Spastic Paraplegia, Optic Atrophy, And Neuropathy

A number sign (#) is used with this entry because of evidence that spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is caused by homozygous mutation in the KLC2 gene (611729) on chromosome 11q13.2.

Description

Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive spastic paraplegia resulting in loss of independent ambulation in the teenage years. Additional features include optic atrophy, later onset of sensorimotor peripheral neuropathy, and progressive joint contractures; cognition remains intact (summary by Melo et al., 2015).

Clinical Features

Macedo-Souza et al. (2005) reported a large consanguineous Brazilian family in which 25 members had a neurologic disorder characterized by congenital optic atrophy, early-onset progressive spastic paraplegia, and distal axonal motor and sensory peripheral neuropathy (SPOAN). Affected patients showed mild motor developmental delay early in life with loss of independent ambulation by 10 years of age; 3 patients never achieved ambulation. Most patients had brisk proximal reflexes and absent distal reflexes, as well as impaired distal sensation to vibration and position; however, pain was not a feature. Dysarthria and distal amyotrophy were apparent in patients over 20 years of age. Exacerbated startle response to sound was present from infancy in all patients. Twelve patients had scoliosis, 5 of whom were severely affected. No patients had ataxia, dystonia, incontinence, or cognitive impairment. Electromyography (EMG) studies were consistent with an axonal motor and sensory neuropathy, and sural nerve biopsy showed decreased numbers of myelinated and unmyelinated fibers, some with bizarre shapes and thin myelin sheaths. Macedo-Souza et al. (2005) noted that the condition is common in Serrinha dos Pintos, an isolated area in northeastern Brazil, with an estimated carrier rate of 1 in 9.

Inheritance

The transmission pattern of SPOAN in the families reported by Macedo-Souza et al. (2005) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a large Brazilian family with SPOAN, Macedo-Souza et al. (2005) identified a 4.79-Mb candidate gene region on chromosome 11q13 between markers D11S1908 and D11S1889 (maximum 2-point lod score of 14.43 at D11S1883).

Macedo-Souza et al. (2009) recalculated linkage of SPOAN by including 44 additional patients from the same geographic area as those reported by Macedo-Souza et al. (2005) and obtained a maximum 2-point lod score of 33.2 at D11S987 and 27.0 at D11S1889. All affected individuals were homozygous for D11S1889 at chromosome 11q13. The critical region was reduced from 4.8 to 2.3 Mb between markers rs1939212 and D11S987. Within the critical region, the KLC2 (611729), CCS (603864), and LRFN4 (612810) genes were sequenced, but no mutations were identified.

Molecular Genetics

In 73 Brazilian patients and 2 sibs of Egyptian descent with SPOAN, Melo et al. (2015) identified a homozygous 216-bp deletion in the noncoding upstream region of the KLC2 gene (611729.0001). The deletion was not identified by whole-exome sequencing, but only by whole-genome sequencing. Patient fibroblasts and pluripotent stem cells induced into motor neurons showed increased expression of the KLC2 gene (increase of 48 to 74% compared to controls). There were no differences in KLC2 expression in peripheral blood cells between patients, heterozygous mutation carriers, and controls, suggesting a tissue-specific effect. Melo et al. (2015) noted that this was a novel molecular disease mechanism: a gain-of-function effect in a recessive disorder.

Animal Model

Melo et al. (2015) found that morpholino knockdown of the klc2 gene in zebrafish embryos resulted in a shortened and twisted tail and an inability to swim, in a dose-dependent manner. Overexpression of the klc2 gene resulted in a similar motor phenotype with increased lethality (over 70%).