Objective: Genetic investigation of a family with inherited cerebellar ataxia.

Background: Despite the identification of an increasing number of genes causing dominant spinocerebellar ataxias (SCAs), a significant proportion of cases are still left without a diagnosis. MJD/SCA3 is the most prevalent SCA worldwide. CACNA1A ataxia-causing sequence variants are typically associated with episodic ataxia type 2 and familial hemiplegic migraine, but may also cause a slowly progressive form of cerebellar ataxia (SCA6).

Methods: We used PCR amplification to rule out triplet expansion diseases, namely SCA2, MJD/SCA3, SCA6, SCA7, SCA10, SCA12, and DRPLA, Sanger sequencing for SCA14 in and a new generation sequencing (NGS) panel to search for pathogenic variants in other ataxia-causing genes.

Results: Two siblings, a 78-year-old man (patient #1) and a 90-year-old woman (patient #2), presented with a slowly progressive cerebellar syndrome, consisting of dysarthria, limb and gait ataxia, starting in their 20s. Family history suggested autosomal dominant inheritance. Brain MRI showed global cerebellar atrophy. Genetic testing for SCA2, MJD, SCA6, SCA7, SCA10, SCA12, SCA14 and DRPLA was “negative”. Patient #3 (son of patient #1) presented at age 26 years with isolated gait ataxia. Brain MRI depicted mild cerebellar atrophy. Genetic investigation was not undertaken because of his father’s negative test results. Moreover, his parents were consanguineous. His mother, who had died at age 30, was said to have had a wide-based gait. The patient subsequently emigrated and was lost to follow-up at our hospital. He later developed nystagmus, dysarthria, pyramidal signs in the lower limbs and a spastic-ataxic gait. Another neurologist, unaware of his father’s genetic test results, requested testing for MJD/SCA3, which showed a pathogenic CAG expansion. Subsequently, a NGS panel for AD ataxias showed that both patient #1 and #2 (but not patient #3) carried a pathogenic variant in CACNA1A, c.1748G>A (p.Arg583Gln). Transmission of the expanded MJD/SCA3 expanded CAG repeat from mother to son (patient #3) is therefore the most likely cause for this unusual occurrence.

Conclusions: Albeit rare, multiple gene mutations responsible for a dominantly-inherited cerebellar ataxia phenotype may coexist in a single family. We highlight the role of NGS in achieving a definite diagnosis in such cases.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/coexisting-cacna1a-pathogenic-variant-and-mjd-expansion-in-the-same-family/