Pigmentary degenerative maculopathy as prominent phenotype in an Italian SPG56/CYP2U1 family

Abstract

SPG56 is an autosomal recessive form of hereditary spastic paraplegia (HSP) associated with mutations in CYP2U1. There is no clear documentation of visual impairment in the few reported cases of SPG56, although this form is complex on clinical ground and visual deficit are extremely frequent in complicated HSP. We report three patients in a consanguineous family harboring the novel homozygous c.1168C>T (p.R390*) in SPG56/CYP2U1, and showing a pigmentary degenerative maculopathy associated with progressive spastic paraplegia. Furthermore, we characterized precisely the ophthalmologic phenotype through indirect ophthalmoscopy, retinal optical coherence tomography and visual evoked potentials. This is the first formal report of pigmentary degenerative maculopathy associated with a CYP2U1 homozygous mutation.

CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56

“…Up to now, 17 variants have been reported in SPG56 families (Table and Figure ) including those described in this work (Citterio et al., ; Iodice et al., ; Kariminejad et al., ; Kumar et al., ; Leonardi et al., ; Masciullo et al., ; Tesson et al., ). Nine of them predict protein truncation and are therefore classified as deleterious according to sequence variant classification and interpretation guidelines (VUS class 5) (Plon et al., ; Richards et al., ).…”

“…Both patients manifested typical early onset complex HSP with severe functional impairment associated with ID and brain MRI abnormalities suggestive of white matter changes and initially interpreted as delayed myelination due to perinatal insults. The clinical spectrum of SPG56 is wide and pure and complex forms of HSP have been described (Citterio et al, 2014;Iodice et al, 2017;Kariminejad et al, 2016;Kumar et al, 2016;Leonardi et al, 2016;Masciullo et al, 2016;Tesson et al, 2012). Cognitive impairment, brain MRI abnormalities, dystonia, and peripheral neuropathy are among the most frequently associated features in complex forms, including SPG56 (Kariminejad et al, 2016).…”

“…To date, 11 families have been reported having variants in CYP2U1 (Citterio et al, 2014;Iodice et al, 2017;Kariminejad et al, 2016;Kumar et al, 2016;Leonardi et al, 2016;Masciullo et al, 2016;Tesson et al, 2012). Among them, truncating and missense variants have been observed either at homozygous or compound heterozygous state.…”

CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia

“…18,3,14,15 Tesson et al 18 reported 11 patients from five families, with complicated HSP and CYP2U1 mutations. They all had spasticity in the lower limbs, three of them had intellectual disability and two had dystonia in the upper limbs.…”

“…He had spasticity, weakness, intellectual disability, thin corpus callosum and periventricular white-matter hyperintensities. Leonardi et al 14 reported a family with three affected members carrying a homozygous mutation in CYP2U1 with onset of visual impairment and spastic paraplegia in their twenties or thirties. Opthalmological investigation revealed pigmentary degenerative maculopathy in all three patients.…”