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.