P.86Depends on how you look: hereditary spastic paraplegia, leukodystrophy or brain iron accumulation

Abstract

Fatty acid hydroxylase-associated neurodegeneration (FAHN), a progressive disorder once classified as hereditary spastic paraplegia (SPG35; 612319), has recently linked to neurodegeneration with brain iron accumulation and leukodystrophies. Two boys (6.5 and 7 years) from unrelated consanguineous families were detected to have homozygous mutations in FA2Hgene through whole exome sequencing. Case 1, born at term, showed normal early development, but presented seizures and acute vision loss at 3.5 years. Vision partially recovered in 3 days. Initially asymmetric, then bilateral progressive weakness in lower extremities, foot deformity, gait disturbance, then speech and perception impairment manifested. On examination he had strabismus, bilateral optic atrophy, spastic-ataxic gait, foot inversion, dysarthria, hyperactive deep tendon reflexes and Babinski sign. Case 2, born at 33th gestational week, had been floppy and delayed in motor and language domains since birth. He walked at 2 years, but gait deteriorated after 2.5 years old with frequent falls, ultimately loss of ambulation and communication. When 7 years old, he had bilateral optic atrophy, central hypotonia, increased tone and scissoring of lower extremities, foot inversion, genu recurvatum, and upper motor neuron findings. Both cases' MRI, around 3 years of age, revealed white matter lesions/thin corpus callosum. Phenotype was most consistent with neuroaxonal dystrophies, leukodystrophies or mitochondrial disorders. WES showed homozygous missense (c.443C>T (p.Pro148Leu)) and deletion (c.685_687delATC (p.Ile229del) mutations in FA2H gene, respectively. FA2H encodes fatty acid 2-hydroxylase, enzyme participating in the synthesis fatty acids of galactolipids. These being an important part of the myelin sheath explains the broad clinical spectrum: spasticity, ataxia, dystonia, optic atrophy, progressive intellectual impairment and seizures, illustrated by our two cases.