Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse disorders that share a primary feature, which is the causation of progressive and generally severe lower extremity weakness and spasticity. The prevalence is estimated to range between 1.3 to 9.6 cases per 100,000 people. HSP classifications are based on the mode of inheritance and genetic linkage. This disorder may segregate as an autosomal dominant, autosomal recessive, X-linked or mitochondrial trait. To date, 72 different spastic disease-loci have been identified, and 55 spastic paraplegia genes (SPGs) have already been cloned.
Autosomal recessive spastic paraplegia type 18 (SPG18) is a rare, complex type of HSP that presents in early childhood. It is characterized by progressive spastic paraplegia associated with delayed motor development, severe intellectual disability and joint contractures. There is no treatment that can prevent or reverse nerve degeneration in HSP.
Al-Yahyaee et al. (2006) described two families diagnosed with autosomal recessive hereditary spastic paraplegia. The first extended family was multiply consanguineous with six affected individuals. They all presented in the first 2 years of life with developmental delay, delayed walking, abnormal gait, and mild to severe mental retardation. They also had spasticity of the lower limbs, and a very thin corpus callosum. In the second family, the parents were first cousins and had a total of seven children, three of whom were affected. By the age of 4-5 years, all affected members presented with walking difficulty and frequent falls, and two of the affected children had frequent epileptic seizures. They all had spasticity of the lower limps predominantly affecting the hamstring and posterior tibial muscles. Using linkage analysis for both families, a disease gene location on chromosome 8 between markers D8S1820 and D8S532 (located on 8p12-p11.21) was identified. Within this interval there were two functional candidate genes, neuregulin and KIF13B.
Anas et al. (2011) described an extended consanguineous Saudi family with five members (two siblings and three maternal uncles) affected with HSP. The first patient was an 8-year old boy, who presented with spasticity and intellectual disability. At 30-months of age, he had progressive tightening of his lower extremities, which progressed to the upper extremities by 4-years of age. By that point he was completely wheel chair-bound. He had seizures at the age of seven years and ECG was severely abnormal with generalized slowing of background, and presence of generalized slow spike and wave activities. His 3-year-old sister had a similar course to him, but with the absence of seizures. Using autozygosity mapping and linkage analysis, a novel 20 kb deletion spanning two protein-coding genes, ERLIN2 and FLJ34378 (a gene of unknown function) were identified in all five patients.
Al-Saif et al. (2012) performed single nucleotide polymorphism arrays for homozygosity mapping for four siblings from the central region of the Arabian Peninsula affected with juvenile primary lateral sclerosis. At the age of 8-months they had difficulty in crawling and suffered spasms in the arms and legs. By the age of 12-years they became wheelchair dependent and were bedridden by the age of 15-years. They developed kyphosis and scoliosis around the age of 13-years. They also had symptoms of pseudobulbar palsy including increased jaw and glabellar reflexes and weak cough sound. They had mild-moderate distal pyramidal weakness, with only a flicker of movement at the fingers and forearms noted. A homozygous splice junction mutation in intron 7 of the ERLIN2 gene (c.499-1G>T) was identified in all affecteds, resulting in an abnormal splicing of the ERLIN2 transcript and nonsense-mediated decay of ERLIN2 mRNA.
Wakil et al. (2012) reported on a consanguineous Saudi family with two Hereditary Spastic Paraplegias (HSP) affected members. Patient 1 was a 7-year-old boy born at full term via spontaneous vaginal delivery. His motor development in the first year of life was found to be delayed and he failed to attain independent ambulation. At the time of presentation, he could walk with the help of a walker. The patient’s speech was dysarthric and limited to two-word sentences. Spasticity was severe in the lower extremities and was accompanied by significant weakness. The upper extremities were found to be mildly hypotonic. Investigations also found the patient to have brisk tendon reflexes and clonus on elicitation. His 19-year-old sister showed milder symptoms. This included moderate leg spasticity and weakness requiring the use of a walker. Her contractures and spasticity were treated with several orthopedic surgeries. Both patients suffered from speech regression and hence their cognitive function could not be properly assessed. Homozygosity mapping helped identify a novel intronic splice acceptor site mutation in the ERLIN2 gene.