Hypomyelinating leukodystrophies in adults: Clinical and genetic features.

BACKGROUND AND PURPOSE: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood. METHODS: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel. RESULTS: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination. CONCLUSIONS: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.

Optical coherence tomography in adult adrenoleukodystrophy: a cross-sectional and longitudinal study.

BACKGROUND: Adrenoleukodystrophy (ALD) encompasses different neurological phenotypes, ranging from the most severe cerebral forms (C-ALD) to the less severe adrenomyeloneuropathy (AMN). As visual system can be varyingly involved, we aimed at exploring whether optical coherence tomography (OCT) may detect retinal abnormalities and their longitudinal changes in adult ALD patients. METHODS: In this cross-sectional and longitudinal study, we measured the thicknesses of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (mGCC), and segmented inner and outer macula at baseline and their changes over time in 11 symptomatic adult ALD males and 10 age- and sex-matched healthy controls. Statistical analyses were performed for the patients as complete group, and splitting them into two subgroups, one (C-ALD) with and the other (AMN) without cerebral parieto-occipital white matter (WM) lesions. RESULTS: In the complete ALD group and in the C-ALD subgroup, the average pRNFL, mGCC, and inner macula were significantly thinner than in controls (p ≤ 0.01), whereas in the AMN subgroup, they were constantly, though non-significantly, thinner. Significant outer macula thinning was also observed (p < 0.01). In the complete ALD group, follow-up assessment (mean 26.8 months, range 8-48) showed mildly progressive thinning of inferior pRNFL, average mGCC, and inner macula. CONCLUSIONS: In adult ALD patients, OCT can reveal retinal abnormalities which are prominent in the more compromised patients, namely those with parieto-occipital WM lesions. The inferior pRNFL, average mGCC and inner macula thicknesses might be sensitive-to-change OCT parameters, but their utility and consistency for short-term longitudinal studies deserve further investigations.

Triheptanoin Supplementation Does not Affect Nutritional Status: A Case Report of Two Siblings With Adult Polyglucosan Body Disease.

Objective: An anaplerotic diet with the odd-chain triglyceride (triheptanoin-C7TG) supplementation was tested as a therapy for Adult Polyglucosan Body Disease (APBD) and is currently being assessed for various metabolic disorders. The aim of this study was to determine any unknown long-term effect of C7TG supplementation on the nutritional status, body composition, resting energy expenditure and biochemical parameters of two siblings with APBD.Methods: Two adult siblings with APBD were treated over a 2-year period with a high fat, low carbohydrate diet, with C7TG oil representing about 30% of the daily caloric intake. We carried out a long-term longitudinal study to determine weight, height, waist circumference; total, intra and extra cellular water by bioimpedance; body fat, lean mass, and bone mineral density by DEXA; resting energy expenditure by indirect calorimeter; glucose and lipid profiles.Results: C7TG supplementation failed to prevent APBD progression, corroborating recent literature. However, long-term C7TG supplementation did not produce any appreciable changes in nutritional status, body composition, resting energy expenditure or biochemical parameters, and no evidence was found of potential adverse effects.Conclusions: Our data suggest that maintenance of C7TG over a 2-year period still leaves a good safety profile in terms of nutritional status, body composition, resting energy expenditure, and biochemical parameters. However further studies involving larger sample sizes, also other diseases, are needed for a deeper understanding of its long-term effects.

Production and characteristics of sewage sludge in Italy.

Results of an extended survey on the production and quality of sewage sludge produced in Italy are herewith reported and discussed. Data are relevant to 2015. They were provided by 84 Italian water utilities responsible for municipal wastewater treatment serving approximately 35 million persons. Total production was estimated at about 395,000 t dry solids/year, of which 9.9% is used in agriculture without further treatments, 26.4% is sent to external plants for compost production, 5.6% is sent to external plant for production of a soil conditioner called 'chalk of defecation', 17.2% is disposed to landfill, and 5.9% is sent to incineration or co-incineration plants. The rest (35%) is sent to external sludge centres for further treatments (manly chemical and physical processes) before recovery/disposal. Regarding chemical characterization the following parameters were investigated: TOC, total nitrogen, total phosphorus, potassium, arsenic, cadmium, copper, nickel, lead, zinc, mercury, total chromium, chromium VI, selenium, hydrocarbons C10-C40, sum of polycyclic aromatic hydrocarbons, sum of polychlorinated biphenyls, sum of polychlorinated dibenzo-p-dioxins/dibenzo-p-furanes (toxic equivalent) salmonella, faecal coliforms, sulphur, sum of absorbable halogenated organic compounds, nonylphenol and nonylphenolethoxylates with one or two ethoxy groups, and di(2-ethylhexyl)phthalate. All the parameters showed that the quality of Italian sewage sludge is consistent with a typical sludge in Europe, Asia and America and the maximum concentrations of pollutants are well below the fixed standards of the European Directive 86/278 and the third draft of the European Commission's Working Document on Sludge.

Leukoencephalopathy With Predominant Infratentorial Involvement Caused by a Novel ABCD1 Mutation: Does the Spinocerebellar Variant of Adrenoleukodystrophy Exist?

INTRODUCTION: X-linked adrenoleukodystrophy (X-ALD) encompasses several clinical and neuroimaging phenotypes, including cerebral X-ALD, the most common phenotype in children, and adrenomyeloneuropathy, the most common phenotype in adults. A spinocerebellar variant of X-ALD has been described in individuals from the Far East, but the criteria for its diagnosis are unclear. CASE REPORT: A 35-year-old man from Albania was assessed because of a familial, slowly progressive spastic-ataxic gait associated with neurogenic bladder, sexual dysfunctions, and manic-like behavior. There was no definite clinical feature that suggested cerebellar involvement (eg, cerebellar limb ataxia, nystagmus, and dysarthria). A few months earlier, he had received a diagnosis of Addison disease. Brain magnetic resonance imaging showed a leukoencephalopathy with predominant cerebellum and brainstem involvement, and FDG-PET revealed marked cerebellar hypometabolism. The diagnosis of X-ALD was made because we found an increase of very long chain fatty acids, and a new ABCD1 mutation (c.1627C>T, p.Pro543Ser). CONCLUSIONS: X-ALD should be included in the differential diagnosis of adult leukoencephalopathies with predominant involvement of infratentorial structures, that is, the cerebellum and brainstem. From a classification perspective, our patient (of white origin), like others (all of Asian origin), should be considered as suffering from a variant of adrenomyeloneuropathy rather than from spinocerebellar X-ALD. Actually, the term "spinocerebellar" or similar ones, such as "cerebello-brainstem dominant form," should be limited to those exceptional cases, in which both the clinical and neuroimaging findings point exclusively (or at least predominantly) to the involvement of infratentorial structures.