Posts Tagged ‘patient’

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder resulting from germline mutations in the APC gene. The APC gene, comprising 15 exons and encoding a protein with 2843 amino acids, is implicated in ~80% of FAP cases1. Extensive genetic analysis has revealed germline variants in FAP patients, and most APC mutations are found in the 5 half of the coding region. Genotypephenotype correlations have been reported for small-nucleotide alterations, including frameshift and nonsense mutations2,3. Large genomic deletions and duplications have been identified using multiplex ligation-dependent probe amplification (MLPA)4. Whole-genome array comparative genomic hybridization (aCGH) was used to identify a large deletion involving the middle portion of the long arm of chromosome 55. Here, we report a case of an FAP patient with intellectual disability that was attributed to a large deletion involving 5q22.2.

The proband was a 28-year-old female who was referred to the emergency hospital with acute abdominal pain. Computed tomography (CT) demonstrated perforation of the descending colon, multiple colorectal polyps, multiple liver metastases and lymph node swelling. She underwent left hemicolectomy, and the subsequent histological diagnosis was moderately differentiated adenocarcinoma (pT4a, pStage IVa). Chemotherapy was selected for treatment of the residual metastasis. Colonoscopy revealed advanced colon cancer with multiple adenomatous polyps (>100). Head CT revealed an osteoma in her skull, and the phenotype was subsequently defined as Gardners syndrome.

The patient had slight intellectual disability without developmental delay or neurogenic abnormalities. She and her mother requested comprehensive genomic panel (CGP) analysis (OncoGuideTM NCC oncopanel, Sysmex, Hyogo, Japan) of surgically resected colon cancer tissue after providing informed consent. This test can detect mutations in 124 genes and differentiate between germline and somatic mutations. The pathogenic mutations detected were KRAS G13D, PIC3CA H1047R, and TP53 M169fs*2, but no targeted therapy was recommended by the expert panel. No germline findings were reported, but whole APC gene deletion was suspected due to the low amplicon depth of the APC gene in both the tumor tissue and blood samples (Fig. S1).

According to her familial history (Fig. 1), her mother (II-3) was treated for sporadic colon cancer. She refused genetic testing due to receiving cancer chemotherapy. Her son (IV-1), whose intelligence was slightly low, had a single-parent history because his father was not identified.

The arrow indicates the patients who underwent genetic counseling. A closed circle indicates an individual with colorectal cancer. Colorectal polyposis was observed in the proband (III-1) but not in her ancestors.

After genetic counseling, aCGH (GenetiSure Dx Postnatal Assay, Agilent, Tokyo, Japan) was performed for further genetic testing. Notably, aCGH revealed the loss of chromosome 5 (chr5) q22.1-q22.2 (Fig. 2), the loss of chr3 p24.1-p23, and the gain of chr15 q15.3. The chr5 deletion included the entire APC gene (chr5:112043195-112181936 in GRCh37) located at 5q22.2 (Fig. S2), according to the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER, https://www.deciphergenomics.org).

A heterozygous 5q22 deletion was detected. The minimal and maximal deletion positions in GRCh37 (start_stop) were 111143360_112213143 and 111118900_112239978, respectively.

This case in which the entire APC gene was deleted, as determined by aCGH, is rare. Chromosome 5p22.1-22.2 deletion causes 1Mb of heterozygous loss, including the APC gene, which was reported as a cytogenetically detected deletion in previous reports. Previously, karyotyping and fluorescence in situ hybridization were used to detect large submicroscopic genomic deletions, and aCGH was used to detect high-resolution copy number variants in whole chromosomes6. aCGH is sensitive and comprehensive, allowing detection of multiple variations, and annotations by specialists are needed. DECIPHER catalogs common copy number changes, enabling the identification of potentially pathogenic variants. aCGH can also be used for sequencing targeted genes. For FAP patients, germline APC variants are identified by direct sequencing using next-generation sequencing (NGS) and MLPA5. Sequencing has been used to detect APC gene variants, but ~20% of FAP patients do not carry these variants. MLPA is useful for detecting whole or large APC gene copy number variants in mutation-negative FAP patients. There are several case reports in which germline variants of FAP were examined via aCGH7,8,9,10.

Our young patient with advanced colon cancer derived from multiple colorectal polyposis was diagnosed with FAP according to the clinical features. A CGP was performed using NGS for cancer precision medicine in this patient. Because metastatic colon cancer is treated by chemotherapy, somatic genomic analysis with CGP was also conducted to determine the optimal chemotherapy regimen. Next, we used NGS to determine the sequence of 100bp amplicons of 124 cancer-related genes from cancer tissue and peripheral blood. A large APC deletion was not detected by this targeted sequence, although both the somatic and germline amplicon depths of the APC gene were slightly low. A large number of APC variants have already been deposited in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/). For several FAP patients in which germline APC variants were not found, investigations of copy number variations have been performed. The genotypephenotype correlation of patients with chromosome 5q deletions has been discussed10. A classical FAP phenotype is associated with a mutation in codons 1681250 or codons 14001580. A severe phenotype is caused by a mutation in codons 12501464. A more attenuated form is associated with mutations in three regions: the 5 region of the APC gene, the alternative splicing region in exon 9, and the extreme 3 end of the gene11.

Whole or partial APC gene deletions can be detected with recently developed genetic techniques9,10,12. MLPA and aCGH are candidates for confirming large deletions or duplications, and the latter genetic test was chosen for our patient. In our patient, two chromosomal losses and one gain were detected. The advantage of chromosomal analysis is that it can reveal unexpected genetic changes even in separate chromosomes. The CGH database includes some patients with large deletions in chromosomal region 5q22, including the APC gene. In a very recent case report, aCGH was utilized to identify a large 19.85Mb deletion12. A case series with a literature review described a patient with intellectual disability and a colon neoplasm with an interstitial deletion of 5q identified by aCGH. Colorectal cancers are observed in some patients with 5q deletions, yet examination of colorectal polyposis in this context is limited. Among the primary dysmorphisms and symptoms linked to 5q deletions, the predominant manifestation identified in the analysis of 12 patients was mental retardation12. The cases documented in both the literature and the DECIPHER database are characterized by common clinical features, including predisposition to cancer, intellectual disability, and neurodevelopmental delay. Patients with these congenital changes should undergo genetic testing, including G-band, fluorescence in situ hybridization (FISH), and aCGH. aCGH offers high resolution, allowing for the detection of changes at the chromosomal level. This high sensitivity is particularly valuable when conventional methods, such as karyotyping or FISH, may not provide detailed information about genomic alterations. Moreover, this approach allows researchers and clinicians to explore potential genetic factors beyond the well-known APC genes. In the near future, long-read sequencing of large deletions may enable us to obtain detailed genomic information13. Additional clinical information is needed to establish the genotypephenotype correlations associated with the 5q22.2 deletion that includes the whole APC gene. The published cases have raised the question of whether whole APC deletion induces colorectal polyposis. Casper et al. reported a case of Gardner syndrome attributable to a substantial interstitial deletion of chromosome 5q, offering a comprehensive review of published cases9. Until 2014, 16 patients with FAP resulting from chromosome 5q deletions were documented, with all but one patient presenting with classic adenomatous polyposis rather than the profuse form. Most of these deletions were de novo alterations, consistent with our reported case in which the patients mother (II-3) exhibited sporadic colon cancer without polyposis. In the familial lineage (Fig. 1), our patients son (IV-1) carried a deletion in the 5q22.1-22.2 region, mirroring the genomic alteration of his mother (III-1). However, the genetic inheritance pattern of this large deletion is unclear. Meticulous follow-up of the young boy is important for addressing this issue.

In conclusion, this study describes a rare FAP patient characterized by a large deletion of chromosome 5q22.1-22.2 identified through comprehensive genomic analysis. The genetic variant was suspected by CGP and eventually identified by aCGH. These findings emphasize the importance of advanced genetic techniques in identifying complex genomic variations and suggest a need for additional research to elucidate the specific features associated with whole-APC gene deletions.

Link:
Genomic insights into familial adenomatous polyposis: unraveling a rare case with whole APC gene deletion and ... - Nature.com

Genetic testing done for a 55-year-old woman diagnosed with an unusually mild case of AADC deficiency revealed a disease-causing gene mutation never before reported, according to researchers.

The newly identified mutation, while indeed found to be a cause of the patients genetic disease, still allowed for the relatively preserved function of the AADC protein. The researchers said in a case report that the increased protein function may be why the patients symptoms were mild.

Details were given in An attenuated, adult case of AADC deficiency demonstrated by protein characterization, which was published in the journal Molecular Genetics and Metabolism Reports. The work was funded in part by PTC Therapeutics, makers of the AADC deficiency gene therapy Upstaza (eladocagene exuparvovec).

The researchers said their approach in the womans case provided the molecular basis for the mild presentation of the disease, and added that the experience can also be useful for personalized therapeutic decisions in other mild AADC deficiency patients.

AADC deficiency is caused by mutations in the DDC gene, which provides instructions for making the eponymous AADC enzyme. This enzyme is needed to make brain signaling molecules, or neurotransmitters, like dopamine and serotonin. Abnormally low levels of these neurotransmitters in AADC deficiency lead to disease symptoms.

Most people with AADC deficiency who do not receive treatment have very little ability to move or speak on their own. In marked contrast to the typical picture of severe disease, this patient had only some cognitive abnormalities and occasionally experienced moments of weakness in her legs. Overall, her cognitive issues were fairly mild, and she was able to walk and ascend stairs without too much difficulty.

The patient reported that her siblings also had experienced cognitive issues, and that, as a child, she had sometimes experienced episodes where her eyes would roll upward when she was tired. With the benefit of hindsight, the researchers suspect these childhood episodes may have been oculogyric crises, a characteristic symptom of AADC deficiency.

The woman sought medical attention in her mid-50s because she was experiencing mood swings, and the episodes of weakness in her legs had been getting worse, leading to sudden falls.

Analyses of the fluid around the patients brain indicated low levels of dopamine and serotonin, consistent with a diagnosis of AADC deficiency.

Tests of her blood showed AADC enzyme activity was about 28% of whats considered normal which is low enough to qualify for AADC deficiency, but only just, given that healthy AADC carriers typically have activity of 35% to 40%.

Every individual has two copies of the DDC gene, with one inherited from each biological parent. AADC deficiency only develops if both copies are mutated. Carriers, meanwhile, have one mutated copy and one healthy copy and, as such, dont develop disease.

Genetic testing of this patient showed one of her DDC genes carried a mutation dubbed p.Arg347Gln, which has previously been reported to cause AADC deficiency. Her other copy of the gene carried another mutation, p.Glu227Gln, which has never been reported before.

To better understand the molecular basis for this patients unusually mild symptoms, the researchers conducted a series of tests to characterize this combination of mutations. The AADC enzyme normally functions as a dimer that is, two individual AADC enzymes join together to carry out the enzymes function.

The researchers found that when an AADC dimer contained two proteins both with the known disease-causing mutation p.Arg347Gln, the dimer had essentially no ability to function at all. By contrast, an AADC dimer with two enzymes carrying the novel p.Glu227Gln mutation had near-normal functionality. A dimer containing one enzyme with each mutation had about 75% of the activity of a normal AADC dimer.

Altogether these data suggest that these two mutations cause AADC deficiency that is characterized by comparatively high enzyme activity likely explaining why this patient had such mild symptoms.

After the diagnosis of AADC deficiency was confirmed, the patient was started on treatment with vitamin B6 (pyridoxine). She reported more energy and less fatigue after starting the treatment.

Interestingly, in the last few years, many previously undiagnosed or misdiagnosed patients have been identified as mild cases of AADC deficiency, expanding the phenotype [characteristics] of this neurotransmitter disease, the researchers wrote.

Read more:
Unusually mild case of AADC deficiency reveals new gene mutation - AADC News

The CI AdvantageStability, Safety, And Security

We have a proven track record of financial security and stability, as well as price stability. CI is the only cryonics organization with no debt, no stockholders, and no landlords. We own our patient care facilities outright, and all of our member officers and directors donate their services voluntarily. Were one of the oldest cryonics organizations in existence and the only such organization that has never raised its prices, even in high-inflation times like the late 70s and early 80s. Adjusting for inflation, our prices have actually steadily declined, and we hope to continue that trend.

As members, each and every one of us has a vested interest in the long-term viability of our organization our facilities, cryostats and finances are built to last into the future were striving toward.

We have a flexible and rapid system of emergency patient care based on widely available networks of mortuary assistance. This means that in the critical early stages, we can bring qualified professionals to you throughout most of the world. In particular, London-based F.A. Albin & Sons funeral directors are trained, practiced, equipped, and prepared to fly a team anywhere in Europe on short notice to help European CI members, tourists or business travellers.

Our prices are lower than any other organization in fact, the most affordable prices anywhere in the world. This is in keeping with our membership philosophy to provide ourselves reliable cryonic services at a reasonable and affordable cost. If we were to raise prices, wed only be charging ourselves more.

Our minimum whole-body suspension fee is $28,000. (For members at a distance, transportation costs and local help will be additional.) Our $28,000 fee is a one-time only payment, with no subsequent charges.Its easily funded by insurance or other means. (For last-minute cases, where the patient was not signed up beforehand, we ordinarily charge $35,000 rather than $28,000, if arrangements can be worked out at all.)

Does that lower fee mean lower quality patient care or services?Absolutely not.We believe that our non-profit status allows us to more successfully control costs. We believe that specific methods and research offered by alternative cryonics organizations differ only slightly from ours and that our procedures and policies give an equal or better chance for patient survival than competing organizations.

See for yourself. Read ourFAQand review The CI Advantage. Remember, many CI members could afford the higher prices of other organizations for themselves and their families, but weve chosen CI because we know its our best bet. And yours.

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About CI - The Cryonics Institute

1976 ROBERT ETTINGER FOUNDS THE CRYONICS INSTITUTE

Then in 1976 a separate organization was formed: the Cryonics Institute, to offer cryostasis services: careful preparation, cooling, and long term patient care in liquid nitrogen.

Our goal was maximum reliability and affordability. And we achieved it. The Cryonics Institute offers clear-cut advantages over all other providers. Such as:

Our prices are lower than any other organization in fact, the most affordable prices anywhere in the world. Our minimum whole-body suspension fee is $28,000. (For members at a distance, transportation costs and local help will be additional.) Our $28,000 fee is a one-time only payment, with no subsequent charges. Its easily funded by insurance or other means, and funds the best care available for our member patients. (For last-minute cases, where the patient was not signed up beforehand, we ordinarily charge $35,000 rather than $28,000, if arrangements can be worked out at all.)

Does that lower fee mean lower quality patient care or services? No. The major part of other organizations fees are earmarked for investment provisions totally unrelated to patient care and preparation. Methods and research differ, but overall we believe our procedures and policies give a better chance for patient survival than any other organizations and this web site will show you the detailed reasons why.

See for yourself. Read our FAQ and see The CI Advantage that compares the different cryonics organizations and why we think CI gives you and those you love the best possible chance for future survival. Remember: most CI members can afford the higher prices of other organizations for themselves and their families and often do give more, in bequests and donations. But weve chosen CI because we know its our best bet. And yours.

We have a unique, proven track record of financial security and stability. Price stability too. CI is the only organization with no debt, no stockholders, and no landlords. We own our patient care facilities outright, and all our officers and directors donate their services voluntarily. Were one of the oldest cryonics organizations in existence and the only such organization that has never raised its prices, even in high-inflation times like the late 70s and early 80s. Adjusting for inflation, our prices have actually steadily declined, and we expect this to continue.

Financially, we are the soundest cryonics organization in existence.

We have a uniquely flexible and rapid system of emergency patient care based on universally available networks of mortuary assistance (and often medical assistance). This means that in the critical early stages, we can bring qualified professionals to you faster than any other system to you, and to travelers, vacationers, and members throughout most of the world. In particular, London-based F.A. Albin & Sons funeral directors are trained, practiced, equipped, and prepared to fly a team anywhere in Europe on short notice to help European CI members or tourists and business travelers.

And finally, we provide a comprehensive source of information here on CIs website. The site youre reading will lead you to everything you need to know about the subject of cryonics, and more. It offers you free information, free books, the latest news, hundreds of links to thousands of sources covering health, science, cutting-edge medicine, nanotechnology, financial help and resources, and supportive people and organizations. And if thats not enough? We personally will answer any question you might have about cryonics or the Cryonics Institute directly by email, or direct you to someone who can. In the world of cryonics, this is the source to visit, and the place to be.

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