The impact of gender, puberty, and pregnancy in patients with POLG disease

Objective To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. Results We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Interpretation Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor.Peer reviewe

Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease

A 2-year-old boy presented with early-onset Charcot-Marie-Tooth disease (CMT). His parents had not been diagnosed previously with CMT, but on careful examination they showed clinical signs of CMT and reduced nerve conduction velocities. Genetic analysis identified the boy as a heterozygote for both a peripheral myelin protein 22 (PMP22) duplication and a mutation in the lipopolysaccharide-induced-tumour-necrosis-factor-alpha-factor(LITAF) gene, whereas each parent only had one mutated CMT gene. This suggests that LITAF mutations can severely affect the CMT phenotype caused by a PMP22 duplicatio

CSTB NULL MUTATION ASSOCIATED WITH MICROCEPHALY, EARLY DEVELOPMENTAL DELAY, AND SEVERE DYSKINESIA

The CSTB gene encodes for cystatin B, an inhibitor of lysosomal cysteine protease (cathepsins B, H, L, and S).(CSTB)-C-1 mutations have been associated with type 1 progressive myoclonic epilepsy, also known as Unverricht-Lundborg (ULD) disease, or Baltic myoclonus.(2,3) A total of 90% of all disease alleles consists of an expansion of at least 30 times of an unstable 12-nucleotide stretch (dodecamer 5-CCCCGCCCCGCG-3) in the CSTB promoter region. Homozygosity for this expansion is considered the founder mutation in the Finnish population. Few other mutations have been described, among these the p.Arg68*, but until now only as compound heterozygous with the dodecamer expansion.(4-6) Expression of the p.Arg68* mutation in vitro indicates that the truncated protein is rapidly degraded, confirming that it is a null mutation.(7) Between the ages of 6 and 16 years, ULD begins with stimulus-sensitive myoclonus and generalized tonic-clonic seizures, which can be worsened by phenytoin, followed by ataxia and slow neurodegeneration. Here we report on the first 2 patients with a homozygous p.Arg68* null mutation

The impact of gender, puberty, and pregnancy in patients with POLG disease

Objective To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. Results We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Interpretation Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor

The impact of gender, puberty, and pregnancy in patients with POLG disease

Objective To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. Results We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Interpretation Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor

Homozygous Nonsense Mutations in KIAA1279 Are Associated with Malformations of the Central and Enteric Nervous Systems

We identified, by homozygosity mapping, a novel locus on 10q21.3-q22.1 for Goldberg-Shprintzen syndrome (GOSHS) in a consanguineous Moroccan family. Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects, as well as Hirschsprung disease, an enteric nervous system defect. Furthermore, since bilateral generalized polymicogyria was diagnosed in all patients in this family, this feature might also be considered a key feature of the syndrome. We demonstrate that homozygous nonsense mutations in KIAA1279 at 10q22.1, encoding a protein with two tetratrico peptide repeats, underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria, establishing the importance of KIAA1279 in both enteric and central nervous system development

The impact of gender, puberty, and pregnancy in patients with POLG disease

Abstract Objective: To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods: Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. Results: We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Interpretation: Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor

Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients

Background: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Patients and results: Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1\ua0bp duplication, two 1\ua0bp deletions, a 3\ua0bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20\ua0years for SUCLA2 and 20\ua0months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38\ua0% of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14\ua0% of cases with SUCLG1 mutations. Long survival, to age 20\ua0years or older, was reported in 12\ua0% of SUCLA2 and in 10\ua0% of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69\ua0% of SUCLA2 and 80\ua0% of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found. Conclusions: To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands