Cerebellar Ataxia, Areflexia, Pes Cavus, Optic Atrophy, And Sensorineural Hearing Loss

A number sign (#) is used with this entry because cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) is caused by heterozygous mutation in the ATP1A3 gene (182350) on chromosome 19q13.

Heterozygous mutation in the ATP1A3 gene can also cause 2 other neurologic disorders that share some clinical features: dystonia-12 (DYT12; 128235) and alternating hemiplegia of childhood-2 (AHC2; 614820).

Description

Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) is an autosomal dominant neurologic disorder characterized by early-childhood onset of recurrent episodes of acute ataxic encephalopathy associated with febrile illnesses. These acute episodes tend to decrease with time, but the neurologic sequelae are permanent and progressive, resulting in gait and limb ataxia and areflexia. Affected individuals also develop progressive visual impairment due to optic atrophy and sensorineural hearing loss beginning in childhood. More variable features include abnormal eye movements, pes cavus, and dysphagia (summary by Demos et al., 2014).

Clinical Features

Nicolaides et al. (1996) reported the cases of a mother and a son and daughter with a relapsing, early-onset cerebellar ataxia, associated with progressive optic atrophy and sensorineural deafness. The 3 patients had areflexia (in the absence of a peripheral neuropathy) and pes cavus deformity and showed varying degrees of severity. Extensive neurologic investigations were normal. The male proband presented at the age of 16 months with a 1-day history of nonspecific febrile illness followed by generalized hypotonia and cerebellar ataxia. This episode resolved over the next few days and he made a full recovery within 3 weeks of onset. At the age of 2 years he experienced a similar febrile illness which was associated with drowsiness and lethargy that lasted for a week. He pursued a relapsing and remitting course thereafter. By the age of 6 years his gait was markedly ataxic and he had other signs of cerebellar ataxia and had developed progressive optic atrophy and sensorineural deafness. The proband's previously well sister had nonspecific febrile illness at the age of 9 months accompanied with marked hypotonia, nystagmus, ataxia, areflexia, and flexor plantar responses. She had a complete recovery over 3 days but had persisting horizontal nystagmus, mild, generalized hypotonia, areflexia, and early optic atrophy. Her hearing responses to low-frequency sounds were significantly raised. Cranial MRI for both the daughter and the son was normal. The mother, age 31 years, had mild cerebellar ataxia, absent deep tendon reflexes, pes cavus, profound sensorineural deafness, horizontal nystagmus, and bilateral optic atrophy. She had been well until the age of 18 months when she developed acute ataxia during a febrile illness. Nicolaides et al. (1996) noted that 2 maternal sibs (a brother and sister) were unaffected and the grandparents were normal on neurologic examination. Demos et al. (2014) reported follow-up of the family with CAPOS reported by Nicolaides et al. (1996). The affected individuals, aged 22, 20, and 49 years, respectively, had had no further acute episodes, but showed slow progression of all symptoms. They had variable difficulties walking due to poor balance, poor vision, and hearing loss. Cognition was unaffected and brain imaging was normal.

Demos et al. (2014) reported 2 previously unreported Caucasian families of European descent with the disorder. In 1 family, a man and his 3 children were affected. All had onset in infancy or early childhood of acute episodic ataxic encephalopathy and/or weakness triggered by a febrile illness. There was poor recovery after these episodes, with variable lingering neurologic abnormalities, including dysarthria, dysphagia, dysmetria, abnormal eye movements, nystagmus, and truncal and gait ataxia. However, the severity of the permanent neurologic sequelae varied. All eventually developed optic atrophy and sensorineural hearing loss, resulting in blindness and profound deafness in the 43-year-old father. Only 1 patient with the most severe phenotype was found to have mild cognitive dysfunction at age 10 years. A mother and her 2 children were affected in the second family. They presented with recurrent acute episodes of neurologic impairment associated with febrile illnesses beginning in the first years of life. Features included weakness, ataxia, and a progressive decline in hearing and vision. The 2 children showed signs of autistic behavior later in childhood. Brain imaging was normal in all patients studied. Among 10 individuals from 3 families, only 1 patient developed cervical dystonia at age 32 years.

Rosewich et al. (2014) reported a German boy, born of unrelated parents, with a phenotype consistent with CAPOS. After normal early development, he presented at age 20 months with neurologic impairment associated with a febrile illness. He had strabismus, anarthria, hypotonia, and weakness of the right arm. Marked ataxia as well as paresis and dystonia of the arm persisted after the episode. Several subsequent febrile episodes were accompanied by motor deterioration with rapid recovery, but with some residual deficits. He had no further episodes after age 6 years. Examination at age 12 years showed dysarthria, postural instability, bradykinesia, ataxia, hypotonia, dystonia, areflexia, impaired vision with partial optic atrophy, and moderate hearing impairment requiring hearing aids. Rosewich et al. (2014) noted the phenotypic overlap of CAPOS and AHC2 in this patient.

Inheritance

The transmission pattern of CAPOS in the family reported by Nicolaides et al. (1996) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 10 patients from 3 unrelated families with CAPOS, including the original family reported by Nicolaides et al. (1996), Demos et al. (2014) identified the same heterozygous missense mutation in the ATP1A3 gene (E818K; 182350.0014). The mutation was found by whole-exome sequencing of 2 of the families. The mutation was demonstrated to have occurred de novo in the oldest affected generation of 1 family, but haplotype analysis could not rule out the possibility of a remote relationship between the other 2 families. Functional studies of the E818K variant were not performed, but Demos et al. (2014) postulated a gain-of-function effect.

In a German boy with CAPOS, Rosewich et al. (2014) identified a de novo heterozygous E818K mutation in the ATP1A3 gene. Functional studies were not performed.