SPG49 is an autosomal recessive complicated form of spastic paraplegia, a neurodegenerative disorder of the corticospinal tracts. It is characterized by delayed psychomotor development, mental retardation, and onset of spastic paraplegia in the first decade. Affected individuals also ... SPG49 is an autosomal recessive complicated form of spastic paraplegia, a neurodegenerative disorder of the corticospinal tracts. It is characterized by delayed psychomotor development, mental retardation, and onset of spastic paraplegia in the first decade. Affected individuals also have dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, which may be fatal (summary by Oz-Levi et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Oz-Levi et al. (2012) reported 5 individuals from 3 apparently unrelated Jewish Bukharian families with a complicated form of spastic paraplegia. Affected individuals presented during the second year of life with hypotonia and developmental delay. Dysmorphic features included ... Oz-Levi et al. (2012) reported 5 individuals from 3 apparently unrelated Jewish Bukharian families with a complicated form of spastic paraplegia. Affected individuals presented during the second year of life with hypotonia and developmental delay. Dysmorphic features included short stature, mild brachycephalic microcephaly, round face, low anterior hairline, dental crowding, short broad neck, and a chubby appearance. They had delayed psychomotor development with moderate to severe intellectual disability. A spastic, rigid, ataxic gait with areflexia developed at the end of the first decade. Other features included dysarthria, hypomimic facies, and dysmetria. All also had recurrent respiratory infections due to gastroesophageal reflux disease. An unusual feature was recurrent episodic central apnea initially occurring during sleep, but evolving into the wake state. Four patients had episodes of decreased alertness, aggravation of hypotonia, and inefficient respiration requiring mechanical ventilation. One patient died at age 5.5 years from aspiration. Two sibs had infrequent seizures. Brain MRI of 2 individuals showed a thin corpus callosum and cerebral and cerebellar atrophy.
By exome sequencing of 4 Jewish Bukharian patients with complicated spastic paraplegia, Oz-Levi et al. (2012) identified a homozygous truncating mutation in the TECPR2 gene (615000.0001). Haplotype analysis suggested a founder effect. Skin fibroblasts from an affected individual ... By exome sequencing of 4 Jewish Bukharian patients with complicated spastic paraplegia, Oz-Levi et al. (2012) identified a homozygous truncating mutation in the TECPR2 gene (615000.0001). Haplotype analysis suggested a founder effect. Skin fibroblasts from an affected individual showed impaired expression of the autophagocytic proteins SQSTM1 (601530) and MAP1LC3B (609604) in response to various conditions that should have increased the levels of these proteins. The findings suggested that TECPR2 mutations cause impairment of the intracellular autophagy pathway, with attenuation of delivery of targeted proteins to the lysosome.