Posterior Column Ataxia With Retinitis Pigmentosa

A number sign (#) is used with this entry because posterior column ataxia with retinitis pigmentosa (AXPC1) is caused by homozygous mutation in the FLVCR1 gene (609144) on chromosome 1q32.

Description

Posterior column ataxia with retinitis pigmentosa is an autosomal recessive neurologic disorder characterized by childhood-onset retinitis pigmentosa and later onset of gait ataxia due to sensory loss (summary by Ishiura et al., 2011).

Clinical Features

Higgins et al. (1997) reported a large kindred in which 6 members had an autosomal recessive form of ataxia. Onset was in childhood with concentric contraction of the visual fields and proprioceptive loss. By the third decade, affected individuals became blind, had severe sensory ataxia, achalasia, scoliosis, and inanition (weakness and wasting). Sensory nerve conduction velocities were absent. MRI showed hyperintense signals in the spinal cord. The original founder of the family was born in 1765 and immigrated to colonial America from a territory along the German-Swiss border. Eleven generations could be traced. Higgins et al. (1997) noted that a similar phenotype with autosomal dominant inheritance, Biemond ataxia (176250), had been described.

Berciano and Polo (1998) reported a consanguineous Spanish family with a phenotype identical to that described by Higgins et al. (1997). The Spanish family had previously been characterized as having early-onset cerebellar ataxia. Rajadhyaksha et al. (2010) provided more clinical details of the Spanish family reported by Berciano and Polo (1998). All affected individuals had visual disturbances due to retinitis pigmentosa during the first decade of life. Gait abnormalities became noticeable by the second decade, and slowly progressed thereafter. One patient, who had onset of ataxia at age 14 years, had a sural nerve biopsy at age 35 that showed a loss of large myelinated fibers.

Rajadhyaksha et al. (2010) reported another family, of French Canadian origin, with the disorder. Affected individuals had a childhood-onset hereditary sensory neuropathy with retinitis pigmentosa and ataxia. Initial presentations included delayed walking, orthopedic deformities, scoliosis, and mild distal weakness of intrinsic hand and foot muscles. Neuropathy was characterized by decreased fine touch and vibration with proprioceptive loss in the feet and areflexia. All lost the ability to walk. Upper limb ataxia was mild. Other features included recurrent urinary tract infections and incontinence.

Ishiura et al. (2011) reported 2 sibs, born of consanguineous Japanese parents, with autosomal recessive PCARP. The index patient developed night-blindness at age 5 years and later developed ataxic gait. On examination at age 31 years, she had retinitis pigmentosa with optic atrophy. She also had mild mental retardation and showed ataxic gait and truncal titubation; Romberg sign was positive. There was decreased muscle tone in the limbs with normal strength. Deep tendon reflexes were decreased in the arms and absent in the legs, and vibratory and position sense were lost in the toes. Peripheral blood smear showed no acanthocytes. Axial MRI showed a hyperintense signal in the posterior half of the cervical spinal cord. Her brother was similarly affected. Ishiura et al. (2011) noted that mental retardation had not previously been described in this disorder and speculated that it may have an alternative cause in this family.

Mapping

By linkage analysis of the affected family reported by Higgins et al. (1997), Higgins et al. (1999) mapped the disease locus, termed AXPC1, to an 8.3-cM region on chromosome 1q31-q32 between markers D1S2692 and D1S414 (maximum lod score of 8.94 at D1S2692).

Higgins et al. (2000) found that the family reported by Berciano and Polo (1998) showed linkage to the AXPC1 locus, with a maximum lod score of 3.56 at D1S414.

By further genetic mapping of the families reported by Higgins et al. (1999) and Berciano and Polo (1998), Rajadhyaksha et al. (2010) narrowed the AXPC1 locus to a 4.2-Mb region between rs10494961 and rs9309430.

Molecular Genetics

In affected members of the German-Swiss family reported by Higgins et al. (1997), Rajadhyaksha et al. (2010) identified a homozygous mutation in the FLVCR1 gene (N121D; 609144.0001). The mutation was found by targeted DNA capture and high-throughput sequencing of the 4.2-Mb AXPC1 locus, followed by bioinformatics analysis and filtering. Further analysis of a Spanish and a French Canadian family with the disorder identified 2 additional homozygous mutations in the FLVCR1 gene (A241T, 609144.0002 and C192R, 609144.0003, respectively). Based on the function of FLVCR1, Rajadhyaksha et al. (2010) hypothesized that a defect in heme regulation or processing in the central nervous system may result in neurodegeneration.

In a Pennsylvania Mennonite patient with posterior column ataxia and retinitis pigmentosa, Puffenberger et al. (2012) identified homozygosity for the N121D mutation in the FLVCR1 gene (609144.0001), previously found in the German-Swiss family originally reported by Higgins et al. (1997). The variant was detected in heterozygosity in 5 of 406 Mennonite control chromosomes, for a population-specific allele frequency of 1.23%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.)

By linkage analysis followed by candidate gene sequencing in 2 Japanese sibs, born of consanguineous parents, with PCARP and mild mental retardation, Ishiura et al. (2011) identified a homozygous mutation in the FLVCR1 gene (G493R; 609144.0004). Each unaffected parent and an unaffected sib was heterozygous for the mutation.