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.

No abstract

T ick-borne encephalitis (TBE) is a severe viral zoonosis caused by TBE virus (TBEV) (1). To date, confi rmed locally acquired human TBEV infections have not been reported in Belgium, although the most common vector, the tick Ixodes ricinus, is abundant in Belgium and seroprevalence studies have revealed the presence of TBEV antibodies in dogs, cattle, roe deer, and wild boar (2,3). We report 3 confi rmed autochthonous TBE cases, diagnosed at the National Reference Centre (NRC) for Arboviruses (Antwerp, Belgium) during summer 2020. The StudyA 48-year-old woman had muscle pain and an elevated body temperature 2 weeks after a tick bite on her right hip. She tested negative for coronavirus disease (COVID-19), and her general practitioner prescribed antimicrobial drugs. A few days later, the patient was hospitalized with asthenia, tremor, drowsiness, and fever. A neurologist determined signs of peripheral facial palsy with brachial weakness and nuchal rigidity. Cerebrospinal fl uid (CSF) showed an elevated leukocyte count (37 cells/µL; reference range 0-5 cells/µL). Borrelia serology and PCR results were negative. Magnetic resonance imaging

Background and purpose Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients. Methods After unremarkable whole‐exome sequencing (WES) analysis, we performed repeat‐primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough. Results In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1−/− cases, RFC1+/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). Conclusions We demonstrate that RFC1 is a frequent cause of (WES‐negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat‐primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy‐ataxia spectrum.