Spinocerebellar Ataxia, Autosomal Recessive 12

A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-12 (SCAR12) is caused by homozygous mutation in the WWOX gene (605131) on chromosome 16q23.

Biallelic mutation in the WWOX gene can also cause early infantile epileptic encephalopathy-28 (EIEE28; 616211), a more severe disorder with some overlapping features.

Description

Autosomal recessive spinocerebellar ataxia-12 is a neurologic disorder characterized by onset of generalized seizures in infancy, delayed psychomotor development with mental retardation, and cerebellar ataxia. Some patients may also show spasticity (summary by Mallaret et al., 2014).

Clinical Features

Gribaa et al. (2007) reported 4 sibs, born of consanguineous Saudi Arabian parents, with early-childhood onset of cerebellar ataxia associated with generalized seizures and delayed psychomotor development. Seizure onset occurred between 9 and 12 months. All showed gait ataxia when they achieved walking, which was delayed until 2 to 3 years of age. Other features included upper and lower limb ataxia, dysarthria, gaze-evoked nystagmus, and learning difficulties. Brain MRI of 2 patients showed mild cerebellar atrophy.

Mallaret et al. (2014) reported 2 sibs, born of consanguineous Israeli Palestinian parents, with onset of generalized tonic-clonic seizures in the first 2 years of life. They also had mental retardation, ataxia, and prominent upper motor neuron signs with leg spasticity and extensor plantar responses.

Inheritance

The transmission pattern of spinocerebellar ataxia in the family reported by Gribaa et al. (2007) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a Saudi Arabian family with complicated autosomal recessive spinocerebellar ataxia, Gribaa et al. (2007) found linkage to a 19-Mb interval on chromosome 16q21-q23 between markers D16S3091 and D16S3050 (lod score of 3.3). Molecular studies excluded mutations in the GAN gene (605379).

Molecular Genetics

In affected members of 2 consanguineous families of Saudi Arabian and Israeli Palestinian descent, respectively, with autosomal recessive spinocerebellar ataxia-12, Mallaret et al. (2014) identified 2 different homozygous missense mutations in the WWOX gene (P47T, 605131.0002 and G372R, 605131.0003). One of the families had previously been reported by Gribaa et al. (2007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient fibroblasts showed normal amounts of the mutant P47T protein, but in vitro functional studies showed that the mutant protein was unable to bind a PPPY-containing oligopeptide, suggesting that the mutation causes a conformational change that alters its ability to interact with normal protein motifs. None of the patients or heterozygous carriers developed cancer. No WWOX mutations were found in 189 additional unrelated ataxic patients.

Animal Model

Mallaret et al. (2014) observed that Wwox-null mice developed spontaneous seizures and noise-induced seizures at around 2 weeks of age. Knockout mice also developed balance disturbances. The progression of these symptoms suggested a neurodegenerative process. These mice died from failure to thrive before age 4 weeks.