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Objectives - To re-evaluate middle-aged Swedish patients diagnosed with dysequilibrium syndrome (DES) in childhood and to compare their clinical and neuroimaging features to DES with VLDLR gene mutations (DES-VLDR). Materials and methods - Six patients from five families underwent neurological examination and magnetic resonance imaging (MRI) of the brain. Blood samples from the patients were screened for serum carbohydrate-deficient transferrin (s-CDT; disialotransferrin). The very-low-density lipoprotein receptor (VLDLR) gene was sequenced. Results - Five patients had non-progressive cerebellar ataxia (NPCA), dysarthria and short stature. Mental retardation and strabismus, characteristic for DES-VLDLR, were inconsistent among our patients. None of our patients had VLDLR mutations or MRI findings characteristic of DES-VLDLR. MRI findings were variable from a normal cerebellum to marked cerebellar hypoplasia or atrophy and signal intensity changes. One patient was diagnosed with congenital disorder of glycosylation type 1a (CDG-1a). Conclusions - DES was originally coined on mainly clinical grounds before MRI and specific genetic tests were available, both of which should be used to arrive at an appropriate diagnosis.

BACKGROUND: Multiple epiphyseal dysplasia (MED) is a common genetically and clinically heterogeneous skeletal dysplasia characterized by early-onset osteoarthritis, mainly in the hip and knee, and mild-to-moderate short stature. Here we report on a 6-generation MED family with 17 affected members. METHOD: The clinical and radiographic data on the 12 affected members still living were scrutinized. A structured inquiry comprising state of health and MED-related symptoms since birth up to the present time and the osteoarthritis outcome (KOOS) questionnaire were sent to all living family members with MED. The 5 known gene loci for autosomal dominant MED were analyzed for linkage, using fluorescence-labeled microsatellite markers. Linkage was ascertained with markers close to the COL9A2 gene, which was analyzed for mutations by sequencing. RESULTS: We identified an exon 3 donor splice mutation in the COL9A2 gene in all affected family members. Clinical, radiographic, and questionnaire data from affected family members suggested that MED caused by COL9A2 mutations starts in early childhood with knee pain accompanied by delayed ossification of femoral epiphyses. The disease then either stabilizes during puberty or progresses with additional joints becoming affected; joint surgery might be necessary. The progression of the disease also affects muscles, with increasing atrophy, resulting in muscle fatigue and pain. Muscular atrophy has not been reported earlier in cases with COL9A2 mutations. INTERPRETATION: In a patient with clinically suspected or verified MED, it is important to perform DNA-based analysis to identify a possible disease-causing mutation. This information can be used to carry out genetic risk assessment of other family members and to achieve an early and correct diagnosis in the children.

To study the prevalence of beta-thalassaemia and sickle cell traits in the Al-Qassim region, Saudi Arabia. The Ministry of Health of Saudi Arabia launched a countrywide programme in February 2004 to allow all Saudis planning marriage to screen their carrier status for beta-thalassaemia and sickle cell traits. This population survey of mandatory premarital screening for beta-thalassaemia and sickle cell heterozygotes provided an opportunity to estimate the prevalence of these traits in the Al-Qassim region. From February 2004 to October 2006 all individuals attending for premarital screening in that region were screened. For each subject, venous blood was taken to determine complete blood count, red cell indices and hemoglobin electrophoresis. Subjects were considered to have beta-thalassaemia trait if mean corpuscular volume was <79 fl, mean corpuscular haemoglobin <27 pg and haemoglobin A2 level >3.5%; and sickle cell trait if sickle cell haemoglobin amounted to 35 to 45% and sickling test was positive. Totally 38,153 individuals were screened during the study period. The prevalence rates of beta-thalassaemia and sickle cell traits were 0.165% (63/38,153) and 0.252% (96/38,153) respectively. Compared with results of previous studies carried out in this region on the same issue, the prevalence of sickle cell heterozygotes seems to be the same but the frequency of beta-thalassaemia carriers is substantially higher. Screening for carriers both of beta-thalassaemia and sickle cell traits is important to prevent at risk marriages through genetic counseling.

BACKGROUND: Mental Retardation is a common heterogeneous neurodevelopment condition, which causes are still largely elusive. It has been suggested that half of the phenotypic variation of intelligence is explained by genetic variation. And genetic or inherited factors indeed account for most of the cases of mental retardation with an identifiable cause. However, only a few autosomal genes have been mapped and identified to date. In this report, the genetic causes for an apparently recessive form of mental retardation, in a large nordern swedish pedigree, are investigated. METHODS: After extensive evaluation of the patients, which ruled out recognizable patterns of malformation and excluded known causes of MR, a comprehensive genome-wide linkage analysis, with 500 microsatellite markers, was performed in 24 members of this family. Additionally, a genome-wide copy number analysis, using an affimetrix 250 K SNP chip, was performed in this pedigree. RESULTS: No significant LOD score was found with either parametric and non-parametric linkage analysis. The highest scores are located at chromosomes 13, 15 and 17. Genome-wide copy number analysis identified no clear cause for the disorder; but rather, several variants were present in the family members, irrespective of their affected status. CONCLUSION: These results suggest that mental retardation in this family, unlikely what was expected, has a heterogeneous aetiology; and that several lower effect genes variants might be involved. To demonstrate such effects, our family may be too small. This study also indicates that the ascertainment of the cause of MR may be challenging, and that a complex aetiology may be present even within a pedigree, constituting an additional obstacle for genetic counselling. Variants in genes involved in molecular mechanisms of cellular plasticity, in genes involved in the development of underlying neural architectures, and in genes involved in neurodevelopment and in the ongoing function of t

BACKGROUND: In the planning of services and health care for individuals with intellectual disability (ID), information is needed on the special requirements for habilitation and medical service and associated disabilities. MATERIAL AND METHODS: An unselected consecutive series of 82 adult persons with ID was studied. The medical examination consisted of the individual's health condition, associated impairments and disabilities. Medical and habilitation services and support were studied. RESULTS: The results indicated that 71% of the persons in the series had severe and 29% mild ID. Forty-seven per cent of the persons with severe ID and 35% of those with mild ID had one or more additional central nervous system (CNS) disabilities. Of the persons with ID, 99% had access to a family doctor and 84% attended regular health visits. Notably, half of persons were referred to a specialist examination as a consequence of their present medical examination. Half of the persons with mental health problems were previously undiagnosed and only a few of these had access to a psychiatrist. CONCLUSION: Our study clearly demonstrates the magnitude and importance of neurological and psychiatric impairments in ID. The findings suggest a strong need for multidisciplinary health service.

I en tvärvetenskaplig prospektiv undersökning har en30-årsuppföljning gjorts av de personer med svår utvecklingsstörningsom föddes i Uppsala län underperioden 1959–1970. Uppföljningen visar att 30 procentav dessa personer hade avlidit – det stora flertaletföre vuxen ålder.Samtliga av de nu levande svårt utvecklingsstördalevde fysiskt integrerade i samhället. De nyttjade denallmänna hälso- och sjukvårdens resurser, men hadeockså kontakt med professionella inom vuxenhabiliteringen.Undersökningen visar dock också att ökad observansoch insats vad gäller psykiska problem, rörelsehandikappoch synförmåga hos vuxna svårt utvecklingsstördaär angeläget.

X-linked mental retardation (XLMR) affects one in 600 males and is highly heterogeneous. We describe here a 29-year-old woman with severe nonsyndromic mental retardation and a balanced reciprocal translocation between chromosomes X and 15 [46,XX,t(X;15)(q13.3;cen)]. Methylation studies showed a 100% skewed X-inactivation in patient-derived lymphocytes indicating that the normal chromosome X is retained inactive. Physical mapping of the breakpoints localised the Xq13.3 breakpoint to within 3.9 kb of the first exon of the ZDHHC15 gene encoding a zinc-finger and a DHHC domain containing product. Expression analysis revealed that different transcript variants of the gene are expressed in brain. ZDHHC15-specific RT-PCR analysis on lymphocytes from the patient revealed an absence of ZDHHC15 transcript variants, detected in control samples. We suggest that the absence of the ZDHHC15 transcripts in this patient contributes to her phenotype, and that the gene is a strong candidate for nonsyndromic XLMR.

Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.