Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review

The system of assigning locus symbols to specify chromosomal regions that are associated with a familial disorder has a number of problems when used as a reference list of genetically determined disorders,including (I) erroneously assigned loci, (II) duplicated loci, (III) missing symbols or loci, (IV) unconfirmed loci and genes, (V) a combination of causative genes and risk factor genes in the same list, and (VI) discordance between phenotype and list assignment. In this article, we report on the recommendations of the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined movement disorders that addresses these problems. We demonstrate how the system would be applied to currently known genetically determined parkinsonism, dystonia, dominantly inherited ataxia, spastic paraparesis, chorea, paroxysmal movement disorders, neurodegeneration with brain iron accumulation, and primary familial brain calcifications. This system provides a resource for clinicians and researchers that, unlike the previous system, can be considered an accurate and criterion-based list of confirmed genetically determined movement disorders at the time it was last updated.

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“…Pyruvate dehydrogenase deficiency: paroxysmal episodes of ataxia, dystonia, occasionally parkinsonism…”

Section: Applying the Recommendationsmentioning

confidence: 99%

Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force

et al. 2016

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“…This gene encodes a protein that may suppress synaptic vesicle release by interacting with RIM1 and RIM2 [20]. Although SLC2A1 , PNKD , and PRRT2 harbor the majority of the causal mutations for the genetically defined cases of PxD [5], a few patients have been reported to carry potentially causal mutations in other genes such as KCNMA1 [21] and PDHA1 [22]. Efforts to identify the mutations responsible for PxD in other families have not yet been successful [6].…”

Section: Introductionmentioning

confidence: 99%

A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia

et al. 2016

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Hereditary paroxysmal dyskinesias (PxD) are a heterogeneous group of movement disorders classified by frequency, duration, and triggers of the episodes. A young-adult onset canine PxD has segregated as an autosomal recessive trait in Soft-Coated Wheaten Terriers. The medical records and videos of episodes from 25 affected dogs were reviewed. The episodes of hyperkinesia and dystonia lasted from several minutes to several hours and could occur as often as >10/day. They were not associated with strenuous exercise or fasting but were sometimes triggered by excitement. The canine PxD phenotype most closely resembled paroxysmal non-kinesigenic dyskinesia (PNKD) of humans. Whole genome sequences were generated with DNA from 2 affected dogs and analyzed in comparison to 100 control canid whole genome sequences. The two whole genome sequences from dogs with PxD had a rare homozygous PIGN:c.398C > T transition, which predicted the substitution of an isoleucine for a highly conserved threonine in the encoded enzyme. All 25 PxD-affected dogs were PIGN:c.398T allele homozygotes, whereas there were no c.398T homozygotes among 1185 genotyped dogs without known histories of PxD. PIGN encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors a variety of proteins including CD59 to the cell surface. Flow cytometry of PIGN-knockout HEK239 cells expressing recombinant human PIGN with the c.398T variant showed reduced CD59 expression. Mutations in human PIGN have been associated with multiple congenital anomalies-hypotonia-seizures syndrome-1 (MCAHS1). Movement disorders can be a part of MCAHS1, but this is the first PxD associated with altered GPI anchor function.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-016-0502-4) contains supplementary material, which is available to authorized users.

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“…In a few patients, paroxysmal MD was the presenting sign, with age at onset 5 months to 15 years, variable distribution (focal/segmental or generalized), and triggering circumstances suggestive of PNKD, PKD, or PED . Almost all patients showed MRI pallidal alterations …”

Section: Treatments Aimed At Correcting Energetic Failurementioning

confidence: 99%

“…A remarkable response to thiamine has been reported in 2 patients with MD, one with isolated PED and the other with acute ataxia during a febrile illness, carrying PDHA1 variants affecting a specific residue located in the TPP binding site (p.Leu‐216) …”

Section: Treatments Aimed At Correcting Energetic Failurementioning

confidence: 99%

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

Galosi

Nardecchia

Leuzzi

2020

Movement Disord Clin Pract

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Background About 80% of monogenic metabolic diseases causing movement disorders (MDs) emerges during the first 2 decades of life, and a number of these conditions offers the opportunity of a disease‐modifying treatment. The implementation of enlarged neonatal screening programs and the impressive rapid increase of the identification of new conditions are enhancing our potential to recognize and treat several diseases causing MDs, changing their outcome and phenotypic spectrum. Methods and Findings A literature review of monogenic disorders causing MDs amenable to treatment was conducted focusing on early clinical signs and diagnostic biomarkers. A classification in 3 broad categories based on the therapeutic approach has been proposed. Some disorders result in irreversible neurotoxic lesions that can only be prevented if treated in a presymptomatic stage, and others present with a progressive neurological impairment that a timely diagnosis and treatment may reverse or improve. Some MDs are the result of the failure of intracellular energy supply or altered glucose transport. The treatment in these conditions includes vitamins or a metabolic shift from a carbohydrate to a fatty acid catabolism, respectively. Finally, a group of highly treatable MDs are the result of defects of neurotransmitter metabolism. In these disorders, the supplementation of precursors or mimetics of neurotransmitters can deeply change the disease natural history. Conclusions To prevent serious and irreversible neurological impairment, the diagnostic work‐up of MDs in children should consider a number of clinical red flags and biomarkers denoting specifically treatable diseases.

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Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review

Cited by 48 publications

References 18 publications

Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force

Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force

A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

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