Novel imaging finding and novel mutation in an infant with molybdenum cofactor deficiency: a mimicker of hypoxic ischaemic encephalopathy

Molybdenum cofactor deficiency is a rare metabolic disorder with neonatal onset seizures, developmental delay, microcephaly and spasticity. In this report, we describe a three-month-old infant presented with neonatal onset, poorly controlled seizures, developmental delay, microcephaly, spastic quadriparesis and visual insufficiency. Magnetic resonance imaging of brain had shown cystic encephalomalacia involving bilateral parieto-occipital lobe, and elevated lactate in magnetic resonance spectroscopy.  Restricted diffusion noted along the corticospinal tract in our case is a novel imaging finding in molybdenum cofactor deficiency.  Low serum uric acid and elevated urine sulphite excretion were observed. A novel homozygous mutation was detected in exon 4 of MOCS2 gene.Early infantile or neonatal onset seizures, developmental delay, microcephaly and cystic encephalomalacia in neuroimaging mimicking hypoxic ischaemic encephalopathy should raise the suspect for molybdenum cofactor deficiency. Screening of all neonates for urinary sulphite metabolites helps in early diagnosis and management. Early diagnosis and treatment with cyclic pyranopterin monophosphate could arrest the progression of this disease. More research is needed to explore further treatment options in this otherwise lethal disorder

Effect of Oral Eliglustat on Splenomegaly in Patients With Gaucher Disease Type 1. The ENGAGE Randomized Clinical Trial

Importance Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. Objective To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. Design, Setting, and Participants Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. Interventions Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures The primary efficacy end point was percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. Results All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, −32.57% to −22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, −2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of −30.03% (95% CI, −36.82% to −23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, −11.37% to −1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non–treatment related); 39 of the 40 patients transitioned to an open-label extension study. Conclusions and Relevance Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up

The Cockayne Syndrome Natural History (CoSyNH) study:clinical findings in 102 individuals and recommendations for care

Purpose: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established. Methods: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians. Results and Conclusion: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses

Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis

DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis

A descriptive pilot study of mitochondrial mutations & clinical phenotype in fibromyalgia syndrome

Background & objectives: Fibromyalgia syndrome (FMS) is one of the most common chronic pain conditions of unknown aetiology. Mitochondrial dysfunction has been reported in FMS with some studies reporting the presence of mitochondrial mutation namely A3243G, which also causes mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. This pilot study was conducted to assess this mutation and also detect large deletions in mitochondrial DNA (mtDNA) in patients with FMS. Methods: Thirty female patients with FMS participated and 30 matched controls were included. Genomic DNA was subjected to polymerase chain reaction (PCR) amplification using specific primers followed by restriction digestion with Apa I enzyme to detect the specific A3243G mtDNA mutation. Long-range PCR was done in two sets to detect the large deletions in the mtDNA. Biochemical parameters including thyroid-stimulating hormone and vitamin D levels were also looked at. Results: None of the patients were found to carry the common mutation or large deletions. Low vitamin D level was a common finding. Hypothyroidism was found in a few patients. Interpretation & conclusions: Although the common mutation or large mtDNA deletions were not detected in blood mtDNA in the FMS patients, mutations in the muscle and sequence variation in mtDNA remained a possibility. Future studies in both blood and muscle tissue including mtDNA sequencing are warranted in such patients to determine if a subset of FMS patients have mitochondrial myopathy

An unusual case of keratinopathic icthyosis: a diagnostic conundrum

Epidermolytic ichthyosis (EI) is a rare inherited ichthyosis related to heterozygous mutations in the Keratin 1 or Keratin 10 genes. Because of the broad phenotypic spectrum, it is sometimes difficult to differentiate it from other keratinopathic ichthyoses (KI) in clinical practice. We report an intriguing case of KI presenting as generalized ichthyosis in a reticulate pattern surrounding islands of normal skin, epidermolytic hyperkeratosis and binucleate cells on histopathology, and heterozygous mutation in KRT10. Through this case, we would like to demonstrate the importance of genetic studies and genotype-phenotype correlation in diagnosing such challenging cases

Three siblings with Woodhouse–Sakati syndrome in an Indian family

Woodhouse–Sakati syndrome consists of alopecia, hypogonadism, diabetes mellitus, mild mental retardation, sensorineural deafness and ECG abnormalities. The proband described here has the above-mentioned features and presented with idiopathic thrombocytopenic purpura not reported before. Phenotypic variability is present in the three affected siblings. The two sisters have hypergonadotropic hypogonadism and the brother has hypogonadotropic hypogonadism. Camptodactyly of fourth and fifth fingers is seen in proband and her brother. We report for the first time three affected siblings of Woodhouse–Sakati syndrome in an Indian family

Patient with mutation in the matrix metalloproteinase 2 (MMP2) gene - A case report and review of the literature

Torg and Winchester syndromes and patients reported by Al-AqeelSawairi as well as nodulosis-arthropathy-osteolysis (NAO) patients, patients with multicentric NAO share autosomal recessive inheritance. The common presenting symptomatology includes progressive osteolysis chiefly affecting the carpal, tarsal and interphalangeal joints. Here, we report a patient with Torg syndrome. Torg syndrome is caused by homozygous or compound heterozygous mutations in the matrix metalloproteinase 2 (MMP2) gene. MMP2 codes for a gelatinase that cleaves type IV collagen, a major component of basement membrane. The clinical presentation of our patient included moderate osteolysis of the small joints of the hands and knees, hirsutism, nodulosis sparing the palms and soles, corneal opacities and mild facial dysmorphism without gum hypertrophy. Genetic analysis showed that the patient was homozygous for a novel base variant c538 G>A (p.D180N) in the MMP2 gene. Both parents were carriers of the same mutated variant. Our patient had some previously unreported endocrine manifestations such as premature thelarche and elevated follicle-stimulating hormone levels