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SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE; SPG46

SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE; SPG46

Autosomal recessive spastic paraplegia-46 (SPG46) is a neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia an...

Autosomal recessive spastic paraplegia-46 (SPG46) is a neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging (summary by Boukhris et al., 2010 and Martin et al., 2013).

For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

▼ Clinical Features

Boukhris et al. (2008) reported a consanguineous Tunisian family (TUN35) in which 5 individuals had a form of early-onset complicated spastic paraplegia. The patients had insidious onset of stiffness and weakness of the lower limbs between 2 and 10 years of age. On physical examination at ages 30 to 35 years, there was a mild to moderate handicap, with only 1 patient requiring a walking aid. All patients showed typical signs of spastic paraplegia, such as spastic gait and weakness of the lower limbs with brisk reflexes and bilateral extensor plantar responses. More variable features included upper limb spasticity and weakness, pseudobulbar dysarthria (in 3), and bladder dysfunction (in 2). Intellectual development was normal in early childhood, but mild cognitive decline appeared progressively as gait difficulties worsened. All also had upper limb dysmetria, suggestive of cerebellar dysfunction, as well as congenital bilateral cataract. Four patients had pes cavus, 2 had scoliosis, and 1 had decreased vibration sense. Brain imaging of 2 patients showed thinning of the corpus callosum and mild cerebellar and cerebral atrophy. Linkage to SPG11 (604360), SPG15 (270700), and other known SPG loci was excluded.

Martin et al. (2013) restudied the Tunisian family reported by Boukhris et al. (2008) and presented 3 additional families with SPG46. There were 11 patients in all. The phenotype was homogeneous: patients presented with progressive difficulty walking due to lower limb spasticity in infancy or childhood (range, 1-16 years), resulting in a need for a cane in their twenties and a wheelchair in their fifties. All developed cerebellar ataxia and cataracts. All patients also had mild to moderate mental impairment, which progressed to dementia in older age. Three patients had hearing loss, and 3 had an axonal neuropathy. Brain MRI showed atrophy of the cerebrum, cerebellum, and corpus callosum. Two affected males had testicular hypotrophy with normal hormone function. Semen analysis of 1 of these men showed severe spermatozoid head abnormalities with necrospermia and reduced velocity, consistent with infertility.

Hammer et al. (2013) reported 4 unrelated Tunisian families with an autosomal recessive neurologic disorder. Three of the families had previously been reported by Bouhlal et al. (2005). All patients presented in the first or second decades with cerebellar ataxia and later developed prominent spasticity with hyperreflexia and extensor plantar responses, as well as an axonal peripheral neuropathy. Only 1 patient had mild cognitive impairment. More variable features included scoliosis, Hoffman sign, and head tremor. Brain imaging was normal, except in 1 patient who had cerebral, cerebellar, and corpus callosum atrophy.

Votsi et al. (2014) reported 3 sibs, born of consanguineous Cypriot parents, with SPG46. The patients presented at ages 14, 13, and 20 years, respectively, with marked spasticity in the lower limbs resulting in gait disturbances. The patients also had cerebellar ataxia, with truncal ataxia and wide-based gait. Other features included upper limb spasticity, pes cavus, tendon contractures, jerky ocular pursuit, and nystagmus. The disorder was progressive, and all became wheelchair-bound within 20 to 25 years of disease onset. Later in the disease course, the patients developed additional features, including mild cognitive impairment, hearing loss, urinary incontinence, spastic dysarthria and dysphagia, and decreased vibration sense in the distal lower limbs. Brain MRI showed cerebellar atrophy.

▼ Inheritance

The transmission pattern of spastic paraplegia in the family reported by Boukhris et al. (2008) was consistent with autosomal recessive inheritance.

▼ Mapping

By genomewide linkage analysis followed by fine mapping in the Tunisian family reported by Boukhris et al. (2008), Boukhris et al. (2010) found linkage to a 15.4-cM (45.1-Mb) region between markers rs9103 and D9S1799 on chromosome 9p21.2-q21.12 (maximum 2-point lod score of 3.27 at D9S304 under stringent conditions). Multipoint analysis using markers in the candidate interval generated a significant lod score of 5.21. The locus was designated SPG46. Sequencing of exons and intron/exon boundaries of 3 candidate genes, CNTFR (118946), DNAJB5 (611328), and FBXO10 (609092), failed to identify any pathogenic mutations.

▼ Molecular Genetics

In 11 patients from 4 unrelated families with autosomal recessive hereditary spastic paraplegia-46, Martin et al. (2013) identified 4 different biallelic mutations in the GBA2 gene (609471.0001-609471.0004). Three of the mutations were truncating, and 1 was a missense mutation that was shown to result in complete loss of enzyme function. The mutations were found by exome sequencing of the candidate region identified by linkage analysis.

In 10 patients from 4 unrelated Tunisian families with autosomal recessive cerebellar ataxia and spasticity, Hammer et al. (2013) identified 3 different homozygous mutations in the GBA2 gene (609471.0005-609471.0007). The first 2 mutations were identified by homozygosity mapping and exome sequencing.

In 3 sibs, born of consanguineous Cypriot parents, with SPG46, Votsi et al. (2014) identified a homozygous mutation in the GBA2 gene (D594H; 609471.0008).

▼ Animal Model

Martin et al. (2013) found that morpholino knockout of the Gba2 gene in zebrafish induced a curly tail phenotype in 12.5% of morphants, but 73.8% had no visible abnormalities. However, 24% of those that appeared normal showed significant motility defects compared to control embryos. These defects were associated with abnormal development of spinal motoneurons and defects in axonal outgrowth. Some of these defects could be rescued when coexpressed with wildtype human GBA2.

Tags: 9p13.3