Abstract Objective To evaluate the efficacy of colchicine in reducing the frequency of attacks in patients with PFAPA. Study design We conducted a 6-month open label, randomized, controlled study ...among patients with PFAPA who attend the Pediatric Rheumatology Clinic at the Rambam Medical Center in Israel. A total of 18 patients aged4 –11 years (males:females ratio = 11:7) were randomized into a control group (I, 10 children) and a study group (II, 8 children). Group I was followed for 6 months without any intervention, and group II was initially followed for 3 months and was thereafter treated with colchicine for 3 additional months, according to standard regimen. During the 6-month period of the study the patients and their physician recorded all the episodes of PFAPA in a constructed log. DNA analyses for the 5 common FMF mutations in Israel were performed in 17 out of the 18 patients. Results The number of episodes during the first 3 months was similar in both groups (group I 3.2 ± 1.5, group II 4.9 ± 2.3; p ≤ 0.12). Group II had significantly less PFAPA attacks in the second period while on colchicine therapy (4.9 ± 2.3 vs. 1.6 ± 1.2; p ≤ 0.01), in opposition to group I, where no difference in the number of attacks was noted between the first and second period of follow-up (3.2 ± 1.5 vs. 2.7 ± 1.5; p = 0.33). Of the 17 patients tested, 8 were carriers for FMF mutations (2 in group I and 6 in group II). Conclusion Colchicine prophylaxis seems to be effective in reducing the number of attacks in PFAPA.
Abstract Aim Familial Mediterranean Fever (FMF) is the most common recurrent autoinflammatory fever syndrome. Still, many issues—e.g.: colchicine dosage adjustment, maximum dosage of colchicine in ...children and adults, definition of colchicine resistance, alternative treatment solutions in colchicine-resistant patients, and genetic screening for asymptomatic siblings—have not yet been standardized. The current paper aims at summarizing consensus recommendations to approach these issues. Methods A literature review concerning these practical management questions was performed through PubMed. On the basis of this analysis, expert recommendations were developed during a consensus meeting of caregivers from France and Israel. Results A patient experiencing more than four FMF attacks a year needs colchicine dose adjustment. In case of persistent attacks (≥6 per year) in patients with maximum doses of colchicine (2 mg in children; 3 mg in adults), alternative treatment to colchicine with IL1 inhibitors should be considered. Routine genetic testing for MEFV mutations in asymptomatic siblings of an index case is not recommended. Conclusion This is a first attempt to resolve practical questions in the daily management of FMF patients.
Ververi‐Brady syndrome (VBS), first reported in 2018, is characterized by intellectual disability, speech delay, and mild dysmorphic facial features. VBS has been linked to de novo loss‐of‐function ...variants in the glutamine‐rich protein 1 (QRICH1) on chromosome 3p21 and was reported until lately in only five individuals. Four additional cases have just been described substantiating the notion that children with VBS are mildly dysmorphic, mildly to moderately intellectually disabled, have linear growth shortage, are picky eaters, and have notable attention and social behavioral deficits. We describe a new patient and review the clinical and genetic information, on all previously reported VBS cases. The child here reported is noted for maladaptive behavior, sensory hypersensitivity, and slow linear growth. He is mainly hyperactive, distractible, impulsive, and inattentive. His speech, initially delayed, is fair and his verbal comprehension age adequate.
A clinical association has been reported between type 1 Gaucher's disease, which is caused by a glucocerebrosidase deficiency owing to mutations in the glucocerebrosidase gene (GBA), and ...parkinsonism. We examined whether mutations in the GBA gene are relevant to idiopathic Parkinson's disease.
A clinic-based case series of 99 Ashkenazi patients with idiopathic Parkinson's disease, 74 Ashkenazi patients with Alzheimer's disease, and 1543 healthy Ashkenazi Jews who underwent testing to identify heterozygosity for certain recessive diseases were screened for the six GBA mutations (N370S, L444P, 84GG, IVS+1, V394L, and R496H) that are most common among Ashkenazi Jews.
Thirty-one patients with Parkinson's disease (31.3 percent; 95 percent confidence interval, 22.2 to 40.4 percent) had one or two mutant GBA alleles: 23 were heterozygous for N370S, 4 were heterozygous for 84GG, 3 were homozygous for N370S, and 1 was heterozygous for R496H. Among the 74 patients with Alzheimer's disease, 3 were identified as carriers of Gaucher's disease (4.1 percent; 95 percent confidence interval, 0.0 to 8.5 percent): 2 were heterozygous for N370S, and 1 was heterozygous for 84GG. Ninety-five carriers of Gaucher's disease were identified among the 1543 control subjects (6.2 percent; 95 percent confidence interval, 5.0 to 7.4 percent): 92 were heterozygous for N370S, and 3 were heterozygous for 84GG. Patients with Parkinson's disease had significantly greater odds of being carriers of Gaucher's disease than did patients with Alzheimer's disease (odds ratio, 10.8; 95 percent confidence interval, 3.0 to 46.6; P<0.001) or control subjects (odds ratio, 7.0; 95 percent confidence interval, 4.2 to 11.4; P<0.001). Among the patients with Parkinson's disease, patients who were carriers of Gaucher's disease were younger than those who were not carriers (mean +/-SD age at onset, 60.0+/-14.2 years vs. 64.2+/-11.7 years; P=0.04).
Our results suggest that heterozygosity for a GBA mutation may predispose Ashkenazi Jews to Parkinson's disease.
Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in
...PLP1. Recently, homozygous mutations in
GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither
PLP1 nor
GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to
PLP1 and
GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in
HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo
E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support
E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.
The purpose of this study was to estimate the extent of protection offered against breast cancer by prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations and to determine to what extent ...risk reduction varies with age at oophorectomy, age at diagnosis, and time elapsed since surgery.
We analyzed 1,439 patients with breast cancer and 1,866 matched controls derived from a registry of BRCA1 and BRCA2 carriers. We estimated odds ratios (ORs) of breast cancer for having had a bilateral oophorectomy, using conditional logistic regression, matched for parity and for oral contraceptive use.
A previous history of oophorectomy was associated with a significant reduction in breast cancer risk of 56% for BRCA1 carriers (OR = 0.44; 95% CI, 0.29 to 0.66) and of 46% for BRCA2 carriers (OR = 0.57; 95% CI, 0.28 to 1.15). The risk reduction was greater if the oophorectomy was performed before age 40 (OR = 0.36; 95% CI, 0.20 to 0.64 for BRCA1 carriers) than after age 40 (OR = 0.53; 95% CI, 0.30 to 0.91). The protective effect was evident for 15 years post-oophorectomy (OR = 0.39; 95% CI, 0.26 to 0.57).
Oophorectomy is an effective means of reducing the risk of breast cancer in carriers of BRCA1 mutations. The data suggest oophorectomy is protective in BRCA2 carriers as well, but needs to be confirmed in other studies.
Based on the fact that Henoch-Schönlein purpura (HSP) occurs in approximately 5% of persons with familial Mediterranean fever (FMF), we assessed the prevalence and significance of FMF gene mutations ...in children with one or more episodes of HSP.
Thirty-four boys and 18 girls treated for HSP at Rambam Medical Center were interviewed and asked to donate blood. Mean age at disease onset was 6.7±2. 4 years, and mean follow-up was 3.8±1.3 years. Six predominant mutations (M694V, M680I, M694I, V726A, K695R, E148Q) in the MEFV gene were studied.
Nine heterozygotes, three homozygotes and two compound heterozygotes, were identified. Altogether, five persons (10%) carried two mutated MEFV alleles, a number significantly exceeding that determined for the general Israeli population (1%–2%). Of these, three displayed genotypes associated with a mild form of disease (M694V/E148Q and V726A/V726A), and two had genotypes normally observed in disease-free persons (E148Q/K695R and E148Q/ E148Q).
Occult FMF cases much more numerous than expected were identified among children presenting with HSP. Such children should be closely monitored for renal complications, and treatment with colchicine should be considered.
PFAPA is a periodic fever disease, of unknown etiology, characterized by aphthous stomatitis, pharyngitis and cervical adenitis. To inquire whether genes implicated in other auto-inflammatory ...diseases might be involved in its pathogenesis, predominant mutations in the genes causing familial Mediterranean fever, TNF receptor-associated periodic fever syndrome, Crohn’s disease and Muckel–Wells syndrome were analyzed in PFAPA patients. Patients (
n
= 57) with PFAPA, according to previously published criteria were recruited, at the Meyer Children Hospital during 2006–2007. Clinical information was complemented during physicians–parents encounter. Predominant mutations in MEFV, TNF1rA, CARD15/NOD2 and NLRP3 genes were tested. Mean age at diagnosis was 30.64 ± 16.4 months. Boys (
n
= 33; 58%) were diagnosed earlier than girls (
n
= 21; 42%) at 26.18 ± 13.83 and 36.41 ± 18.32 months, respectively (
P
= 0.05). Fifteen patients (27%) carried an MEFV mutation; two patients (3.6%) a CARD15 mutation, one patient (1.8%) a variance in TNF1rA and another had both an MEFV and a CARD15 mutation. Clinical symptoms were equally manifested in carriers and non-carriers. The high carrier rate of MEFV mutations in our PFAPA cases compares well with that of the general population in Israel. It is debated whether MEFV mutations, when mediated by the presence of additional modifiers, may expose a transient fever condition, namely PFAPA.
PDF
