Hereditary spastic paraplegia type 35 in a family from Mali

Abstract

Variants in FA2H have been associated with a wide range of phenotypes including hereditary spastic paraplegia type 35 (SPG35); however, genetically confirmed cases have not been reported in Africa. We report here the first African family with a variant in the FA2H gene causing SPG35. Four affected siblings with consanguineous parents presented with walking difficulty at age 2-3 and progressive limb weakness. They became wheelchair-bound two years after disease onset. Neurological examination confirmed lower greater than upper limb weakness and atrophy, brisk reflexes throughout, and spasticity with scissor legs. The patients also had choking, urinary urgency and mental retardation. A brain MRI showed thin corpus callosum and periventricular leucodystrophy. Testing of 58 SPG genes showed a homozygous variant in FA2H at the exon 5 donor site c.786+1G>A, which has previously been shown to cause skipping of exons 5 and 6 of the gene transcript. This variant segregated with the disease in the family. This variant has been reported previously with a similar phenotype and slow progression in a population with different background. Here we confirm its pathogenicity and expand its genetic epidemiology. Studying diverse populations may help to increase understanding of the disease mechanism and ultimately lead to therapeutic targets.

Two Novel Biallelic Variants in TECPR2 and FA2H Genes Causing Complicated Hereditary Spastic Paraplegia in Iranian families from lur Ethnicity: Case Series.

“…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][2][3] Clinically, 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.…”

“…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. 1,2 Almost, 21 HSP-associated genes involved in the autosomal recessive (AR) form of these disorders.…”

“…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. 1,2 Almost, 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).…”

Two novel biallelic variants in TECPR2 and FA2H genes causing complicated hereditary spastic paraplegia in Iranian families from Lur ethnicity: Case series

“…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 1‐3 . Clinically, these conditions share the primary symptoms of progressive spasticity, hyperreflexia, and mild weakness of the lower limbs in the “Pure” form.…”

“…Clinically, 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 …”