especially in the aged population. The general evaluative approach is to first identify the type of peripheral neuropathy prior to investigating for a possible underlying etiology, which is an increasingly important endeavor, as many causes of peripheral neuropathy are now recognized as treatable. To this end, laboratory testing plays an important adjunctive role to a detailed history and examination. This review will discuss possible diagnostic laboratory testing pathways for different types of peripheral neuropathy, with the goal of minimizing costs and false-positive results while maximizing the likelihood of identifying a potentially reversible etiology.

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“…In the more than 100 described human hereditary ataxias, similar phenotypes can be caused by variants in different genes and different variants in the same gene can cause different phenotypes. 2 Described genetic variants, often in genes from conserved pathways, are repeat expansions, SNVs and INDELs, and follow a dominant, recessive, X-linked or mitochondrial inheritance. The prevalence of hereditary ataxias in humans varies in different populations, but ranges between 1-9 in 100 000 (ref.…”

Section: Introductionmentioning

confidence: 99%

Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

et al. 2019

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Clinical, pathological and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described and compared with its human counterpart. Based on the family history and the phenotype/genotype relationships already described in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole exome sequencing identified the SLC12A6 c.178_181delinsCATCTCACTCAT (p.(Met60Hisfs*14)) truncating variant. This lossof-function variant perfectly segregated within the affected Malinois family in an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, including Malinois. In humans, SLC12A6 variants cause "agenesis of the corpus callosum with peripheral neuropathy" (ACCPN, alias Andermann syndrome), due to a dysfunction of this K +-Clcotransporter. However, depending on the variant (including truncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoform described so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis of the corpus callosum nor obvious mental retardation have been observed in dogs. On the other hand, progressive spinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis and myokymia-like muscle contractions have not been described in humans with ACCPN so far. Since this is the first report of a naturally occurring disease-causing SLC12A6 variant in a nonhuman species, the canine model will be highly valuable to better understand the complex molecular pathophysiology of SLC12A6-related neurological disorders and to evaluate novel treatment strategies.

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Molecular genetic testing for hereditary ataxia

Cited by 21 publications

References 9 publications

Prevalence of RFC1 -mediated spinocerebellar ataxia in a North American ataxia cohort

Prevalence of RFC1 -mediated spinocerebellar ataxia in a North American ataxia cohort

Laboratory Evaluation of Peripheral Neuropathy

Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

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