ACO2 clinicobiological dataset with extensive phenotype ontology annotation

Pathogenic variants of the aconitase 2 gene (ACO2) are responsible for a broad clinical spectrum involving optic nerve degeneration, ranging from isolated optic neuropathy with recessive or dominant inheritance, to complex neurodegenerative syndromes with recessive transmission. We created the first public locus-specific database (LSDB) dedicated to ACO2 within the “Global Variome shared LOVD” using exclusively the Human Phenotype Ontology (HPO), a standard vocabulary for describing phenotypic abnormalities. All the variants and clinical cases listed in the literature were incorporated into the database, from which we produced a dataset. We followed a rational and comprehensive approach based on the HPO thesaurus, demonstrating that ACO2 patients should not be classified separately between isolated and syndromic cases. Our data highlight that certain syndromic patients do not have optic neuropathy and provide support for the classification of the recurrent pathogenic variants c.220C>G and c.336C>G as likely pathogenic. Overall, our data records demonstrate that the clinical spectrum of ACO2 should be considered as a continuum of symptoms and refines the classification of some common variants.

INCIDENCE OF CONSANGUINITY IN INDIAN CHILDREN WITH CEREBRAL PALSY: A SURVEY STUDY

Cerebral palsy is a non-progressive neurodevelopmental disorder. Cerebral palsy is 2.5 times higher in consanguineous marriage due to autosomal recessive transmission. In India, the estimated incidence is 3 per 1000 live births. The objective of this study is to evaluate the incidence of consanguinity in children with cerebral palsy and measures taken to create awareness. A survey study in the form of semi structured interview was conducted by eliciting the history from the parents of 50 cerebral palsy children in Hassan, Bangalore and Udupi within the period of 3 months using pretested questionnaires, where cerebral palsy patient’s cases were taken and symptoms, age of their parents, presence of consanguinity and its degree were noted and compared with other neurological and genetic conditions to exclude them. Thus obtained results were tabulated and analysis is done by statistical method. It was found that, the incidence rate of consanguinity in children with Cerebral palsy is 18%. And 22% of cases presented with dysmorphism, which suggests multiple genetic factors in the form of autosomal recessive gene mutation contributing for Cerebral palsy. Findings suggests that the incidence rate of consanguinity in children with Cerebral palsy is 18% those children also presented with dysmorphism, so when these two are taken into consideration we can conclude that consanguinity as a risk factor for cerebral palsy.

Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia

Background: Hereditary spastic paraplegia (HSP) caused by mutations in ALDH18A1 have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B). SPG9 is rare and has shown phenotypic and genotypic heterogeneity in previous reports.Methods: This study screened ALDH18A1 mutations in autosomal recessive HSP patients using combined whole exome sequencing and RNA splicing analysis. We conducted in silico investigations, co-segregation analysis, and ELISA-based analysis of P5CS (Δ1-pyrroline-5-carboxylate synthetase; encoded by ALDH18A1) concentration to validate the pathogenicity of the detected ALDH18A1 variants. All previously reported bi-allelic ALDH18A1 mutations and cases were reviewed to summarize the genetic and clinical features of ALDH18A1-related HSP.Results: A novel missense mutation c.880T>C, p.S294P and an intronic splicing mutation c.-28-13A>G were both detected in ALDH18A1 in an autosomal recessive family presenting with a complicated form HSP. ELISA assays revealed significantly decreased P5CS concentration in the proband's plasma compared with that in the healthy controls. Moreover, review of previously reported recessive cases showed that SPG9B patients in our cohort presented with milder symptoms, i.e., later age at onset and without cognitive impairment.Conclusion: The present study expands the genetic and clinical spectrum of SPG9B caused by ALDH18A1 mutation. Our work defines new genetic variants to facilitate future diagnoses, in addition to demonstrating the highly informative value of splicing mutation prediction in the characterization of disease-related intronic variants.

Deep Dermatophytosis

Deep dermatophytosis is a rare fungal infection described for the first time by Hadida and Schousboe. It is a chronic dermatophytic infection of the skin and viscera, mainly described in the Maghreb where it has an autosomal recessive transmission. Immunological studies have revealed a deficiency of cellular immunity leading to dermatophytes tolerance. Commonly, first lesions begin in childhood. Both superficial and deep dermatophytic lesions are possible. A 17 years old male patient with a history of chronic generalized pruritic erythematous-squamous lesions presented for subcutaneous abscesses of scalp and trunk. He underwent multiple antibiotic courses and surgical excisions with persistent relapses. Trichophyton rubrum was identified in skin biopsy and all samples sites. It was found no immunodeficiency within the limits of the blood tests conducted. Search for CARD9 protein deficiency was positive. Treatment based on Terbinafine and surgical drainage with mid improvement

Congenital Adrenal Hyperplasia (CAH) and Gitelman Syndrome (GS): Overlapping Symptoms in an Uncommon Association

Background. Classical salt-wasting (SW) congenital adrenal hyperplasia (CAH) and Gitelman syndrome (GS) are two genetic conditions in which dyselectrolytemia may occur. No association between the two conditions has been previously described. Case Presentation. We present the case of a boy with a neonatal diagnosis of SW-CAH who showed low potassium blood levels from the age of 15 years. This electrolytic alteration was, at first, attributed to an excessive action of mineralocorticoid drugs. Due to persistence of hypokalemia, SLC12A3 whole genome sequencing was performed, showing a heterozygous C to T base pair substitution at position 965 in gene SLC12A3. This mutation is related to Gitelman syndrome with autosomal recessive transmission. Conclusions. SW-CAH and GS determine opposite values of potassium in the absence of specific therapy, with a natural tendency to compensate each other. The symptom overlap makes diagnosis difficult. Organic causes of hypokalemia in patients undergoing life-saving therapy should not be excluded.

Familial distal renal tubular acidosis

We report the case of a family in which two sisters have distal renal tubular acidosis (dRTA). Familial dRTA is a rare disorder, with both autosomal dominant and recessive transmission. This is a report of familial dRTA from China.

Usher Deafblindnes

Pigmentary retinopathy refers to a group of inherited degenerative diseases of the retina, which primarily affects the photoreceptor cells in the retina. The association with congenital hearing loss defines Usher syndrome. Usher syndrome is a rare pathology of autosomal recessive transmission with a double sensory impairment (auditory and visual). We report the observation of a 12-year-old patient from a consanguineous marriage with congenital deafness, normal vestibular function and pigmentary retinopathy composing type 2 of Usher syndrome.

A novel homozygous frameshift variant in the cellular retinaldehyde-binding protein 1 (RLBP1) gene causes retinitis punctata albescens

Background Retinitis punctata albescens is a form of retinitis pigmentosa characterized by white fleck-like deposits in the fundus, in most cases caused by pathogenic variants in RLBP1 gene. The purpose of this work is to report the phenotypic and genotypic data of a patient with retinitis punctata albescens carrying a deletion in the RLBP1 gene. Results An 8-year-old Caucasian female has been complaining of nyctalopia for the last 2 years. No other ocular symptoms were present. No relevant past medical or familiar history was described. At clinical examination, the patient’s best-corrected visual acuity was 20/20 in both eyes. Anterior segment evaluation and intraocular pressure were normal in both eyes. At fundoscopy, multiple punctate whitish-yellow fleck-like lesions were observed in the proximity of temporal superior and inferior vascular arcades. Scotopic electroretinogram demonstrated severely reduced rod response, without improvement or recovery of rod system function after prolonged dark adaptation. Blood DNA samples of this patient and from her parents were screened for causal variants in RLBP1, RDH5, and PRPH2. Conclusion A probable pathogenic frameshift variant was identified in homozygosity in the RLBP1 gene with an autosomal recessive transmission as another cause of retinitis punctata albescens. This DNA variant will aid ongoing functional studies and add to our understanding of the molecular pathology about RLBP1-associated retinopathies.

Glucose transporter deficienc y syndrome type 1: a case report

The authors present a unique clinical observation of the case of a hereditary deficiency of a type 1 glucose transporter, also called de Vivo disease. The type 1 glucose transporter deficiency syndrome (OMIM: 606777, ORPHA: 71277) is an extremely rare genetic disease associated with mutations in the SCL2A gene encoding the transfer of glucose across the blood-brain barrier. The clinical case, given in the article, replenishes the piggy bank of genetically verified glucose transport disruption syndromes leading to the development of polymorphic neurological disorders. The syndrome is most often inherited by an autosomal dominant pathway, but rare cases of autosomal recessive transmission are known. About 500 clinical cases of the present syndrome are described, although, according to various authors, the number of clinically verified cases not confirmed by genetic verification is much higher. In addition to the given data of the clinical course of the disease, detailed results of the genetic interpretation of the hereditary syndrome are given, the modern method of pathogenetic therapy is considered – the ketogenic diet.

Study on Cystic Fibrosis Evolution in Children

Cystic fibrosis (CF) or mucoviscidosis, although considered a rare disease, is the most common genetic disease with autosomal recessive transmission of the Caucasian race. The study included 13 children aged between 0 and 18 years diagnosed with CF between 01.01.2000 and 31.12.2018, being recorded, monitored and treated in the Regional Center for CF Craiova from the Pediatrics II Clinic, County Emergency Clinical Hospital Craiova, Romania. For each patient we evaluated the following parameters: the year of CF diagnosis, the age at diagnosis, sex and environment of origin, clinical manifestations at onset, evolution of treatment cases by 2018. Of the 13 children with CF in study, most of them (11) are male. The most common clinical manifestations were the respiratory ones. Genetic tests were performed on all children, highlighting that 6 out of 13 children were homozygous �F508 and 2 children had mutations not genetically identified, requiring sequencing.