Publications by authors named "Mari Auranen"

42 Publications

De novo SPTAN1 mutation in axonal sensorimotor neuropathy and developmental disorder.

Brain 2020 12;143(12):e104

Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa344DOI Listing
December 2020

Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease.

Ann Clin Transl Neurol 2020 10 19;7(10):1962-1972. Epub 2020 Sep 19.

Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Objective: ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot-Marie-Tooth disease gene.

Methods: Whole-exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease-causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca imaging.

Results: Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca -transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function.

Interpretation: Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease-causing gene for CMT and indicates altered Ca homeostasis in disease pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545616PMC
October 2020

Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease.

J Inherit Metab Dis 2021 Mar 21;44(2):469-480. Epub 2020 Sep 21.

Research Programs Unit, Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy taken <12 months apart, a mitochondrial disorder would have been identified in 70% with analysis of FGF21 and GDF15 compared to 50% of patients whom could have been identified with muscle biopsy alone. Muscle findings were nondiagnostic in 72% (children) and 45% (adults). Induction of FGF21 and GDF15 suggest a mitochondrial etiology as an underlying cause of a muscle manifesting disease. Normal biomarker values do not, however, rule out a mitochondrial disorder, especially if the disease does not manifest in muscle. We suggest that FGF21 and GDF15 together should be first-line diagnostic investigations in mitochondrial disease complementing muscle biopsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jimd.12307DOI Listing
March 2021

Niacin Cures Systemic NAD Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy.

Cell Metab 2020 06 7;31(6):1078-1090.e5. Epub 2020 May 7.

Research Program of Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; HUSlab, Helsinki University Hospital, Helsinki 00290, Finland; Neuroscience Center, HiLife, University of Helsinki, Helsinki 00290, Finland. Electronic address:

NAD is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD depletion occurs in patients with degenerative disorders and whether NAD repletion improves their symptoms has remained open. Here, we report systemic NAD deficiency in adult-onset mitochondrial myopathy patients. We administered an increasing dose of NAD-booster niacin, a vitamin B3 form (to 750-1,000 mg/day; clinicaltrials.govNCT03973203) for patients and their matched controls for 10 or 4 months, respectively. Blood NAD increased in all subjects, up to 8-fold, and muscle NAD of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%. Our evidence indicates that blood analysis is useful in identifying NAD deficiency and points niacin to be an efficient NAD booster for treating mitochondrial myopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.04.008DOI Listing
June 2020

Attitudes towards genetic testing and information: does parenthood shape the views?

J Community Genet 2020 Oct 4;11(4):461-473. Epub 2020 Apr 4.

Research Programs Unit, Stem Cells and Metabolism, University of Helsinki, Helsinki, Finland.

This study examines how parents of pediatric patients might differ in their views and attitudes towards genetic technology and information when compared to adult patients. There is surprisingly little evidence on how parents compare to other parts of population in their attitudes. Previous empirical studies often relate health-related preferences and attitudes to factors such as age, education, and income instead of parental status, thus evading comparison of parents to others as health-related decision makers. Findings related to the parental status can be useful when implementing genetic technology in clinical practice. We conducted a survey of views on genetic technology and information for groups of adult neurology patients (n = 68) and parents of pediatric neurology patients (n = 31) to shed some light on this issue. In addition to our own survey instrument, we conducted other surveys to gain insight on psychosocial factors that might affect these attitudes. The results suggest that parents are more concerned about their children's genetic risk factors when compared to the attitudes of adult patients about their own risk. For both groups, negative emotional state was associated with more concerns towards genetic information. Our study provides insights on how parental views might affect the acceptance of genetic technology and information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12687-020-00462-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475141PMC
October 2020

Beneficial Effects of Ketogenic Diet on Phosphofructokinase Deficiency (Glycogen Storage Disease Type VII).

Front Neurol 2020 4;11:57. Epub 2020 Feb 4.

Unit of Clinical Physiology, HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

A deficiency of muscle phosphofructokinase (PFKM) causes a rare metabolic muscle disease, the Tarui disease (Glycogen storage disease type VII, GSD VII) characterized by exercise intolerance with myalgia due to an inability to use glucose as an energy resource. No medical treatment for GSD VII currently exists. The aim of this study was to determine whether a dietary intervention with excessive fat intake would benefit GSD VII. A ketogenic diet (KD) intervention implemented as a modified Atkins diet was established for one patient with PFKM deficiency, with a low late lactate response and very high ammonia levels associated with exercise. We recorded the KD intervention for a total of 5 years with clinical and physiotherapeutic evaluations and regular laboratory parameters. Cardiopulmonary exercise testing, including breath gas analysis and venous lactate and ammonia measurements, was performed before KD and at 3, 8 months and 5 years after initiation of KD. During the 5 years on KD, the patient's muscle symptoms had alleviated and exercise tolerance had improved. In exercise testing, venous ammonia had normalized, the lactate profile remained similar, but oxygen uptake and mechanical efficiency had increased and parameters showing ventilation had improved. This study is the first to show a long-term effect of KD in GSD VII with an alleviation of muscle symptoms, beneficial effects on breathing, and improvement in exercise performance and oxygen uptake. Based on these findings, KD can be recommended under medical and nutritional supervision for selected patients with GSD VII, although further research of this rare disease is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010930PMC
February 2020

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions.

Cell Metab 2019 12 12;30(6):1040-1054.e7. Epub 2019 Sep 12.

Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; Department of Neurosciences, Helsinki University Central Hospital, 00290 Helsinki, Finland; Neuroscience Center, University of Helsinki, 00290 Helsinki, Finland. Electronic address:

Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISR) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISR progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISR (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2 metabolic ISR stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3 ISR stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2019.08.019DOI Listing
December 2019

Recessive PYROXD1 mutations cause adult-onset limb-girdle-type muscular dystrophy.

J Neurol 2019 Feb 4;266(2):353-360. Epub 2018 Dec 4.

Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.

Objective: To describe adult-onset limb-girdle-type muscular dystrophy caused by biallelic variants in the PYROXD1 gene, which has been recently linked to early-onset congenital myofibrillar myopathy.

Methods: Whole exome sequencing was performed for adult-onset neuromuscular disease patients with no molecular diagnosis. Patients with PYROXD1 variants underwent clinical characterization, lower limb muscle MRI, muscle biopsy and spirometry. A yeast complementation assay was used to determine the biochemical consequences of the genetic variants.

Results: We identified four patients with biallelic PYROXD1 variants. Three patients, who had symptom onset in their 20s or 30s, were homozygous for the previously described p.Asn155Ser. The fourth patient, with symptom onset at age 49, was compound heterozygous for p.Asn155Ser variant and previously unknown p.Tyr354Cys. All patients presented with a LGMD-type phenotype of symmetric muscle weakness and wasting. Symptoms started in proximal muscles of the lower limbs, and progressed slowly to involve also upper limbs in a proximal-predominant fashion. All patients remained ambulant past the age of 60. They had restrictive lung disease but no cardiac impairment. Muscle MRI showed strong involvement of anterolateral thigh muscles. Muscle biopsy displayed chronic myopathic changes. Yeast complementation assay demonstrated the p.Tyr354Cys mutation to impair PYROXD1 oxidoreductase ability.

Conclusion: PYROXD1 variants can cause an adult-onset slowly progressive LGMD-type phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-018-9137-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373352PMC
February 2019

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy.

Muscle Nerve 2019 03 4;59(3):354-357. Epub 2018 Dec 4.

Department of Neurology, Tampere University Hospital and Faculty of Medical and Life Sciences, University of Tampere, Tampere, Finland.

Introduction: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting.

Methods: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed.

Results: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD.

Discussion: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59:354-357, 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26348DOI Listing
March 2019

Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases.

Neurobiol Dis 2018 11 6;119:159-171. Epub 2018 Aug 6.

Université Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, France. Electronic address:

Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10 mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10 allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10 allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2018.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015038PMC
November 2018

Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy.

Neurol Genet 2018 Jun 5;4(3):e244. Epub 2018 Jun 5.

Research Programs Unit (M.T.S., E.Y., L.M., M.A., H.T.), Molecular Neurology, University of Helsinki; Clinical Neurosciences, Neurology (E.Y., M.A.), University of Helsinki and Helsinki University Hospital; Institute for Molecular Medicine Finland (FIMM) (J.L., P.M.), University of Helsinki; Neuromuscular Research Center (J.P.), Tampere University Hospital and University of Tampere; and Department of Medical and Clinical Genetics (H.T.), University of Helsinki, Finland.

Objective: We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light () underlying early-onset Charcot-Marie-Tooth (CMT) disease.

Methods: Motor neurons were differentiated from induced pluripotent stem cells of a patient with early-onset CMT carrying a novel homozygous nonsense mutation in . Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons.

Results: We show that the recessive nonsense mutation causes a nearly total loss of messenger RNA (mRNA), leading to the complete absence of NEFL protein in patient's cultured neurons. Yet the cultured neurons were able to differentiate and form neuronal networks and neurofilaments. Single-neuron gene expression fingerprinting pinpointed as the most downregulated gene in the patient neurons and provided data of intermediate filament transcript abundancy and dynamics in cultured neurons. Blocking of nonsense-mediated decay partially rescued the loss of mRNA.

Conclusions: The strict neuronal specificity of neurofilament has hindered the mechanistic studies of recessive nonsense mutations. Here, we show that such mutation leads to the absence of NEFL, causing childhood-onset neuropathy through a loss-of-function mechanism. We propose that the neurofilament accumulation, a common feature of many neurodegenerative diseases, mimics the absence of NEFL seen in recessive CMT if aggregation prevents the proper localization of wild-type NEFL in neurons. Our results suggest that the removal of NEFL as a proposed treatment option is harmful in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991776PMC
June 2018

Focal atrophy of the unilateral masticatory muscles caused by pure trigeminal motor neuropathy: case report.

Clin Case Rep 2018 May 30;6(5):939-943. Epub 2018 Mar 30.

Clinical Neurosciences, Neurology University of Helsinki and Helsinki University Hospital Helsinki Finland.

Patients with unknown clinical or radiological asymmetry in the face structures combined with atrophy and weakness of the masticatory muscles should be comprehensively examined clinically and with MRI, neurophysiological measurements, and serologically. Malignant lesions or benign idiopathic unilateral trigeminal motor neuropathy should be considered as an etiological explanation for the asymmetry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.1495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930203PMC
May 2018

CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency.

Hum Mol Genet 2018 02;27(4):706-715

Department of Neurology, Ulm University, 89081 Ulm, Germany.

Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p.R15L and p.G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p.P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p.R15L and p.G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p.R15L, but not of CHCHD10 p.G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p.G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p.P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddx436DOI Listing
February 2018

Diagnostics and current care of myasthenia gravis.

Duodecim 2017;133(11):1053-62

Myasthenia gravis (MG) is the most common neuromuscular transmission disorder, causing weakness of skeletal muscles on exertion. The course of the disease is highly variable, symptoms and signs may change rapidly due to infection or pregnancy. MG is classified using serological, electrophysiological and pharmaceutical tools. A precise diagnosis allows for the choice of right treatment, predicts the course of disease and hence helps with the follow-up. In this review we present Finnish guidelines for diagnostics, treatment and follow-up of MG patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2018

Adrenomyeloneuropathy due to mutation in the ABCD1 gene as underlying factor in spastic paraparesis.

Duodecim 2017;133(7):683-7

We present a Finnish family in which adrenomyeloneuropathy (AMN) caused by the mutation in the ABCD1 gene was revealed as the cause of spastic paraparesis. . Two patients had hypoadrenalism, which is in some cases some associated with the disease . AMN is a hereditary disease manifested both in men and women. but owing to the location of the gene in the X chromosome the symptoms are usually more severe in male patients. . Diagnoses was trucked down with gene-panel sequencing and confirmed through detection of an elevated level of very long-chain fatty acids in the serum of the patients. Specific molecular genetic diagnosis is beneficial, because it enables precise genetic counseling as well as recognition and treatment of associated symptoms, such as severe cortisol deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2018

Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C.

Cold Spring Harb Mol Case Stud 2017 Nov 21;3(6). Epub 2017 Nov 21.

Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki 00014, Finland.

Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 () gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment. Our patient underwent a 52-wk treatment in which the L-serine dose was titrated up to 400 mg/kg/day. She was followed up by repeated clinical examination, nerve conduction testing, and skin biopsies to document effects on small nerve fibers. Serum was assayed for 1-deoxySL and metabolomics analysis of 111 metabolites. We found a robust lowering of 1-deoxySL, which correlated in a near-linear fashion with increased serum L-serine levels. Metabolomics analysis showed a modest elevation in glycine and a marked reduction in the level of cytosine, whereas most of the other assayed metabolites did not change. There were no direct side effects from the treatment, but the patient developed a transitory toe ulceration during the course of the study. The Charcot-Marie-Tooth neuropathy score increased by 1 point. We conclude that oral supplementation of L-serine decreases 1-deoxySL in HSAN1C without major global effects on metabolism. L-serine is therefore a potential treatment for HSAN1C.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a002212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701299PMC
November 2017

ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.

Hum Mol Genet 2017 04;26(8):1432-1443

Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.

De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddx042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393146PMC
April 2017

Decreased Aerobic Capacity in ANO5-Muscular Dystrophy.

J Neuromuscul Dis 2016 11;3(4):475-485

Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Finland.

Background: Anoctaminopathies are muscle diseases caused by recessive mutations in the ANO5 gene. The effects of anoctaminopathy on oxidative capacity have not previously been studied in a controlled setting.

Objective: To characterize oxidative capacity in a clinically and genetically well-defined series of patients with anoctaminopathy.

Methods: We sequenced the ANO5 gene in 111 Finnish patients with suspected LGMD2. Patients with positive findings underwent close clinical examination, including electromyography, muscle MRI, and, in selected cases, muscle biopsy. Oxidative capacity was analyzed using spiroergometry and compared to age-matched healthy controls.

Results: We characterized 12 newly identified and 2 previously identified patients with ANO5 mutations from 11 families. Our material was genetically homogeneous with most patients homozygous for the Finnish founder variant c.2272C>T (p.Arg758Cys). In one family, we found a novel p.Met470Arg variant compound heterozygous with p.Arg758Cys. Lower limb muscle MRI revealed progressive fatty degeneration of specific posterior compartment muscles. Patients' spiroergometric profiles showed that anoctaminopathy significantly impaired oxidative capacity with increasing ventilation.

Conclusions: Our findings support earlier reports that anoctaminopathy progresses slowly and demonstrate that the disease impairs the capacity for aerobic exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-160186DOI Listing
November 2016

mutations and motor neuron disease: the distribution in Finnish patients.

J Neurol Neurosurg Psychiatry 2017 03 3;88(3):272-277. Epub 2016 Nov 3.

Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2016-314154DOI Listing
March 2017

Modified Atkins diet induces subacute selective ragged-red-fiber lysis in mitochondrial myopathy patients.

EMBO Mol Med 2016 11 2;8(11):1234-1247. Epub 2016 Nov 2.

Research Program of Molecular Neurology, Biomedicum Helsinki University of Helsinki, Helsinki, Finland

Mitochondrial myopathy (MM) with progressive external ophthalmoplegia (PEO) is a common manifestation of mitochondrial disease in adulthood, for which there is no curative therapy. In mice with MM, ketogenic diet significantly delayed progression of the disease. We asked in this pilot study what effects high-fat, low-carbohydrate "modified Atkins" diet (mAD) had for PEO/MM patients and control subjects and followed up the effects by clinical, morphological, transcriptomic, and metabolomic analyses. All of our five patients, irrespective of genotype, showed a subacute response after 1.5-2 weeks of diet, with progressive muscle pain and leakage of muscle enzymes, leading to premature discontinuation of the diet. Analysis of muscle ultrastructure revealed selective fiber damage, especially in the ragged-red-fibers (RRFs), a MM hallmark. Two years of follow-up showed improvement of muscle strength, suggesting activation of muscle regeneration. Our results indicate that (i) nutrition can modify mitochondrial disease progression, (ii) dietary counseling should be part of MM care, (iii) short mAD is a tool to induce targeted RRF lysis, and (iv) mAD, a common weight-loss method, may induce muscle damage in a population subgroup.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/emmm.201606592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5090657PMC
November 2016

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders.

Neurology 2016 Nov 28;87(22):2290-2299. Epub 2016 Oct 28.

From the Research Programs Unit, Molecular Neurology (J.M.L., S.F., H.L., M.A., P.I.), Faculty of Medicine/Clinicum, Oncology (P.O.), and Finland Genome Scale Biology Program (S.L.), University of Helsinki, Finland; Mitochondrial Medicine Group (E.B., C.V., M.Z.), Medical Research Council Mitochondrial Biology Unit, Cambridge, UK; Center for Physiology and Pathophysiology (O.R.B., R.J.W.), Institute of Vegetative Physiology, University of Köln, Germany; Transplantation and Liver Surgery Clinic (H.I., K.H.), Department of Oncology (P.O., S.L.), and Heart and Lung Center, Department of Cardiology (T.H.), Helsinki University Hospital; School of Medicine (M.H., J.J., R.L.), University of Tampere; Anaesthesiology, Intensive Care and Pain Medicine (R.M.), Clinical Neurosciences, Neurology (H.L., M.A., A.S.), and Child Neurology, Children's Hospital (P.I.), University of Helsinki and Helsinki University Hospital, Finland; Dyslipidemia Center (G.M.), Cardiotoracovascular Department, Niguarda Hospital, Milan, Italy; PEDEGO Research Unit (J.U.) and Biocenter Oulu (J.U.), University of Oulu; Finnish Clinical Biobank Tampere (R.L.), Tampere University Hospital, Finland; Nijmegen Centre for Mitochondrial Disorders (J.S.), Radboud University Medical Centre, Nijmegen, the Netherlands; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) (R.J.W.), Köln; Center for Molecular Medicine Cologne (R.J.W.), CMMC, University of Köln, Germany; Faculty of Life and Environmental Sciences (K.N.), University of Tsukuba, Japan; and Medical Research Center Oulu (J.U.), Oulu University Hospital and University of Oulu, Finland.

Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use.

Methods: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions.

Results: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions.

Conclusions: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics.

Classification Of Evidence: This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000003374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270510PMC
November 2016

Unique Exercise Lactate Profile in Muscle Phosphofructokinase Deficiency (Tarui Disease); Difference Compared with McArdle Disease.

Front Neurol 2016 30;7:82. Epub 2016 May 30.

Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Clinical Neurosciences, Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

Introduction: Glycogen storage disease V (GSDV, McArdle disease) and GSDVII (Tarui disease) are the most common of the rare disorders of glycogen metabolism. Both are associated with low lactate levels on exercise. Our aim was to find out whether lactate response associated with exercise testing could distinguish between these disorders.

Methods: Two siblings with Tarui disease, two patients with McArdle disease and eight healthy controls were tested on spiroergometric exercise tests with follow-up of venous lactate and ammonia.

Results: A late increase of lactate about three times the basal level was seen 10-30 min after exercise in patients with Tarui disease being higher than in McArdle disease and lower than in the controls. Ammonia was increased in Tarui disease.

Discussion: Our results suggest that follow-up of lactate associated with exercise testing can be utilized in diagnostics to distinguish between different GSD diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2016.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885106PMC
June 2016

Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency.

Am J Hum Genet 2016 Jun;98(6):1130-1145

Metabolism Unit, Department of Pediatrics, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.

Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908180PMC
June 2016

Specific functional pathologies of Cx43 mutations associated with oculodentodigital dysplasia.

Mol Biol Cell 2016 07 25;27(14):2172-85. Epub 2016 May 25.

Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada

Oculodentodigital dysplasia (ODDD) is a rare genetic disease that affects the development of multiple organs in the human body. More than 70 mutations in the gap junction connexin43 (Cx43) gene, GJA1, are associated with ODDD, most of which are inherited in an autosomal dominant manner. Many patients exhibit similar clinical presentations. However, there is high intrafamilial and interfamilial phenotypic variability. To better understand this variability, we established primary human dermal fibroblast cultures from several ODDD patients and unaffected controls. In the present study, we characterized three fibroblast lines expressing heterozygous p.L7V, p.G138R, and p.G143S Cx43 variants. All ODDD fibroblasts exhibited slower growth, reduced migration, and defective cell polarization, traits common to all ODDD fibroblasts studied so far. However, we found striking differences in overall expression levels, with p.L7V down-regulated at the mRNA and protein level. Although all of the Cx43 variants could traffic to the cell surface, there were stark differences in gap junction plaque formation, gap junctional intercellular communication, Cx43 phosphorylation, and hemichannel activity among Cx43 variants, as well as subtle differences in myofibroblast differentiation. Together these findings enabled us to discover mutation-specific pathologies that may help to predict future clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1091/mbc.E16-01-0062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945137PMC
July 2016

Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy.

Am J Hum Genet 2016 05;98(5):1020-1029

Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands. Electronic address:

Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863565PMC
May 2016

PFKM gene defect and glycogen storage disease GSDVII with misleading enzyme histochemistry.

Neurol Genet 2015 Jun 4;1(1):e7. Epub 2015 Jun 4.

Research Programs Unit (M.A., E.Y., H.T.), Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Clinical Neurosciences (M.A.), Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Neuromuscular Research Center (J.P., S.S., K.V., B.U.), Tampere University Hospital and University of Tampere, Tampere, Finland; Department of Pathology (S.H., H.H.), Fimlab Laboratories, University Hospital and University of Tampere, Tampere, Finland; Department of Pathology (A.P.), HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Neurology (S.S.), Seinäjoki Central Hospital, Seinäjoki, Finland; and Unit of Clinical Physiology (P.P.), HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland.

Objective: To elaborate the diagnostic methods used as "gold standard" in one of the most common glycogen storage diseases (GSDs), Tarui disease (GSDVII).

Methods: Two siblings with disease suggestive of GSD underwent thorough clinical analysis, including muscle biopsy, muscle MRI, exercise tests, laboratory examinations, and whole-exome sequencing (WES).

Results: Both siblings had juvenile-onset exercise intolerance with cramping and infrequent myoglobinuria. Muscle biopsy showed extralysosomal glycogen accumulation, but because of normal phosphofructokinase histochemistry, GSDVII was thought to be excluded. However, WES revealed a causative homozygous PFKM gene defect, R39Q, in both siblings, establishing the diagnosis of GSDVII, which was confirmed by very low residual phosphofructo-1-kinase (PFK) enzyme activity in biochemical studies.

Conclusions: We suggest that in patients with suspicion of GSD and extralysosomal glycogen accumulation, biochemical activity assay of PFK followed by molecular genetics should be performed even when enzyme histochemistry is normal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821086PMC
June 2015

CHCHD10 variant p.(Gly66Val) causes axonal Charcot-Marie-Tooth disease.

Neurol Genet 2015 Jun 26;1(1):e1. Epub 2015 Mar 26.

Research Programs Unit (M.A., E.Y., M.S., H.T.), Molecular Neurology, University of Helsinki; Clinical Neurosciences, Neurology (M.A., S.K.-E.), University of Helsinki and Helsinki University Hospital; Department of Pathology (A.P.), HUSLAB & University of Helsinki; Department of Clinical Neurophysiology (J.P.T.), Medical Imaging Center, Helsinki University Hospital; and Department of Medical Genetics (H.T.), Haartman Institute, University of Helsinki, Finland.

Objective: We describe the phenotype consistent with axonal Charcot-Marie-Tooth disease type 2 (CMT2) in 4 families with a c.197G>T (p.(Gly66Val)) variant in CHCHD10.

Methods: We sequenced the CHCHD10 gene in a cohort of 107 families with CMT2 of unknown etiology. The patients were characterized by clinical examination and electroneuromyography. Muscle MRI and biopsy of the muscle or nerve were performed in selected cases. Neuropathologic autopsy was performed in 1 case.

Results: The c.197G>T variant in CHCHD10 was found in 6 families, 4 of which included multiple individuals available for detailed clinical study. Variants in this gene have recently been associated with amyotrophic lateral sclerosis-frontotemporal dementia, mitochondrial myopathy, or spinal muscular atrophy Jokela type (SMAJ), but not with CMT2. Our patients had a late-onset distal axonal neuropathy with motor predominance, progressing to involve sensory nerves. Neurophysiologic and neuropathologic studies confirmed the diagnosis of sensorimotor axonal neuropathy with no loss of anterior horn neurons. Muscle biopsies showed occasional cytochrome c oxidase-negative fibers, combined with small amounts of mitochondrial DNA deletions.

Conclusions: CHCHD10 c.197G>T (p.(Gly66Val)) is a cause of sensorimotor axonal neuropathy. This gene should be considered in patients presenting with a pure CMT2 phenotype, particularly when motor symptoms predominate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821082PMC
June 2015

Myotonia in ion channel diseases of muscle.

Duodecim 2016;132(19):1810-4

Ion channel dysfunctions of the muscular cell membrane are usually inheritable, rare diseases. They may become manifest as relatively mild symptoms of muscle stiffness and pain, myotonia or paralysis. We describe two young patients who had an inherited ion channel disease of the muscular cell membrane with mild symptoms. The first patient had a chloride channel dysfunction of the muscular cell membrane, the second one a sodium channel dysfunction. In electromyography findings typical of the respective ion channel disease were detected in both patients. Closer examination of the patients' myotonic sequences occurring in electromyography of the relaxed muscle revealed differences that already enable the evaluation of the type of ion channel disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2018

Truncated HSPB1 causes axonal neuropathy and impairs tolerance to unfolded protein stress.

BBA Clin 2015 Jun 11;3:233-42. Epub 2015 Mar 11.

Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki 00290, Finland ; Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki 00290, Finland.

Background: HSPB1 belongs to the family of small heat shock proteins (sHSP) that have importance in protection against unfolded protein stress, in cancer cells for escaping drug toxicity stress and in neurons for suppression of protein aggregates. sHSPs have a conserved α-crystalline domain (ACD), flanked by variable N- and C-termini, whose functions are not fully understood. Dominant missense variants in HSPB1, locating mostly to the ACD, have been linked to inherited neuropathy.

Methods: Patients underwent detailed clinical and neurophysiologic characterization. Disease causing variants were identified by exome or gene panel sequencing. Primary patient fibroblasts were used to investigate the effects of the dominant defective HSPB1 proteins.

Results: Frameshift variant predicting ablation of the entire C-terminus p.(Met169Cfs2*) of HSPB1 and a missense variant p.(Arg127Leu) were identified in patients with dominantly inherited motor-predominant axonal Charcot-Marie-Tooth neuropathy. We show that the truncated protein is stable and binds wild type HSPB1. Both mutations impaired the heat stress tolerance of the fibroblasts. This effect was particularly pronounced for the cells with the truncating variant, independent of heat-induced nuclear translocation and induction of global transcriptional heat response. Furthermore, the truncated HSPB1 increased cellular sensitivity to protein misfolding.

Conclusion: Our results suggest that truncation of the non-conserved C-terminus impairs the function of HSPB1 in cellular stress response.

General Significance: sHSPs have important roles in prevention of protein aggregates that induce toxicity. We showed that C-terminal part of HSPB1 is critical for tolerance of unfolded protein stress, and when lacking causes axonal neuropathy in patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbacli.2015.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661565PMC
June 2015