Objective: We describe the case of a male patient of German ancestry with SCA 42.

Background: Hereditary spinocerebellar ataxia (SCA) describes a heterogeneous group of disorders inherited in an autosomal dominant manner, most often characterized by ataxia, although other movement phenomenology, eye movement abnormalities, cognitive impairment, pyramidal signs, and peripheral neuropathy can also be seen.  In 2015, two publications described a novel disease-causing mutation (p.Arg1715His) in the CACNA1G gene manifesting as SCA 42.  We present a case of confirmed SCA 42 in a patient of German ancestry with slowly progressive cerebellar signs and cognitive impairment.

Methods: A 75-year-old man who was evaluated in the Stanford Movement Disorders Clinic for complaints of dysarthria and imbalance.  He reported 7 years of slowly progressive slurring of speech, imbalance, cognitive decline, and clumsiness of his hands. Family history was significant for similar symptoms in his father, 2 paternal aunts, and a paternal cousin.  His paternal lineage was of German ancestry. Examination was notable for moderate dysarthria, hypermetric saccades and axial>appendicular ataxia.  He scored a 24/30 on the MoCA with deficits in delayed recall and language.

Results: Negative work-up included HIV, RPR, TSH, B12, MMA, SPEP, UPEP, ESR, and serum paraneoplastic antibody panel.  Testing for SCA 1, 2, 3, 5, 6, 7, 8, 10, 13, 14, and 17 was negative as was testing for DRPLA, FXTAS and familial coenzyme Q deficiency.  A recessive variant involving a single base pair (G>A at codon 489) on the SETX gene was thought to be unrelated to his presentation.

The patient’s DNA was then analyzed via the University of Chicago ataxia exome panel, revealing a disease-causing heterozygous mutation (c.5144G>A; p.Arg1715His) in CACNA1G.

Conclusions: SCA 42 is an autosomal dominant condition caused by a change in the voltage-sensing portion of a T-type calcium channel commonly expressed in the cerebellum, leading to a slowly-progressive cerebellar syndrome with oculomotor abnormalities and variable cognitive impairment, as was seen in our patient of German ancestry.

References:

1. Coutelier, M., Blesneac, J., Montiel, A., Monin, M., Ando, K., Mundwiller, E., Brusco, A., Le Ber, I., Anheim, M, Castrioto, A, Duyekaerts, C., Brice, A., Durr, A., Lory, P., & Stevanin, G (2015).  A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.  The American Journal of Human Genetics.  97, 729-737.
2. Morino, H., Matsuda, Y., Muguruma, K., Miyamoto, R., Ohsawa, R., Ohtake, T., Otobe, R., Watanabe, M, Maruyama, H., Hashimoto, K., & Kawakami, H. (2015).  A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia.  Molecular Brain.  8:89.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/autosomal-dominant-spinocerebellar-ataxia-secondary-to-cacna1g-in-a-patient-of-german-ancestry/