Polymerase gamma 1 mutations: clinical correlations.
ABSTRACT Mitochondrial disorders result from primary defects in the mitochondrial DNA (mtDNA) or from defects in nuclear genes which cause disease by affecting the mtDNA. POLG1 is a nuclear gene which encodes for the catalytic subunit of the mtDNA polymerase gamma, essential for mtDNA replication. Less than a decade ago, POLG1 mutations were discovered in patients with progressive external ophthalmoplegia. Since then, it has emerged that POLG1 mutations can result in a spectrum of clinical manifestations, resulting in autosomal recessive or dominant mitochondrial diseases.
Here we summarize the common clinical phenotypes associated with POLG1 mutations. Alpers syndrome, progressive external ophthalmoplegia with or without limb myopathy, ataxia-neuropathy syndrome, and epilepsy are frequent clinical manifestations of the POLG1-related disease. Childhood progressive encephalopathy, Parkinsonism, stroke-like events, and isolated exercise intolerance can occur in association with POLG1 mutations. Muscle biopsy can show signs of mitochondrial dysfunction by histologic and biochemical studies or it can be unrevealing. mtDNA analysis of affected tissues can reveal depletion, multiple deletions or point mutations, but it can be occasionally noninformative by routine analysis.
: POLG1 mutations result in extremely heterogenous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes. The lack of signs of mitochondrial dysfunction in the muscle biopsy does not exclude a POLG1-related disease. Analysis of mtDNA of clinically affected tissues is often informative, but not always. Molecular analysis of POLG1 is essential when POLG1-related disease is suspected. Sodium valproate should be avoided because of the risk of liver failure.
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ABSTRACT: Previous studies have explored the efficacy and safety of botulinum neurotoxin (BoNT) treatment for Focal hand dystonia (FHD), but none have followed a large number of patients for 10 years or more. Retrospective study, with benefit and weakness assessed on a 0 to 4 subjective scale. Demographic, clinical and treatment characteristics were analyzed using t tests and Pearson correlations. Twenty FHD patients had 10 years or longer treatment. Interinjection intervals were variable. Musicians were more likely to wait longer between injections and had less complex dystonia. There was a trend for larger benefit in women and with shorter intervals. The dose increased over time. Dystonia characteristics did not predict response or side-effects, but benefit magnitude predicted longer compliance. No serious side-effects or antibody-mediated resistance occurred. This is the longest reported period of BoNT treatment in the largest FHD cohort. BoNT therapy for FHD remains safe and effective after more than a decade of treatment.Movement Disorders 03/2011; 26(4):750-3. DOI:10.1002/mds.23504 · 5.63 Impact Factor
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ABSTRACT: Background: Parkinson’s disease (PD) and essential tremor (ET) may share some etiopathogenic factors. A genome-wide association study has shown that LINGO1 gene variants are associated with increased risk of ET. We hypothesized that LINGO1 variants could increase susceptibility to PD. Methods: A large series of PD subjects and healthy controls were genotyped for rs9652490 and rs11856808 LINGO1 single nucleotide polymorphisms (SNPs). Results: We found an increased frequency of the rs11856808T/T genotype in PD compared with controls (odds ratio 5 1.46; corrected P value 5 0.02). A recessive genetic model was the best fit for rs11856808 influence on PD (recessive gene action test: corrected P value 5 0.01). Stratification analysis showed that rs11856808T/T genotype frequency was higher in the tremor-dominant PD and the classical PD (C-PD) subgroups (recessive gene action test for the C-PD subgroup: corrected P value 5 0.004). Discussion: Our results indicate that LINGO1 variants could increase risk of PD, specifically those presenting the non-rigid-akinetic phenotypes, which suggests that LINGO1 may have a role in the etiology of tremor in PD at least in the Spanish population.Movement Disorders 03/2011; 3922221(26):605-608. DOI:10.1002/mds.23452 · 5.63 Impact Factor
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ABSTRACT: Spinocerebellar ataxias (SCAs) constitute a group of autosomal dominant neurodegenerative disorders with no current treatment. The insulin/insulin-like growth factor 1 (IGF-1) system (IIS) has been shown to play a role in the neurological dysfunction of SCAs and other polyglutamine disorders. We aimed to study the biomarker profile of serum IIS components in SCA3. We performed a case-control study with 46 SCA3 patients and 42 healthy individuals evaluating the peripheral IIS profile (insulin, IGF-1, IGFBP1 and 3) and the correlation with clinical, molecular, and neuroimaging findings. SCA3 patients presented lower insulin and IGFBP3 levels and higher insulin sensitivity (HOMA2), free IGF-I, and IGFBP1 levels when compared with controls. IGFBP-1 levels were directly associated with CAG expanded repeat length; IGF-1 was associated with the volumetries of specific brainstem regions on magnetic resonance imaging (MRI). Insulin levels and sensitivity were related to age at onset of symptoms. Our findings indicate an involvement of IIS components in SCA3 neurobiology and IGFBP-1 as a potential biomarker of the disease.Movement Disorders 03/2011; 26(4):731-5. DOI:10.1002/mds.23428 · 5.63 Impact Factor