A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome.

INTRODUCTION: Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. METHODS AND RESULTS: Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. CONCLUSIONS: We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.

Clinical and radiological features in young individuals with nevoid basal cell carcinoma syndrome.

PURPOSE: Nevoid basal cell carcinoma syndrome is an autosomal dominant disorder characterized by multiple basal cell carcinomas, jaw cysts, palmar/plantar pits, spine and rib anomalies, and falx cerebri calcification. Current diagnostic criteria are suboptimal when applied to pediatric populations, as most common symptoms often do not begin to appear until teenage years. METHODS: We studied minor and major clinical features in 30 children/teenagers and compared the findings with 75 adults from 26 families with nevoid basal cell carcinoma syndrome. RESULTS: Fifty percent of children/teenagers and 82% of adults had at least one basal cell carcinoma. Jaw cysts occurred in 60% of children/teenagers and 81% of adults. Palmar/plantar pits were the most frequent feature seen in affected individuals at all ages. Macrocephaly was seen in 50% of affected and 8% of unaffected children/teenagers. Frontal bossing, hypertelorism, Sprengel deformity, pectus deformity, and cleft lip/palate were seen among affected children/teenagers but not among their unaffected siblings. Falx calcification, the most frequent radiological feature, was present in 37% of individuals <20 and 79% of those >20 years. CONCLUSION: We report clinical and radiological manifestations of nevoid basal cell carcinoma syndrome in children/teenagers, many of whom lacked major features such as basal cell carcinomas, jaw cysts, and falx calcification. Evaluations for palmar/plantar pits, craniofacial features, and radiological manifestations permit early diagnosis and optimum surveillance.

HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies.

Chaperone-assisted selective autophagy (CASA) is a highly selective pathway for the disposal of misfolding and aggregating proteins. In muscle, CASA assures muscle integrity by favoring the turnover of structural components damaged by mechanical strain. In neurons, CASA promotes the removal of aggregating substrates. A crucial player of CASA is HSPB8 (heat shock protein family B (small) member 8), which acts in a complex with HSPA, their cochaperone BAG3, and the E3 ubiquitin ligase STUB1. Recently, four novel HSPB8 frameshift (fs) gene mutations have been linked to neuromyopathies, and encode carboxy-terminally mutated HSPB8, sharing a common C-terminal extension. Here, we analyzed the biochemical and functional alterations associated with the HSPB8_fs mutant proteins. We demonstrated that HSPB8_fs mutants are highly insoluble and tend to form proteinaceous aggregates in the cytoplasm. Notably, all HSPB8 frameshift mutants retain their ability to interact with CASA members but sequester them into the HSPB8-positive aggregates together with two autophagy receptors SQSTM1/p62 and TAX1BP1. This copartitioning process negatively affects the CASA capability to remove its clients and causes a general failure in proteostasis response. Further analyses revealed that the aggregation of the HSPB8_fs mutants occurs independently of the other CASA members or from the autophagy receptors interaction, but it is an intrinsic feature of the mutated amino acid sequence. HSPB8_fs mutants aggregation alters the differentiation capacity of muscle cells and impairs sarcomere organization. Collectively, these results shed light on a potential pathogenic mechanism shared by the HSPB8_fs mutants described in neuromuscular diseases.Abbreviations : ACD: α-crystallin domain; ACTN: actinin alpha; BAG3: BAG cochaperone 3; C: carboxy; CASA: chaperone-assisted selective autophagy; CE: carboxy-terminal extension; CLEM: correlative light and electron microscopy; CMT2L: Charcot-Marie-Tooth type 2L; CTR: carboxy-terminal region; dHMNII: distal hereditary motor neuropathy type II; EV: empty vector; FRA: filter retardation assay; fs: frameshift; HSPA/HSP70: heat shock protein family A (Hsp70); HSPB1/Hsp27: heat shock protein family B (small) member 1; HSPB8/Hsp22: heat shock protein family B (small) member 8; HTT: huntingtin; KO: knockout; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MD: molecular dynamics; MTOC: microtubule organizing center; MYH: myosin heavy chain; MYOG: myogenin; NBR1: NBR1 autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NSC34: Neuroblastoma X Spinal Cord 34; OPTN: optineurin; polyQ: polyglutamine; SQSTM1/p62: sequestosome 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TARDBP/TDP-43: TAR DNA binding protein; TAX1BP1: Tax1 binding protein 1; TUBA: tubulin alpha; WT: wild-type.

Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy.

Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget's disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group's conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.

Humoral immune deficiency and hemifacial microsomia seen in one family.

We present a patient with hemifacial microsomia and immune deficiency. The patient is a 5-year-old with grade III microtia and Pruzansky type I right mandibular hypoplasia. She developed 25 pulmonary infections in 3 years, required hospitalization every 6 weeks to receive antibiotics, and experienced recurrent herpes stomatitis and esophagitis, staphylococcal bacteremia, urinary tract, sinus, and ear infections. She had low total IgG, IgG1, IgG2, IgA, and anti-pneumococcal antibody levels. She was unable to maintain protective pneumococcal titers following vaccination. The patient's 7-year-old sister also suffered from recurrent infections, had a left facial skin tag, and a left arachnoid cyst. We conclude that immune deficiency can occur in association with hemifacial microsomia.

Subglossopalatal synechia in association with cardiac and digital anomalies.

A 1-day-old boy in respiratory distress had a midline soft tissue band between the floor of the mouth and the posterior edge of the hard palate. There was also a soft palatal cleft, cardiac anomalies, and a hypoplastic right fifth finger and toe. Although his airway initially improved following urgent excision of the subglossopalatal band, he continued to have episodic desaturations. A tongue-lip adhesion opened his airway, and he subsequently underwent resection of juxtaductal aortic coarctation and ligation of patent ductus arteriosus and left superior vena cava. Congenital oral synechiae are uncommon. Affected infants often require prompt intervention secondary to respiratory distress and feeding difficulty. Review of the literature indicates that midline subglossopalatal synechia with cardiac and digital anomalies may be in the oromandibular-limb hypogenesis spectrum.

Cockayne syndrome: the developing phenotype.

Cockayne syndrome is a rare autosomal recessive condition comprising microcephaly, "cachectic dwarfism" and progressive neurological degeneration. We present a 21-year-old woman who was not diagnosed with Cockayne syndrome type I until she was 21 years old. Family photographs demonstrated that the phenotype of Cockayne syndrome did not become evident until she was 8 years old. She had severe microcephaly, micrognathia, protruding ears, dental overcrowding with caries, progressive spastic quadriparesis, and severe developmental regression. Her head computed tomography (CT) showed bilateral calcification of the globus pallidus and global atrophy. The purpose of this clinical report is to alert clinicians to the fact that the phenotypic features of Cockayne syndrome may be very subtle early in the course of the disease.

Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome.

PURPOSE: Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal-dominant disorder characterized by multiple basal cell carcinomas, jaw cysts, palmar/plantar pits, calcification of the falx cerebri, and spine and rib anomalies. NBCCS is due to mutations in PTCH1, the human homologue of the Drosophila segment polarity gene patched. Mutations are detected in approximately 60% to 85% of individuals tested by sequencing of PTCH1; therefore, clinical examination and x-rays remain important in diagnosis of NBCCS. METHODS: We studied 82 NBCCS patients and 38 of their unaffected siblings at the NIH between 1985 and 1994. Chest, rib, spine, skull, hand and foot x-rays, brain MRI or CT, and pelvic ultrasound (in females) were obtained in the affected individuals and compared to their unaffected relatives. RESULTS: The following features were significantly more frequent in those with NBCCS: calcification of the falx cerebri, the most frequent radiological feature, was present in 79% of patients > 20 years and in 37% <20 years, calcification of the tentorium cerebellum was present in 20%, bridging of the sella in 68%, and abnormal frontal sinus aeration in 18% of affected individuals. Bifid ribs most often involving the third, fourth, and fifth ribs were seen in 26%; splayed, fused, and misshapen ribs in a further 16%, and widened ends of clavicles in 12%. Spine X-rays revealed calcification of the nuchal ligament in 18%, fusion of vertebrae in 10%, and hemivertebrae in 15%. Flame-shaped lucencies of the metacarpals and/or phalanges were present in 30%, modeling deformities of the phalanges in 14%, and polydactyly of the feet in 4%. The frequency of scoliosis, cervical ribs, absent or rudimentary ribs, spina bifida occulta, or short 4th metacarpal was not higher in the affected individuals as compared to their unaffected relatives. Except for falx calcification, the frequency of radiological manifestations was similar in different age groups. Cranial CT or MRI in 42 affected individuals revealed asymmetric or dilated ventricles in 24%, cerebral atrophy in 10%, cavum septum pellucidum in 19%, dysgenesis or agenesis of the corpus callosum in 10%, and meningioma in 5%. Ovarian fibromas were detected in 17% of females. CONCLUSIONS: This study reports the varied radiological manifestations of NBCCS. In the absence of major features such as basal cell carcinomas, jaw cysts, or falx calcification, which is often not evident until the teen years, other radiological manifestations of the disorder can permit early diagnosis of NBCCS in childhood. This will allow optimum surveillance for medulloblastoma and other neoplasms (cardiac fibromas and basal cell carcinomas) associated with NBCCS.