De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.

Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.

Importance: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. Objectives: To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. Design, Setting, and Participants: An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015. Main Outcome and Measures: The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants. Results: Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes. Conclusions and Relevance: The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder.

ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.

Marfan syndrome: clinical diagnosis and management.

Marfan syndrome is a multisystem connective tissue disorder usually associated with mutation in fibrillin, and occasionally with mutation in TGFBR1 or 2. The clinical diagnosis is made using the Ghent nosology, which will unequivocally diagnose or exclude Marfan syndrome in 86% of cases. Use of a care pathway can help implementation of the nosology in the clinic. The penetrance of some features is age dependent, so the nosology must be used with caution in children. Molecular testing may be helpful in this context. The nosology cannot be used in families with isolated aortic dissection, or with related conditions such as Loeys-Dietz syndrome, although it may help identify families for further diagnostic evaluation because they do not fulfill the nosology, despite a history of aneurysm. Prophylactic medical (eg beta-blockade) and surgical intervention is important in reducing the cardiovascular complications of Marfan syndrome. Musculoskeletal symptoms are common, although the pathophysiology is less clear--for example, the correlation between dural ectasia and back pain is uncertain. Symptoms in other systems require specialist review such as ophthalmology assessment of refractive errors and ectopia lentis. Pregnancy is a time of increased cardiovascular risk for women with Marfan syndrome, particularly if the aortic root exceeds 4 cm at the start of pregnancy. High-intensity static exercise should be discouraged although low-moderate intensity dynamic exercise may be beneficial. The diagnosis and management of Marfan syndrome requires a multidisciplinary team approach, in view of its multisystem effects and phenotypic variability.

Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy.

UNLABELLED: Isolated sulphite oxidase deficiency (ISOD) is a rare autosomal recessive inborn error of metabolism, which may present at birth with intractable seizures (often of prenatal onset) and severe neurological abnormalities. In infants who survive, lens dislocation may occur from 8 weeks of age. The neuropathological findings in ISOD are similar to those seen in severe perinatal asphyxia. We describe two siblings with ISOD born to healthy non-consanguineous parents. The first child presented within 48 h of birth with poor feeding and seizures. He died from septicaemia on day 20 of life. The clinical presentation, neuroradiology and autopsy suggested a diagnosis of severe hypoxic ischaemic encephalopathy with a low recurrence risk. The second child presented with seizures within an hour of birth. She lived for 16 months during which time she failed to make developmental progress and continued to experience intractable seizures. Her neuroradiology was similar to her brother's. A diagnosis of ISOD was suggested from high urinary S-sulphocysteine in the second child and confirmed by the absence of sulphite oxidase activity in skin fibroblast culture. The diagnosis has enabled the couple to access prenatal testing in a subsequent pregnancy. CONCLUSION: Isolated sulphite oxidase deficiency is an autosomal recessive condition which may mimic ischaemic encephalophathy. The disorder should be considered in all cases of intrauterine seizures, intractable seizures in the newborn period and infants with clinical and radiological features of ischaemic encephalophathy, especially when no obvious insult can be determined.

Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study.

Bardet-Biedl syndrome (BBS) and Laurence-Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism. They are differentiated by the presence of spasticity and the absence of polydactyly in LMS. The aims of this study were to describe the epidemiology of BBS and LMS, further define the phenotype, and examine genotype-phenotype correlation. The study involved 46 patients (26 males, 20 females) from 26 families, with a median age of 44 years (range 1-68 years). Assessments were performed in 1986, 1993, and 2001 and included neurological assessments, anthropometric measurements, and clinical photographs to assess dysmorphic features. The phenotype was highly variable within and between families. Impaired co-ordination and ataxia occurred in 86% (18/21). Thirty percent (14/46) met criteria for psychiatric illness; other medical problems included cholecystectomy in 37% (17/46) and asthma in 28% (13/46). Dysmorphic features included brachycephaly, large ears, and short, narrow palpebral fissures. There was no apparent correlation of clinical or dysmorphic features with genotype. Two patients were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct. The lack of a genotype-phenotype correlation implies that BBS proteins interact and are necessary for the development of many organs.

Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome.

CFC (cardiofaciocutaneous) syndrome (MIM 115150) has been considered by several authors to be a more severe expression of Noonan syndrome. Affected patients present with congenital heart defects, cutaneous abnormalities, Noonan-like facial features and severe psychomotor developmental delay. We have recently demonstrated that Noonan syndrome can be caused by missense mutations in PTPN11(MIM 176876), a gene that encodes the non-receptor protein tyrosine phosphatase SHP-2. In this report, we have evaluated the possible involvement of mutations in PTPN11 in CFC syndrome. A cohort of 28 CFC subjects rigorously assessed as having CFC based on OMIM diagnostic criteria was examined for mutations in the PTPN11 coding sequence by using DHPLC analysis. The results showed no abnormalities in the coding region of the PTPN11 gene in any CFC patient, nor any evidence of major deletions within the gene suggesting that mutations in other gene(s) are responsible for this syndrome.

A Schinzel-Giedion-like syndrome--a milder version or a separate condition?

We report two 12-year-old monozygotic twins followed from birth. Their features include midface hypoplasia, a prominent forehead, coarse features, sensorineural deafness, short stature with thoracic kyphosis and lumbar lordosis and intellectual delay. As they have developed, their features have been reminiscent of a storage disorder but mucopolysaccharidoses, mucolipidoses and gangliosidoses have been excluded by biochemical testing. We discuss the phenotypic overlap with the Schinzel-Giedion syndrome but highlight the important differences. Individuals with Schinzel-Giedion syndrome tend to have renal and cardiac malformations and to have a very poor outlook, often dying in the first 3 years of life. We suggest that these twins have a previously undescribed Schinzel-Giedion like syndrome.

Ophthalmic findings in fetal anticonvulsant syndrome(s).

PURPOSE: To report the prevalence of ocular abnormalities in a group of children diagnosed with fetal anticonvulsant (FAC) syndrome(s). DESIGN: Retrospective, observational, noncomparative case series. PARTICIPANTS: Forty-six children, age range 8 months to 16 years 5 months (mean, 7 years 1 month), with a confirmed diagnosis of an FAC syndrome. Thirty-seven subjects were exposed in utero to sodium valproate (29 as monotherapy), and the remainder (n = 9) to other anticonvulsants, mainly carbamazepine. METHODS: A total of 46 subjects underwent ophthalmic assessment consisting of visual acuity, cover test, ocular movements, analysis of spectacle lens power, cycloplegic refraction, and anterior segment examination with portable slit lamp, plus direct and indirect ophthalmoscopy. MAIN OUTCOME MEASURES: Refraction and ocular motility status. RESULTS: Thirty-one of 46 (67%) had ocular abnormalities, most commonly errors of refraction (19 of 46; 41%). Myopia was common (14 of 28; 50%) in those exposed to valproate monotherapy and there were high frequencies of strabismus (20%), astigmatism (24%), and anisometropia (11%) in the group as a whole. Thirty-one percent of myopes and 27% of astigmates did not wear glasses, of whom three subjects and two subjects, respectively, were less than 8 years old and therefore at risk of anisometropic or ametropic amblyopia. One subject had epicanthus, one color vision deficiency, and one bilateral congenital cataract. CONCLUSIONS: We conclude that (1) abnormal ophthalmic findings are common in subjects with confirmed FAC syndrome, in particular myopia in those with fetal valproate syndrome; (2) children with FAC syndrome should receive preschool vision testing; (3) preschool vision testing should be considered in all children exposed to anticonvulsants in utero.