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At least 19 recordsLinked to original sources
PubMed1977

Intermodulation product pair 2f1 +/- fh: masking and growth.

To examine the question of whether the distortion product 2f1 - fh is unique--whether a special nonlinear mechanism is responsible for its production--estimates of 2f1 - fh and of 2f1 + fh amplitudes were obtained in three listeners. Threshold shifts measured with a tone-on-tone masking paradigm for each distortion product suggest that each have similar properties and are masked by other tones as if they had a physical realization in the cochlea. Their masking is not a function of stimulus fine-time structure. The 1 dB/dB growth of 2f1 - fh was not changed by rendering it inaudible as previously suggested. Possible explanations of the 1 dB/dB growth of 2f1 - fh compared with the accelerated growth of 2f1 + fh are examined.

Auditory Perception↗
PubMed2024

Case report: response to immunotherapy and association with the fh gene in hereditary leiomyomatosis and renal cell cancer-associated renal cell cancer.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.

Humans↗
PubMed1977

Gene dosage effect for fumarate hydratase (FH; E.C. 4.2.1.2) in partial trisomy 1.

A strain of fibroblasts partially trisomic for the larger part of 1q (Norwood and Hoehn, 1974) contains about 1.5 times as much fumarate hydratase (FH) as various control-strains. This gene dosage effect was ascertained by (1) comparative measurements of the specific activity; (2) relating the specific activity of FH to that of reference enzymes, not influenced by the chromosomal anomaly; and (3) by immunoprecipitation methods, using a rabbit antiserum against pig heart FH which cross-reacts with the human enzyme. Among others, this gene dosage effect can be demonstrated numerically by the following parameters: Ratio of the average specific activity of FH in the trisomic strain to that of the control strains: 1.53. Corresponding ratio after dividing FH activity by that of reference enzymes; for acid phosphatase: 1.58, for glutamate dehydrogenase: 1.53. Average ratio of the immunoprecipitation areas obtained upon radial immunodiffusion according to Mancini et al. (1965): 1.56.

Acid Phosphatase↗
PubMed2025

Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC and renal cancer.

PURPOSE: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This article quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH. METHODS: We collated clinical diagnostic testing data on germline FH variants from 387 individuals with HLRCC and 1780 individuals with renal cancer and compared the frequency of "very-rare" variants in each phenotypic cohort with 562,295 population controls. We generated pan-gene very rare variant likelihood ratios (PG-VRV-LRs), domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log2.08 likelihood ratios (LLRs) as applicable within the updated American College of Medical Genetics and Genomics/Association for Molecular Pathology variant classification framework. RESULTS: For HLRCC, the PG-VRV-LR was estimated to be 2669.4 (95% CI 1843.4-3881.2, LLR 10.77) for truncating variants and 214.7 (95% CI 185.0-246.9, LLR 7.33) for missense variants. For renal cancer, the PG-VRV-LR was 95.5 (95% CI 48.9-183.0, LLR 6.23) for truncating variants and 5.8 (95% CI 3.5-9.3, LLR 2.39) for missense variants. Clustering analysis in HLRCC cases revealed 3 "hotspot" regions wherein the DS-VRMV-LR increased to 1226.9. CONCLUSION: These data provide quantitative measures for very rare missense and truncating variants in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer and may be applicable in clinical variant classification.

Humans↗
PubMed1992

RFLPs of the LDL-receptor gene: their use in the diagnosis of FH and in evaluation of different levels of gene expression on normal subjects.

The usefulness of the RFLPs of the LDL-receptor gene in early diagnosis of Familial Hypercholesterolemia (FH) was investigated in 122 FH-families. Four RFLPs, produced by digestion with the enzymes PvuII, ApaLI and AvaII/XbaI were able to detect the affected gene and to follow the inheritance of the disease in 72 out of 97 families (74%). In the remaining 25 families, unambiguous diagnosis was possible in 66% of the cases by use of PvuII, ApaLI and BstEII/EcoRI RFLPs. The RFLPs were also useful to distinguish true homozygotes from compound heterozygotes and to detect families where recombination events occurred or where hypercholesterolemia was not due to a defect of the LDL-receptor gene. In a normal population PvuII RFLP account for 9.6% of the total variance of the LDL cholesterol levels adjusted for confounding variables. The P2 allele was associated with lower LDL cholesterol concentrations (average excess -9.1 mg/dl). This finding allows us to presume there is a DNA sequence, close to the variable PvuII cutting site in intron 15, which could act as an enhancer of the LDL-receptor gene expression.

Adult↗
PubMed1979

Further characterization of the human fumarase variant, FH 2--1.

1. Further investigation of fumarase using lymphoblastoid cells derived from an individual of the FH 2--1 phenotype has confirmed that the mitochondrial (FHM) and soluble (FHS) forms of fumarase are determined at the same structural locus. 2. The FH 2--1 variant is associated with enzyme deficiency: c. 70% of normal in lymphoblastoid cells and c. 20% of normal in red cells. 3. The pH optimum and apparent Michaelis constant of the variant fumarase were normal but heat-inactivation studies suggest that the isozymes containing polypeptides determined by the variant allele are unstable.

Cell Line↗
PubMedDate not supplied

Instability of the minisatellite sequence in the first intron of the rat renin gene and localization of the gene to chromosome 13q13 between FH and PEPC loci.

A minisatellite sequence in the first intron of the rat renin gene showed five-allelic polymorphism in 11 inbred rat strains. A new allelic variant, which was thought to be generated in the germ line, was observed in 136 animals of two sets of backcross progenies originating from parental strains with different alleles. These facts suggested that the minisatellite is genetically unstable. A linkage analysis using the backcross progenies confirmed the assignment of renin locus (REN) on linkage group (LG) X at a site between FH (fumarate hydratase) and PEPC (peptidase) loci. Fluorescence in situ hybridization allowed mapping of the renin gene on rat chromosome 13q13.

Alleles↗
PubMed2026

Management and Consequences of Genotype-Positive Familial Hypercholesterolemia.

IMPORTANCE: Familial hypercholesterolemia (FH) is a common genetic condition that causes hypercholesterolemia and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The prevalence, management, and consequences of genetically confirmed FH across the US are poorly understood. OBJECTIVE: To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management. DESIGN, SETTING, AND PARTICIPANTS: In the All of Us (AoU) cohort study, whole-genome sequencing and phenotypic data from US adult participants enrolled between May 2018 and July 2022 were analyzed to identify and study genotype-positive FH. Data were analyzed between May 2024 and May 2025. EXPOSURE: FH variants (pathogenic or likely pathogenic) in LDLR, APOB, and PCSK9 genes were manually classified with standard criteria. MAIN OUTCOMES AND MEASURES: The primary outcomes were demographic characteristics, lipid measurements, ASCVD, and prevalence of FH and noncarriers in AoU. Lipid management was then characterized among individuals with FH through lipid-lowering therapy (LLT) documentation and guideline-based low-density lipoprotein cholesterol (LDL-C) targets. RESULTS: A total of 245&#x202f;388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145&#x202f;563 female participants (59.3%). Genotype-positive FH was identified in 865 participants (prevalence, 0.35%; 95% CI, 0.33%-0.38%; 1 in 287 participants). Among individuals with genotype-positive FH, 349 (40%) were prescribed statins, and 332 (38.4%) had LDL-C measured. Coronary artery disease, peripheral artery disease, and transient ischemic attack or stroke were significantly more common in genotype-positive FH carriers compared to noncarriers (coronary artery disease: odds ratio [OR], 2.91; 95% CI, 2.34-3.58; peripheral artery disease: OR, 1.51; 95% CI, 1.16-1.96; and transient ischemic attack or stroke: OR, 1.54; 95% CI, 1.11-2.09). Only 30.1% of participants positive for FH variants had LDL-C less than 100 mg/dL at their most recent result compared to 48.2% of noncarriers (P&#x2009;<&#x2009;.001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (<70 mg/dL; 19.33% vs 43.12%; P&#x2009;<&#x2009;.001) compared to noncarriers. CONCLUSIONS AND RELEVANCE: This cohort study finds a prevalence of genotype-positive FH in All of Us participants of 0.35% (95% CI, 0.33%-0.38%), with state-level variation. A minority of individuals with genotype-positive FH met guideline-recommended LDL-C targets and had increased rates of ASCVD.

Humans↗
PubMed1992

Ultrasonography in the detection of Achilles tendon xanthomata in heterozygous familial hypercholesterolemia.

We have examined the usefulness of ultrasound (US) in the detection of Achilles tendon (AT) xanthomata in heterozygous familial hypercholesterolemia. Our study is based on 30 adult subjects with heterozygous familial hypercholesterolemia (FH) (16 men, 14 women), 27 subjects with other non-familial forms of severe hypercholesterolemia (non-FH) with serum total cholesterol levels > or = 8 mmol/l (13 men and 14 women) and 31 subjects without marked hypercholesterolemia of the same age (control group; serum total cholesterol < 8 mmol/l) (15 men, 16 women). The three groups were comparable with respect to age, sex and body mass index. In the control group the mean sagittal thickness of AT was 4.5 mm (95% CI 3.2, 5.9 mm) and the mean coronal breadth of AT 11.0 (95% CI 9.0, 13.0 mm). Mean thickness of AT was 4.9 (range 4-7) mm in the non-FH group and 11.1 (5-16) mm in the FH group. The mean breadth of AT was in these groups 12.0 (10-17) mm and 19.2 (12-27) mm, respectively. Using the upper 95% confidence interval cut-off point in the control group as a criterion for normal AT thickness and breadth, 6 (22%) of non-FH and 29 (97%) of FH patients had increased AT thickness and 5 (19%) vs. 26 (87%) patients had increased AT breadth, respectively. The sensitivity of AT thickness for identifying FH was 0.97, specificity 0.78 and positive predictive value 0.83. The sensitivity of AT breadth in identifying FH was 0.87, specificity 0.81 and positive predictive value 0.84. None of the control subjects and none of the non-FH patients showed structural abnormalities of AT in the US, whereas 89% of FH-patients showed hypoechogenicity of AT. FH-score obtained by summing up the number of abnormal US findings gave a sensitivity of 0.93, a specificity of 0.96 and a positive predictive value of 0.96 for AT US in discriminating FH from non-FH. In conclusion, US examination of AT is a useful method in the detection of AT xanthomata and thus of help in the diagnosis of heterozygous FH.

Achilles Tendon↗
PubMed1992

Diagnosis of heterozygous familial hypercholesterolemia. DNA analysis complements clinical examination and analysis of serum lipid levels.

The concordance of clinical and molecular genetic diagnoses of heterozygous familial hypercholesterolemia (FH) was studied in 65 subjects (10 propositi and 55 first-degree relatives) from 10 families with FH. Nine propositi were carriers of the FH-Helsinki deletion of the low density lipoprotein (LDL) receptor gene, prevalent in the Finnish population, while a new deletion, extending from intron 14 to intron 15 of the LDL receptor gene, was identified in one family. Serum LDL cholesterol levels used in the clinical diagnosis (less than 5.0 mmol/l, not FH; 5.0-5.9 mmol/l, possible FH; greater than or equal to 6.0 mmol/l, FH; limits are 1 mmol/l lower for those less than 18 years) were derived from an authoritative recommendation. Tendon xanthomas constituted an additional criterion. With the DNA analysis as the reference, 55 (85%) subjects could be correctly classified clinically as FH patients or subjects without FH. The remaining 10 subjects were misclassified or were in the "possible FH" category. When the age- and sex-specific 95th percentile LDL cholesterol levels were used instead of the rigid values for both adults and children, the percentage of correct diagnoses rose to 95%. Common genetic polymorphisms of apolipoproteins E and B did not markedly affect LDL cholesterol levels in FH patients, whereas increasing age and obesity were associated with elevated LDL levels. In conclusion, DNA analysis is a valuable adjunct to the diagnosis of FH that is applicable to families with a known mutation of the LDL receptor gene. If DNA methods are not available, age- and sex-specific LDL levels should be used as an aid in the clinical diagnosis of FH.

Adolescent↗
PubMed1979

Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo.

To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). The turnover of (125)I-labeled low-density lipoprotein (LDL) was measured in all of the normals, all but one of the FH heterozygotes, and in all of the homozygotes. Chemical cholesterol balance was performed simultaneously with the (125)I-LDL turnover in all seven of the homozygotes. With regard to (125)I-LDL turnover, FH homozygotes, who possess two doses of the mutant FH gene, exhibited a threefold increase in the rate of apoLDL synthesis while the fractional catabolic rate (FCR) for the apoprotein was only about one-third of normal. Heterozygotes, who have only one dose of the mutant FH gene, exhibited intermediate values for both parameters; that is, the FCR was two-thirds of normal and the apoLDL synthetic rate was 1.7-fold greater than normal. THE DATA INDICATE THAT THE SINGLE GENE DEFECT IN FH PRODUCES TWO DISTINCT ABNORMALITIES OF LDL METABOLISM: (a) an increase in the synthetic rate for apoLDL and (b) a decrease in the efficiency of apoLDL catabolism. Both defects are more severe in FH homozygotes than in heterozygotes. The FCR for apoLDL in the homozygotes appeared to be fixed at congruent with 17%/d whereas the plasma LDL level varied about twofold. These findings suggest that the twofold variation in plasma LDL levels observed in these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943. The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount of the cholesterol liberated from LDL degradation must be reused.

Adolescent↗
PubMed1992

Treatment of refractory familial hypercholesterolemia by low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. The Liposorber Study Group.

A subgroup of patients with familial hypercholesterolemia (FH) respond inadequately to standard diet and drug therapy, and are therefore at high risk for the premature development or progression of coronary artery disease. This study evaluated low-density lipoprotein (LDL) cholesterol and lipoprotein (a) removal in a multicenter, controlled trial with a new LDL apheresis procedure (Liposorber LA-15 System). The study comprised patients with FH who had not responded adequately to diet and maximal drug therapy. There were 54 patients with heterozygous FH (45 randomized to treatment and 9 control subjects) and 10 with homozygous FH (all of whom received LDL apheresis). The study included three 6-week treatment phases and a 4-week rebound phase. Treatments were administered at 7- to 14-day intervals. Mean acute reductions in LDL cholesterol were 76% in heterozygous FH patients and 81% in homozygous ones. Time-averaged levels of LDL cholesterol were reduced 41% (243 to 143 mg/dl) in heterozygous FH patients and 53% (447 to 210 mg/dl) in homozygous ones. The substantial acute reduction of lipoprotein (a) (means: 65%, heterozygous FH; 68%, homozygous FH) has not been reported with other therapies. The Liposorber LA-15 System represents an important therapeutic option in FH patients who respond inadequately to diet and drug therapy.

Adult↗
PubMed1992

Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism.

The present article summarizes some comparative studies of the Fawn-Hooded (FH) rat, a potential animal model of ethanol preference, and the Flinders Sensitive Line (FSL) rat, a potential animal model of depression. Both FH and FSL rats exhibit high degrees of immobility in the forced swim test and have difficulty learning a two-way active avoidance task. However, there were no differences between the FH and FSL rats in the elevated plus maze. Studies of ethanol preference indicated high rates of ethanol intake (greater than 4 g/kg) and preference (greater than 50%) in the FH rats, but low rates of ethanol intake (less than 1.1 g/kg) and preference (less than 20%) in FSL rats. It is concluded that the FSL rats exhibit behaviors consistent with their being an animal model of depression, whereas the FH rats exhibit features consistent with their being an animal model of both depression and alcoholism. Psychopharmacological challenges indicated that both FSL and FH rats were more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist. However, FSL rats were also more sensitive to serotonergic agonists, and some of the present results and other investigators have reported serotonergic subsensitivity in the FH rats. Thus, FSL rats exhibit both cholinergic and serotonergic supersensitivity, whereas FH rats exhibit cholinergic supersensitivity but normal or reduced serotonergic sensitivity. Progeny from a genetic cross between FH and FSL rats exhibit cholinergic supersensitivity and have high ethanol preference scores. These data are consistent with genetic models suggesting that ethanol preference may be influenced by dominant genes, whereas cholinergic sensitivity may be influenced by recessive genes.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Serum apolipoproteins in heterozygous familial hypercholesterolemia.

In order to characterize the abnormalities of the lipoprotein profile in familial hypercholesterolemia (FH), serum apolipoprotein AI, AII, B, CII, CIII, and E levels were determined by the turbidimetric immunoassay in 48 patients with heterozygous FH. Apolipoprotein B levels in FH were about 2.5 fold higher (203 +/- 48 mg/dl, mean +/- S.D.) than the 30 age-matched normolipidemic control subjects (84 +/- 13 mg/dl). Significant increments of apolipoprotein CII, CIII, and E levels were observed in FH (4.6 +/- 1.6, 11.0 +/- 3.6 and 6.4 +/- 1.7 mg/dl, respectively) as compared with those in normal subjects (3.0 +/- 0.9, 7.7 +/- 1.6 and 4.5 +/- 1.1 mg/dl, respectively). Apolipoprotein AI and AII levels in FH were 130 +/- 27 and 32 +/- 6.0 mg/dl, respectively, which were not significantly different from the levels in normal subjects (131 +/- 18 and 31 +/- 5.4 mg/dl, respectively). The ratio of low density lipoprotein (LDL) cholesterol to apolipoprotein B was significantly higher in FH (1.3 +/- 0.3) than that in normal subjects (1.2 +/- 0.1). This indicates that the LDL of FH was cholesterol-rich in comparison with that of normal subjects. The ratio of high density lipoprotein (HDL) cholesterol to apolipoprotein AI in FH (0.34 +/- 0.07) was significantly lower than that in normal subjects (0.39 +/- 0.05). This difference might possibly be produced by an abnormal HDL metabolism of FH patients, a topic which remains to be elucidated by further investigation.

Adult↗
PubMed2026

Genetic screening of children for familial hypercholesterolaemia: the VRONI study.

BACKGROUND AND AIMS: The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS: In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration &#x2265;3.36 mmol/L (&#x2265;130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS: Out of 25 431 children screened so far, 1689 children had an LDL-C &#x2265; 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS: The prevalence of FH determined in this study is significantly higher than previously published estimates (&#x223c;1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.

Humans↗