Author Affiliation: (1) Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy (2) Unit of Neuroradiology, ...Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (3) Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (4) Neuroscience PhD Program, University of Milano-Bicocca, Monza, Italy (a) chiara.benzoni1@unimi.it Article History: Registration Date: 12/14/2020 Received Date: 11/16/2020 Accepted Date: 12/14/2020 Online Date: 01/08/2021 Byline:
Summary Why is peripheral neuropathy common but mild in many mitochondrial disorders, and why is it, in some cases, the predominant or only manifestation? Although this question remains largely ...unanswered, recent advances in cellular and molecular biology have begun to clarify the importance of mitochondrial functioning and distribution in the peripheral nerve. Mutations in proteins involved in mitochondrial dynamics (ie, fusion and fission) frequently result in a Charcot-Marie-Tooth phenotype. Peripheral neuropathies with different phenotypic presentations occur in mitochondrial diseases associated with abnormalities in mitochondrial DNA replication and maintenance, or associated with defects in mitochondrial respiratory chain complex V. Our knowledge of mitochondrial disorders is rapidly growing as new nuclear genes are identified and new phenotypes described. Early diagnosis of mitochondrial disorders, essential to provide appropriate genetic counselling, has become crucial in a few treatable conditions. Recognising and diagnosing an underlying mitochondrial defect in patients presenting with peripheral neuropathy is therefore of paramount importance.
...the patient was very old at disease onset, being 86 years (which would be the latest age at HLDS onset ever reported), and had multiple risk factors for leukoaraiosis, including hypertension, ...diabetes, hyperlipidemia, smoking, and kidney failure. ...no examination such as cerebral PET and CSF analysis for investigating common causes of dementia has been reported, and no consideration about genetic variant and disease co-segregation has been given. 1 Finally, in vitro functional analysis should be interpreted carefully, as the CSF1R function depends on the dimerization of two CSF1R, and in HLDS patients, a wild-type CSF1R is co-expressed with the mutant one, in contrast to in vitro experiments. 3 Hence, the impact of loss-of-function (LOF) variants in vivo might be different based on their position in the TyrKD or IgLD (Fig. 1). In the presence of CSF1, CSF1R monomers undergo non-covalent dimerization (wild-type WT/WT) followed by autophosphorylation and signaling through activation of multiple kinase pathways including JNK.10 (B) Loss-of-function (LOF) variants (red stars) altering residues in the intracellular tyrosine kinase domain (TyrKD) impair the autophosphorylation of intracellular tyrosine residues required for downstream signaling, whereas it is unlikely that they affect the CSF1-dependent dimerization of CSF1R.4 Consequently, in the presence of WT monomers and monomers with a TyrKD mutation (WT/mutTyrKD), CSF1R should form in vivo WT homodimers (~25%), WT-mutant heterodimers (~50%), and mutant homodimers (~25%).2 The mutant CSF1R subunit of the dimer cannot phosphorylate the WT subunit, and also, by a dominant negative effect, should impair the phosphorylation activity of the normal subunit.2,7 Therefore, in HLDS patients, the LOF should be ~75%, given that the nonfunctional mutant receptors are threefold in excess in comparison with the WT receptors.2 (C) The hypothesis illustrated in the subfigure B may explain why patients with CSF1R variants such as the p.Gln481*, which cause non-sense mediated RNA decay, do not develop HLDS. ...in the presence of WT monomers and monomers with an IgLD mutation (WT/mutIgLD), CSF1R should form in vivo only functional WT homodimers, the LOF will be ~50%, and the patients should not develop HLDS.4 HLDS, hereditary leukodystrophy with spheroids.
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.
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.
A brain MRI pattern suggestive of hypomyelination can be the prominent feature of adult‐onset genetic conditions. Adult neurologists should be trained in recognizing this pattern, as its presence implies different diagnostic work‐up and prognosis. An inclusive genetic screening can allow diagnosis in almost half of cases.
Recessive mutations in GJA12/GJC2, the gene that encodes the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), an early onset dysmyelinating disorder of the CNS, ...characterized by nystagmus, psychomotor delay, progressive spasticity and cerebellar signs. Here we describe three patients from one family with a novel recessively inherited mutation, 99C>G (predicted to cause an Ile>Met amino acid substitution; I33M) that causes a milder phenotype. All three had a late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development, preserved walking capability through adulthood, and no nystagmus. MRI and MR spectroscopy imaging were consistent with a hypomyelinating leukoencephalopathy. The mutant protein forms gap junction plaques at cell borders similar to wild-type (WT) Cx47 in transfected cells, but fails to form functional homotypic channels in scrape-loading and dual whole-cell patch clamp assays. I33M forms overlapping gap junction plaques and functional channels with Cx43, however, I33M/Cx43 channels open only when a large voltage difference is applied to paired cells. These channels probably do not function under physiological conditions, suggesting that Cx47/Cx43 channels between astrocytes and oligodendrocytes are disrupted, similar to the loss-of-function endoplasmic reticulum-retained Cx47 mutants that cause PMLD. Thus, GJA12/GJC2 mutations can result in a milder phenotype than previously appreciated, but whether I33M retains a function of Cx47 not directly related to forming functional gap junction channels is not known.
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