A mixed-ethnicity myoclonus-dystonia patient with a novel SGCE nonsense mutation: a case report

Background Myoclonus-dystonia is a rare movement disorder with an autosomal dominant inheritance pattern characterized by a combination of myoclonic jerks and dystonia that may have psychiatric manifestations. Our aim is to present neurologic and psychiatric phenotypic characteristics in the first Filipino bi-ethnic myoclonus-dystonia patient and her father. Case presentation We investigated a Filipino myoclonus-dystonia patient with a positive family history. This 21-year-old woman of mixed Filipino-Greek ethnicity presented with involuntary jerking movements of her upper extremities, head, and trunk. Her symptoms affected her activities of daily living which led her to develop moderate depression, mild to moderate anxiety, and mild obsessive-compulsive disorder (OCD). Her 49-year-old Greek father suffered from adolescence-onset myoclonus-dystonia. Conclusion Genetic testing revealed a novel epsilon-sarcoglycan (SGCE) gene nonsense mutation c.821C > A; p.Ser274* that confirmed our clinical diagnosis. For co-morbid anxiety, depression, and OCD, this patient was given duloxetine, in addition to clonazepam for the myoclonus and dystonia.

A Novel Variant of SMARCB1 in Rare Familial Schwannomatosis Identified by Whole-Exome Sequencing and Genotype-Phenotype Correlation Analysis.

Background: Variants in the tumor suppressor gene SMARCB1 could cause different conditions. In some cases, germline and somatic variants in SMARCB1 are implemented in schwannomatosis. But the genotype and phenotype correlation for variants in SMARCB1 has not been determined.Methods: A Chinese schwannomatosis family with an autosomal dominant inheritance pattern was recruited. Whole-exome sequencing (WES) was performed to discover the causative variant, followed by Sanger sequencing. We evaluated the Human Gene Mutation Database (HGMD) regarding SMARCB1 variants and validated associated phenotype records to assess phenotype-genotype relationships. Results: A novel deletion variant c.885_896delGAAGCTGTGCTC p.(295_299del） in SMARCB1 was identified in the affected family members and cosegregated with phenotypes in the pedigree. About 51.1% of variants in SMARCB1 located in Snf5 subunit, 80.7% of variants were loss-of-function (LOF) variants, and more variants located in the Snf5 subunit of SMARCB1 in Rhabdoid tumour (67.8%) than that in schwannomatosis (25.7%).Conclusions: Our study expands the variant spectrum of SMARCB1 and the genetic background of schwannomatosis, confirms the clinical indications for genetic screening of the SMARCB1 gene, and has implications for genetic counseling in this disease.

Pattern Dystrophies

Pattern dystrophies have been known since 1950 which have autosomal dominant inheritance pattern. Pattern dystrophies have been classified based on the pattern of the pigment distribution. Despite significant retinal changes, good visual acuity is often maintained. However, complications such as choroidal neovascular membrane and retinal atrophy may develop in older patients and can significantly decrease visual acuity. There is no specific treatment, but when complications arise, treatment should be done by reason.

Genetic Screening Revealed Latent Keratoconus in Asymptomatic Individuals

PurposeTo adopt molecular screening in asymptomatic individuals at high risk of developing keratoconus as a combinative approach to prevent subclinical patients from post-refractive surgery progressive corneal ectasia.MethodsIn this study, 79 Chinese and nine Greek families with keratoconus were recruited, including 91 patients with clinically diagnosed keratoconus as well as their asymptomatic but assumptive high-risk first-degree relatives based on underlying genetic factor. Mutational screening of VSX1, TGFBI, and ZEB1 genes and full clinical assessment including Pentacam Scheimpflug tomography were carried out in these individuals.ResultsFive variants in VSX1 and TGFBI genes were identified in three Chinese families and one Greek family, and four of them were novel ones. Surprisingly, ultra-early corneal changes in Belin/Ambrosio Enhanced Ectasia Display of Pentacam corneal topography together with co-segregated variants were revealed in the relatives who had no self-reported symptoms.ConclusionsVariants of VSX1 and TGFBI genes identified in both the clinically diagnosed and subclinical patients may cause the keratoconus through an autosomal dominant inheritance pattern, with different variable expressivity. Combining genetic with Belin/AmbrosioEnhanced Ectasia Display can be used to identify patients with latent keratoconus. This study indicates that genetic testing may play an important supplementary role in re-classifying the disease manifestation and evaluating the preoperative examination of refractive surgery.

ACTIVATED PHOSPHOINOSITIDE 3-KINASE δ SYNDROME – A RARE FORM OF PRIMARY IMMUNODEFICIENCY

The activated phosphoinositide 3-kinase δ syndrome (APDS) refers to primary immunodeficiencies (PIDs) with autosomal dominant inheritance pattern and belongs to the PID group with immune dysregulation syndrome. APDS is caused by gain-of-function mutation in phosphoinositide 3-kinase δ (PI3Kδ) subunit coding genes which leads to PI3Kδ pathway overactivation, dysfunction of the adaptive T-cell and B-cell immunity. APDS is characterized by recurrent sinopulmonary infections leading to the progressive structural airway defects, herpesviral infections, lymphoproliferative syndrome with increased risk of B-cell lymphoma. We would like to present a late diagnostics APDS case in 5-years old female patient. The BCG-itis at 3 months was the first appeared symptom. Further, it was followed by recurrent bronchitis, severe and prolonged pneumonia, fibrous changes in the lungs with lymphoproliferation symptoms. Laboratory data: increased IgM with normal IgA and IgG levels, decreased CD3+, CD19+, and lymphocytes. Genetic analysis showed heterozygous PIK3CD gene mutation: c.3061G>A p.E1021K. In conclusion, children with early onset of prolonged respiratory tract infections especially if associated with the lymphoproliferative syndrome have to be administered with immunological and genetic tests for early diagnostics of the PID.

Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy

Epileptic encephalopathy related to <i>CACNA1E</i> has been described as a severe neurodevelopmental disorder presenting with early-onset refractory seizures, hypotonia, macrocephaly, hyperkinetic movements, and contractures and is associated with an autosomal dominant inheritance pattern. Most pathogenic variants described to date are missense variants with a gain of function effect, and the role of haploinsufficiency has yet to be clarified. We describe 2 cases of <i>CACNA1E</i> encephalopathy. Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia. We further compared the key phenotypic features depending on variant location. In conclusion, the appearance of congenital contractures, areflexia, and movement disorders before the onset of epilepsy may provide key guidance in the diagnosis of epileptic <i>CACNA1E</i> encephalopathy. A genotype-phenotype correlation was found between the presence of movement disorders and severe intellectual disability and the location of the variant in the <i>CACNA1E</i> gene.

Titinopathy, an atypical respiratory failure

Hereditary myopathy with early respiratory failure is a neuromuscular disease with an autosomal dominant inheritance pattern. Clinical presentation is characterised by proximal and distal muscle weakness, exertional dyspnoea and generalised fatigue. There is no disease-modifying therapy and the prognosis is unknown. Herein we present a case of a 40-year-old woman with long-standing asthenia and apathy and, more recently, daytime sleepiness, dyspnoea and difficulty in walking. A hypercapnic respiratory failure with severe acidemia was identified. The muscle biopsy showed the presence of cytoplasmatic bodies and rimmed vacuoles, suggestive of a hereditary myopathy with early respiratory failure disease. The genetic study confirmed this diagnosis identifying a heterozygous mutation on c.95134T>C (p.Cys31712Arg) in exon 343 in the titin gene. The patient was discharged home under supportive treatment with non-invasive ventilation.

Insight into the autosomal-dominant inheritance pattern of SOD1-associated ALS from native mass spectrometry

About 20% of all familial amyotrophic lateral sclerosis (ALS) cases are associated with mutations in superoxide dismutase (SOD1), a homodimeric protein. The disease has an autosomal-dominant inheritance pattern. It is, therefore, important to determine whether wild-type and mutant SOD1 subunits self-associate randomly or preferentially. A measure for the extent of bias in subunit association is the coupling constant determined in a double-mutant cycle type analysis. Here, cell lysates containing co-expressed wild-type and mutant SOD1 subunits were analyzed by native mass spectrometry to determine these coupling constants. Strikingly, we find a linear positive correlation between the coupling constant and the duration of the disease. Our results indicate that inter-subunit communication and a preference for heterodimerization greatly increase the disease severity.

Expanding the phenotype of hypomaturation amelogenesis imperfecta due to a novel SLC24A4 variant

Objectives Biallelic variants in solute carrier family 24 member 4 (SLC24A4) have been previously reported to cause non-syndromic autosomal recessive amelogenesis imperfecta (AI) of the pigmented hypomaturation type (MIM #615887). We here describe a novel variant in SLC24A4 causing mild enamel hypomaturation defects also in heterozygous individuals. Materials and methods In the present pedigree analysis, a large consanguineous Syrian family with AI of the hypomaturation type was investigated by clinical and dental evaluation, and exome and Sanger sequencing. Dental histological investigations of seven primary and two permanent teeth were performed. Results Homozygous variants in SLC24A4 (c.1604G>A; p.Gly535Asp) were identified in five individuals with brown discolorations and irregular pits and grooves of the teeth. Severe attritions, occlusal abfractions, and the radiological lack of contrast between enamel and dentin point out a mineralization defect. Histological dental investigations confirmed the clinical diagnosis of AI of the hypomaturation type. In two heterozygous individuals, a mild hypomaturation defect was present with white and light brown enamel discolorations. Conclusions This is the first report of heterozygous SLC24A4 variants causing mild hypomaturation defects, providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis. Clinical relevance The present report is expanding the clinical phenotype of SLC24A4 variants to more severe forms of amelogenesis imperfecta. An autosomal-dominant inheritance pattern with mild clinical phenotypes in heterozygotes has to be considered.