Correction to: Metachromatic leukodystrophy with late adult-onset: diagnostic clues and differences from other genetic leukoencephalopathies with dementia

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Effectiveness of valproate for the treatment of manic-like behavior in X-linked adrenoleukodystrophy

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Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms

<p>Abstract</p> <p>Background</p> <p>Approximately 20% of adrenoleukodystrophy (X-ALD) female carriers may develop clinical manifestations, typically consisting of progressive spastic gait, sensory deficits and bladder dysfunctions. A skewing in X Chromosome Inactivation (XCI), leading to the preferential expression of the X chromosome carrying the mutant <it>ABCD1 </it>allele, has been proposed as a mechanism influencing X-linked adrenoleukodystrophy (X-ALD) carrier phenotype, but reported data so far are conflicting.</p> <p>Methods</p> <p>To shed light into this topic we assessed the XCI pattern in peripheral blood mononuclear cells (PBMCs) of 30 X-ALD carriers. Since a frequent problem with XCI studies is the underestimation of skewing due to an incomplete sample digestion by restriction enzymes, leading to variable results, we developed a pyrosequencing assay to identify samples completely digested, on which to perform the XCI assay. Pyrosequencing was also used to quantify <it>ABCD1 </it>allele-specific expression. Moreover, very long-chain fatty acid (VLCFA) levels were determined in the same patients.</p> <p>Results</p> <p>We found severely (≥90:10) or moderately (≥75:25) skewed XCI in 23 out of 30 (77%) X-ALD carriers and proved that preferential XCI is mainly associated with the preferential expression of the mutant <it>ABCD1 </it>allele, irrespective of the manifestation of symptoms. The expression of mutant <it>ABCD1 </it>allele also correlates with plasma VLCFA concentrations.</p> <p>Conclusions</p> <p>Our results indicate that preferential XCI leads to the favored expression of the mutant <it>ABCD1 </it>allele. This emerges as a general phenomenon in X-ALD carriers not related to the presence of symptoms. Our data support the postulated growth advantage of cells with the preferential expression of the mutant <it>ABCD1 </it>allele, but argue against the use of XCI pattern, <it>ABCD1 </it>allele-specific expression pattern and VLCFA plasma concentration as biomarkers to predict the development of symptoms in X-ALD carriers.</p

A cross‐sectional, prospective ocular motor study in 72 patients with Niemann‐Pick disease type C

Objective: To characterize ocular motor function in patients with Niemann-Pick disease type C (NPC). Methods: In a multicontinental, cross-sectional study we characterized ocular-motor function in 72 patients from 12 countries by video-oculography. Interlinking with disease severity, we also searched for ocular motor biomarkers. Our study protocol comprised reflexive and self-paced saccades, smooth pursuit, and gaze-holding in horizontal and vertical planes. Data were compared with those of 158 healthy controls (HC). Results: Some 98.2% of patients generated vertical saccades below the 95% CI of the controls' peak velocity. Only 46.9% of patients had smooth pursuit gain lower than that of 95% CI of HC. The involvement in both downward and upward directions was similar (51°/s (68.9, [32.7-69.3]) downward versus 78.8°/s (65.9, [60.8-96.8]) upward). Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit correlated best to disease severity. Compensating strategies such as blinks to elicit saccades, and head and upper body movements to overcome the gaze palsy, were observed. Vertical reflexive saccades were more impaired and slower than self-paced ones. Gaze-holding was normal. Ocular-motor performance depended on the age of onset and disease duration. Conclusions: This is the largest cohort of NPC patients investigated for ocular-motor function. Vertical supranuclear saccade palsy is the hallmark of NPC. Vertical upward and downward saccades are equally impaired. Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit can be used as surrogate parameters for clinical trials. Compensating strategies can contribute to establishing a diagnosis

Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis

Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing (WGS) data from nearly 10,000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n=6 from 5 families), AAGGC (n=2 from 1 family), AGAGG (n=1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, here we show a pathogenic role for large AAAGG repeat configuration expansions (n=5). Long read sequencing was used to fully characterise the entire repeat sequence and revealed a pure AGGGC expansion in six patients, whereas the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs seem to have arisen from a common haplotype and are predicted to form highly stable G quadruplexes, which have been previously demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions, since the AAAGG motif when very large (>500 repeats) or in the presence of AAGGG interruptions. Accurate sizing and full sequencing of the satellite repeat with long read is recommended in clinically selected cases, in order to achieve an accurate molecular diagnosis and counsel patients and their families

Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic

Metachromatic Leukodystrophy: Too Frequent (Mis)Diagnosis

Recently, Wu et al1 reported the case of an adult patient with late-onset cobalamin C disease who received an incorrect diagnosis of adult metachromatic leukodystrophy (MLD). In this patient, the disease onset was characterized by acute psychiatric symptoms and spastic paraparesis. A brain magnetic resonance imagining (MRI) scan performed 2 months after the onset showed an area of hyperintensity on fluid-attenuated inversion recovery images in the right occipital subcortical white matter. The involvement of bilateral occipital white matter and centrum semiovale was evident at a follow-up MRI that was performed 21 months after the onset. At this time, arylsulfatase A (ARSA) enzyme activity was tested in peripheral blood leukocytes, and the results showed that the levels were half of the normal lower limit. Metachromatic leukodystrophy was suspected and the patient underwent genetic testing. This is an interesting case, but in our opinion, it is confounding to emphasize MLD in the differential diagnosis because it could have been ruled out much sooner

Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia

The neurotropism of human coronaviruses has already been demonstrated in small animals, and in autoptic studies the severe acute respiratory syndrome coronavirus (SARS-CoV), which was responsible for the SARS outbreak during 2002 to 2003, was found in the brains of patients with infection. It has been proposed that the neuroinvasive potential of the novel SARS-CoV-2, responsible for coronavirus disease 2019 (COVID-19), may be at least partially responsible for the respiratory failure of patients with COVID-19.2 In this article, we share the magnetic resonance imaging (MRI) evidence of in vivo brain alteration presumably due to SARS-CoV-2 and demonstrate that anosmia can represent the predominant symptom in COVID-19

Spinal cord involvement in adult-onset metabolic and genetic diseases

In adulthood, spinal cord MRI abnormalities such as T2-weighted hyperintensities and atrophy are commonly associated with a large variety of causes (inflammation, infections, neoplasms, vascular and spondylotic diseases). Occasionally, they can be due to rare metabolic or genetic diseases, in which the spinal cord involvement can be a prominent or even predominant feature, or a secondary one. This review focuses on these rare diseases and associated spinal cord abnormalities, which can provide important but over-ridden clues for the diagnosis. The review was based on a PubMed search (search terms: \u27spinal cord\u27 AND \u27leukoencephalopathy\u27 OR \u27leukodystrophy\u27; \u27spinal cord\u27 AND \u27vitamin\u27), further integrated according to the authors\u27 personal experience and knowledge. The genetic and metabolic diseases of adulthood causing spinal cord signal alterations were identified and classified into four groups: (1) leukodystrophies; (2) deficiency-related metabolic diseases; (3) genetic and acquired toxic/metabolic causes; and (4) mitochondrial diseases. A number of genetic and metabolic diseases of adulthood causing spinal cord atrophy without signal alterations were also identified. Finally, a classification based on spinal MRI findings is presented, as well as indications about the diagnostic work-up and differential diagnosis. Some of these diseases are potentially treatable (especially if promptly recognised), while others are inherited as autosomal dominant trait. Therefore, a timely diagnosis is needed for a timely therapy and genetic counselling. In addition, spinal cord may be the main site of pathology in many of these diseases, suggesting a tempting role for spinal cord abnormalities as surrogate MRI biomarkers