Spastic Paraplegia 39, Autosomal Recessive

A number sign (#) is used with this entry because spastic paraplegia-39 (SPG39) is caused by homozygous or compound heterozygous mutation in the PNPLA6 gene (603197) on chromosome 19p13.

Description

The form of motor neuron disease designated spastic paraplegia-39 (SPG39) by Rainier et al. (2008) is an autosomal recessive progressive spastic paraplegia associated with distal upper and lower extremity wasting.

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.

Clinical Features

Rainier et al. (2008) reported a consanguineous family of Ashkenazi Jewish ancestry and an unrelated nonconsanguineous family of northern European ancestry in which affected subjects developed childhood onset of insidiously progressive lower extremity spastic weakness and progressive wasting of distal upper and lower extremity muscles. Electrophysiologic studies were consistent with a motor axonopathy affecting upper and lower limbs. Magnetic resonance imaging demonstrated spinal cord atrophy, particularly in the thoracic region. The affected phenotype in each family conformed both to organophosphorous (OP) compound-induced delayed neuropathy (OPIDN) and to Troyer syndrome (275900), an autosomal recessive hereditary spastic paraplegia associated with distal muscle wasting. However, additional neurologic and systemic abnormalities seen in Troyer syndrome, including delayed milestone acquisition, skeletal abnormalities, and cerebellar, extrapyramidal, and cognitive impairment, were not observed.

Synofzik et al. (2014) reported a 56-year-old German woman with SPG39 who developed spasticity with hyperreflexia and extensor plantar responses at age 20 years. She had no other abnormalities and brain imaging was normal. A 48-year-old unrelated German man developed spastic gait ataxia at age 4 years. He had hyperreflexia, extensor plantar responses, and cerebellar atrophy on brain imaging. The phenotypes of these patients illustrate the clinical variability that is associated with SPG39.

Mapping

Rainier et al. (2008) performed genomewide linkage analysis in a large consanguineous Ashkenazi family and in a second nonconsanguineous family. An extended linkage haplotype that spanned 22 cM between D19S565 and D19S884 on chromosome 19p13 was defined in the consanguineous family; in the nonconsanguineous family the same markers also resulted in haplotype sharing in affected subjects, consistent with genetic linkage of the region.

Molecular Genetics

In affected members of 2 families with motor neuron disease, Rainier et al. (2008) detected homozygosity or compound heterozygosity for mutations in the NTE gene. Affected subjects in the consanguineous kindred were homozygous for a disease-specific NTE mutation, 3034A-G, that disrupted an interspecies-conserved residue in NTE's catalytic domain (M1012V; 603197.0001). Affected subjects in the nonconsanguineous family were compound heterozygotes: 1 allele carried a 2669G-A mutation that disrupted an interspecies-conserved residue in NTE's catalytic domain (R890H; 603197.0002), and the other allele had an insertion that caused frameshift and protein truncation (603197.0003).

In 2 unrelated German patients with SPG39, Synofzik et al. (2014) identified compound heterozygous mutations in the PNPLA6 gene (see, e.g., 603197.0009 and 603197.0010).