ATGL-mediated lipolysis is essential for myocellular mitochondrial function, mitochondria-lipid droplet interaction and mitochondrial network connectivity.

Isolated Right Ventricular Hypertrophy: A Novel Cardiac Manifestation of Neutral Lipid Storage Disease.

Congenital ichthyosis (CI) represents a heterogeneous group of inherited keratinization disorders that typically present at birth or in early childhood. While some forms are limited to cutaneous involvement, syndromic variants may also affect the liver, musculoskeletal system, and nervous system. The advent of next-generation sequencing has improved delineation of the genetic basis of CI, enabling precise diagnosis and genetic counseling. We report three children with CI evaluated at a tertiary care center. The first case was a 19-month-old girl with lamellar scaling, ectropion, strabismus, hepatosplenomegaly, and cytoplasmic vacuoles in neutrophils. Whole-exome sequencing (WES) confirmed Chanarin-Dorfman syndrome due to a homozygous ABHD5 pathogenic variant. She was managed with emollients, topical retinoids, dietary fat modification, and multidisciplinary support. The second case, a 2-year-old boy with diffuse scaling, growth failure, rickets, and developmental delay, had a pathogenic 15q11.2 microdeletion in addition to a homozygous NIPAL4 mutation on WES, consistent with autosomal recessive congenital ichthyosis. He received nutritional rehabilitation, skin-directed therapy, and genetic counseling. The third case involved a fetus with antenatally detected growth restriction, microcephaly, clubfeet, and ambiguous genitalia. Following termination, dysmorphic features and skeletal anomalies were noted. WES confirmed Neu-Laxova syndrome due to a homozygous PSAT1 nonsense mutation. This case series highlights the broad phenotypic and genotypic spectrum of congenital ichthyosis, ranging from multisystem lipid storage disorders to dual genetic diagnoses and lethal syndromic presentations. Detailed clinical evaluation combined with genomic diagnostics is critical for establishing an accurate diagnosis, guiding multidisciplinary management, and providing informed genetic counseling.

Defective targeting of PNPLA1 to lipid droplets causes ichthyosis in ABHD5-syndromic epidermal differentiation disorder

Inherited ichthyosis comprises a spectrum of genetic disorders related to over 50 pathogenic genes. However, there are limited data summarizing the clinical and molecular characteristics of Chinese patients. To broaden the knowledge of clinical and genetic characteristics of inherited ichthyosis and to optimize disease diagnosis and therapies, cases diagnosed with inherited ichthyosis in 1 tertiary centre from 2019 to 2023 were collected, excluding ichthyosis vulgaris and X-linked recessive ichthyosis, genomic sequencing was then performed, and clinical details of the patients were assessed. A total of 35 patients from Jiangsu and Anhui provinces of China were enrolled, 31 of whom were diagnosed with non-syndromic ichthyosis. Within this group, there were cases of autosomal recessive congenital ichthyosis (18/31), epidermolytic ichthyosis (9/31), and superficial epidermolytic ichthyosis (4/31). Additionally, 4 patients were diagnosed with syndromic ichthyosis, comprising 1 case of Chanarin-Dorfman syndrome and 3 cases of Netherton syndrome. The genetic analysis revealed a total of 47 variants across 13 genes, of which 19 were identified as novel variants. This study describes the clinical spectrum of rare inherited ichthyosis in the Jiangsu-Anhui region of China and further expands the genetic characteristics of the disease.

BackgroundNeutral lipid storage disease with myopathy (NLSDM) is a rare genetic myopathy caused by mutations in the patatin-like phospholipase domain-containing protein (PNPLA2) gene. To date, the number of reported cases remains limited and the correlation between disease phenotypes and genotypes remains unclear.ResultsOur study presents eight NLSDM patients from a Chinese neuromuscular center, identifying two PNPLA2 novel mutations through next-generation sequencing. Demographic and clinical data, as well as information from muscle electrophysiological, imaging, pathological, and genetic analyses, were collected. Several patients in the cohort were found to have right upper extremity weakness as the initial clinical manifestation. Notably, the first patient with facial muscle involvement was reported in this series. Muscle histopathology revealed a characteristic accumulation of lipid droplets predominantly in type 1 muscle fibers, featuring type 1 fiber atrophy concurrent with type 2 fiber hypertrophy, which was systematically described first in a summary manner.ConclusionsThis study prompted us to summarize abnormal clinicopathological features and explore the relationship between gene mutations and disease phenotypes in NLSDM.

Introduction: Chanarin–Dorfman syndrome (CDS) is a rare genetic disorder caused by impaired lipid metabolism, leading to the accumulation of lipid vacuoles in various types of cells. CDS is characterized by multi-organ involvement, most notably non-bullous ichthyosiform erythroderma. Herein, we reported a patient with Chanarin–Dorfman syndrome presenting a new clinical symptom. Case presentation: The case involved a 32-year-old woman with a molecular diagnosis of CDS who exhibited reduced breast milk production during both of her breastfeeding periods. The patient had previously been diagnosed with CDS based on the clinical features and gene sequencing results of a mutation in the abhydrolase domain containing 5 (ABHD5) gene. The patient had experienced two uncomplicated pregnancies and deliveries. Based on laboratory tests and imaging findings, common causes of decreased lactation were ruled out. Discussion: ABHD5 gene encodes a cofactor for adipose triglyceride lipase, which is a member of the patatin-like phospholipase family. While ichthyosis was the predominant symptom of CDS, other common clinical manifestations included hepatomegaly, cataracts, and muscle weakness, among others. Decreased breast milk production is an unusual symptom, which is not be reported by . We explore whether this symptom may be related to a mutation in the abhydrolase domain containing 5 (ABHD5) gene. We propose two possible mechanisms: first, that gene mutation may alter the gene regulation involved in breast milk production, and second, that it may increase the risk of metabolic syndrome, which could impair lactation. Conclusion: This case report provides a unique and noteworthy contribution by identifying a previously unreported clinical manifestation of CDS and suggesting a potential role for the ABHD5 gene in lactation biology. Our findings may have implications for genetic counseling in women with CDS who are planning to have children.

A case of Chanarin-Dorfman syndrome

BackgroundChanarin-Dorfman syndrome (CDS) is a multisystemic autosomal recessive rare disorder. CDS is caused by variants in the abhydrolase domain containing 5 (ABHD5) encoding gene (CGI-58), which ultimately leads to excessive lipid storage, and therefore a high abundance of cellular lipid droplets (LDs). Although the molecular etiology of the disease was described many years ago, no treatment for CDS is currently available.ResultsTo further characterize the molecular basis of the disease and to uncover new treatment avenues, we used skin fibroblasts originating from a young patient diagnosed with CDS due to a homozygous nonsense mutation. We show that dysfunctional ABHD5 does not only affect LDs, but also influences other metabolic-related organelles; the mitochondria and peroxisomes. Additionally, we found that expressing functional ABHD5 in CDS patient cells reduced LD number. Finally, we developed and applied a high content-based drug repurposing screen based on a collection of ∼2500 FDA approved compounds, yielding several compounds that affected LD total area and size.ConclusionsOur findings enhance the understanding of the dysfunction underlying CDS and propose new avenues for the treatment of CDS patients.

ObjectivesChanarin-Dorfman syndrome is a rare disease inherited in an autosomal recessive pattern whose prevalence does not exceed 130 cases worldwide.Case presentationA 4-year-old patient with generalized erythematous-desquamative ichthyosiform syndrome since birth. The main laboratory finding was persistent hypertransaminasemia. Supplementary studies included peripheral blood smear (PBS), which revealed the presence of multiple cytoplasmatic vacuoles in polymorphonuclear leukocytes (PMN) and platelets. Ichthyosiform lesions concomitant to the presence of lipid vacuoles in peripheral blood PMNs are signs of Chanarin-Dorfman syndrome. Diagnostic suspicion was confirmed by genetic sequencing.ConclusionsChanarin-Dorfman syndrome is characterized by a mutation in the CGI-58 gene. This gene is involved in the catabolism of long-chain triglycerides stored in cytoplasmic lipid droplets. Jordans’ anomaly is a congenital alteration characterized by the presence of multiple vacuoles in the granulocytic series due to defective lipid metabolism. In this syndrome, long-chain triglycerides build up in tissues, thereby causing dermatological manifestations that are controllable through diet.

BackgroundNeutral Lipid Storage Disease with Myopathy (NLSDM) is a rare lipid metabolism disorder caused by PNPLA2 gene mutations. Clinical manifestations are heterogeneous, and diagnosis is often delayed, usually gaining patients’ attention due to the increased risk of cardiomyopathy.Case presentationWe herein report a 36-year-old Asian male presenting with progressive limb weakness, muscle atrophy of limbs and trunk, dysarthria, and heart failure. Electromyography indicated myogenic changes, and muscle biopsy results revealed characteristics of lipid storage myopathy. Genetic analysis of PNPLA2 revealed two heterozygous mutations: c.757 + 1G > T (chr11-823588, splice-5) on intron 6 and c.919delG (chr11-823854, p.A307Pfs*13) on exon 7. The patient improved limb strength, and dysarthria disappeared after the Medium Chain Fatty Acids diet.ConclusionsIn conclusion, we report for the first time that the two heterozygous mutations PNPLA2 c.919delG and c.757 + 1G > T together induced NLSDM, which was confirmed by muscle biopsy.

To explore the clinical phenotype and genetic basis of a child with Neutral lipid storage disease with myopathy (NLSDM). A child who was admitted to the First Affiliated Hospital of Zhengzhou University in February 2021 for a history of elevated creatine kinase (CK) for over 2 months was selected as the study subject. Clinical and laboratory examinations were carried out, and the child was subjected to whole exome sequencing. Candidate variants were validated by Sanger sequencing of her family members. The patient, a 9-year-old female, had exhibited weakness in the lower limbs, elevated CK level, and refractory cardiomyotrophy. Genetic testing revealed that she has harbored c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene, which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PM1+PM2_Supporting+PP3+PP4). The c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene probably underlay the myasthenia gravis and elevated creatine kinase in this child.

Ichthyosis belongs to the group of Mendelian disorders of cornification. Congenital ichthyosis is inherited as an autosomal recessive trait, so it is also known as autosomal recessive congenital ichthyosis (ARCI). ARCI is classified into two types: syndromic and non-syndromic ARCI. Non-syndromic ARCIs include lamellar ichthyosis, congenital ichthyosiform erythroderma and Harlequin ichthyosis. Syndromic-ARCI is associated with multisystemic involvement, which includes Netherton syndrome, Chanarin-Dorfman disease and others. Other systemic diseases associated with ichthyosis include Gaucher disease type II and hypothyroidism. Chanarin-Dorfman and Gaucher disease-II are additionally associated with hepatosplenomegaly (HSM) and anaemia. We describe a child of congenital ichthyosis with HSM and anaemia thought to be syndromic-ARCI, but diagnosed for beta-thalassaemia (b-thal) concurrently. An infant presented with peeling skin along with absent sweating since birth and recent onset paleness of the body. Examination revealed Ichthyosis (Lamellar-variant), severe pallor and HSM, raising the possibility of Chanarin-Dorfman syndrome and Gaucher’s disease. The investigation revealed an Erlenmeyer flask deformity of the knee, but no Gaucher’s cells were found in the bone marrow. In the absence of lipid vacuoles leaden leukocytes (Jordan’s anomaly), Chanarin-Dorfman disease was also ruled out. Haemoglobin (Hb) high-performance liquid chromatography revealed β-thal major, and both parents were traits, giving us the diagnosis, which was further confirmed by the next-generation gene sequencing for clinical exomes. This report was to highlight non-syndromic ARCI involving the CYP4F22 gene variant, which is a rare finding, and the association of such ichthyosis with β-thal major was an unexpected result. Genetic counselling was provided to the parents in light of the autosomal recessive nature of both diseases. Genes of congenital ichthyosis and β-thal were unrelated, but simultaneous expressions of two autosomal-recessive diseases together are merely by chance or a new entity.

Eponyms that honor Jewish dermatologists: A celebration and a remembrance, Part three: Jewish physicians who practiced during the Holocaust and in its aftermath

Comorbidity of bathing suit ichthyosis and limb-girdle muscular dystrophy type 2 A in a Tunisian patient revealed by Whole Exome Sequencing

Eponyms and clinical entities from the land of Israel

Neutral lipid storage disease with myopathy: clinicopathological and genetic features of nine Iranian patients

Chanarin-Dorfman Syndrome diagnosed at the stage of liver transplantation: A rare lipid storage disease

HyperCKemia: An early sign of childhood-onset neutral lipid storage disease with myopathy

Abstract Background and Aims Neutral lipid storage diseases (NLSD) are rare conditions caused by an inborn error of neutral lipid metabolism that results in a deficit in the degradation of cytoplasmic triglycerides and a consequent abnormal storage of the neutral lipids. Their accumulation in cytoplasmic lipid droplets in most tissues of the body results in a very heterogeneous phenotype: myopathic syndrome, intellectual deficit, cataract, neuropathy, cardiomyopathy, hepatomegaly are the main clinical manifestations. Less frequent conditions are diabetes, chronic pancreatitis and renal involvement. Method A 27-year-old woman visited our hospital on November 2022 because of progressive onset of edema, dyspnea, nausea and loss of appetite. The medical history showed that 4 years before she was diagnosed with diabetes mellitus and she has been suffering from severe muscle weakness (she was helping herself with the wheelchair) for two years. In 2017 a proctological evaluation showed an anal hypotonia from likely neuropathy. Blood chemistry tests revealed a metabolic acidosis, a decreased renal function, anaemia and nephrotic range proteinuria at the urinalysis. A bilateral pleural effusion was described at the chest radiograph and a circumferential pericardial effusion at a first echocardiogram. The ultrasound of the abdomen described a small size of the right kidney (90 mm) and an angiomyolipoma on the left kidney. Neurological examination showed a mild intellectual disability, facies with dysmorphic appearance and hypotonia of proximal and distal muscular masses of the upper limbs. Lower limbs showed a more pronounced strength deficit on the left and a hypotonia to proximal muscle masses. Electromyography showed a condition of severe sensitivity polyneuropathy: signs of chronic denervation and morphological alterations of the motor unit especially in the proximal districts of the lower limbs. Ophthalmological examination showed an advanced cataract. Cardiological evaluation through heart echo scanshowed a dilated heart disease with ventricular function and dilation of the pulmonary artery. A quadriceps muscle biopsy finally revealed myogenic features consistent with neutral lipid storage disease. Fabry test came back negative. Despite several drug treatments, the patient continued to be asthenic, inappetent and the oxygen therapy could not be removed because frequent episodes of desaturation. The deterioration of the patient's clinical conditions required the onset of dialysis immediately. Unfortunately, despite adequate information on the risks of possible refusal, the patient denied consent for central venous catheter placement and hence the beginning of renal replacement therapy. Sadly, the patient was lost to follow up and it was not possible to carry out other diagnostic investigations. Results Our patient developed an end-stage renal disease in the framework of a neutral lipid storage disease. Since cytoplasmic lipid droplets are ubiquitous organelles, we can assume that in this case, kidney involvement is due to a pathogenetic mechanism similar to that of other storage diseases such as Fabry disease (Table 1). Conclusion Here we describe a 27-year-old NLSD female patient showing late onset myopathy and difficulties in mobilization in association with severe cardiac and ocular involvement, mild intellectual disability, diabetes mellitus type 2 and end stage renal disease. Our data expand the clinical manifestations of NLSD, providing further evidence for clinical NLSD heterogeneity and mainly, further evidence for storage diseases with renal involvement.