DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, a growing number of human diseases have been found to be associated with aberrant DNA methylation. The study of these diseases has provided new and fundamental insights into the roles that DNA methylation and other epigenetic modifications have in development and normal cellular homeostasis.

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Dna methylation and human disease

The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.

Trinucleotide Repeat Disorders

ContextGermline mutations of the genes encoding succinate dehydrogenase subunits
B (SDHB) and D (SDHD) predispose
to paraganglioma syndromes type 4 (PGL-4) and type 1 (PGL-1), respectively.
In both syndromes, pheochromocytomas as well as head and neck paragangliomas
occur; however, details for individual risks and other clinical characteristics
are unknown.ObjectiveTo determine the differences in clinical features in carriers of SDHB mutations and SDHD mutations.Design, Setting, and PatientsPopulation-based genetic screening for SDHB and SDHD germline mutations in 417 unrelated patients with
adrenal or extra-adrenal abdominal or thoracic pheochromocytomas (n = 334)
or head and neck paragangliomas (n = 83), but without syndromic features,
from 2 registries based in Germany and central Poland, conducted from April
1, 2000, until May 15, 2004.Main Outcome MeasuresDemographic and clinical findings with respect to gene mutation in SDHB vs SDHD compared with nonmutation
carriers.ResultsA total of 49 (12%) of 417 registrants carried SDHB or SDHD mutations. In addition, 28 SDHB and 23 SDHD mutation carriers
were newly detected among relatives of these carriers. Comparison of 53 SDHB and 47 SDHD total mutation
carriers showed similar ages at diagnosis but differences in penetrance and
of tumor manifestations. Head and neck paragangliomas (10/32 vs 27/34, respectively, P<.001) and multifocal (9/32 vs 25/34, respectively, P<.001) tumors were more frequent in carriers of SDHD mutations. In contrast, SDHB mutation
carriers have an increased frequency of malignant disease (11/32 vs 0/34, P<.001). Renal cell cancer was observed in 2 SDHB mutation carriers and papillary thyroid cancer in 1 SDHB mutation carrier and 1 SDHD mutation
carrier.ConclusionsIn contrast with SDHD mutation carriers (PGL-1)
who have more frequent multifocal paragangliomas, SDHB mutation
carriers (PGL-4) are more likely to develop malignant disease and possibly
extraparaganglial neoplasias, including renal cell and thyroid carcinomas.
Appropriate and timely clinical screening is recommended in all patients with
PGL-1 and PGL-4.

https://jamanetwork.com/journals/jama/articlepdf/199313/joc32091.pdf

Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.

The list of developmental and degenerative diseases that are caused by expansion of unstable repeats continues to grow, and is now approaching 20 disorders. The pathogenic mechanisms that underlie these disorders involve either loss of protein function or gain of function at the protein or RNA level. Common themes have emerged within and between these different classes of disease; for example, among disorders that are caused by gain-of-function mechanisms, altered protein conformations are central to pathogenesis, leading to changes in protein activity or abundance. In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes.

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Diseases of unstable repeat expansion: mechanisms and common principles.

We present a series of 26 patients, all >50 years of age, who are carriers of the fragile X premutation and are affected by a multisystem, progressive neurological disorder. The two main clinical features of this new syndrome are cerebellar ataxia and/or intention tremor, which were chosen as clinical inclusion criteria for this series. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetrical regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter are thought to be highly sensitive for this neurologic condition, and their presence is the radiological inclusion criterion for this series. Molecular findings include elevated mRNA and low-normal or mildly decreased levels of fragile X mental retardation 1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation–associated tremor/ataxia syndrome and distinguishes it from other movement disorders.

Fragile X Premutation Tremor/Ataxia Syndrome: Molecular, Clinical, and Neuroimaging Correlates

The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

This is the first report that details an association between fragile X syndrome (FXS) and selective mutism (SM). This 12-year-old girl with heterozygous full mutation at FMR1 has a long history of social anxiety and shyness in addition to SM. Her sister also has the full mutation and a history of SM that resolved in adolescence. A beneficial response to fluoxetine and psychotherapy is described. The FMR1 mutation appears to be the first gene mutation associated with SM and further studies are recommended to assess what percentage of patients with SM have the FMR1 mutation.

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Fragile X syndrome and selective mutism.

We report on a 15-year-old compound heterozygous young woman with fragile X syndrome who has a full mutation of 363 repeats on one X chromosome and a premutation of 103 repeats on the other X chromosome. As predicted, subsequent testing demonstrated that her father carries a premutation (98 repeats) as does her mother (146 repeats). There is only one previous report of a compound heterozygous female with fragile X syndrome. By quantitation of Southern blot signals, the activation ratio for the premutation (the proportion of the premutation on the active X chromosome) was determined to be 0.78. Immunocytochemistry of blood smears showed fragile X mental retardation-1 protein (FMRP) expression in 63.5% of lymphocytes. Cognitively, this woman is functioning in the midrange of involvement for fragile X females. She attends regular classes and receives supplemental assistance for her learning disabilities. She experiences behavior characteristics typical of females with fragile X syndrome including severe shyness, anxiety, panic episodes, mood swings, and attention deficits. She has responded very well to appropriate treatment including fluoxetine for anxiety, methylphenidate for attentional problems, and educational therapy. Am. J. Med. Genet. 83:318–321, 1999. © 1999 Wiley-Liss, Inc.

Compound heterozygous female with fragile X syndrome.

We report on an individual with developmental delays, short stature, skeletal abnormalities, normal pubertal development, expansion of the fragile X triplet repeat, as well as an isodicentric X chromosome. S is a 19-year-old woman who presented for evaluation of developmental delay. Pregnancy was complicated by a threatened miscarriage. She was a healthy child with intellectual impairment noted in infancy. Although she had global delays, speech was noted to be disproportionately delayed with few words until age 3.5 years. Facial appearance was consistent with fragile X syndrome. Age of onset of menses was 11 years with normal breast development. A maternal male second cousin had been identified with fragile X syndrome based on DNA studies. The mother of this child (S's maternal first cousin) and the grandfather (S's maternal uncle) were both intellectually normal but were identified as carrying triplet expansions in the premutation range. S's mother had some school difficulties but was not identified as having global delays. Molecular analysis of S's fragile X alleles noted an expansion of more than 400 CGG repeats in one allele. Routine cytogenetic studies of peripheral blood noted the presence of an isodicentric X in 81of 86 cells scored. Five of 86 cells were noted to be 45,X. Cytogenetic fra(X) studies from peripheral blood showed that the structurally normal chromosome had the fragile site in approximately 16% of the cells. Analysis of maternal fragile X alleles identified an allele with an expansion to approximately 110 repeats. FMRP studies detected the expression of the protein in 24% of cells studied. To our knowledge, this is the first patient reported with an isodicentric X and fragile X syndrome. Whereas her clinical phenotype is suggestive of fragile X syndrome, her skeletal abnormalities may represent the presence of the isodicentric X. Treatment of S with 20 mg/day of Prozac improved her behavior. In the climate of cost con trol, this individual reinforces the recommendation of obtaining chromosomes on individuals with developmental delay even with a family history of fragile X syndrome.

J. Hills

Papers

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

Fragile X syndrome and selective mutism.

Compound heterozygous female with fragile X syndrome.

Fragile X syndrome and an isodicentric X chromosome in a woman with multiple anomalies, developmental delay, and normal pubertal development.