Ataxia, Combined Cerebellar And Peripheral, With Hearing Loss And Diabetes Mellitus

A number sign (#) is used with this entry because of evidence that combined cerebellar and peripheral ataxia with hearing loss and diabetes mellitus (ACPHD) is caused by homozygous mutation in the DNAJC3 gene (601184) on chromosome 13q32. One such family has been reported.

Clinical Features

Synofzik et al. (2014) reported 3 adult sibs, from a 'likely consanguineous' (Synofzik, 2015) Turkish family, with juvenile-onset insulin-dependent diabetes mellitus and central and peripheral nervous system abnormalities. The neurologic features included combined cerebellar and afferent ataxia, mild upper motor neuron damage, demyelinating sensorimotor peripheral neuropathy, and sensorineural hearing loss. All 3 patients had onset of diabetes between 15 and 18 years of age. The age at onset of the neurologic features ranged widely: 1 sib had onset of hearing loss and gait disturbances at age 6, another had onset of these symptoms in the teenage years, and the third had onset of hearing loss at age 27 and gait disturbances at age 34. The patients also had an 'isolated cognitive deficit in backward calculation of serial sevens.' Synofzik et al. (2014) also reported 2 sisters, born of consanguineous parents, with a similar disorder. The sisters were 20 and 14 years old and had onset of insulin-dependent diabetes mellitus at ages 14 and 11 years, respectively. One sister had onset of hearing loss and gait disturbance at age 2 years, whereas the other had normal hearing and onset of gait disturbance at age 11 years. All 5 patients had short stature and low body mass index, as well as biochemical evidence of residual endogenous insulin secretion. One patient from each family had extensor plantar responses, indicating upper motor neuron damage. Brain imaging of 1 patient from each family showed generalized supra- and infratentorial cerebral atrophy pronounced in the cervical cord, cerebellum, and midbrain.

Inheritance

The transmission pattern of ACPHD in the families reported by Synofzik et al. (2014) was consistent with autosomal recessive inheritance.

Cytogenetics

In 2 sisters, born of consanguineous parents, with ACPHD, Synofzik et al. (2014) identified a homozygous 72-kb deletion in the DNAJC3 gene, resulting in the deletion of exons 6 to 12 of DNAJC3 and the last exon of the neighboring UGGT2 gene (605898), which is transcribed in the opposite direction. The proband in this family was ascertained from 8 individuals with a similar phenotype who underwent Sanger sequencing of the DNAJC3 gene. Patient fibroblasts showed absence of the DNAJC3 protein. Synofzik (2015) stated that this family was Turkish.

Molecular Genetics

In 3 sibs from a Turkish family with ACPHD, Synofzik et al. (2014) identified a homozygous truncating mutation in the DNAJC3 gene (R194X; 601184.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed absence of the DNAJC3 protein. There were no morphologic or functional abnormalities of the endoplasmic reticulum (ER) in patient fibroblasts, but Synofzik et al. (2014) noted that such changes may be found only in specific tissues, such as pancreas or neurons, which were not available for testing. (There was a discrepancy in the article by Synofzik et al. (2014) regarding consanguinity in this family; Synofzik (2015) stated that the family was 'likely consanguineous.')

Animal Model

Ladiges et al. (2005) found that Dnajc3-null mice developed glucosuria and hyperglycemia associated with decreased insulin resulting from increased apoptosis of pancreatic islet cells. Mutant mice were also smaller than control mice due to decreased body fat. Ladiges et al. (2005) noted that Dnajc3 acts to downregulate the ER stress response, and suggested that their findings implicated a role for ER stress-mediated apoptosis in the development of diabetes mellitus.