Spinocerebellar Ataxia 37

A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-37 (SCA37) is caused by heterozygous mutation in the DAB1 gene (603448) on chromosome 1p32.

Description

Spinocerebellar ataxia-37 (SCA37) is an autosomal dominant neurologic disorder characterized by adult onset of slowly progressive gait instability, frequent falls, and dysarthria associated with cerebellar atrophy on brain imaging (summary by Seixas et al., 2017).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Clinical Features

Serrano-Munuera et al. (2013) reported a large, multigenerational Spanish kindred with spinocerebellar ataxia. Detailed clinical data was available for 9 affected individuals. Initial symptoms of increased falls due to gait instability, dysarthria, and clumsiness appeared at a mean age of 48 years (range, 38-64). Clinical progression was slow, and 4 patients became wheelchair-bound 10 to 33 years after onset. More variable features included trunk ataxia, dysmetria, and dysphagia. All patients had abnormal ocular movements, consisting mostly of dysmetric vertical saccades and irregular vertical pursuit, and most patients later developed abnormal horizontal pursuit. A few patients had nystagmus. Electroocular studies performed on 2 symptomatic patients confirmed these findings. One asymptomatic family member had vertical eye movement abnormalities on electroocular studies, and he was found to carry the disease haplotype. Brain imaging showed cerebellar atrophy with sparing of the brainstem. None of the patients had sensory deficits or cognitive impairment.

Seixas et al. (2017) reported 6 families from southern Portugal with SCA37. Three of the pedigrees (pedigrees M, G, and R) were large and multigenerational with 35 affected individuals. The 3 additional families had 6 affected individuals. The patients had mainly adult onset (range, late teens to early 60s) of dysarthria and ataxic gait. Brain imaging showed cerebellar atrophy.

Corral-Juan et al. (2018) reported 4 unrelated families from the same area of southern Spain with SCA37. One of the families (AT-901) had previously been reported by Serrano-Munuera et al. (2013). Among all families, there were 25 affected individuals and 7 asymptomatic mutation carriers. The age at symptom onset ranged from 25 to 64 years (mean of 43 years), and the age of the asymptomatic mutation carriers ranged from 20 to 39 years. Affected individuals presented with clumsiness, falls, and/or dysarthria, with slow progression to a pure cerebellar syndrome with scanning speech, mild truncal ataxia, and severe dysmetria mostly in the legs. Vertical eye movement abnormalities were apparent early in the disease, whereas horizontal eye movement abnormalities occurred later. Additional features included dysphagia, tremor, oscillopsia, nystagmus, and saccadic eye intrusions. Patients became wheelchair-bound 10 to 33 years from onset, with the exception of 1 patient who became wheelchair-bound in 5 years. None of the patients had cognitive impairment. Brain imaging showed progressive cerebellar atrophy. Some asymptomatic mutation carriers showed vertical eye movement abnormalities and variable cerebellar vermis atrophy. Neuropathologic examination of 2 patients showed cerebellar atrophy with extensive and generalized Purkinje cell loss with abundant astrogliosis in the cerebellar cortex. Remaining Purkinje cells showed severe nuclear changes such as lobulation, irregular shape, and hyperchromatism, as well as aberrant dendrite arborization. Phosphoneurofilament immunoreactivity revealed many empty baskets with stained perikarya, and ubiquitinated perisomatic granules that immunostained with DAB1.

Inheritance

The transmission pattern of SCA37 in the family reported by Serrano-Munuera et al. (2013) and the families reported by Seixas et al. (2017) was consistent with autosomal dominant inheritance.

In the families reported by Seixas et al. (2017), there was evidence of instability upon transmission of the pathogenic repeat insertion, with an increase in length particularly when the father was the transmitting parent.

Mapping

By genomewide linkage analysis of a Spanish family with autosomal dominant SCA, Serrano-Munuera et al. (2013) found linkage to a 0.66-cM interval on chromosome 1p32 between markers D1S200 and D1S2742 (Zmax of 6.539). Exome sequencing did not identify the causative mutation.

Molecular Genetics

In 35 affected individuals from 3 large, multigenerational kindreds (pedigrees M, G, and R) from southern Portugal with SCA37, Seixas et al. (2017) identified a heterozygous 5-bp ATTTC(n) insertion in the 5-prime untranslated region intron 3 of the DAB1 gene. The insertion was within a simple ATTTT/AAAAT repeat that localized to the polymorphic middle A-rich region of an AluJb sequence. The insertion mutation, which was found by a complex process of linkage analysis, next-generation sequencing, PCR analysis, Southern blot analysis, and Sanger sequencing, segregated with the disorder in the families. Six affected individuals from 3 additional Portuguese families with SCA37 also carried the pathogenic insertion. Haplotype analysis was consistent with a founder effect in all 6 families. The insertion was not detected in 520 control Portuguese chromosomes. The heterozygous ATTTC(n) insertion, ranging from 31 to 75 repeats, was always flanked by (ATTTT)n tracts larger than 58 repeats. There was an inverse correlation between ATTTC insertion size and age of onset. In addition, there was instability upon transmission of the pathogenic repeat, with an increase in length particularly when the father was the transmitting parent. In every disease allele, the insertion site was identical and placed in the middle of the normal ATTTT repeat, thus maintaining the pentanucleotide repeat structure. Sequence analysis of 260 control individuals showed that none contained the pathologic ATTTC repeat insertion. The distribution of normal ATTTT/AAAAT repeats in over 500 control subjects showed mostly alleles shorter than 30 repeats, with a rare group of larger alleles ranging from 30 to 400 repeats (about 7%). In vitro cellular expression studies showed that the ATTTC(n) insertion resulted in the formation of abnormal RNA aggregates with a nuclear localization. Injection of RNA containing the pathologic DAB1 repeat insertion into zebrafish embryos resulted in developmental defects and increased lethality.

In affected members of 4 unrelated families with SCA37, all from the same region in southern Spain, Corral-Juan et al. (2018) identified an unstable intronic ATTTC(n) pentanucleotide repeat within a noncoding regulatory region of the DAB1 gene. One of the families had previously been reported by Serrano-Munuera et al. (2013). The ATTTC repeat ranged from 46 to 71 repeats, and there was a significant inverse correlation between repeat size and age at onset in males, but not in females. Neuropathologic analysis of 2 patients showed that DAB1 was overexpressed in the cerebellum compared to controls, and DAB1 showed abnormal perisomatic and perinuclear punctate staining in remaining Purkinje cells. There was also dysregulated expression of DAB1 transcripts, reelin proteins, and upregulation of the reelin-DAB1 signaling pathway, which may adversely affect neuronal migration. Corral-Juan et al. (2018) suggested that the mutation resulted in a gain of function.