Spinocerebellar Ataxia, Autosomal Recessive 7

A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-7 (SCAR7) is caused by compound heterozygous mutation in the TPP1 gene (607998) on chromosome 11p15.

Biallelic mutation in the TPP1 gene can also cause neuronal ceroid lipofuscinosis-2 (CLN2; 204500).

Description

Autosomal recessive spinocerebellar ataxia is a neurologic disorder characterized by onset of progressive gait difficulties, eye movement abnormalities, and dysarthria in the first or second decade of life (summary by Dy et al., 2015).

Clinical Features

Breedveld et al. (2004) reported a Dutch family in which 5 sibs were affected with childhood-onset, slowly progressive spinocerebellar ataxia. The authors assumed autosomal recessive inheritance. All patients were examined as adults (age range from 46 to 64 years). Common clinical features included difficulty walking and writing, dysarthria, limb ataxia, and cerebellar atrophy. Three patients had nystagmus, 4 had saccadic pursuit eye movements, 2 had postural tremor, 4 had hyperreflexia, and 2 had extensor plantar responses. Three patients had decreased vibration sense, suggesting posterior column involvement. Two patients became wheelchair-dependent late in life. The severity of symptoms varied from mild to severe. Loci for common causes of autosomal dominant and autosomal recessive cerebellar ataxia were excluded.

Sun et al. (2013) reported a 51-year-old Dutch woman with SCAR7 confirmed by genetic analysis. She had onset of diplopia at the age of 18 years. She developed gait abnormalities 2 years later and was diagnosed with cerebellar atrophy at age 28. The disorder was slowly progressive, and she could still walk independently in middle age. Other features included loss of dexterity, dysarthria, swallowing difficulties, urinary urgency, and hyperreflexia. Brain MRI showed diffuse cerebellar atrophy, and laboratory studies showed decreased TPP1 activity. There was no family history of a similar disorder.

Dy et al. (2015) reported an 11-year-old girl with SCAR7 confirmed by genetic analysis. She developed fine motor difficulties at age 4 years, followed by gait, balance, coordination, and academic performance issues at age 6. Examination at age 7 showed impaired neurocognitive function with poor language skills and scanning speech. Other features included nystagmus, saccadic pursuits, oculomotor apraxia, dysmetria, truncal titubation, and unsteady gait. Brain imaging showed cerebellar and pontine atrophy as well as ill-defined white matter lesions in the posterior periventricular white matter.

Inheritance

The transmission pattern of SCAR7 in the family reported by Breedveld et al. (2004) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a Dutch family with autosomal recessive spinocerebellar ataxia, Breedveld et al. (2004) identified a 5.9-cM candidate disease locus on chromosome 11p15 between markers D11S4088 and D11S1331 (maximum lod score of 3.3 at D11S1871).

Molecular Genetics

In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7, originally reported by Breedveld et al. (2004), Sun et al. (2013) identified compound heterozygous mutations in the TPP1 gene: a splice site mutation resulting in premature termination (607998.0004) and a missense mutation (V466G; 607998.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. Electron microscopic analysis of 1 affected family member's skin fibroblasts showed some granular osmiophilic deposits (GROD) and fingerprint profiles, but no curvilinear profiles. Analysis of the unrelated Dutch woman's fibroblasts showed no abnormalities. Sun et al. (2013) suggested that V466G yields a hypomorphic allele with residual functional TPP1 activity, which likely results in a later age at onset and a less severe phenotype in patients with SCAR7 compared to patients with CLN2 (204500), an allelic disorder.

In an 11-year-old girl with SCAR7, Dy et al. (2015) identified compound heterozygous mutations in the TPP1 gene: the common splice site mutation (607998.0004) and a missense mutation (E343D; 607998.0011). The mutations were found by whole-exome sequencing. TPP1 activity in patient cells was significantly decreased (3 to 15%) compared to controls.