Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia

Journal of Neurology - STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1...     

Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.     

Choréo-acanthocytose sans acanthocytes

Introduction

Chorea-acanthocytosis (ChAc) is one of the neuroacanthocytosis syndromes which form a group of disorders characterized by the association of neurological abnormalities and spiculated red blood cells called acanthocytes. ChAc patients exhibit involuntary movements, psychiatric abnormalities and progressive cognitive deterioration. We report a case of ChAc in which blood smears failed to demonstrate acanthocytes.

Case report

A 26-year-old man presented since two years with hyperkinetic movements. The family history was non contributive, parents were consanguineous. Neurological examination revealed choreatic hyperkinesia and dystonia, predominant in the orofacial region. Mild cognitive decline and behavior abnormalities were noted with repetitive activities. Brain MRI showed striatal atrophy. Molecular testing for Huntington's disease was negative. Routine biological screening was normal except for elevated CPK and LDH. Copper and ceruloplasmin blood levels were normal, as well as purine metabolism and lipoproteins. Further screening for metabolic diseases showed no significant abnormality. Expression of Kell antigens was normal. In several blood smears no acanthocytes were seen. Electromyographic studies showed slight neuropathic changes. Despite the absence of acanthocytes, chorein western blot was performed on blood samples which revealed an absent or markedly reduced level of chorein in erythrocyte membranes. A mutation of the ChAc gene was thus likely so the diagnosis of ChAc was retained. Genetic studies for VPS13A are pending.

Discussion

ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein. Absence or late appearance of acanthocytes in ChAc has been described in a few case reports. In conclusion ChAc is a rare disorder in which the presence of acanthocytes is not mandatory. In case of doubt, chorein western blot can be useful.     

Neurosarcoidosis treated with mycophenolate mofetil: two cases

INTRODUCTION: Neurosarcoidosis is a rare (5 cases for one million) immune-mediated disease generally observed in young adults. Neurological symptoms are present in the half of patients, and symptoms remain limited to neurological system in 10p.cent. Histological criteria are mandatory to prove the diagnosis. The sensitivity and complications of biopsy are variable. The best sensitivity appears to be achieved with muscle biopsies which in addition have a lower risk of complications. Neurosarcoidosis is usually treated with corticosteroid therapy and immunosuppressive drugs (cyclophosphamide, cyclosporine, aziathoprine, methotrexate), but frequently resists standard schedules. In addition the many contraindications, side effects and cumulated toxicities of immunosuppressive drugs compromises their use. Knowledge of the effectiveness of other treatments would therefore be useful. Mycophenolate mofetil (MMF) has been used for treatment of many immune-mediated neurological diseases, like polymyositis, multifocal motor neuropathy, myasthenia or chronic inflammatory demyelinating polyradiculoneuropathy. MMF is efficient and well tolerated, but there is no case-report about neurosarcoidosis. CASE REPORT: We report two observations of young patients (14 and 27 years) with a diagnosis of resistant neurosarcoidosis treated with MMF (2 g/j) and corticosteroids. A significant and rapid effectiveness was clinically and radiologically observed, with good clinical and hematologic tolerance. CONCLUSION: The MMF seems to be an interesting rescue treatment for neurosarcoidosis. Further evaluation is needed.     

Monogenic diabetes syndromes: Locus‐specific databases for Alström,Wolfram, and Thiamine‐responsive megaloblastic anemia

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%–100%]; specificity 78% [73%–82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org .