ARC Syndrome Research Articles

A novel VPS33B mutation in an ARC syndrome patient presenting with osteopenia and fractures at birth

A novel VPS33B mutation in an ARC syndrome patient presenting with osteopenia and fractures at birth

Clinical and molecular genetic features of ARC syndrome

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900-1,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.

Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet α-granule biogenesis

Bleeding problems are associated with defects in platelet alpha-granules, yet little is known about how these granules are formed and released. Mutations affecting VPS33B, a novel Sec1/Munc18 protein, have recently been linked to arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP). Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of delta-granules, and completely absent alpha-granules. Soluble and membrane-bound alpha-granule proteins were significantly decreased or undetectable in ARC platelets, suggesting that both the releasable protein pools and membrane components of alpha-granules were absent. The role of VPS33B in platelet granule biogenesis was evaluated by immunofluorescence microscopy in normal human megakaryocytes. VPS33B colocalized appreciably with markers of alpha-granules, moderately with late endosomes/lysosomes, minimally with delta-granules/lysosomes, and not with cis-Golgi complexes. VPS33B protein expression determined by immunoblotting confirmed the presence of VPS33B in control fibroblasts but not in ARC fibroblasts, and in normal megakaryocytes but not in platelets. We conclude that like other Sec1/Munc18 proteins, VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet alpha-granules but not for granule secretion.

Ichthyosis Associated with ARC Syndrome: ARC Syndrome is One of the Differential Diagnoses of Ichthyosis

The arthrogryposis, renal tubular dysfunction and cholestasis syndrome is rare. Novel identification of the mutation in VPS33B in this syndrome, which involves intracellular protein trafficking by regulation of vesicle-to-target sensory nerve action potential receptor (SNARE) family, might explain the consistent combination of membrane fusion defects. We can guess the defective lamellar body secretion mediated by the soluble N-ethylmaleimide-sensitive factor attachment protein receptor or SNARE protein pathway in the epidermis might result in the ichthyosiform phenotype. In the English-language literature, half of the reported instances of this syndrome are associated with ichthyosis. We report an infant with ichthyosis in association with arthrogryposis, renal tubular dysfunction, and cholestasis syndrome, and review the literature. Our findings suggest that the differential diagnosis of ichthyosis during infancy should include this syndrome.

Arthrogryposis, renal tubular acidosis and cholestasis (ARC) syndrome: two new cases and review

ARC syndrome, the association of arthrogryposis, renal tubular dysfunction and cholestasis, is a rare genetic disorder. We report two Saudi infants from two different families with ARC syndrome. Magnetic resonance imaging of the brain of one of the infants showed lissencephaly, a previously unreported finding in this syndrome. We also review 39 ARC cases reported in the literature using the Medline database from January 1966 to September 2004.

Comparative evolutionary analysis of VPS33 homologues: genetic and functional insights

VPS33B protein is a homologue of the yeast class C vacuolar protein sorting protein Vps33p that is involved in the biogenesis and function of vacuoles. Vps33p homologues contain a Sec1 domain and belong to the family of Sec1/Munc18 (SM) proteins that regulate fusion of membrane-bound organelles and interact with other vps proteins and also SNARE proteins that execute membrane fusion in all cells. We demonstrated recently that mutations in VPS33B cause ARC syndrome (MIM 208085), a lethal multisystem disease. In contrast, mutations in other Vps33p homologues result in different phenotypes, e.g. a mutation in Drosophila melanogaster car gene causes the carnation eye colour mutant and inactivation of mouse Vps33a causes buff hypopigmentation phenotype. In mammals two Vps33p homologues (e.g. VPS33A and VPS33B in humans) have been identified. As comparative genome analysis can provide novel insights into gene evolution and function, we performed nucleotide and protein sequence comparisons of Vps33 homologues in different species to define their inter-relationships and evolution. In silico analysis (a) identified two homologues of yeast Vps33p in the worm, fly, zebrafish, rodent and human genomes, (b) suggested that Carnation is an orthologue of VPS33A rather than VPS33B and (c) identified conserved candidate functional domains within VPS33B. We have shown previously that wild-type VPS33B induced perinuclear clustering of late endosomes and lysosomes in human renal cells. Consistent with the predictions of comparative analysis: (a) VPS33B induced significantly more clustering than VPS33A in a renal cell line, (b) a putative fly VPS33B homologue but not Carnation protein also induced clustering and (c) the ability to induce clustering in renal cells was linked to two evolutionary conserved domains within VPS33B. One domain was present in VPS33B but not VPS33A homologues and the other was one of three regions predicted to form a t-SNARE binding site in VPS33B. In contrast, VPS33A induced significantly more clustering of melanosomes in melanoma cells than VPS33B. These investigations are consistent with the hypothesis that there are two functional classes of Vps33p homologues in all multicellular organisms and that the two classes reflect the evolution of organelle/tissue-specific functions.

ARC syndrome

Acta PaediatricaVolume 94, Issue 2 p. 254-255 ARC syndrome N Laforgia, Corresponding Author N Laforgia Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalyCorresponding author: N Laforgia, Dipartimento di Biomedicina dell'Età Evolutiva, Sez. Neonatologia e TIN, Policlinico, Piazza G. Cesare 11, 70124, Bari, Italy, Tel: +39 0805592220. Fax: +39 0805593329. n.laforgia@neonatologia.uniba.itSearch for more papers by this authorMG Burattini, MG Burattini Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalySearch for more papers by this authorS Giannuzzo, S Giannuzzo Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalySearch for more papers by this authorS Storelli, S Storelli Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalySearch for more papers by this authorA Mautone, A Mautone Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalySearch for more papers by this author N Laforgia, Corresponding Author N Laforgia Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalyCorresponding author: N Laforgia, Dipartimento di Biomedicina dell'Età Evolutiva, Sez. Neonatologia e TIN, Policlinico, Piazza G. Cesare 11, 70124, Bari, Italy, Tel: +39 0805592220. Fax: +39 0805593329. n.laforgia@neonatologia.uniba.itSearch for more papers by this authorMG Burattini, MG Burattini Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalySearch for more papers by this authorS Giannuzzo, S Giannuzzo Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalySearch for more papers by this authorS Storelli, S Storelli Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalySearch for more papers by this authorA Mautone, A Mautone Sez. Neonatologia e TIN, Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Bari, ItalySearch for more papers by this author First published: 02 January 2007 https://doi.org/10.1111/j.1651-2227.2005.tb01903.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume94, Issue2February 2005Pages 254-255 RelatedInformation

ARC syndrome

ARC syndrome

Liver biopsy complicated by hemorrhage in a patient with ARC syndrome

ARC syndrome is a rare disorder consisting of arthrogryposis, renal tubular acidosis and cholestatic liver disease. We report the case of a 5-week-old patient who underwent a percutaneous liver biopsy complicated by hemorrhage, and was subsequently diagnosed with ARC syndrome. A review of the literature demonstrates that these patients are at increased risk of bleeding caused by platelet dysfunction. The evaluation and management of unexpected hemorrhage in pediatric patients as a result of undiagnosed congenital bleeding problems is discussed.

Nonsyndromic paucity of interlobular bile ducts: report of 10 patients.

Only a few reports of nonsyndromic paucity of interlobular bile ducts (NS-PILBD) have been published. The authors' aim was to outline the clinical and laboratory profile of patients with NS-PILBD diagnosed at a tertiary referral center. The authors reviewed all the reports of pediatric liver biopsies performed between 1991 and 2000 at their institution. Upon diagnosis of NS-PILBD, patients' records were examined for clinical, laboratory, and histologic data, and liver biopsy specimens were re-evaluated. Three hundred biopsies were performed in children during the study period, of which 64 were in infants younger than 1 year. NS-PILBD was diagnosed in 10 of 64 (16%) biopsy specimens. Mean age at presentation was 10 days (range, 1 day-6 weeks), and mean follow-up was 4.5 years (range, 1-9 years). An underlying condition was identified in 70% of children with NS-PILBD: namely congenital cytomegalovirus (n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), mitochondrial DNA depletion (n = 1), Niemann-Pick type C (n = 1), and arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC syndrome; n = 1). All children presented with jaundice. Four children had initially acholic stools. At their last follow-up visit, failure to thrive was present in five children, and cholestasis in six children. Mortality was noted only in children with metabolic diseases (n = 2). In the study, NS-PILBD was common in young children undergoing liver biopsy. Although NS-PILBD is nonspecific, a wide survey for inborn errors of metabolism should be included in the diagnostic work-up of NS-PILBD. In the authors' center, the association of certain metabolic diseases with NS-PILBD carries a grave prognosis.

Nonsyndromic Paucity of Interlobular Bile Ducts: Report of 10 Patients

ABSTRACTObjectivesOnly a few reports of nonsyndromic paucity of interlobular bile ducts (NS‐PILBD) have been published. The authors' aim was to outline the clinical and laboratory profile of patients with NS‐PILBD diagnosed at a tertiary referral center.MethodsThe authors reviewed all the reports of pediatric liver biopsies performed between 1991 and 2000 at their institution. Upon diagnosis of NS‐PILBD, patients' records were examined for clinical, laboratory, and histologic data, and liver biopsy specimens were re‐evaluated.ResultsThree hundred biopsies were performed in children during the study period, of which 64 were in infants younger than 1 year. NS‐PILBD was diagnosed in 10 of 64 (16%) biopsy specimens. Mean age at presentation was 10 days (range, 1 day–6 weeks), and mean follow‐up was 4.5 years (range, 1–9 years). An underlying condition was identified in 70% of children with NS‐PILBD: namely congenital cytomegalovirus (n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), mitochondrial DNA depletion (n = 1), Niemann‐Pick type C (n = 1), and arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC syndrome; n = 1). All children presented with jaundice. Four children had initially acholic stools. At their last follow‐up visit, failure to thrive was present in five children, and cholestasis in six children. Mortality was noted only in children with metabolic diseases (n = 2).ConclusionsIn the study, NS‐PILBD was common in young children undergoing liver biopsy. Although NS‐PILBD is nonspecific, a wide survey for inborn errors of metabolism should be included in the diagnostic work‐up of NS‐PILBD. In the authors' center, the association of certain metabolic diseases with NS‐PILBD carries a grave prognosis.

Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: Additional findings or a new syndrome (ARCC‐NDI)?

Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: Additional findings or a new syndrome (ARCC‐NDI)?

Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: Additional findings or a new syndrome (ARCC-NDI)?

We report on 4 children from 2 unrelated families who appear to have the lethal ARC syndrome (arthrogryposis, renal tubular dysfunction, and cholestasis) together with the additional findings of nephrogenic diabetes insipidus and cerebral anomalies, including deafness. With increased survival time in our patients, paucity of the intrahepatic bile ductules and cholestasis progressed to cirrhosis, growth was severely impaired, and severe mental retardation became apparent. No evidence was found for peroxisomal, chromosomal, or mitochondrial disorders. We propose to amend the ARC mnemonic to ARCC-NDI (A-Arthrogryposis, R-renal Fanconi, C-cerebral, C-cholestasis, NDI-nephrogenic diabetes insipidus) to name the major manifestations of this syndrome, several of which have not been appreciated.

Tuberculose pulmonaire et séropositivité HIV à l'hôpital principal de Dakar (Sénégal)

In a prospective survey conducted in 1990 in the Principal Hospital of Dakar, pulmonary tuberculosis was 2.3 times more frequent in HIV seropositive patients (12.5%) than in HIV seronegative patients. We studied 22 cases of pulmonary tuberculosis in HIV+ patients and compared them with a control group of HIV- patients admitted for pulmonary tuberculosis. Tuberculosis occurred in 6 out of 22 asymptomatic HIV+ patients, in 15 out of 22 patients with clinical AIDS and in 1 patient with ARC syndrome. Clinical signs were the same as in controls, except for patients with advanced AIDS who developed cardinal signs. TB intra-dermal reactions were more often negative in HIV+ patients, notably those with HDV1, expressing immunodepression. Radiological images were typical in 81% of patients and in 86% of controls. However, concomitant infections were common in both groups, with atypical radiology and hyperleukocytosis. At light microscopy, there was no difference in the frequency of acid and alcohol fast bacilli between the two groups. The mortality rate was increased in HIV+ patients, but this was not due to tuberculosis. Relapses were frequent in both groups, due to poor compliance with treatment.

The role of the coracoacromial ligament in the impingement syndrome. A clinical, radiological and histological study.

Seventeen patients with a painful arc syndrome and tenderness over the coracoacromial ligament were selected to demonstrate the changes in the coracoacromial ligament in the impingement syndrome. Plain X-ray examination was normal and a preoperative subacromial bursogram demonstrated impingement in only three out of 17 patients. However, at operation the subacromial space under the coracoacromial ligament, which normally admits the tip of the little finger, appeared unusually tight and barely accessible in 15 out of 17 patients. Histological examination of the biopsied ligament showed degenerative changes but no increase in fibrous tissue. We conclude that in the absence of bony overgrowth the initial change is an increased volume of the soft tissues in the subacromial space. Consequently, the space is compromised by the swelling of its contents, which exert abnormal pressure on the overlying coracoacromial ligament and cause degenerative changes in the ligament. The symptoms of impingement appear because of the unyielding nature of the coracoacromial ligament. Subacromial bursography may not be a reliable test when the coracoacromial ligament is the site of impingement.

Surgical Treatment for the Painful Arc Syndrome

Surgical Treatment for the Painful Arc Syndrome

Coracoacromial ligament division.

The object of this paper is to report on the findings of a retrospective study of 40 patients with 41 shoulders with persistent painful arc syndrome secondary to a chronic coracoacromial ligament inflammation who underwent simple coracoacromial ligament division at the Toronto East General and Orthopaedic Hospital between January 1973 and June 1979. Initial therapy was always nonoperative. Surgical intervention was reserved for patients who did not respond to conservative management and who had a painful arc with tenderness of the coracoacromial ligament. The aim of the coracoacromial ligament division was to relieve impingement by releasing the coracoacromial arch. Patients were carefully examined to rule out associated neck pathology, rotator cuff problems, and lesions of the acromioclavicular joint. Any patients with significantly large osteophytes under the anterior acromion were excluded. Forty patients (41 shoulders) were questioned and examined in followup. There were 29 males and 11 females. The ages ranged from 21 to 72 years (average 43.5 years). In 21 shoulders (51%), there was a history of trauma as the initiating factor. The follow-up ranged from 8 to 76 months (average 36.3 months). According to a described rating system, the results were satisfactory to excellent in 39 of 41 shoulders (95%) and unsatisfactory in two of 41 shoulders (5%). The back to work time ranged from 1 to 16 weeks (average 5.7 weeks).(ABSTRACT TRUNCATED AT 250 WORDS)

The Four-in-One Arthroplasty for the Painful Arc Syndrome

The painful arc syndrome of the shoulder is a manifestation of rotator cuff tendinitis associated with tenosynovitis of the long head of the biceps under and just distal to the transverse humeral ligament. Eighty-nine patients with clinical signs of the painful arc syndrome were proven to have an associated biceps tenosynovitis by arthrography and at surgical treatment. The four-in-one arthroplasty consists of: (1) excision of the coracoacromial ligament; (2) acromioclavicular arthroplasty; (3) excision of the anterior inferior area of the acromion process; and (4) transfer and tenodesis of the long head of the biceps. The operation decompresses the acromial arch and also eliminates the biceps tenosynovitis by tenodesis. Almost invariably, there was relief of pain within four to five months of postoperative rehabilitation, and at an average follow-up of two to eight years.

Shoulder impingement syndromes in athletes and their surgical management.

The painful arc syndrome may be produced by impingement of the supraspinatus tendon, the biceps tendon, or the greater tuberosity of the humerus against the coracoacromial arch. Where conservative measures have failed, surgical intervention may provide considerable symptomatic relief by decompressing the coracoacromial arch. In 20 cases surgically treated for biceps or supraspinatus impingements, 17 patients have returned to sporting activities without symptoms. The painful arc syndrome persists in three patients but they are symptomatically improved. Six patients with complete rotator cuff tears and subsequent impingement of the greater tuberosity of the humerus against the coracoacromial arch underwent widespread decompression. Five of the patients have returned to sporting activities much improved. Failure to recognize the associated acromioclavicular joint pathology is a frequent cause of failure of surgical treatment.

Acromioplasty of the Post-traumatic Painful arc Syndrome

Acromioplasty of the Post-traumatic Painful arc Syndrome