Diagnostic journey and genetic analysis of a novel homozygous CYP2U1 mutation causing autosomal recessive spastic paraplegia type 56 (SPG56) in a consanguineous family

Abstract

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder, with spastic paraplegia type 56 (SPG56) being an exceptionally rare, autosomal recessive subtype caused by mutations in the CYP2U1 gene. This study reports a complex case of an adult female from a consanguineous family who presented with cognitive developmental delays, short stature, and progressive neurological symptoms. At age 39, she developed unilateral tremors, which progressed to generalized tremors and leg weakness with a tiptoe gait. The clinical findings included hypertonia in the upper limbs, exaggerated reflexes in the lower limbs, vague speech, and emotional disturbances. Brain MRI revealed corpus callosum thinning, "ears of the Lynx" sign, bilateral globus pallidus calcifications, and mild brain atrophy. Comprehensive genomic analysis, including whole exome sequencing (WES), copy number variation (CNV) assessment, mitochondrial DNA sequencing, variant filtering, and Sanger sequencing, identified a homozygous c.913 C > T (p.His305Tyr) mutation in CYP2U1 (NM_183075). The heterozygous carriers presented no symptoms. This case contributes to the phenotypic spectrum of SPG56, offering new insights into its diagnosis and genetic underpinnings.

Keywords: CYP2U1; Complex HSP; Consanguinity; Ears of the Lynx; Hereditary spastic paraplegia; SPG56.

Fig. 1

Prediction diagram of the CYP2U1 protein structure. (a) The overall structure of the CYP2U1 protein; (b) Local structural diagram of the histidine residue at position 305; (c) Local structural diagram of the tyrosine residue at position 305; (d) Hydrogen bonding between histidine at position 305 and adjacent amino acids; (e) Hydrogen bonding between tyrosine at position 305 and adjacent amino acids; Black represents hydrogen bonds

Fig. 2

Brain and cervical MRI images of proband V8. (a, b, e) Brain MRI image showing patchy, hyperintense T1 and T2 signals within the cerebral hemisphere and basal ganglia. T2-FLAIR images revealed mildly elevated signals in certain lesions, notably within the central left hemisphere and left frontal lobe. The bilateral globus pallidus presented with scattered, slightly hypointense T1 signals. Mild widening of the sulci and cisterns was observed, with atrophy noted in the bilateral cerebellar hemispheres. The midline structures are symmetrical. The red arrow points to the characteristic “lynx ears” sign. (c, f) Cervical spine imaging revealed marginal hyperosteophytes at the edges of the vertebral bodies, with slight flattening observed at C6, and no significant signal abnormalities were detected. Reduced T2 signal intensity is noted in certain cervical intervertebral discs, with mild posterior protrusions at C3–4, C5–6, and C6–7, causing minimal compression of the local dural sac. The cervical spinal cord morphology and signal remained normal, with no evidence of lesions within the spinal canal. (d) CT image showing bilateral basal ganglia calcification

Fig.3

Family diagram and the Sanger sequencing map. (a) Pedigree illustrating autosomal recessive inheritance of spastic paraplegia type 56 (SPG56) due to a homozygous mutation in CYP2U1 (c.913 C > T, p.His305Tyr) within a consanguineous family. Half-shaded symbols indicate carriers of the heterozygous CYP2U1 variant (c.913 C > T, p.His305Tyr), and the fully shaded symbol denotes the proband (V8), who exhibits HSP with the homozygous variant (c.913T, p.305Tyr). (b) Sanger sequencing map of the homozygous variation of c.913T (p.305Tyr) in exon 2 of CYP2U1 (NM_183075). (c) Sanger sequence diagram of the carrier of the heterozygote c.913 C > T (p.His305Tyr). (d) Wild-type sequencing map of c.913C (p.His305)