Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays

Incidence and progression to cirrhosis of new hepatitis C virus infections in persons living with human immunodeficiency virus

Objective: To estimate the incidence of hepatitis C virus (HCV) seroconversion and the risk of severe fibrosis/cirrhosis in HCV seroconverters among persons with human immunodeficiency virus (HIV) infection. Methods: We analysed data on 4059 persons with HIV enrolled in a cohort study in Italy. Results: Incidence rate of seroconversion was 0.6/100 person-years overall, and drug users and menwho-have-sex-with-men were at highest risk. The cumulative risk of progression to severe fibrosis/cirrhosis was 30% by 10 years after seroconversion. Conclusions: New HCV infections have a rapidly progressive course in this population. Persons with HIV and HCV superinfection should be prioritized for treatment with anti-HCV direct-acting antivirals