Molecular genetics of autism spectrum disorders in the Finnish population

Väitöskirja; ohj Leena Peltonen-Palotie ja Irma Järvel

Myotonia lihaksen ionikanavataudeissa

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

Background: 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.Patient and Methods: 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.Results: 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.Conclusions: 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.Peer reviewe

Perinnöllinen neuropatia ja spastinen parapareesi

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Motoneuronitautien lääkehoito - uutuuksia näköpiirissä

Vertaisarvioitu.Motoneuronitaudit ovat ryhmä harvinaisia tauteja, jotka johtavat usein kuolemaan ja joihin on toistaiseksi ollut tarjolla vain oireenmukaista hoitoa. Geenivirheiden osuus näiden tautien etiologiassa vaihtelee tuntemattomasta myötävaikuttavan kautta täydelliseen. Karttuva tieto sairauksien ja niille altistavien tekijöiden geneettisestä taustasta on mahdollistanut täsmälääketieteen esiinmarssin eli lisännyt räätälöityjen hoitojen tarjontaa. Yhtenä ongelmana on kustannus-hyötysuhde, koska uudet hoidot ovat kalliita. Esittelemme yleisimpien motoneuronitautien, amyotrofisen lateraaliskleroosin (ALS) ja spinaalisen lihasatrofian (SMA) hoitojen nykytilaa ja lähitulevaisuuden näkymiä.Peer reviewe

IMPDH2 : a new gene associated with dominant juvenile-onset dystonia-tremor disorder

The aetiology of dystonia disorders is complex, and next-generation sequencing has become a useful tool in elucidating the variable genetic background of these diseases. Here we report a deleterious heterozygous truncating variant in the inosine monophosphate dehydrogenase gene (IMPDH2) by whole-exome sequencing, co-segregating with a dominantly inherited dystonia-tremor disease in a large Finnish family. We show that the defect results in degradation of the gene product, causing IMPDH2 deficiency in patient cells. IMPDH2 is the first and rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders. We report IMPDH2 as a new gene to the dystonia disease entity. The evidence underlines the important link between guanine metabolism, dopamine biosynthesis and dystonia.Peer reviewe

ABCD1-geenin mutaatiosta johtuva adrenomyeloneuropatia spastisen parapareesin taustatekijänä

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

Objective: We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light (NEFL) 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 NEFL. 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 NEFL 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 NEFL 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 NEFL mRNA. Conclusions: The strict neuronal specificity of neurofilament has hindered the mechanistic studies of recessive NEFL 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.Peer reviewe