Judit Kárteszi

Congenital disorder of glycosylation type Ix: review of clinical spectrum and diagnostic steps.

SummaryCongenital disorder of glycosylation type I (CDG I) represent a rapidly growing group of inherited multisystem disorders with 13 genetically established subtypes (CDG Ia to CDG Im), and a high number of biochemically unresolved cases (CDG Ix). Further diagnostic effort and prognosis counselling are very challenging in these children. In the current study, we reviewed the clinical records of 10 CDG Ix patients and compared the data with 13 CDG Ix patients published in the literature in search for specific symptoms to create clinical subgroups. The most frequent findings were rather nonspecific, including developmental delay and axial hypotonia. Several features were found that are uncommon in CDG syndrome, such as elevated creatine kinase or arthrogryposis. Distinct ophthalmological abnormalities were observed including optic nerve atrophy, cataract and glaucoma. Two subgroups could be established: one with a pure neurological presentation and the other with a neurological-multivisceral form. The first group had a significantly better prognosis. The unique presentation of microcephaly, seizures, ascites, hepatomegaly, nephrotic syndrome and severe developmental delay was observed in one child diagnosed with CDG Ik. Establishing clinical subgroups and increasing the number of patients within the subgroups may lead the way towards the genetic defect in children with a so far unsolved type of the congenital disorders of glycosylation. Raising awareness for less common, non-CDG specific clinical features such as congenital joint contractures, movement disorders or ophthalmological anomalies will encourage clinicians to think of CDG in its more unusual presentation. Clinical grouping also helps to determine the prognosis and provide better counselling for the families.

Small inherited terminal duplication of 7q with hydrocephalus, cleft palate, joint contractures, and severe hypotonia.

We report a 14-month-old girl with submucous cleft palate, resolving mild hydrocephalus, severe hypotonia and joint contractures. The finding of extreme hydrocephalus, cleft palate and club feet in a fetus of the mothers previous pregnancy suggested an inherited defect. Chromosome analysis and FISH studies in the proband revealed an abnormal homolog 13 resulting in a duplication of distal chromosome 7q, 7q35-qter, and a very small associated deletion of distal chromosome 13q, 13q34-qter. The mother showed the balanced translocation. Similar clinical signs have been described with larger distal 7q duplications. Our findings suggest that 7q35-qter, and possibly the gene for sonic hedgehog (SHH) on 7q36, is the critical region for the typical facial features and the profound hypotonia observed in the ‘trisomy of distal 7q’ syndrome.

Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia

Abstract. Cleidocranial dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal dysplasia characterised by hypoplastic clavicles, patent fontanelles, short stature, tooth anomalies and other variable skeletal changes. Different mutations of the RUNX2/CBFA1 gene (MIM 600211) have been detected in patients with CCD. We investigated a mother and daughter with features of CCD presenting with reduced plasma alkaline phosphatase activity, increased urinary phosphoethanolamine excretion and decreased bone density. The latter findings were suggestive of hypophophatasia but mutation analysis showed no mutation in the tissue-nonspecific alkaline phosphatase gene (TNSALP; MIM 171760). However, a heterozygous mutation (Arg169Pro caused by nucleotide change 506G>C) was detected in the RUNX2 gene. Metabolic alterations gradually improved in both mother and daughter but bone-specific alkaline phosphatase remained low (less than 30% of normal) and mild phosphoethanolaminuria persisted. Recent studies in the Cbfa1 knock-out mouse showed decreased expression of alkaline phosphatase in differentiating bone. Conclusion: we suggest that the observed metabolic alterations are secondary to the RUNX2 gene mutation affecting early bone maturation and turnover. This is the first description of biochemical findings of hypophosphatasia in patients with cleidocranial dysplasia.

Clinical and genetic heterogeneity in frontometaphyseal dysplasia: severe progressive scoliosis in two families.

Frontometaphyseal dysplasia is a rare genetic syndrome affecting the skeletal system and connective tissue. It is believed to be inherited as an X‐linked trait. Features of frontometaphyseal dysplasia overlap with other skeletal dysplasias. Prominent supraorbital ridges, radiologic evidence of cranial hyperostosis, and flared metaphyses are characteristic. Scoliosis, a rare associated finding, is usually mild, and familial progressive scoliosis has not been reported so far. The skeletal dysplasia and the associated clinical findings show significant intra‐ and interfamilial variability. The syndrome has been suggested to be an allelic variant of the Melnick‐Needles osteodysplasty, an X‐linked (dominant) entity. We present two families with frontometaphyseal dysplasia, in which both males and females showed the facial and skeletal features of the syndrome in association with progressive scoliosis. Some of the affected members also had hearing loss and urogenital anomalies, supporting the existence of the recently suggested entity “fronto‐otopalatodigital‐osteodysplasty syndome”.

Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations.

Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C>T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G>T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G>T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.

Cardiac Arrest in Kearns–Sayre Syndrome

The prognosis of progressive ophthalmoplegia in patients with large-scale mitochondrial DNA deletions is highly variable and almost unpredictable. The risk to develop cardiac involvement and sudden cardiac death is strikingly high, especially in patients with Kearns-Sayre syndrome (KSS). The most typical cardiac complications of the disease are conduction defects, which usually begin with left anterior fascicular block with or without right bundle branch block (RBBB), progressing sometimes rapidly to complete atrioventricular block. Other cardiac manifestations reported are first or second degree of AV block, QT prolongation, torsades de pointes ventricular tachycardia, and rarely dilated cardiomyopathy. Most frequently syncope, sometimes even sudden cardiac death, is the first clinical sign of the cardiac disease in KSS. Due to these life-threatening cardiac conditions, patients should be carefully monitored for cardiac signs and symptoms and pacemaker implantation should be suggested early to avoid sudden cardiac arrest in KSS.Here, we present two cases of KSS with life-threatening syncope due to complete atrioventricular block. To emphasize the importance of an early pacemaker implantation, we review the literature on cardiac complications in KSS in the last 20 years. In almost all of the reviewed cases, ophthalmoplegia or ptosis was present before the cardiac manifestations. In most of the cases, syncope was the first symptom of the cardiac involvement. There was no correlation between the age of the onset of the disease and the onset of cardiac manifestations.With our current report, we increase awareness for life-threatening cardiac complications in patients with KSS.

Mutation analysis of MECP2 and determination of the X-inactivation pattern in Hungarian Rett syndrome patients

Mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) have been associated with the causation of Rett syndrome [Buyse et al., 2000], an X-linked dominant neurodevelopmental disorder with characteristic, although variable phenotype. Since no consistent correlation is known yet between the type of mutation and the clinical manifestation or outcome, other modulating effects have been investigated to understand genotype–phenotype correlation [Amir et al., 2000]. Recently, Weaving et al. [2003] reported in this Journal a higher rate of skewed X-inactivation than would be expected. They also suggested that the type or domain location of the mutation, and X-inactivation might influence the phenotype through complex interactions. This finding prompted us to report on our similar observation. We performed mutation analysis of MECP2 in 27 Hungarian Rett syndrome patients and found mutation in 19 cases (70%). This percentage is similar to that reported by other authors [Nielsen et al., 2001]. Nine previously described mutations were detected in 16 patients (R294X in three patients, R106W, R133C, R168X, T158M, and R270X in two patients each, P152R, R255X, and 1157del41 once each) and three novel mutations in three patients (276insG; 1160del7; 1121del191, 1332del9) (a detailed report is in preparation). Of the 19, 15 patients have the classical and four the atypical form of the disease. X-inactivation analysis was performed in 15 patients with mutation (in four cases, we could not obtain blood samples from both parents). In three patients X-inactivation pattern was not informative, in five patients random, and in seven patients non-random X-inactivation was found. The incidence of skewed X-inactivation (7/15) is similar to that in Weaving et al. [2003] study (43%). Although the number of patients in our study is much less than theirs, this result supports the suggestion of Weaving et al. that in Rett syndrome patients with confirmed mutation skewed X-inactivation is a significant modulating factor in about half of the cases.

Ulnar/fibular ray defect and brachydactyly in a family: A possible new autosomal dominant syndrome

&NA; The ulnar‐mammary syndrome (MIM 181450) includes postaxial ray defects, abnormalities of growth, delayed sexual development, and mammary and apocrine gland hypoplasia. Brachydactyly type E (MIM 113300) presents with shortening of the metacarpals and phalanges in the ulnar ray in association with moderately short stature. We describe a three‐generation family with variable expression of ulnar/fibular hypoplasia, brachydactyly, ulnar ray defects and short stature. The proband had ulnar hypoplasia with missing IV‐Vth fingers, fibular hypoplasia on the right, bilateral club feet, growth retardation, a hypoplastic midface, an ASD and hemangiomas. She had normal mammary tissue and normal sweating. The mother had short stature, midfacial hypoplasia, a hypoplastic ulna and hypoplasia of the IVth metacarpal (brachydactyly) on the right without other associated malformations. The maternal grandfather had mild bilateral fibular hypoplasia and midphalangeal brachydactyly of the IV‐Vth toes. His sister had mild short stature and shortening of the IVth metacarpal of the left hand. Two‐point linkage analysis with microsatellite markers spanning the Ulnar‐Mammary locus at 12q24.1 did not confirm linkage. The patients may have a previously undescribed syndrome. Clin Dysmorphol 12:161‐165

Psychological aspects of presymptomatic diagnosis in Huntington disease

INTRODUCTION Huntington disease is an autosomal dominant, progressive neurodegenerative disorder, starting in adulthood. International recommendations were created for presymptomatic testing (genetic test performed before symptoms appear). During the initial preparation for presymptomatic testing, a genetic counsellor, neurologist and psychologist attend. AIM The authors evaluated whether the international recommendations could be used in the 10 cases examined, and how much the process must be individualized. METHOD The authors stated a protocol based on the literature, and utilized it for the purpose of obtaining informed consent. Psychological preparation was an important part of this process. Ten cases are presented in whose families Huntington disease was determined, and therefore they asked for their own presymptomatic testing. RESULTS From the ten persons who asked for examination, four changed their minds during the psychological process; four were attended in the process, and two asked for the test without any psychological preparation. CONCLUSION Along with the following of the protocol steps individual factors need to be taken into account in order to ideally plan the preparation process of presymptomatic testing. Authors recommend keeping contact with the individuals after genetic testing.

A Huntington-betegség preszimptómás genetikai vizsgálatát kérők pszichológiai felkészítése@@@Psychological aspects of presymptomatic diagnosis in Huntington disease

INTRODUCTION Huntington disease is an autosomal dominant, progressive neurodegenerative disorder, starting in adulthood. International recommendations were created for presymptomatic testing (genetic test performed before symptoms appear). During the initial preparation for presymptomatic testing, a genetic counsellor, neurologist and psychologist attend. AIM The authors evaluated whether the international recommendations could be used in the 10 cases examined, and how much the process must be individualized. METHOD The authors stated a protocol based on the literature, and utilized it for the purpose of obtaining informed consent. Psychological preparation was an important part of this process. Ten cases are presented in whose families Huntington disease was determined, and therefore they asked for their own presymptomatic testing. RESULTS From the ten persons who asked for examination, four changed their minds during the psychological process; four were attended in the process, and two asked for the test without any psychological preparation. CONCLUSION Along with the following of the protocol steps individual factors need to be taken into account in order to ideally plan the preparation process of presymptomatic testing. Authors recommend keeping contact with the individuals after genetic testing.