A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-18B (SPG18B) is caused by homozygous mutation in the ERLIN2 gene (611605) on chromosome 8p11.

Heterozygous mutation in the ERLIN2 gene causes autosomal dominant spastic paraplegia-18A (620512).

Spastic paraplegia-18B (SPG18B) is a severe autosomal recessive neurologic disorder characterized by onset in early childhood of progressive spastic paraplegia resulting in motor disability. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures (summary by Alazami et al., 2011 and Yildirim et al., 2011).

Al-Yahyaee et al. (2006) reported 2 unrelated consanguineous Omani families with autosomal recessive complicated SPG. In 1 family (family B), 3 affected individuals presented with walking difficulties between ages 4 and 6 years. Physical examination showed lower limb spasticity primarily affecting the hamstring and posterior tibial muscles. Two of the children also had epilepsy; all had normal brain CT scans and normal mental development. Affected individuals from the second family (family A) had early-onset spasticity, mental retardation, and thin corpus callosum on brain MRI. Family A was later found by Schuurs-Hoeijmakers et al. (2012) to have SPG54 (615033), caused by mutation in the DDHD2 gene (615003) on chromosome 8p11.

Alazami et al. (2011) reported a consanguineous Saudi family with a complicated form of SPG. One of 2 affected sibs was described in detail. At age 30 months, he developed progressive tightening of the lower extremities with later involvement of the upper extremities, rendering him wheelchair-bound at age 4 years. He had a history of delayed early motor development and intellectual disability, and failed to acquire language. He also developed seizures at age 7 years, and EEG was severely abnormal, with generalized slowing of background and generalized slow spike and wave activities compatible with atypical absence epilepsy. Brain MRI was normal. His younger sister had a similar disease course, except without seizures. Three maternal uncles, who were not examined, reportedly had severe intellectual disability, aphasia, and marked hypertonia, all without seizures.

Yildirim et al. (2011) reported a very large, highly consanguineous family from eastern Turkey with a neurologic disorder that the authors termed 'intellectual disability, motor dysfunction, and joint contractures' (IDMDC). Affected individuals presented between ages 6 months and 2 years with an arrest and regression of motor function. Nine patients had infantile febrile seizures. Distal limb deformities became evident after the age of 1 or 2 years and progressed very slowly, but each child finally assumed a specific fixed position. Contractures seemed to begin from the feet and spread in an ascending manner, involving the ankles, knees, and elbows, and finally involving the spine and the neck. Examination of 11 patients between ages 4 and 22 years revealed that none of the patients could walk or crawl; only 2 were still able to sit. All had severe intellectual disability, and none could speak, read, or write. Features suggestive of spasticity included hyperactive reflexes, ankle clonus, and extensor plantar responses, but the neurologic examination was difficult to perform in most. Muscle biopsy of 2 patients, EMG of 4 patients, and brain imaging of 3 patients were all normal. Electron microscopy of white blood cells from 2 affected sibs showed large membrane-bound vacuoles containing flocculent material in 7 to 10% of cells, and these vacuoles appeared to be associated with the endoplasmic reticulum.

Al-Saif et al. (2012) reported 4 sibs, born of consanguineous parents from the central region of the Arabian peninsula, with a clinical diagnosis of severe juvenile primary lateral sclerosis. The patients showed difficulty in crawling and limb spasticity around 8 months of age. The motor problems were progressive: patients had delayed motor development, required crutches and walkers at age 5 to 6 years, were wheelchair-bound at age 11 to 12 years, and were bedridden by age 15. Speech and articulation regressed after age 2 years, and the patients were unable to communicate verbally. Cognition was difficult to assess, but was apparently delayed. Other features included kyphosis, scoliosis, high-arched palate, abnormal smooth pursuit, and pseudobulbar palsy as manifest by increased jaw and glabellar reflexes and weak cough. There was distal muscle weakness, overall decreased muscle bulk, and increased muscle tone with hyperreflexia and extensor plantar responses. Seizures were not reported, and brain MRI showed no significant abnormalities.

The transmission pattern of the neurologic disease in the families reported by Yildirim et al. (2011) and Al-Saif et al. (2012) was consistent with autosomal recessive inheritance.

By genomewide linkage analysis in 2 unrelated Omani families with SPG, Al-Yahyaee et al. (2006) identified a candidate disease locus, referred to here as SPG18B, on chromosome 8p12-p11.21 (2-point maximum lod score of 5.91 at D8S1820; combined multipoint lod score of 7.08 at D8S505). Haplotype analysis of both families delineated a 9-cM candidate region between D8S1820 and D8S532. The locus did not overlap with SPG5A (270800). One of the families (family A) was later found to have SPG54, which also maps to 8p11 (Schuurs-Hoeijmakers et al., 2012).

By autozygosity mapping of a consanguineous Saudi family with complicated SPG, Alazami et al. (2011) found linkage to an 18.2-Mb interval on chromosome 8p12-q11.22 (maximum lod score of 4.205), which overlapped with the SPG18B locus delineated by Al-Yahyaee et al. (2006).

By autozygosity mapping followed by candidate gene sequencing in a consanguineous Saudi family with complicated SPG, Alazami et al. (2011) identified a homozygous 20-kb deletion on chromosome 8, with the distal breakpoint near physical position 37,694,857 (NCBI36) and the proximal breakpoint near 37,714,575 immediately upstream of exon 2 of the ERLIN2 gene (611605). This 20-kb interval spans 2 protein-coding genes, ERLIN2 and FLJ34378. RT-PCR analysis of patient lymphoblasts showed loss of ERLIN2 transcription, consistent with a null allele. Alazami et al. (2011) noted that ERLIN2 is involved in the endoplasmic reticulum degradation (ERAD) pathway, and postulated that loss of ERLIN2 may result in persistent activation of IP3 signaling and neuronal channel activity since ERAD normally degrades IP3 receptors (see, e.g., ITPR1, 147265). Alazami et al. (2011) also concluded that ERLIN2 depletion caused the phenotype, although they could not exclude a role for FLJ34378.

In affected members of a consanguineous Turkish family with autosomal recessive intellectual disability, motor dysfunction, and contractures, Yildirim et al. (2011) identified a homozygous truncation mutation in the ERLIN2 gene (611605.0001). The mutation was found by linkage analysis followed by candidate gene sequencing.

In 4 sibs, born of consanguineous parents from the central region of the Arabian peninsula, with a clinical diagnosis of juvenile primary lateral sclerosis, Al-Saif et al. (2012) identified a homozygous splice site mutation in the ERLIN2 gene (611605.0002). The mutation was found by homozygosity mapping followed by candidate gene sequencing and segregated with the disorder in the family. Analysis of patient cells demonstrated that the mutation caused premature termination and a decrease in levels of ERLIN2 mRNA (about 15% of controls), and that the mutant transcript underwent nonsense-mediated mRNA decay, resulting in a loss of function. Knockdown of ERLIN2 in mouse neuronal cells resulted in decreased cellular growth compared to controls, supporting a deleterious effect of loss of Erlin2 in patient neurons.