Biallelic Pathogenic Variants Research Articles

SURF1 Deficiency: Expanding on Disease Phenotype and Assessing Disease Burden by Describing Clinical and Biochemical Phenotype.

Leigh syndrome, a severe neurological disorder is commonly caused by homozygous or bi-allelic pathogenic variants in the SURF1 gene. SURF1 deficiency leads to dysfunction of Cytochrome C Oxidase (COX) activity, which is crucial for mitochondrial oxidative phosphorylation. Understanding COX activity's correlation with disease severity is essential for developing SURF1 Leigh Syndrome biomarkers. This study assesses the disease burden in SURF1 Leigh Syndrome and evaluates COX activity as a treatment biomarker. We reviewed records and questionnaires from 17 individuals, classifying them into phenotypic and genotypic groups. We compared COX activity assays in patient fibroblasts to age-matched controls, clinical data, and neuroimaging findings. Patient COX activity was at most 50% of controls, averaging 32% (p < 0.001). Common clinical features included brainstem abnormalities (93.3%), motor regression (92.3%), bi-allelic heterozygous SURF1 variants (88.2%), and delayed growth/development (35.7%). Homozygous and heterozygous nonsense/frameshift variants showed more severe phenotypes (p = 0.008) and more MRI abnormalities (p = 0.005). Significant COX activity reduction is linked to SURF1 Leigh Syndrome, with genotype influencing disease severity. Clinical and neuroimaging correlations show potential for prognostic indicators. This study lays the groundwork for future research and clinical application of COX activity as a SURF1 Leigh Syndrome biomarker.

Accumulation of ether phospholipids in induced pluripotent stem cells and oligodendrocyte-lineage cells established from patients with Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive leukodystrophy characterized by ichthyosis, intellectual disability, and progressive spastic paralysis caused by biallelic pathogenic variants in the ALDH3A2 gene that encodes the fatty aldehyde dehydrogenase, fatty aldehyde dehydrogenase (FALDH); FALDH catalyzes several metabolic reactions involved in fatty aldehyde oxidation. Only a few studies have been performed to determine the lipid profile of patients with SLS. In a previous postmortem study of the brain of a 65-year-old patient with SLS, lipidomic analysis revealed an accumulation of long-chain unsaturated ether lipid species in the white matter and gray matter. In the present study, we established a disease model using patient-derived neuronal and oligodendrocyte lineage cells to analyze the lipid metabolism and gene expression profiles in SLS. To achieve this, we generated induced pluripotent stem cells (iPSCs) from two patients with the SLS phenotype carrying previously known ALDH3A2 pathogenic variants: One was a compound heterozygote (c.1339A>G:p.(Lys447Glu) and c.57_132dup:p.(Ile45Serfs*34)) and the other was a homozygote (c.1339A>G: p.(Lys447Glu)). The FALDH activity was almost zero in the SLS-iPSC lines established from both patients. Phospholipid analysis of neurospheres, and oligospheres (spheres enriched with oligodendrocyte-lineage cells) derived from the iPSCs by liquid chromatography-mass spectrometry showed accumulation of ether phospholipids in the Sjögren-Larsson patient-derived neurospheres and oligospheres. The results are consistent with the previously reported accumulation of ether lipids in the postmortem brain tissue of an SLS patient. Therefore, iPSCs and iPSC-derived neurospheres and oligospheres established from SLS patients can be useful tools for future pathological analysis of the central nervous system pathophysiology in SLS.

Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.

Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes. Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells. We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T-lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands' fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies. Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024;96:1209-1224.

The phenotypic spectrum of CEP250 gene variants

ABSTRACT Introduction Classically, Usher syndrome is characterized by the association of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP) and possible vestibular dysfunction. Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors 20 dysfunction without vestibular signs. To date, only 19 scattered descriptions have been reported. In this study, we present detailed clinical and genetic description of 7 unrelated individuals with CEP250 related disease, along with a literature review to provide new insight on the severity and course of the disease. Methods We retrospectively recruited 7 unrelated individuals who underwent genetic testing (targeted gene panel or whole genome sequencing) and were found to carry CEP250 pathogenic variants. Results Most patients (5/7) 25 exhibit both retinal dystrophy and SNHL. Two patients appear to present either isolated hearing loss or visual impairment, but further investigations are needed to confirm a possible non-syndromic presentation. All patients harbored isolated truncating variants. Discussion CEP250 pathogenic variants are associated with post-lingual SNHL, and most often progressive photoreceptor dysfunction. The disease may begin with ocular features or hearing loss. We strongly recommend genetic analysis of classical and atypical Usher 30 related-genes, in patients with isolated retinal dystrophy or SNHL. We also recommend ophthalmological evaluation and follow-up in patients with isolated SNHL, and conversely. The coexistence of loss- and gain-of-function effects may exist, complicating the development of gene therapy.

Three Iranian patients with rare subtypes of hereditary spastic paraplegia (HSP): SPG76, SPG56, and SPG69.

Some subtypes of hereditary spastic paraplegia (HSP), especially with autosomal recessive inheritance (AR-HSP), have been reported rarely. In this study, we report the clinical features and molecular results of three unrelated Iranian patients with rare subtypes of HSP, including SPG76, SPG56, and SPG69; thereafter, we compare them to other reported cases. Three patients who were clinically diagnosed with HSP and born to consanguineous parents underwent molecular assessment by whole-exome sequencing (WES), followed by Sanger sequencing and co-segregation analysis. Two patients carried biallelic pathogenic variants in CAPN1, or CYP2U1, resulting in SPG76, and SPG56, respectively. Additionally, another patient presented with a variant of uncertain significance (VUS) in the gene associated with SPG69, known as RAB3GAP2. Variants of CAPN1 and RAB3GAP2 are novel while the CYP2U1 variant has been previously reported. The patient with the RAB3GAP2 variant is the second reported SPG69 case. Our findings emphasize that the rare forms of AR-HSP may be more prevalent in communities with a high rate of consanguineous marriages, and WES can be a highly effective tool for identifying pathogenic variants in these communities. Also, the CYP2U1 variant seems to be a founder mutation because it was previously reported in 8 patients of three families from the Middle East. These results expand the variant spectrum of the CAPN1 and RAB3GAP2 genes. Also, given the association of variants in CAPN1 and RAB3GAP2 with a diverse array of phenotypes, we propose the use of the terms "CAPN1-related disorders" and "RAB3GAP2-related disorders" as alternatives to HSP76 and HSP69, respectively.

Immune-Mediated Megaconial Myopathy: A Novel Subtype of Autoimmune Myopathy.

To describe a novel subtype of autoimmune myopathy, immune-mediated megaconial myopathy (IMMM), myopathologically characterized by giant mitochondria (megaconia). In this case series, we reviewed the Mayo Clinic Muscle Pathology database, between 2018 and 2023, to identify patients with megaconial pathology, subacute progressive weakness, and hyperCKemia, clinically resembling myositis. We recruited 1 patient from another institute, who had similar clinicopathologic features. Five patients were identified. Age at onset of weakness ranged from 19 to 45.5 years. All patients had proximal weakness, elevated creatine kinase levels (1,214 to 5,920 U/L), negative myositis antibodies, necrotizing myopathology, and nonnecrotic myofibers harboring giant mitochondria. Immunohistochemical studies conducted in 4 patients showed sarcolemmal MHC-1 and C5b9 immunoreactivities. Megaconial pathology was considered pathognomonic of congenital muscular dystrophy due to biallelic pathogenic variants in CHKB. Sequencing of CHKB in 4/5 patients was unrevealing. Immunomodulatory therapy improved weakness and hyperCKemia in 4 treated patients. Of interest, all patients had coexisting pancreatic diseases (3 cystic fibrosis-related exocrine pancreatic insufficiency, 1 pancreatic cancer, and 1 pancreatitis). In addition to incurable CHKB-congenital muscular dystrophy, giant mitochondria can also occur in this new subtype of treatable autoimmune myopathy, IMMM. The association between IMMM and pancreatic disorders remains to be elucidated.

Intermittent episodes of acute severe encephalomyopathy and early death in two siblings caused by biallelic likely pathogenic variants in FASTKD2: Expanding phenotype and literature review.

Combined oxidative phosphorylation (OXPHOS) deficiency 44 (COXPD44; MIM# 618855) is caused by biallelic pathogenic variants in FAS-activated serine-threonine kinase domain 2 (FASTKD2) (MIM# 612322). COXPD44 is characterized by variable clinical features-developmental delay, chronic epileptic encephalopathy, seizure disorder/status epilepticus and cerebellar ataxia. We ascertained one sibwith episodic acute encephalomyopathy triggered by acute gastroenteritis and associated with haematological abnormalities, rhabdomyolysis leading to acute kidney injury, hypotensive shock leading to early death and a similarly affected sib with early death. Both siblings were normal neurologically in between the acute episodes. Whole exome sequencing (WES) was performed in the elder sibling. Mitochondrial respiratory chain enzyme activity assaywas performed in fibroblast cells and muscle tissue of the elder sibling. Also, Adenosine triphosphate (ATP) determination assay was done in fibroblast cells of the elder sibling. WES revealed compound heterozygous missense likely pathogenic variants in FASTKD2. Mitochondrial respiratory chain enzyme activity in muscle tissue showed reduced complex IV activity and ATP determination assay showed a reduction of ATP in skin fibroblasts. Herein, we report two siblings with novel clinical phenotype associated with COXPD44. Our report further validates the biallelic variants in FASTKD2 associated with the variable phenotypes and mitochondrial OXPHOS defect.

Novel biallelic GNE variants identified in a patient with chronic thrombocytopenia without any symptoms of myopathy.

GNE encodes a rate-limiting enzyme that regulates the biosynthesis of a sialic acid precursor. As sialic acids are critical for the platelet membrane and muscle fibers, GNE variants cause GNE-related thrombocytopenia and GNE-related myopathy. Here, we report a neonate with thrombocytopenia that initially met the criteria for neonatal allo-immune thrombocytopenia (NAIT) but was resistant to treatments and then revealed novel biallelic heterozygous GNE variants without any symptoms of myopathy when diagnosed. NAIT was initially diagnosed due to alloantibodies against HPA5 and its mismatch between the patient and his mother. However, intravenous immunoglobulin therapy and platelet transfusions showed minimal improvement in the platelet count. Platelet counts remained around 60 × 109/L, suggesting congenital thrombocytopenia. Gene panel sequencing at the age of 13 identified biallelic pathogenic variants of GNE. The patient did not exhibit any symptoms of muscular weakness, suggesting GNE-related myopathy. We demonstrated a GNE-related thrombocytopenia patient with novel biallelic heterozygous GNE variants. Clinical trials have involved the use of sialic acids or their precursors, as well as gene therapy, to treat GNE-related myopathy, which may slow or halt the progression of the disease. Therefore, early diagnosis of this disease may significantly impact its clinical course.

A Comparative Evaluation of the Genetic Variant Spectrum in the USH2A Gene in Russian Patients with Isolated and Syndromic Forms of Retinitis Pigmentosa.

Pathogenic variants in the USH2A gene are the primary cause of both non-syndromic autosomal recessive inherited retinitis pigmentosa (RP) and the syndromic form, characterized by retinal degeneration and sensorineural hearing loss. This study presents a comparative assessment of the genetic variant spectrum in the USH2A gene among Russian patients in two clinical groups. A retrospective analysis was conducted on massive parallel panel sequencing data from 2415 blood samples of unrelated patients suspected of having hereditary retinal diseases. The copy number of USH2A exons was determined using the quantitative MLPA method with the MRC-Holland SALSA MLPA kit. Biallelic pathogenic and likely pathogenic variants in the USH2A gene were identified in 69 patients (8.7%). In the group of patients with isolated hereditary RP (55 patients), the most frequent pathogenic variants were p.(Glu4445_Ser4449delinsAspLeu) (20.9%), p.(Trp3955*) (15.5%), and p.(Cys934Trp) (5.5%). In patients with the syndromic form (14 patients), the most frequent variants were p.(Trp3955*) (35.7%) and c.8682-9A>G (17.9%). It was found that patients with isolated vision impairment rarely had two "null" variants (17.8%), whereas this was common among patients with both hearing and vision impairment (71.4%) (p ≤ 0.05), explaining the severity of the disease and the earlier onset of clinical symptoms in the syndromic form of RP. Ten previously undescribed loss-of-function variants were identified. The estimated prevalence of USH2A-associated retinal dystrophy in Russia was 1.9 per 100,000 individuals. The obtained data on the differences in the spectra of genetic variants in the USH2A gene in the two studied groups highlight the importance of establishing genotype-phenotype correlations and predicting disease severity, aiming at potential early cochlear implantation and selection of target therapy.

Protean Cutaneous Manifestation Caused by ABCA12 variants: Erythrokeratodermia Variabilis-like Ichthyosis and Unique Palmoplantar Keratoderma.

ABCA12 is crucial for skin barrier function and traditionally linked to severe congenital ichthyosis, such as harlequin ichthyosis. However, its genotype-phenotype relationship may be more nuanced. Using whole-exome sequencing and Sanger sequencing, we identified four cases of mild ichthyosis with biallelic ABCA12 pathogenic variants. In addition to a milder phenotype, the palmoplantar keratoderma (PPK) in these cases had a distinct "mosaic-tile like" pattern. Two cases with missense variants in the N-terminus of ABCA12 also presented an annular ichthyosis pattern resembling erythrokeratodermia variabilis et progressiva (EKVP). Our findings suggest a correlation between ABCA12 missense variant location and clinical presentation, expanding the phenotype spectrum associated with ABCA12 variants and highlighting the potential for annular patterns or "mosaic-tile like" PPK in these patients.

Familial Mediterranean Fever in Childhood.

Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disorder, characterized by recurrent fever and serositis. It primarily affects individuals of Mediterranean descent, including Arabs, Armenians, Turks, and Jews. The Mediterranean fever (MEFV) gene, responsible for FMF, was discovered in 1997. Biallelic pathogenic variants lead to excessive activation of the pyrin inflammasome, resulting in inflammation. Clinical manifestations include recurrent fever, abdominal pain, and joint involvement, with attacks typically lasting 12-72 hours. Diagnosis relies on clinical criteria and is supported by genetic testing. Colchicine is the primary treatment to reduce attack frequency and prevent the complications like renal amyloidosis. Despite advancements in understanding FMF, including its genetic basis and treatment options, challenges remain in distinguishing it from other autoinflammatory diseases. Co-existing conditions such as juvenile idiopathic arthritis and inflammatory bowel disease are common among FMF patients. Ongoing research should aim to clarify the development of the disease, enhance diagnostic accuracy, and address its clinical presentation and genetic variability, with a focus on identifying new genetic mutations and epigenetic factors that contribute to its pathogenesis.

Characterization of Dnajc12 knockout mice, a model of hypodopaminergia.

Homozygous DNAJC12 c.79-2A>G (p. V27Wfs*14) loss-of-function mutations were first reported as a cause of young-onset Parkinson's disease. However, bi-allelic autosomal recessive pathogenic variants in DNAJC12 may lead to an alternative constellation of neurological features, including infantile dystonia, developmental delay, intellectual disability and neuropsychiatric disorders. DNAJC12 is understood to co-chaperone aromatic amino acid hydroxylases to foster the synthesis of biogenic amines. In vitro, we discover overexpressed DNAJC12 forms a complex with guanine triphosphate cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, a cofactor paramount for biogenic amines synthesis. We also confirm DNAJC12's interaction with tyrosine (TH) and tryptophan hydroxylase (TPH), which are rate-limiting enzymes for synthesis of biogenic amines dopamine (DA) and serotonin (5-HT). In-vitro knock-down of DNAJC12 with a siRNA destabilizes the DNAJC12-TH-GCH1 complex, reducing GCH1 levels, whereas reciprocal overexpression of both TH and GCH1 increases endogenous DNAJC12, alluding to the significance of modulating the DNAJC12-TH-GCH1 complex as a therapy for DNAJC12 and other biogenic amine disorders. We extend these investigations to a Cre-conditional knock-out mice (cDKO) in which loxP sites flanking Dnajc12 exon 2 enable its excision by cre-recombinase. With germline Cre expression, we have created a constitutive Dnajc12 knock-out (DKO). DKO mice exhibit reduced locomotion/ exploratory behavior at 3 months in automated open-field testing, accompanied by increased plasma phenylalanine which is a cardinal feature of patients with pathogenic DNAJC12 variants. In striatal tissue, total DA and 5-HT, their metabolites, and electrically-evoked DA release are all reduced. Biochemical alterations in synaptic proteins are also apparent, with enhanced phosphorylation of Th pSer31 and pSer40 reflecting biological compensation. Most immediately, cDKO and DKO mice present models to develop and refine therapeutic approaches for biogenic amines disorders, including dystonia and parkinsonism. They will also enable the pleiotropic functions of biogenic amines (including DA), usually synthesized in the brain or periphery, to be separated.

Report of the sixth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Paris, France, November 16th 2022.

Biallelic germline pathogenic variants in one of the four mismatch repair genes (MSH2, MSH6, MLH1 and PMS2) cause a very rare, highly penetrant, childhood-onset cancer syndrome, called constitutional mismatch repair deficiency (CMMRD). The European consortium "Care for CMMRD" (C4CMMRD) was founded in Paris in 2013 to facilitate international collaboration and improve our knowledge of this rare cancer predisposition syndrome. Following initial publications on diagnostic criteria and surveillance guidelines for CMMRD, several partners collaborating within the C4CMMRD consortium have worked on and published numerous CMMRD-related clinical and biological projects. Since its formation, the C4CMMRD consortium held meetings every 1-2years (except in 2020 and 2021 due to the Covid 19 pandemic). The sixth C4CMMRD meeting was held in Paris in November 2022, and brought together 42 participants from nine countries involved in various fields of CMMRD healthcare. The aim was to update members on the latest results and developments from ongoing research, and to discuss and initiate new study proposals. As previously done for the fifth meeting of the C4CMMRD group, this report summarizes data presented at this meeting.

A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis.

Heterozygous variants of sequestosome-1 gene (SQSTM1) have been reported in patients with various neurological disorders, whereas biallelic pathogenic variants of SQSTM1 can cause child-onset and multisystem neurodegeneration, including cerebellar ataxia, dystonia, and vertical gaze palsy (NADGP). Here, we describe two cases of NADGP in a Japanese family. We performed clinical and genetic laboratory evaluations of the two patients and their healthy parents. By whole-exome sequencing, we identified compound heterozygous variants in SQSTM1(NM_003900.5): c.1A>G p.(Met1?) in the initial codon, and c.969G>A, located at the 3' end of exon 6, which is novel and seemingly a synonymous but is actually a truncating variant causing aberrant splicing. An SQSTM1 protein expression assay using urine-derived cells (UDCs) demonstrated that both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of premessenger RNA. Cerebellar ataxia is a characteristic manifestation of this disorder; however, brain magnetic resonance imaging studies have not shown significant cerebellar atrophy. Our patients experienced chorea during adolescence. Only a few reports have highlighted the presence of chorea; however, our findings suggest that NADGP should be considered as a differential diagnosis of hereditary chorea. This study also demonstrates the utility of UDCs, obtained using noninvasive approaches, in functionally analyzing genetic diseases.

Primary hyperoxaluria type 3: from infancy to adulthood in a genetically unique cohort.

Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder caused by bi-allelic genetic variants in the 4 hydroxy-2 oxoglutarate aldolase (HOGA-1) gene. We report the natural history of PH3 in a 16-patient cohort, 15 from a unique genetically isolated population. This retrospective single-center study followed PH3 patients between 2003 and 2023 with demographic, clinical, radiographic, genetic, and biochemical parameters. Genetic population screening was performed in four villages to determine carrier frequency and identify couples at risk in a genetically isolated population. Sixteen patients with biallelic (or homozygous) pathogenic variants (PV) in HOGA-1 (c.944_946 del, c.119C > A, c.208C > T) were included in the study, 15 Druze and one Jewish, aged 0-63years at diagnosis (4 adults and 12 pediatric patients). All symptomatic patients had clinical or imaging signs of nephrolithiasis. One developed chronic kidney disease (CKD) stage 5; biopsy showed focal mesangial sclerosis and chronic tubulo-interstitial changes with few oxalate deposits. Two other patients had CKD stage 2 (eGFR 87 and 74mL/min/1.73m2) upon their last visit. The remaining cohort showed preserved kidney function until the latest follow-up. Of 1167 healthy individuals screened, 90 carriers were found, a rate of 1:13 in the genetically unique cohort screened. A high prevalence of PH3 patients was found among a unique cohort, but probably still underdiagnosed due to relatively mild disease course. The carrier rate is high. There is no specific therapy for PH3, but early diagnosis can prevent redundant diagnostic efforts and provide early treatment for kidney stone disease. Even in our homogeneous cohort, kidney stone disease severity and CKD degree were variable, supporting a suspected contribution of yet unknown genetic or environmental factors.

COX15 deficiency causes oocyte ferroptosis

Mitochondria play diverse roles in mammalian physiology. The architecture, activity, and physiological functions of mitochondria in oocytes are largely different from those in somatic cells, but the mitochondrial proteins related to oocyte quality and reproductive longevity remain largely unknown. Here, using whole-exome sequencing data from 1,024 women (characterized by oocyte maturation arrest and degenerated or morphologically abnormal oocytes) and 2,868 healthy controls, we performed a population and gene-based burden test for mitochondrial genes and identified a candidate gene, cytochrome c oxidase assembly protein 15 (COX15). We report that biallelic COX15 pathogenic variants cause human oocyte ferroptosis and female infertility in a recessive inheritance pattern. COX15 variants impaired mitochondrial respiration in Saccharomyces cerevisiae and led to reduced protein levels in HeLa cells. Oocyte-specific deletion of Cox15 led to impaired Fe2+ and reactive oxygen species homeostasis that caused mitochondrial dysfunction and ultimately sensitized oocytes to ferroptosis. In addition, ferrostatin-1 (an inhibitor of ferroptosis) could rescue the oocyte ferroptosis phenotype in vitro and ex vivo. Our findings not only provide a genetic diagnostic marker for oocyte development defects but also expand the spectrum of mitochondrial disorders to female infertility and contribute to unique insights into the role of ferroptosis in human oocyte defects.

Chronic acid sphingomyelinase deficiency diagnosed in infancy/childhood in Polish patients: 2024 update.

Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disease (LSD) associated with biallelic pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. The aim of this study was to provide the 2024 update on chronic visceral and neurovisceral ASMD diagnosed in the infancy/childhood in Polish patients. All the patients diagnosed in the pediatric age (0-18 years) with ASMD, both chronic neurovisceral and visceral type, and then systematically followed up, were enrolled into the study. A total number of 7 patients were enrolled into the study. Four patients were previously reported. Two patients were newly recognized with ASMD - 1 with chronic visceral and 1 with chronic neurovisceral ASMD. Splenomegaly was noted in all the patients while a mild liver enlargement was observed in 4 of 7 patients. All patients presented with decreased high-density lipoprotein cholesterol (HDL-C) and decreased serum 25-hydroxy-vitamin D concentration while almost all (6 of 7) with hypercholesterolemia. Cherry-red spot was observed in 5 of 7 patients, including 1 patient with neurovisceral type. Seven various SMPD1 gene variants were identified and missense variants were the most common types of genetic lesions, comprising 71% of all alleles. In all the screened patients, lyso-sphingomyelin (lyso-SM) in dried blood spot (DBS) was found elevated; however, the greater values were observed for patients with chronic neurovisceral type. Chronic acid sphingomyelinase deficiency (ASMD) is a slowly progressive disease. Pediatric ASMD is characterized by spleno-hepatomegaly, dyslipidemia (with decreased HDL-C as the most characteristic) and infiltrative (interstitial) lung disease. Both visceral and neurovisceral chronic ASMD patients could present with cherry-red spot. Both acid spingomyelinase activity and lyso-spingomyelin concentration in DBS should be regarded as a first-tier screening method into ASMD.

Clinical and Genetic characteristics of patients with Peripheral Retinal Fleck in Koreans.

To describe the clinical and genetic features of Korean patients with peripheral retinal flecks unrelated to aging. A retrospective analysis was conducted on the clinical characteristics of patients with symmetric peripheral retinal flecks. Age-related deposits such as reticular pseudodrusen were excluded, as well as secondary deposits related to intraocular inflammation, tumor, and drug toxicity. Multimodal imaging, electrophysiological examinations, and genetic testing were analyzed. A total of 10 patients (2 males and 8 females) with bilateral peripheral flecks were enrolled in this study. A mean age at diagnosis was 30.5±19.6 years (4-59 years). Within the 10 patients, 6 were genetically confirmed with monogenic retinal disorders. Biallelic pathogenic variants in RDH5 were found in 5 patients, and 1 patient was diagnosed with retinopathy related to Alport syndrome due to a pathogenic variant in COL4A5. Although not genetically confirmed, one case associated with nanophthalmos and another case showing chorioretinal mottling in a carrier of ocular albinism have been identified. In one patient, genetic testing also revealed unknown causes. The mean logMAR initial visual acuity was 0.12±0.18 and 0.07±0.18 in right and left eyes, respectively. Night blindness was reported by 4 patients (40%), with 3 showing decreased or delayed rod response in electroretinogram, particularly those with RDH5 mutations. Differences in the deposit layers and the patterns of flecks were observed on multimodal imaging. In the study population, we observed various causes and clinical differences in the retinal fleck patterns among Koreans, including RDH5-related fundus albipunctatus and Alport syndrome. Despite reports of night blindness symptoms in some cases, all patients demonstrated satisfactory corrected visual acuity.

Biallelic pathogenic variants in the LSS gene cause congenital alopecia-cataract syndrome.

Biallelic variants in the LSS gene have been reported in individuals affected by alopecia-intellectual disability syndrome 4, cataract 44, hypotrichosis 14, and palmoplantar keratoderma-congenital alopecia syndrome type 2. The present report described a Chinese girl with congenital alopecia universalis, cataract, esotropia, and nystagmus caused by compound heterozygous variants of c.1025T>G (p.Ile342Ser) and previously unreported c.1011G>A (p.Pro337=) in the LSS gene. Minigene assay confirmed the synonymous variant Pro337= at the edge of exon 9 could produce a novel splice site, leading to a 46-bp insertion of the 5' sequence of the intron 9, likely resulting in a frameshift effect. We consider that the clinical manifestations of this case represent a new type of LSS-related disease, namely congenital alopecia-cataract syndrome (CACS). Our data expand the phenotypic and genetic spectrum of LSS-related diseases.

Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease

The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset ≤35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.