Spinocerebellar Ataxia 48 Patient With a Novel De Novo Variant of STUB1

Dear Editor,

Spinocerebellar ataxia (SCA) is an autosomal dominant progressive neurodegenerative disease characterized by ataxia, gait disturbance, dysmetria, and dysarthria. SCA48 (OMIM #618093) was firstly discovered in a Spanish family with a heterogeneous variant of STUB1, which was previously recognized as a gene that causes autosomal recessive cerebellar ataxia.¹ Cerebellar ataxia, cerebellar atrophy, and prominent cognitive psychiatric disorder are the characteristic clinical features of SCA48.¹,² Various pyramidal and extrapyramidal symptoms have also been found.² To date, ten pathologic, four likely pathologic, and two variants of uncertain significance have been reported to the ClinVar archive,³ most of which were from the Mediterranean Basin. Of these, only one de novo case of SCA48 has been reported.⁴,⁵ Here we report the first SCA48 case with a novel de novo variant of STUB1 in Korea.

A 42-year-old female with progressive dysarthria, gait disturbance, and memory impairment visited the neurology clinic. The symptoms had slowly progressed over 7 years, and their daily activities were affected by gait disturbance and cognitive decline. A neurologic examination revealed hypermetric saccade, dysmetria of their upper left arm, and incoordination of the bilateral lower limbs. Smooth pursuits and saccades were normal. The patient demonstrated wide-based ataxic gait and poor balance with tandem gait (Supplementary Video 1 in the online-only Data Supplement) and scored 14 on the Scale for Assessment and Rating of Ataxia. She did not have other abnormal movements such as parkinsonism, dystonia, chorea, or myoclonus. Tendon reflexes were normal. The Babinski sign was positive in their bilateral feet. She had no family history of neurologic disorders. Their past medical history was uneventful, and no perinatal problems had been reported (Fig. 1A). Brain magnetic resonance imaging (MRI) indicated severe cerebellar atrophy, bilateral parietal lobe atrophy (Fig. 1B), and bilateral hyperintensity of the dentate nucleus on an axial T2-weighted image (Fig. 1C-1). A nerve conduction study indicated no evidence of peripheral neuropathy or other abnormalities. The patient had cognitive deficit in frontal/executive function (go/no-go test, semantic fluency, phonemic fluency, color-word Stroop test, digit-symbol coding, and Trail-Making Test), spatial cognition (Rey-Osterrieth Complex Figure Test, and clock-drawing test), and affective disorder (Beck Depression Inventory) (Fig. 1E; Supplementary Table 1 in the online-only Data Supplement). The genetic tests for SCA1, -2, -3, -6, -7, -8, and -17, and dentatorubral-pallidoluysian atrophy were negative. Whole-exome sequencing identified a heterozygous missense variant in exon 1 of STUB1 (NM_005861.2, c.90G>C [p.Lys30Asn]). The de novo variant was confirmed by the Sanger sequencing of the parents, which was not presence in population databases such as gnomAD (https://gnomad.broadinstitute.org). We classified the variant as likely pathogenic based on the American College of Medical Genetics and Genomics guideline (PS2+PM2) (Supplementary Table 2 and sequencing depth was described at Supplementray Table 3 in the online-only Data Supplement).

Fig. 1. Family pedigree, brain MRI and neuropsychological test of the patient. Family pedigree (A). Brain magnetic resonance imaging (MRI) shows severe cerebellar atrophy in the sagittal T1-weighted image (arrowhead) (B-1), and bilateral parietal lobe atrophy in the sagittal and axial T2-weighted images (asterisk) (B-1 and B-2). Bilateral hyperintensity of the dentate nucleus are shown in the axial T2-weighted (arrow) (C-1) and axial fluid-attenuated inversion recovery images (C-2). The dentate nucleus of the index case showed hypointensity in the axial (C-3) and coronal (C-4) T1-weighted images. In contrast, in the healthy control, the dentate nucleus shows hypointensity in the T2-weighted image (arrow) (D-1) and isointensity in the T1-weighted image (D-2). Comprehensive neuropsychologic tests using the Seoul Neuropsychological Screening Battery revealed severe cognitive impairment in multiple cognitive domains including attention, visuospatial function, memory, and frontal/executive function. The language domain was relatively preserved. The percentile scores were corrected for age, education, and sex (E).

Most reported cases of SCA48 have a family history, but de novo occurrence of the loss-of-function variant of STUB1 has also been reported previously.⁵ The two cases were reported as suspected SCA48, but the variants were classified of uncertain significance because their segregations could not be evaluated since the parents of the proband were deceased.⁶ In the present study, family segregation analysis confirmed the variants as de novo, novel, and likely pathogenic.

The index case was diagnosed as SCA48 with a novel heterozygous de novo variant of STUB1. The clinical symptoms of our patient were correlated with previously reported SCA48 cases. The progressive ataxia and cerebellar cognitive affective syndrome (CCAS) are characteristic features of SCA48.¹ The cognitive domains involved and the severity of the cognitive impairments can vary from normal or mild executive dysfunction to severe memory/language dysfunction or diffuse severe cognitive impairment.²,⁴,⁷ The patient also presented with diffuse cognitive impairment despite the absence of definite frontal, temporal, or general cortical atrophy, which are findings that often accompany CCAS.⁸ The brain MRI findings of the case indicated a typical appearance of SCA48, with posterolateral cerebellar atrophy, dentate nucleus involvement (crab sign), and parietal lobe atrophy.⁵,⁹

The penetrance rate of STUB1 remains unclear due to its rarity. Roux et al.⁸ suggested the possibility of sex-dependent penetrance of the STUB1 pathogenic variant that favored females. Most reported cases of SCA48 have been from the Mediterranean Basin.⁴ A Taiwanese case with a novel pathogenic variant was recently reported.¹⁰ Our patient is the first SCA48 case with a novel de novo variant in Korea.

In summary, the diagnosis of SCA48 remains challenging. The penetrance rate is unclear. A de novo pathogenic variant may develop independently of race. SCA48 should therefore be considered if a patient presents with cerebellar ataxia, crab sign, and CCAS.

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.3988/jcn.2022.18.6.714.

Video 1

A neurologic examination revealed hypermetric saccade, dysmetria in their left arm, and bilateral incoordination. The patient demonstrated wide-based ataxic gait and poor balance with tandem gait.

Supplementary Table 1

Result of detailed neuropsychiatric tests

Supplementary Table 2

Criteria for classifying pathogenic variants

Supplementary Table 3

Sequencing depth