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Audiograms from the proband at the age of 37. a Audiogram of the left ear. b Audiogram of the right ear. In pure-tone audiometry measurements, similar air and bone thresholds are indicative of hearing loss due to dysfunction of the inner ear, which demonstrates bilaterally sensorineural hearing loss especially at high frequency. Audiograms were created using the AudGen online tool (version 0.71) (http://audsim.com/audgen/)
Source publication
Background
Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically.
Case presentation
We reported a consanguineous family (two affected sisters) with Perrault s...
Context in source publication
Citations
... There are other cases of Type 2 Perrault syndrome associated with variants of HSD17B4 (Chen et al. 2017;Demain et al. 2017;Kim et al. 2013) for a total of 10 variants (Fig. 1). One or both of the Perrault syndrome-associated HSD17B4 variants are located in 9 of its 24 exons and at least one of the two alleles results in an amino acid substitution in one of the two catalytic domains of the two HSD17B4 proteins. ...
Hearing loss and impaired fertility are common human disorders each with multiple genetic causes. Sometimes deafness and impaired fertility, which are the hallmarks of Perrault syndrome, co-occur in a person. Perrault syndrome is inherited as an autosomal recessive disorder characterized by bilateral mild to severe childhood sensorineural hearing loss with variable age of onset in both sexes and ovarian dysfunction in females who have a 46, XX karyotype. Since the initial clinical description of Perrault syndrome 70 years ago, the phenotype of some subjects may additionally involve developmental delay, intellectual deficit and other neurological disabilities, which can vary in severity in part dependent upon the genetic variants and the gene involved. Here, we review the molecular genetics and clinical phenotype of Perrault syndrome and focus on supporting evidence for the eight genes (CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, RMND1, TWNK) associated with Perrault syndrome. Variants of these eight genes only account for approximately half of the individuals with clinical features of Perrault syndrome where the molecular genetic base remains under investigation. Additional environmental etiologies and novel Perrault disease-associated genes remain to be identified to account for unresolved cases. We also report a new genetic variant of CLPP, computational structural insight about CLPP and single cell RNAseq data for eight reported Perrault syndrome genes suggesting a common cellular pathophysiology for this disorder. Some unanswered questions are raised to kindle future research about Perrault syndrome.
... In addition, HSD17B4 is also one of the genes responsible for Perrault syndrome (PRLTS), manifesting with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females, and neurological feature. Chen et al. (14) gave a report of a PRLTS family in China and found an HSD17B4 mutation c298G>T (p.A100S) to confirm the relationship. Here, we report the first case of a Chinese neonatal-onset D-BPD patient with novel compound heterozygous mutations of HSD17B4 (OMIM601860), including a splicing mutation and a missense mutation, detected by exome sequencing. ...
Background: D-Bifunctional protein deficiency (D-BPD) is an autosomal recessive disorder caused by peroxisomal β-oxidation defects. According to the different activities of 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase protein units, D-bifunctional protein defects can be divided into four types. The typical symptoms include hypotonia and seizures. The gene that encodes D-BP was HSD17B4 , which is located in chromosome 5q23.1.
Case Presentation: We report the first case of D-BPD in a Chinese patient with neonatal onset. Cosmetic malformations, severe hypotonia and seizures are prominent. The blood bile acid profile showed increased taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid. Very-long-chain fatty acids (VLCFAs) revealed significant increases in hexacosanoic acid (C26:0), tetracosanoic acid/docosanoic acid (C24:0/C22:0), and hexacosanoic acid/docosanoic acid (C26:0/C22:0). Cranial MRI revealed bilateral hemispheric and callosal dysplasia, with schizencephaly in the right hemisphere. EEG showed loss of sleep–wake cycle and epileptiform discharge. Other examinations include abnormal brainstem auditory evoked potentials (BAEPs) and temporal pigmented spots on the optic disc in the right eye. After analysis by whole-exome sequencing, heterozygous c.972+1G>T in the paternal allele and c.727T>A (p.W243R) in the maternal allele were discovered. He was treated with respiratory support, formula nasogastric feeding, and antiepileptic therapy during hospitalization and died at home due to food refusal and respiratory failure at the age of 5 months.
Conclusions: Whole-exome sequencing should be performed in time to confirm the diagnosis when the newborn presents hypotonia, seizures, and associated cosmetic malformations. There is still a lack of effective radical treatment. Supportive care is the main treatment, aiming at controlling symptoms of central nervous system like seizures and improving nutrition and growth. The disease has a poor outcome, and infants often die of respiratory failure within 2 years of age. In addition, heterozygous deletion variant c.972+1G>T and missense mutations c.727T>A (p.W243R) are newly discovered pathogenic variants that deserve further study.
... Mutations of the HSD17B4 gene also cause juvenile-onset DBP deficiencies [4][5][6][7][8] and Perrault syndrome. [9][10][11] As both clinical phenotypes overlap and are less severe than those of infant-onset DBP deficiencies, patients with these disorders survive until adolescence/adulthood. Patients with juvenileonset DBP deficiencies and Perrault syndrome present with hearing loss, cerebellar ataxia, peripheral neuropathy, infertility, and normal plasma VLCFA levels. ...
... Collection of clinical data and pathogenicity scoring Previously reported mutations and clinical data were collected from the literature [4][5][6][7][8][9][10][11][18][19][20][21][22][23][24] and ClinVar. Mutations were used if they were reported with sufficient clinical detail. ...
... 28 In juvenile-onset DBP deficiency, a remarkable reduction in HSD17B4 mRNA and protein has been observed in patients' fibroblasts and lymphoblasts and overexpressed HEK293T cells with a mutant HSD17B4. 4,8,9,11 In adult-onset cases, the levels of mRNA expression were normal, and the expression levels of DBP remained moderate. The impaired enzyme activities result from dysfunction or reduction of the protein, but our data suggest that the delayed onset of disease may be attributed to the remaining DBP protein function. ...
Objective:
To determine the genetic underpinnings of slowly progressive spinocerebellar ataxia, autosomal recessive (SCAR), we performed exome analysis and examined the relationship between clinical severity and functional change induced by the mutation.
Methods:
Homozygosity fingerprinting and exome sequencing were performed to identify causative mutations in 2 consanguineous families. We assessed the expression of D-bifunctional protein (DBP) and the amount of dimerized DBP in fibroblasts by immunoblot and quantitative reverse transcription PCR. The pathogenicity of the mutation was evaluated using the Combined Annotation-Dependent Depletion (CADD) scores; these results were compared with the scores of previously reported mutations.
Results:
We identified a homozygous mutation as causative of middle age-onset SCAR: p.Ala175Thr, which is located in HSD17B4 that encodes peroxisomal DBP. The patients developed cerebellar ataxia, and the subsequent progression was slow. The symptoms presented were milder than those in previously reported cases. The messenger RNA expression levels were normal, but protein levels were diminished. Dimerization of DBP was also reduced. The CADD score of the identified mutation was lower than those of previously reported mutations.
Conclusions:
This is the report of middle age-onset DBP deficiency. Residual functional DBP caused relatively mild symptoms in the affected patients, i.e., slowly progressive ataxia and hearing loss. This study broadens the scope of DBP deficiency phenotypes and indicates that CADD scores may be used to estimate the severity of DBP deficiencies.
... The sequencing was carried out by Illumina HiSeq X-ten platform. The variants screen protocol was as previously reported [18]. The candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. ...
Background
Hereditary spastic paraplegias (HSP) are of great clinical and genetic heterogeneity. According to the clinical features, HSP can be divided into pure or complicated subtypes which combined with other neurological symptoms including cerebellar ataxia. Up to date, 78 loci or genes have been implicated in HSP. CAPN1 was a novel gene detected recently for spastic paraplegia 76 (SPG76).
Methods
Patients referred to our clinic with spastic or spastic-ataxic gait were collected. Genetic testing of the probands were performed by target sequencing of a panel containing over 4000 known virulence genes. And the candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. The clinical materials of these patients were demonstrated retrospectively.
Results
Two Chinese patients, both from consanguineous families, each carried a novel homozygous mutation of CAPN1, p.R48X and p.R339X. The male proband presented pure HSP subtype while the female proband presented complicated HSP symptoms with cerebellar ataxia. We then reviewed all the literatures of HSP patients carrying CAPN1 mutations and summarized the molecular spectrum and clinical characteristics of CAPN1-related SPG76.
Conclusion
These two SPG76 patients carrying CAPN1 mutations were the first reported in China. By reviewing the clinical manifestations of SPG76 patients, we validated the “spastic-ataxia” phenotype and emphasized the association between spasticity and ataxia, indicating the importance of CAPN1 screening in HSP patients.
... The number of cases with mutations in each of the six known genes is still small to establish definite genotypephenotype correlations. So far, all patients with PRLTS due to mutations in HSD17B4 and TWNK present with neurological manifestations (clinical type II) [4,8,[10][11][12][13][14]. Mutations in CLPP or LARS2 may result in clinical types I or II [6,7,12,[14][15][16][17][18][19][20]. ...
... Moreover, establishing genotype-phenotype correlations with the existing data is still hampered by the small number of cases carrying mutations in each gene (Table 4). Neurological signs have been reported in patients with PRLTS and mutations in the HSD17B4, TWNK, CLPP and LARS2 genes [4,7,8,[10][11][12][13][14][15][16]20; and this work]. For CLPP and LARS2, there are also reports of patients without neurological signs [6,7,12,14,[17][18][19], like all the patients with mutations in HARS2 or ERAL1 who have been reported to date [5,9,14]. ...
... It is clear that clinical and genetic characterization of additional patients, like those reported here, is needed to progress in understanding the genotype-phenotype correlations in subjects with mutations in TWNK. c.244G>T p.Val82Phe [12] c.298G>T p.Ala100Ser [11] c.587C>T p.Ala196Val [10] c.650A>G p.Tyr217Cys [4] c.1704T>A p.Tyr568* [4] 12-kb deletion (exons 10-13) [10] HARS2 (NM_012208.3) c.598C>G p.Leu200Val [5] c.1010A>G p.Tyr337Cys [14] c.1102G>T p.Val368Leu [5] CLPP (NM_006012.2) c.21delA p.Ala10Profs*117 [16] c.270+4A>G [7] c.425C>T p.Pro142Leu [16] c.430T>C p.Cys144Arg [12] c.433A>C p.Thr145Pro [7] c.439T>A p.Cys147Ser [14] c.440G>C p.Cys147Ser [7] c.484G>A p.Gly162Ser [16] c.624C>G p.Ile208Met [17] c.685T>G p.Tyr229Asp [15] Deletion of several exons [16] LARS2 (NM_015340.3) ...
Background:
Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations.
Methods:
Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene.
Results:
Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern.
Conclusions:
Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.
... POI may develop in an isolated manner in an apparently healthy woman (non-syndromic POI) or as part of a pleiotropic genetic disorder (syndromic POI). Perrault syndrome, harboring mutations of the peroxisomal matrix enzyme HSD17B4, also known as D-bifunctional protein (DBP) or peroxisomal multifunctional enzyme (MFE-2), is until now the only peroxisomal disorder associated with female gonadal insufficiency (Pierce et al., 2010, Chen et al., 2017. Syndromic conditions explain only 1% of cases of POI but elucidating the roles that these genes have in reproduction may aid in a better understanding of ovarian biology (Qin et al., 2015). ...
Study question:
What is the timing of onset and clinical course of premature ovarian insufficiency (POI) in patients with Mulibrey nanism (MUL), a monogenic disorder caused by mutations of the peroxisomal TRIM37 gene?
Summary answer:
The number of ovarian follicles is highly reduced already in infant and young MUL girls and the majority of them will have early depletion of follicles resulting in clinical and biochemical signs of POI.
What is known already:
Both female and male patients with MUL show failure of sexual maturation, signs of hypogonadism and infertility.
Study design, size, duration:
We studied the gonadal function, pubertal development and ovarian reserve in 33 MUL patients aged 5.1-47.3 years (median age 22.3) at the end of observation. The patients were followed between 2004 and 2014 and 19 pubertal or postpubertal patients were enrolled in a cross-sectional study.
Participants/materials, setting, methods:
The period of postnatal activation of the hypothalamic-pituitary-gonadal axis (minipuberty), pubertal development and menstrual history were assessed longitudinally. The cross-sectional study included gynecological examination, analysis of reproductive hormones and ultrasonography with evaluation of ovarian volume and antral follicle count.
Main results and the role of chance:
Infant girls experienced a transient minipuberty with a high FSH surge. In childhood, gonadotropins were normal or slightly elevated but began to rise to hypergonadotropic levels in prepuberty. Anti-Müllerian hormone (AMH) levels remained undetectable or low throughout childhood. The onset of puberty occurred spontaneously and the median age at menarche was 12.5 years. Of the patients, 54% never attained regular menses and 10 years from menarche, only 8% of the women menstruated regularly. In the cross-sectional study, none of the patients had normal ovarian morphology under ultrasonography. Ovaries were hypoplastic and 82% had no or fewer than two visible antral follicles. AMH levels were undetectable in the vast majority (89%).
Limitations, reasons for caution:
The Finnish MUL patients genotypically form a homogenous group and therefore it is possible, that different TRIM37 mutations lead to different hypogonadal phenotypes. However, to date there is no known genotype-phenotype correlation in MUL.
Wider implications of the findings:
In MUL, AMH is a useful marker of ovarian function. MUL should be added to the list of syndromes associated with POI and correspondingly, TRIM37 should be added to the list of genes associated with POI. To our knowledge, TRIM37 is the first known gene coding for a peroxisomal membrane protein associated with female gonadal failure and infertility. Elucidating the role of syndromic genes in reproduction may aid in a greater understanding of ovarian biology.
Study funding/competing interest(s):
This study was supported by the Finnish Foundation for Pediatric Research, Finska Läkaresällskapet, the Sigrid Jusélius Foundation and Helsinki University Hospital Research Funds. The authors declare no conflicts of interest.
Trial registration number:
Not applicable.
... Apart from mitochondrial functions, mutations in a multifunctional peroxisomal enzyme involved in fatty acid ß-oxidation and steroid metabolism, 17b-hydroxysteroid dehydrogenase type 4 [HSD17B4, also known as D-bifunctional protein (DBP)] also cause PS [66][67][68]. Mutations of this gene were already identified in autosomal recessive mode in a severe disorder of peroxisomal fatty acid b-oxidation. ...
Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.
Inborn errors of metabolism (IEMs) are a large group of debilitating hereditary disorders, commonly manifesting during infancy and early childhood. They are categorized mainly according to the chemical nature of the characteristic metabolites accumulating in each disease. Major categories include aminoacidopathies, organic acid disorders, lysosomal storage disorders, fatty acid oxidation defects, and many others. Collectively, they constitute over 1,000 individual genetic disorders resulting in substantial societal and financial burdens overloading families, communities, and health care authorities worldwide.
Overtime, the technologies used, and the metabolites discovered for the newborn screening of various IEMs have significantly advanced. Furthermore, with the recent discovery of novel therapeutic modalities for many inborn errors of metabolism, such as enzyme replacement therapies and substrate reduction therapies, the importance of newborn screening for these disorders is gaining more momentum. Especially that for most inborn errors, the earlier the specific therapy starts, the better the prognosis will be. Currently, hundreds of regional and national health care authorities all over the world have running programmes for the newborn screening of IEMs, which usually vary widely depending on the disease spectrum and financial limitations of each country.
This Research Topic collection includes 13 articles from several countries applying newborn screening and genetic diagnosis for the detection of IEMs.
Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized by the presence of non-progressive congenital contractures in multiple body areas. Scoliosis, defined as a coronal plane spine curvature of ≥10 degrees as measured radiographically, has been reported to occur in approximately 20% of children with AMC. To identify genes that are associated with both scoliosis as a clinical outcome and AMC, we first queried the DECIPHER database for copy number variations (CNVs). Upon query, we identified only two patients with both AMC and scoliosis (AMC-SC). The first patient contained CNVs in three genes (FBN2, MGF10, and PITX1), while the second case had a CNV in ZC4H2. Looking into small variants, using a combination of Human Phenotype Ontogeny and literature searching, 908 genes linked with scoliosis and 444 genes linked with AMC were identified. From these lists, 227 genes were associated with AMC-SC. Ingenuity Pathway Analysis (IPA) was performed on the final gene list to gain insight into the functional interactions of genes and various categories. To summarize, this group of genes encompasses a diverse group of cellular functions including transcription regulation, transmembrane receptor, growth factor, and ion channels. These results provide a focal point for further research using genomics and animal models to facilitate the identification of prognostic factors and therapeutic targets for AMC.
RMND1 (required for meiotic nuclear division 1 homolog) pathogenic variants are known to cause combined oxidative phosphorylation deficiency (COXPD11), a severe multisystem disorder. In one patient, a homozygous RMND1 pathogenic variant, with an established role in COXPD11, was associated with a Perrault-like syndrome. We performed a thorough clinical investigation and applied a targeted multigene hearing loss panel to reveal the cause of hearing loss, ovarian dysfunction (two cardinal features of Perrault syndrome) and chronic kidney disease in two adult female siblings. Two compound heterozygous missense variants, c.583G>A (p.Gly195Arg) and c.818A>C (p.Tyr273Ser), not previously associated with disease, were identified in RMND1 in both patients, and their segregation with disease was confirmed in family members. The patients have no neurological or intellectual impairment, and nephrological evaluation predicts a benign course of kidney disease. Our study presents the mildest, so far reported, RMND1-related phenotype and delivers the first independent confirmation that RMND1 is causally involved in the development of Perrault syndrome with renal involvement. This highlights the importance of including RMND1 to the list of Perrault syndrome causative factors and provides new insight into the clinical manifestation of RMND1 deficiency.
