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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.

Autonomic manifestations have been frequently studied in adults with epilepsy. Here, we evaluated cardiac autonomic (ANS) functions in children with epilepsy in the interictal period and determined the risks for their dysfunctions. This study included 60 patients (boys = 25; girls = 35 age: 14.53 ± 2.54 yrs) and 25 controls. Patients were well-controlled on antiseizure medications (ASMs). The battery of testing included measuring resting heart rate (HR) and blood pressure (BP), 30:15 ratio, HR variability (HRV) response to deep breathing, Valsalva ratio and BP changes in response to standing, isometric exercise and cold. Dizziness was reported in 25%. Autonomic dysfunctions were found in 45% (n = 27). Manifestations included high frequencies of abnormal 30:15 ratio (22%), HRV responses to deep breathing (45%), Valsalava ratio (45%), and BP responses to standing (35%), isometric exercise (27%) and cold (27%), indicating parasympathetic and sympathetic hypofunctions. There were positive correlations between parasympathetic and sympathetic dysfunctions. Logistic analysis showed that the durations of epilepsy and ASMs therapy were associated with ANS dysfunctions [95% CI: 0.895–4.719, p = 0.004]. Parasympathetic and sympathetic autonomic hypofunctions are common in children with epilepsy. This could be due to the depressant effect of sodium channel blocker ASMs on central and/or cardiac autonomic systems. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a common cause of restless leg syndrome (RLS). RLS is under-recognized, misdiagnosed and undertreated disorder in our locality. In this study, we aimed to determine the prevalence of RLS due to CKD and its predictors. This cross-sectional study included 520 patients [male = 200; female = 320; age: 48.45 ± 3.63yrs; uremia duration: 6.44 ± 1.65yrs; CKD5D = 400; CKD3D = 120). RLS diagnosis was done by clinical interviewing according to International RLS Study Group criteria. All underwent detailed biochemical testing and iron and ferritin levels' measurements. Insomnia, depression and anxiety severities were assessed using insomnia sleep index (ISI), Beck Depression Inventory (BDI-II) and State-Trait Anxiety Inventory for Adults (STAI-AD) scales. RLS was found in 22.31% [ESKD = 26%, CKD3D = 10%]. Insomnia, depression and anxiety were found in 76.15%, 91.15% and 44.23%, respectively. Insomnia was correlated with depression (r = 0.488, p = 0.001) and anxiety (r = 0.360, p = 0.006) but not RLS. Multiple linear regression analysis showed that ESKD (OR = 3.8, 95%CI = 2.5–8.5, p = 0.001), inadequate dialysis (OR = 4.6, 95%CI = 3.5–8.6, p = 0.001), hyperparathyroidism (OR = 5.1, 95%CI 3.2–13.7, p = 0.0001) and peripheral neuropathy (OR = 5.6, 95%CI = 3.8–12.8, p = 0.0001) were independently associated with RLS. The prevalence of RLS with CKD is 22.31%. It is 2.6 times more frequent and severe with ESKD compared to CKD3D. It seems that RLS may occur early with CKD and becomes worse with progressive kidney impairment. Also, insomnia, depression and anxiety are common with CKD, however, their severities were not correlated with RLS. Predictors for RLS were ESKD, inadequacy of dialysis, hyperparathyroidism and peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Vestibular system is critical for maintaining balance. This study aimed to determine the function of the saccule of the otolith organ in adults with type 1 diabetes (T1D) using cervical vestibular evoked myogenic potential (cVEMP) and its independently associated demographic, clinical and laboratory variables. This case-control cross-sectional study included 60 patients (male = 15; female = 45) and 30 healthy adults. They underwent cVEMP. Patients had mean age of 30.63 ± 4.20 years and duration of illness of 14.68 ± 3.65 years. More than 50% had frequent diabetic ketoacidosis (DKA), 30% had frequent hypoglycaemic attack, 35% had comorbid hyperlipidaemia, and 40% had peripheral neuropathy. Dizziness was reported in 30%. Compared to controls, 40% of patients had significantly delayed absolute latencies of P1 and N1 (p = 0.01) either unilateral or bilateral and 80% had reduced P1-N1 amplitudes (p = 0.001). Higher frequencies of abnormalities were present bilaterally. Asymmetry ratio (AR) was reported in 25%. Patients with longer duration of diabetes (>5 year), dizziness, HbA1c (>7%), frequent DKA or hypoglycaemic attacks and peripheral neuropathy had significantly prolonged P1 and N1 latencies and reduced P1-N1 amplitudes compared to those with shorter duration of diabetes, without dizziness, with HbA1c% ≤7%, low frequency of DKA hypoglycaemic attacks and those without peripheral neuropathy. Multiple regression analysis showed that presence of delayed P1 latencies and reduced P1-N1 amplitudes were significantly correlated with duration of diabetes > 5 years [OR = 3.60 (95%CI = 1.80–6.44), p = 0.01; OR = 4.56 (95%CI = 2.80–7.80), p = 0.01] and HbA1c levels >7% [OR = 5.26(95%CI = 3.83–8.05), p = 0.001; OR = 4.55(95%CI = 2.45–8.55), p = 0.001]. The dysfunctions of the saccule of otolith organ and/or its pathway are prevalent in adults with T1D and correlated with duration and severity of diabetes. Therefore, optimal control of glycemic control is essential. [ABSTRACT FROM AUTHOR]