1 Introduction
Hereditary spastic paraplegia (HSPs) refers to a heterogeneous group of rare inherited neurodegenerative disorders. They are generally characterized by progressive and length-dependent degeneration of distal retrograde axons of the corticospinal tracts (CST) and posterior columns of the spinal cord.1-3Clinically, these conditions share the primary symptoms of progressive spasticity, hyperreflexia and mild weakness of the lower limbs in the “Pure” form. In the “complicated/complex” form, additional symptoms such as peripheral nerve involvement, extrapyramidal disturbances, cerebellar ataxia, polyneuropathy, cognitive impairment, optic atrophy and seizures might be added.2, 4, 5
So far, at least 76 clinical types of HSPs and around 80 corresponding genes with different patterns of inheritance have been reported.1, 2Almost, 21 HSP-associated genes involved in the autosomal recessive (AR) form of these disorders. One of the complicated HSPs with AR inheritance pattern is spastic paraplegia 35 (SPG35, MIM 612319), also known as fatty acid hydroxylase-associated neurodegeneration (FAHN). The condition is caused by pathogenic alterations in FA2H , located on chromosome 16q23.1. This gene encodes endoplasmic reticulum (ER) enzyme fatty acid 2-hydroxylase. The enzyme is a membrane-bound protein with NADPH-dependent mono oxygenase activity, converting free fatty acids to 2-hydroxy fatty acids (hFAs), which, subsequently are incorporated into membrane sphingolipids as essential components of myelin. These compounds show particular temporal expression pattern and are unessential in early development, but are required as the individual matures.6-9Considering the substantial role of the enzyme in the maintenance of the myelin sheath around neuronal axons, deficiency of its coding gene can manifest diverse demyelinating phenotypes such as dysmyelinating, leukodystrophy associated cognitive decline, dysarthria, spastic paraparesis with or without dystonia and neurodegeneration with brain iron accumulation (NBIA).10-14Although the frequency of FA2H mutations in patients with HSPs has been obscure at least in Asia, it was considered as the second most common subtype of AR-HSP.5SPG35 has early onset and shows heterogeneous neuroimaging patterns such as a variable degree of white matter lesions (WMLs), thin corpus callosum, cortical and cerebellar atrophy and iron accumulation in the globus pallidus.4, 7, 10, 15In addition, genetic alterations in TECPR2 , tectonin beta-propeller repeat containing 2 (TECPR), have been reported with another complicated form of autosomal recessive HSP called Spastic Paraplegia 49 (SPG49).16 This gene encodes a protein which contains two main domains, tryptophan-aspartic acid repeat (WD repeat) and TECPR, and plays a significant role in autophagy process.17-19 The disorder characterized by developmental delay, generalized hypotonia, microcephaly, short stature and dysmorphic faces. Affected individuals evolved progressive spasticity in the lower body muscles. However, in 2016 three more affected individuals with additional autonomic-sensory neuropathy features have been introduced.20 Therefore, Heimer et al reclassified disorder as a new subtype of hereditary sensory-autonomic neuropathy, adding controversy to the exact class of this disorder. So far, only three pathogenic variations have been reported in TECPR2 , implying that SPG49 is a rare genetic disorder with unknown frequency and heterogenous phenotype.16, 20
We herein report two Iranian Lur families with typical features of HSPs. Subsequent genomics and bioinformatics analyses have suggested novel pathogenic variants in TECPR2 and FA2H genes.