[Fragile X syndrome: new therapeutic strategies]. / Fragiele-X-syndroom: nieuwe therapeutische strategieën.

BACKGROUND: Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disability and autism spectrum disorders. Targeted treatment is currently lacking. In the past decades an enormous amount of knowledge has been obtained concerning the involved molecular pathways, introducing potential targets for disease modifying therapy.
AIM: To present an overview of the development of targeted treatment for fxs.
METHOD: Several important publications were collected and indexed.
RESULTS: While preclinical animal model studies with targeted interventions are promising, the translation to the clinic has been disappointing.
CONCLUSION: Targeted treatment for fxs is necessary and could be applied in other causes of autism spectrum disorders and intellectual disability. Factors relating to translation, study design and outcome measures are possibly contributing to the disappointing results. The clustering of patient care in a center of expertise is required to clinically implement future therapeutic strategies and to facilitate research. In addition, this improves patient care, one example being the recent medical guideline for children with fxs.

Aceruloplasminemia presents as Type 1 diabetes in non-obese adults: a detailed case series.

AIM: To detect features that might lead to the early diagnosis and treatment of aceruloplasminemia, as initiation of treatment before the onset of neurological symptoms is likely to prevent neurological deterioration. METHODS: The PubMed and OMIM databases were searched for published cases of aceruloplasminemia. Diagnostic criteria for aceruloplasminemia were undetectable or very low serum ceruloplasmin, hyperferritinemia and low transferrin saturation. Clinical, biochemical and radiological data on the presentation and follow-up of the cases were extracted and completed through e-mail contact with all authors. RESULTS: We present an overview of 55 aceruloplasminemia cases, including three previously unreported cases. Diabetes mellitus was the first symptom related to aceruloplasminemia in 68.5% of the patients, manifesting at a median age of 38.5 years, and often accompanied by microcytic or normocytic anaemia. The combination preceded neurological symptoms in almost 90% of the neurologically symptomatic patients and was found 12.5 years before the onset of neurological symptoms. CONCLUSIONS: There is a diagnostic window during which diabetes and anaemia are present although there is an absence of neurological symptoms. Screening for aceruloplasminemia in adult non-obese individuals presenting with antibody-negative, insulin-dependent diabetes mellitus and unexplained anaemia is recommended. The combination of ferritin and transferrin saturation provides a sensitive initial measure for aceruloplasminemia.

Prenatal testing for Huntington's disease in the Netherlands from 1998 to 2008.

This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Yeast artificial chromosome cloning of the Xq13.3-q21.31 region and fine mapping of a deletion associated with choroideremia and nonspecific mental retardation.

Microscopically detectable deletions and X;autosome translocations have previously facilitated the construction of a high-resolution interval map of the Xq21 region. Here, we have generated three yeast artificial chromosome contigs spanning approximately 7 megabases of the Xq13.3-q21.31 region. In addition, a novel deletion associated with choroideremia and mental retardation was identified and mapped in detail. The proximal deletion endpoint was positioned between the loci DXS995 and DXS232, which enabled us to confirm the critical region for a locus involved in mental retardation. The distal deletion endpoint is situated in the Xq21.33 band, which allowed us to refine the order of several markers in this region.

Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis.

BACKGROUND: International prevalence estimates of autosomal dominant cerebellar ataxias (ADCA) vary from 0.3 to 2.0 per 100,000. The prevalence of ADCA in the Netherlands is unknown. Fifteen genetic loci have been identified (SCA-1-8, SCA-10-14, SCA-16, and SCA-17) and nine of the corresponding genes have been cloned. In SCA-1, SCA2, SCA3, SCA6, SCA7, SCA-12 and SCA-17 the mutation has been shown to be an expanded CAG repeat. Previously, the length of the CAG repeat was found to account for 50 to 80% of variance in age at onset. Because of heterogeneity in encoded proteins, different pathophysiologic mechanisms leading to neurodegeneration could be involved. The relationship between CAG repeat length and age at onset would then differ accordingly. METHOD: Based on the results of SCA mutation analysis in the three DNA diagnostic laboratories that serve the entire Dutch population, the authors surveyed the number of families and affected individuals per SCA gene, as well as individual repeat length and age at onset. Regression analysis was applied to study the relationship between CAG repeat length and age at onset per SCA gene. The slopes of the different regression curves were compared. RESULTS: On November 1, 2000, mutations were found in 145 ADCA families and 391 affected individuals were identified. The authors extrapolated a minimal prevalence of 3.0 per 100,000 (range 2.8 to 3.8/100,000). SCA3 was the most frequent mutation. CAG repeat length contributed to 52 to 76% of age at onset variance. Regression curve slopes for SCA-1, SCA2, SCA3, and SCA7 did not differ significantly. CONCLUSIONS: The estimated minimal prevalence of ADCA in the Netherlands is 3.0 per 100,000 inhabitants. Except for SCA6, the relationship between age at onset and CAG repeat expansion does not differ significantly between SCA-1, SCA2, SCA3, and SCA7 patient groups in our population, indicating that these SCA subtypes share similar mechanisms of polyglutamine-induced neurotoxicity, despite heterogeneity in gene products.

Total situs inversus associated with the oculo-auriculo-vertebral spectrum.

A patient is reported with the association of the oculo-auriculo-vertebral spectrum and situs inversus. Conditions with overlapping features and previously reported conditions associated with the oculo-auriculo-vertebral spectrum are reviewed. These conditions, as well as the reported association of the oculo-auriculo-vertebral spectrum and situs inversus can probably be seen as a part of the mesodermal malformation spectrum, due to an early abnormality in the development of the primitive streak or embryonic mesoderm.

A case with blepharophimosis resembling Ohdo syndrome.

Another possible sporadic case of the Ohdo blepharophimosis syndrome is described and compared with the seven patients previously reported. It can be considered a distinctive syndrome showing blepharophimosis, ptosis, dental hypoplasia, mental retardation and deafness. This case helps to define the spectrum of the phenotypic anomalies.

[From gene to disease; HD gene and Huntington disease]. / Van gen naar ziekte; het HD-gen en de ziekte van Huntington.

Huntington's disease (HD) is a late onset, incurable, autosomal dominantly-inherited, progressive neuropsychiatric disease, characterised by chorea, changes in personality, mood and behaviour, and dementia. Huntington's disease is a clinical diagnosis. The advent of DNA diagnosis has made predictive, prenatal and preimplantation testing possible for at-risk persons or asymptomatic carriers. The prevalence is estimated to be 3-10/100,000 among individuals of European descent; HD is less common in other ethnic groups. Huntington's disease is caused by an expanded trinucleotide CAG repeat in the HD gene on chromosome 4. The gene encodes for the protein huntingtin, with an as yet unknown function. The mutated huntingtin has an elongated stretch of glutamines which leads to a gain of function such as overactivity, excitotoxicity, or to interactions with other proteins.

[Phenylketonuria in spite of screening]. / Fenylketonurie ondanks screening.

A girl with psychomotor retardation is described in whom the diagnosis phenylketonuria (PKU) was made at the age of 6.5 years. Previous investigations were not carried out as she was screened for PKU when she was a baby. Since the nationwide neonatal screening for PKU was started in 1974, 4 children have been detected with a false negative test result.

[The significance of an elevated cobalamin concentration in the blood]. / De betekenis van een te hoge cobalamineconcentratie in het bloed.

Elevated levels of serum cobalamin may be a sign of a serious, even life-threatening, disease. Diseases such as chronic myeloid leukaemia, promyelocytic leukaemia, polycythaemia vera and hypereosinophilic syndrome are often accompanied by markedly elevated levels of cobalamin in the blood. A rise in the serum cobalamin concentration is one of the diagnostic criteria for polycythaemia vera and hypereosinophilic syndrome. In haematological disorders, the increase in circulating cobalamin levels is predominantly caused by enhanced production of haptocorrin. Several liver diseases such as acute hepatitis, cirrhosis of the liver, hepatocellular carcinoma and metastatic liver disease can also be accompanied by an increase in circulating cobalamin. In liver diseases, the increase in cobalamin is predominantly caused by cobalamin release during hepatic cytolysis and/or through decreased clearance of circulating cobalamin by the affected liver. Liver disorders are not an indication for determining the serum cobalamin concentration. However, a coincidentally observed elevated serum cobalamin concentration is reason for further investigation.

[Dysmaturity as symptom of the ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome]. / Dysmaturitas als symptoom van het ectrodactylie-ectodermale dysplasie-clefting (EEC) syndroom.

Low birthweight as a symptom of the ectrodactyly ectodermal dysplasia clefting (EEC) syndrome is described before by Annerén. By presenting two patients (father and son) we give a brief review of the major and minor symptoms. We would like to add low birthweight as a minor symptom.

Distinct genetic forms of frontotemporal dementia.

BACKGROUND: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. METHODS: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. RESULTS: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 +/- 9.9 years) was higher than MAPT patients (52.4 +/- 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. CONCLUSION: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease.

Diagnosis and management of early- and late-onset cerebellar ataxia.

Cerebellar ataxias represent a heterogeneous group of neurodegenerative disorders. Two main categories are distinguished: hereditary and sporadic ataxias. Sporadic ataxias may be symptomatic or idiopathic. The clinical classification of hereditary ataxias is nowadays being replaced by an expanding genotype-based classification. A large spectrum of degenerative and metabolic disorders may also present with ataxia early or late in the course of disease. We present a diagnostic algorithm for the adult patient presenting with subacute cerebellar ataxia, based on family history and straightforward clinical characteristics of the patient. Along with the algorithm, an overview of the autosomal dominant, autosomal recessive, X-linked, mitochondrial, symptomatic and idiopathic subtypes of cerebellar ataxia is presented. An appropriate diagnosis is of utmost importance to such considerations as prognosis, genetic counselling and possible therapeutic implications.

Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism. METHODS: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases. RESULTS: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later. CONCLUSIONS: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.

Concurrent Whipple's disease and Giardia lamblia infection in a patient presenting with weight loss.

Whipple's disease is an uncommon systemic disease caused by the recently cultured Tropheryma whippelii, classically presenting with gastrointestinal symptoms. We report a patient with weight loss and malabsorption in which Whipple's disease and concurrent Giardia lamblia infection were diagnosed. Moreover, multiple small bowel polyps were present. The relationship between concurrent Whipple's disease and Giardia lamblia infection is discussed.

A large retinoblastoma detected in a fetus at 21 weeks of gestation.

The facial tumour described here is the first reported case of a large retinoblastoma detected early in pregnancy and adds another item to the differential diagnosis of facial tumours visualized by prenatal ultrasound examination. Ultrasound examination of the fetal eyes can be offered in cases of retinoblastomas where prenatal DNA diagnosis is otherwise impossible.

G-CSF-induced decrease of the anti-granulocyte autoantibody levels in a patient with autoimmune granulocytopenia.

We present a case of an 81-year-old man with secondary autoimmune granulocytopenia in association with autoimmune thrombocytopenia. Treatment with granulocyte colony-stimulating factor (G-CSF) (5 micrograms/ kg/day s.c.) resulted in a rapid increase in the number of circulating granulocytes with a pronounced left shift. These changes were accompanied by up-regulation of the surface expression of Fc gamma RI (CD64) and Fc gamma RII (CD32) on the granulocytes. In addition, we noted a strong up-regulation of the Fc gamma RIII (CD16) and the activation markers CD11b and CD66b on the granulocytes. The increase in the number of circulating granulocytes was followed by a dramatic decrease in the level of cell-bound as well as circulating anti-granulocyte antibodies. It is hypothezised that the decrease in the level of cell-bound as well as circulating anti-granulocyte antibodies may be the result of an increased adsorption of the antibodies by the granulocytes.

Family history and DNA analysis in patients with suspected Huntington's disease.

OBJECTIVES: Until recently a definite diagnosis of Huntington's disease could be made by a combination of clinical findings, a positive family history, and pathological confirmation. Prevalence data are based on these criteria. After finding the gene and its pathogenic mutation direct diagnostic confirmation became available. The aim of this study was to determine to what extent the direct assessment of CAG repeat length has allowed the diagnoses of additional patients, with atypical psychiatric or neurological disease, or those without a family history, that could otherwise not be diagnosed using traditional criteria. PATIENTS AND METHODS: From all 191 referred patients suspected of having Huntington's disease between July 1993 and January 1996 CAG repeat length was determined and the family history was reviewed in the Leiden roster. After a retrospective search the patients were subdivided in positive, negative, suspect, and unknown family histories. Patients with an expanded repeat (>35) were finally diagnosed as having Huntington's disease. The family history was compared with the repeat length and the clinical features. RESULTS: Clinical information was obtained for 172 patients. Of these, 126 patients had an expanded repeat, 77 had a positive, eight a negative, 40 a suspect, and one an unknown family history. Of the 44 patients with a normal repeat length four had a positive family history. Of the two patients with an intermediate repeat (between 30-36 repeats), one with a negative family history received a clinical diagnosis of Gilles de la Tourette's syndrome. The other had an unknown family history. CONCLUSION: Despite verification of the family history through the Leiden roster, many more patients and families could be diagnosed with the new approach than would have been possible with the traditional criteria. Because prevalence studies have been based on this type of information, the data suggest an underestimation of the prevalence of Huntington's disease in the community of 14%.