Martin Rios AM, Gibbs LH, Stepien KM, Hall K, Hall PL , et al.
Neurology. Genetics •
β-mannosidosis is an ultra-rare lysosomal storage disorder caused by a deficiency of β-mannosidase, which catalyzes the last step of glycoprotein degradation. Owing to the limited number of reported cases, information on the natural history of the disease and brain imaging is scarce. We report 6 new cases and review them together with all the previously reported cases in the literature. We describe the clinical features of 6 unrelated patients with β-mannosidosis, their variants in , enzyme activity, urine oligosaccharide profiles, brain MRI findings, and longitudinal MRI changes in 2 of them. We also review previously reported patients to broaden the spectrum of clinical features and identify genotype-phenotype correlations. Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort. Nystagmus in association with β-mannosidosis was also found in 1 patient. Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter. A new oligosaccharide was found in the urine of the 2 most severely affected patients. Including our 6 patients, a total of 46 cases from 37 different families have been reported. The mean age of diagnosis is 12.8 years, and the mean age of symptom onset is 2.4 years. Hearing loss was the initial symptom most frequently reported, and intellectual disability was the most frequent symptom overall. Across the cohort, 29 pathogenic variants were identified, 61.8% were private, and 38.2% have the recurrent c.2158-2A>G variant. Neuroimaging abnormalities were reported in 40% of published cases and included cortical and subcortical atrophy, basal ganglia and white matter calcification, hydrocephalus, periventricular and subcortical white matter hyperintensities, and delayed myelination. Genotype-phenotype correlation in β-mannosidosis remains elusive, likely due to phenotypic variability, disease rarity, and lack of association between the enzyme activity and the clinical severity. Modifier genes in the N-glycan degradation pathway, such as , may influence disease expression. β-mannosidosis should be considered as a differential diagnosis in patients with syndromic or apparently nonsyndromic hearing loss, unexplained brain hypomyelination, behavioral disturbances, and intellectual disability.
Themistocleous AC, Baskozos G, Blesneac I, Comini M, Megy K , et al.
Brain communications •
The aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine the prevalence of known pathogenic variants and to understand the relationship between pathogenic variants and clinical presentation. Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK and underwent whole genome sequencing as part of the National Institute for Health and Care Research Bioresource Rare Diseases project. A multidisciplinary team assessed the pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels. The results include the following: (i) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1. (ii) Clinically relevant variants were most common in voltage-gated sodium channels (Na). (iii) c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls and causes a gain of function of Na1.7 after cooling (the environmental trigger for non-freezing cold injury). (iv) Rare variant association testing showed a significant difference in distribution for genes NGF, , , , , and the regulatory regions of genes , , and between European participants with neuropathic pain and controls. (v) The p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain-of-channel function to agonist stimulation. Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to a better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain-of-function Na1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers.
Erythromelalgia clinically presents with episodic burning, erythema, and warmth of acral sites. It can be divided into primary and secondary associated with myeloproliferative and autoimmune conditions. Histology commonly shows capillary proliferation, swelling of endothelial cells, perivascular edema, and chronic inflammation with sparse lymphocytic infiltrate. We report a case of a 55-year-old man with classical secondary erythromelalgia clinically; however, he had unusual histological findings on biopsy comprising of acute perivascular infiltrate and perivascular mucin. This is the first report of such findings in the context of secondary erythromelalgia.