Spinocerebellar Ataxia 29

A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-29 (SCA29), also known as congenital nonprogressive cerebellar ataxia (CNPCA), is caused by heterozygous mutation in the ITPR1 gene (147265) on chromosome 3p26.

Description

Spinocerebellar ataxia-29 is an autosomal dominant neurologic disorder characterized by onset in infancy of delayed motor development and mild cognitive delay. Affected individuals develop a very slowly progressive or nonprogressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor (summary by Huang et al., 2012).

Heterozygous mutation in the ITPR1 gene also causes SCA15 (606658), which is distinguished by later age at onset and normal cognition.

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

Clinical Features

Tomiwa et al. (1987) reported affected mother and daughter with nonprogressive congenital cerebellar ataxia and normal intelligence. Computed tomography revealed localized atrophy of the cerebellar vermis. Kattah et al. (1983) described a family in which 5 members had primary position vertical nystagmus.

Fenichel and Phillips (1989) described a family in which 4 persons in 3 generations had nonprogressive ataxia from birth. Magnetic resonance imaging in 1 child showed hypoplasia or partial aplasia of the cerebellar vermis. Patients had delayed motor development, truncal ataxia, nystagmus, and normal intelligence. Fenichel and Phillips (1989) were impressed with the fact that 12 of 14 reported persons were female and that 2 affected males were more severely affected than were their female relatives. This led them to suggest both X-linked dominant and autosomal dominant inheritance as possibilities. Rivier and Echenne (1992) described a mother and her 2 daughters with congenital, nonprogressive cerebellar ataxia and atrophy of the cerebellar vermis. Slowly progressive improvement of motor abilities in all 3 patients was an unusual feature. Imamura et al. (1993) described a mother and daughter with early-onset nonprogressive cerebellar ataxia. The mother had a broad-based unsteady gait with frequent falling dating from the first years of life. She had cerebellar signs, including bilateral horizontal nystagmus. MRI at the age of 29 demonstrated increased sulcation of the cerebellar hemispheres and atrophic vermian lobules and hemispheric folia, especially in the anterior part. The basal cistern was enlarged. One of her 2 children, a daughter, was floppy from birth and at 8 months also demonstrated delayed development and truncal ataxia. Cerebellar atrophy, which could not be detected by CT at the age of 12 months, was clearly discernible by MRI at the age of 3. Male-to-male transmission was reported by Kornberg and Shield (1991). A preponderance of female patients seems to have been observed.

Dudding et al. (2004) reported a 4-generation Australian kindred of Caucasian ancestry in which at least 20 members had congenital nonprogressive ataxia inherited in an autosomal dominant pattern. All affected individuals had congenital onset of ataxia or delayed walking and wide-based gait as a young child. In addition, all affected members had cognitive impairment of varying degrees, which was more disabling than the ataxia. Although dysarthria was common, nystagmus and dysdiadochokinesis were only observed in 1 and 2 patients, respectively. Five family members reported a slight improvement in coordination with increasing age. Three of 7 patients who agreed to testing had atrophy of the cerebellar vermis on MRI, and there was no association between cerebellar hypoplasia and the degree of either ataxia or cognitive impairment. Linkage analysis excluded the major loci for spinocerebellar ataxia.

Titomanlio et al. (2005) reported a father and son with a mild form of isolated cerebellar vermis aplasia, confirming an autosomal dominant mode of inheritance of the disease. Both patients showed progressive improvement of their motor abilities; neurologic examination of the father at age 35 was normal except for mild mental retardation.

Huang et al. (2012) reported a 3-generation Canadian family in which 4 individuals had early-onset nonprogressive spinocerebellar ataxia. The proband, in the third generation, was noted to have delayed psychomotor development at age 8 months. Physical examination at age 28 months showed language delay, gaze-evoked nystagmus, hypotonia, truncal titubation, appendicular dysmetria, poor speech, and lack of independent ambulation. Brain MRI showed mild atrophy of the cerebellar vermis, which progressed on reassessment several years later. At age 5 years, she developed complex partial seizures that responded to medication. Her 45-year-old father had delayed motor development and reported academic difficulties, although he completed high school and some college courses. Physical examination of the father showed saccadic eye movements, end-range nystagmus, dysarthria, gait and limb ataxia, and intention tremor. Brain MRI showed diffuse cerebellar atrophy. The proband's paternal aunt showed delayed ambulation and learning difficulties, and the paternal grandmother was similarly affected. Sensation was not affected in this family.

Parolin Schnekenberg et al. (2015) reported 2 unrelated children with a clinical diagnosis of ataxic cerebral palsy who were found to carry 2 different de novo heterozygous mutations in the ITPR1 gene (see, e.g., 147265.0004). Both patients showed delayed motor development, ataxic gait, and moderate intellectual disability. Other more variable features included nystagmus and hyperreflexia. Brain imaging was normal in both patients. Functional studies of the variants were not performed.

Inheritance

The transmission pattern of congenital ataxia in the family reported by Dudding et al. (2004) was consistent with autosomal dominant inheritance.

Mapping

By genomewide analysis of a large kindred with congenital nonprogressive cerebellar ataxia, Dudding et al. (2004) identified linkage to an 18.9-cM region on chromosome 3p (maximum 2-point lod score of 4.26 at marker D3S3630). The disease locus lies distal to D3S1304 in the pter region of chromosome 3. Approximately 8 cM of the candidate region overlaps with the locus defined for SCA15 (606658). In a review of the literature, Dudding et al. (2004) noted the phenotypic variability of autosomal dominant congenital nonprogressive cerebellar ataxia and suggested that it may be a genetically heterogeneous condition.

Genetic Heterogeneity

Furman et al. (1985) reported a family in which a mother and 2 daughters had an early-onset nonprogressive form of ataxia. The mother presented with oscillopsia and visual blurring at the age of 32 years. She had been clumsy all her life, without progression of symptoms. She had normal intelligence, truncal ataxia, mild limb dysmetria, upbeating nystagmus, and gaze-provoked horizontal nystagmus. All 3 affected members had localized atrophy of the cerebellar vermis on brain MRI. Jen et al. (2006) provided follow-up of the family reported by Furman et al. (1985); 2 additional affected children were identified. The disorder was found to be nonprogressive: older family members showed no change in cerebellar atrophy on MRI. The initial presentation of primary position upbeat nystagmus resolved to only gaze-evoked nystagmus. Older individuals developed episodes of vertigo and ataxia with vertical oscillopsia, similar to an episodic ataxia syndrome. Of all 5 affected family members, 2 showed developmental delay and learning difficulties. Using genomewide microarray analysis, Jen et al. (2006) excluded linkage of the family reported by Furman et al. (1985) to chromosome 3p, as well as other loci reported for dominantly inherited SCA syndromes. Jen et al. (2006) found suggestive linkage (lod scores near 1.8) to chromosomes 1q44, 5q35, 7q36, and 9q31-q32. The findings indicated genetic heterogeneity for autosomal dominant nonprogressive congenital ataxia.

Molecular Genetics

By exome sequencing of a member of the family with SCA29 reported by Dudding et al. (2004), Huang et al. (2012) identified a heterozygous mutation in the ITPR1 gene (V1553M; 147265.0003). The mutation was confirmed by Sanger sequencing and segregated with the disorder in this family. Direct sequencing of the ITPR1 gene in a Canadian family with a similar disorder identified a different heterozygous missense mutation (N602D; 147265.0004). Both mutations occurred at highly conserved residues in the coupling/regulatory domain that modulates channel function, possibly resulting in dysregulation of intracellular calcium signaling.

Animal Model

Ogura et al. (2001) found that heterozygous Itpr1 knockout mice (Itpr1 +/-) demonstrated impaired motor coordination compared to wildtype mice as shown on the rotarod test.