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A Kohlschütter

Publications and source records attributed to A Kohlschütter.

At least 19 recordsLinked to original sources
PubMed2006

A new type of leukoencephalopathy with metaphyseal chondrodysplasia maps to Xq25-q27.

BACKGROUND: The authors report a three-generation family with four male patients presenting with a novel type of X-chromosomal leukoencephalopathy associated with skeletal abnormalities. METHODS: The index patient and his brother reached their early motor milestones in due time and had normal language development. Between the ages of 2 and 3 years, first signs of spastic paraplegia were noticed. Furthermore, the patients developed tremor, ataxia, optic atrophy, and spastic tetraparesis. Both boys had broad wrists and knees without significant contractures. A maternal uncle and a granduncle had the same disease. RESULTS: Leukoencephalopathy (MRI, MRS) and metaphyseal chondrodysplasia (X-ray, MRI) were diagnosed. MRS showed a reduction of choline-containing compounds in the white matter. An autopsy on one of the patients, who died at age 37 years, revealed an orthochromatic type of leukoencephalopathy. In bone and cartilage tissue, unspecific signs of a mild chondrodysplasia were found. At the PLP gene locus an obligate recombination was observed, which excludes the Pelizaeus-Merzbacher locus on Xq21-22. However, affected males share a fragment of the long arm of chromosome X. CONCLUSION: The authors report a new type of leukoencephalopathy associated with metaphyseal chondrodysplasia located on Xq25-q27.

Adult↗
PubMed2006

[The role of the ophthalmologist in the management of juvenile neuronal ceroid lipofuscinosis].

BACKGROUND: Neuronal ceroid lipofuscinoses (NCL) are storage diseases leading to severe somatic and mental deterioration with blindness and death. To date, there are no therapeutic options. Juvenile NCL (JNCL), also known as Batten's disease, is one of the most prevalent forms of NCL. MATERIALS AND METHODS: A 6-year-old boy with the primary diagnosis of retinitis pigmentosa was examined. The parents reported a rapid deterioration of vision during the past months. In view of this history, additional, non-ophthalmological diagnostic procedures have been performed (peripheral blood smear, molecular genetics). RESULTS: The eye examination showed a considerable reduction of visual acuity, a concentric visual field constriction, an extinguished electroretinogram and a bull's eye maculopathy. The peripheral blood smear revealed vacuolated lymphocytes. Molecular genetic investigation confirmed the diagnosis of juvenile NCL by detecting a homozygous (1-kb deletion of the CLN3-gene). CONCLUSIONS: The ophthalmologist plays a key role for an early diagnosis of juvenile NCL. An early diagnosis is important for the affected families because only then they can handle this stroke of fate.

Child↗
PubMed2005

Cystic leukoencephalopathy without megalencephaly: a distinct disease entity in 15 children.

OBJECTIVE: To describe a distinctive syndrome of nonprogressive encephalopathy, normo- or microcephaly, and early onset of severe psychomotor impairment in 15 white patients, including two siblings and two first cousins. METHODS AND RESULTS: MRI revealed bilateral cysts in the anterior part of the temporal lobe and white matter abnormalities with pericystic abnormal myelination and symmetric lesions in frontal and occipital periventricular regions. None of the usual inborn errors of metabolism/infectious diseases associated with leukoencephalopathy and bilateral anterior temporal lobe cysts were detected. CONCLUSIONS: These patients' clinical signs and cranial MRI abnormalities are strikingly similar and may represent a distinctive disease with autosomal-recessive inheritance: cystic leukoencephalopathy without megalencephaly.

Adolescent↗
PubMed2005

The ratio of alpha-galactosidase to beta-glucuronidase activities in dried blood for the identification of female Fabry disease patients.

Female heterozygous patients with Fabry disease are difficult to identify because of the relatively high residual activity of alpha-galactosidase. We systematically evaluated the activities of various lysosomal enzymes in dried blood samples from Fabry patients and found that the beta-glucuronidase activity was frequently elevated. The ratio of alpha-galactosidase to beta-glucuronidase proved to be a helpful tool for the diagnosis of female Fabry disease patients.

Blood↗
PubMed2005

Cumulative incidence rates of the mucopolysaccharidoses in Germany.

In order to estimate the cumulative incidence rates of the mucopolysaccharidoses (MPS) in Germany, a retrospective epidemiological survey covering the period between 1980 and 1995 was implemented. Multiple ascertainment sources were used to identify affected patients. A prevalence of approximately 0.69 cases per 100,000 births was obtained for MPS I (Hurler phenotype). Within the study period, 4 patients with Hurler/Scheie phenotype and 7 cases with Scheie disease were detected. The cumulative incidence for MPS II (Hunter syndrome) was estimated as 0.64 cases per 100,000 births (1.3 cases per 100,000 male live births); that for MPS III (Sanfilippo syndrome types A, B and C) as 1.57 cases in 100,000 births; that for MPS IV A (Morquio syndrome) as 0.38 cases in 100,000; and that for MPS VI (Maroteaux-Lamy syndrome) as 0.23 cases per 100,000 births. Two cases of MPS IVB (beta-galactosidase deficiency) have been identified, but no patients with MPS VII or MPS IX. A relatively high number of patients with MPS IIIB, MPS IVA and MPS VI were of Turkish origin. The crude rate for all types of mucopolysaccharidoses is approximately 3.53 cases in 100,000 live births. The cumulative incidence pattern of MPS in Germany was compared with the corresponding rates among other industrial nations obtained from recent literature: the crude cumulative rates for all types of mucopolysaccharidoses (3.4-4.5 in 100,000 live births) were similar among all published populations; however, different frequencies of the various forms of MPS were observed.

Female↗
PubMed2005

Two novel CLN6 mutations in variant late-infantile neuronal ceroid lipofuscinosis patients of Turkish origin.

Neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative childhood-onset disorders characterized by autosomal recessive inheritance, epileptic seizures, progressive psychomotor deterioration, visual failure, and premature death. At least seven subtypes of childhood-onset NCLs have been identified of which the late-infantile-onset forms (LINCLs) are genetically the most heterogeneous with four underlying genes identified. A variant form of LINCL (vLINCL) present in Turkish patients has been considered a distinct clinical and genetic entity (CLN7). However, we recently showed that mutations in the CLN8 gene account for a subset of Turkish vLINCL. Toward identifying the CLN7 gene we here screened the known NCL loci for homozygosity in nine Turkish vLINCL families. These loci were excluded in seven families that are likely to represent the 'true' Turkish vLINCL. In two families, we identified two novel homozygous mutations in the CLN6 gene: an intronic base substitution (c.542+5G>T) affecting the splicing of the transcript and a nonsense mutation (c.663C>G) creating a stop codon at tyrosine 221. These data indicate that CLN6 mutations, in addition to those of CLN8, should be considered a diagnostic alternative in Turkish vLINCL patients. The genetic background of the 'true' Turkish vLINCL, CLN7, remains to be defined.

Age of Onset↗
PubMed2004

Efficiency of long-term tetrahydrobiopterin monotherapy in phenylketonuria.

Phenylketonuria, an inborn error of phenylalanine metabolism, occurs with a frequency of about 1 in 10,000 births and is treated with a strict dietary regimen. Recently, some patients with PKU have been found to show increased tolerance towards phenylalanine intake while receiving tetrahydrobiopterin (BH(4)) supplementation. We have treated two infants with BH(4)-responsive PKU with BH(4) for more than 2 years. No additional dietary control was required to maintain blood phenylalanine concentrations in the desired range. Both children have shown normal development. Generally, our results suggest that BH(4) treatment might be an option for some patients with mild PKU, as it frees them from dietary restrictions and thus improves their quality of life.

Biopterins↗
PubMed2003

A hypothesis on the biochemical mechanism of BH(4)-responsiveness in phenylalanine hydroxylase deficiency.

We describe six children with tetrahydrobiopterin (BH(4)) responsive phenylalanine hydroxylase (PAH) deficiency. All patients carry two mutant alleles in the PAH gene. Cofactor deficiency was excluded. The effect of BH(4) administration was studied by correlating different oral BH(4) doses with plasma phenylalanine levels under defined protein intake. Our results indicate that oral BH(4) supplementation may be used as long-term treatment for individuals with BH(4)-responsive PAH deficiency, either without or in combination with a less restrictive diet. Previous in vitro studies have demonstrated that BH(4) inhibits PAH tetramers but activates PAH dimers. This may indicate, that BH(4)-responsiveness results from BH(4) induced stabilization of mutant PAH dimers. In addition, interindividual differences in the cellular folding apparatus may determine the tertiary structure and the amount of mutant PAH dimers and hence may account for divergent BH(4)-responsiveness reported for the same PAH genotype.

Biopterins↗
PubMed2003

Towards quality assurance in the determination of lysosomal enzymes: a two-centre study.

The definitive diagnosis of lysosomal storage disorders depends on the determination of enzymatic activities in cells, tissues or body fluids. At present, neither an evaluation of the different methods nor an interlaboratory quality assurance scheme is available. We have therefore determined the activities of total hexosaminidase, hexosaminidase A and beta-galactosidase in the same samples (n = 15) at two metabolic centres in Germany. Three different enzymatic methods were employed, two of which were based on leukocytes as enzyme source and one on dried blood spots. The results obtained by the two different methods using leukocytes proved comparable. In contrast, assays with dried blood spots showed poor correlation with results from leukocytes, possibly because enzymatic activity in dried blood is mainly derived from soluble plasma proteins. Nevertheless, accurate detection of a true enzyme deficiency was also possible in dried blood spots. All enzymes were highly stable when mailed frozen (recovery 98-120%). Enzymatic activities in dried blood samples were also stable at room temperature and were not affected even by exposure to elevated temperatures (50 degrees C for 3 h). Dried blood seems to be especially well suited for mailing from distant healthcare facilities, although more accurate results can be expected from leukocytes. In summary, comparability and pitfalls within a lysosomal quality assurance programme were evaluated.

Adult↗
PubMed2003

Infantile cobalamin deficiency with cerebral lactate accumulation and sustained choline depletion.

A remarkable, intermittent sudden-onset vigilance and movement disorder in an exclusively breast-fed infant is reported, which was caused by cobalamin depletion due to maternal vitamin B12 malabsorption. The lack of cobalamin caused a severe encephalopathy in the infant, whose brain displayed a striking loss of volume and a delay of myelination. Proton magnetic resonance spectroscopy revealed an accumulation of lactate in the gray and white matter of the brain and a sustained depletion of choline-containing compounds in the white matter, reflecting a reversible disturbance of oxidative energy metabolism in brain cells and a long-lasting hypomyelination disorder. The clinical picture in conjunction with MRI and spectroscopic data of this case study yields more insight into the functions of cobalamin in the cerebral metabolism.

Brain Diseases↗
PubMed2001

Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress.

The impairment of nitric oxide (NO)-mediated vasodilation in diabetes has been attributed to increased vascular oxidative stress. Lipoic acid has been shown to have substantial antioxidative properties. The aim of this study was to assess the effect of lipoic acid on NO-mediated vasodilation in diabetic patients in comparison with the well-recognized effect of ascorbic acid. Using venous occlusion plethysmography, we examined the effects of lipoic acid (0.2 mM) and ascorbic acid (1 and 10 mM) on forearm blood flow responses to acetylcholine, sodium nitroprusside and concomitant infusion of the NO-inhibitor, N(G)-monomethyl-L-arginine, in 39 diabetic patients and 11 control subjects. Plasma levels of antioxidants and parameters of lipid peroxidation were measured and correlated to endothelial function tests. Lipoic acid improved NO-mediated vasodilation in diabetic patients, but not in controls. NO-mediated vasodilation was improved by ascorbic acid at 10 mM, but not 1 mM. Improvements of endothelial function by ascorbic acid and lipoic acid were closely related. The beneficial effects of lipoic acid were positively related to plasma levels of malondialdehyde and inversely related to levels of ubiquinol-10. These findings support the concept that oxidative stress contributes to endothelial dysfunction and suggest a therapeutic potential of lipoic acid particularly in patients with imbalance between increased oxidative stress and depleted antioxidant defense.

Acetylcholine↗
PubMed2001

Altered levels of high-energy phosphate compounds in fibroblasts from different forms of neuronal ceroid lipofuscinoses: further evidence for mitochondrial involvement.

The pathogenesis of neurodegeneration in neuronal ceroid lipofuscinosis (NCL) is still not clear despite progress in mutation analysis of these diseases. We have recently observed anomalies at the level of the mitochondrial ATPsynthase (complex V of the respiratory chain) in fibroblasts from children with CLN1, CLN2, CLN3 and in an ovine model (OCL6). The measurements were carried out in vitro. If these alterations were of relevance in vivo as well, contents of high-energy phosphate compounds should be reduced. In the present study, we measured levels of creatine phosphate (CP), ATP, ADP and AMP in fibroblasts from children with CLN1, CLN2, CLN3 and in OCL6. ATP was reduced to about 50% of normal in CLN1, CLN2 and CLN3, ADP was about 30% of normal in these cells, and CP was 50% of normal in CLN1 and CLN2 but remained normal in CLN3. In fibroblasts of NCL-sheep, however, CP and ADP were increased to 690% and 220% of normal, respectively, while ATP remained normal. If the anomalies found in cellular energy metabolism in fibroblasts were expressed in neurons from NCL patients and NCL sheep 'slow-onset excitotoxicity' could occur leading to cellular dysfunction and eventually to cell death.

Adenosine Diphosphate↗
PubMed2001

Cause of progression in Duchenne muscular dystrophy: impaired differentiation more probable than replicative aging.

Replicative aging of myogenic cells (satellite cells) owing to enhanced myofiber turnover is a common explanation of the progression of Duchenne muscular dystrophy (DMD). This hypothesis has been reexamined recently by telomere length measurements in dystrophic tissue. We evaluate the controversial results of these studies. We also review a large body of in vitro, animal (mdx), and patient data which indicate that impaired differentiation, but not replicative aging, is the leading cause of progression in DMD. We recommend in vivo investigations of cell kinetics in DMD muscle, as well as telomere length and telomerase analyses of DMD satellite cells in vitro for a definite judgement of the replicative aging hypothesis. Analogous investigations were helpful in AIDS research where replicative aging was embraced as a simple explanation of the paradigmatic CD4 lymphocyte decline but had to be rejected in favour of more complex models of disturbed lymphocyte homeostasis and regeneration. The question of replicative aging versus impaired differentiation is relevant for the understanding of therapeutic failures and the design of new strategies. Impaired differentiation is compatible with the failure of myoblast transfer in DMD and calls for further studies on the myofiber environment. Replicative aging, on the other hand, could possibly be treated by telomerase gene delivery.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Impaired plasma antioxidative defense and increased nontransferrin-bound iron during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation.

To analyze the effects of radiochemotherapy on the pro-oxidative/antioxidative balance in plasma, we measured the total radical antioxidant parameter of plasma (TRAP) and single plasma antioxidants (uric acid, sulfhydryl groups, alpha-tocopherol, ubiquinone-10/total coenzyme-Q10 ratio, ascorbate, and bilirubin) every 12 h during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation (BMT). Nontransferrin-bound iron (NTBI) was monitored as a potential pro-oxidant. Plasma levels of polyunsaturated fatty acids (PUFA) were measured as substrates, and thiobarbituric acid-reactive substances (TBARS) were measured as products of lipid peroxidation. Allantoin was analyzed as the product of uric acid oxidation. Patients receiving busulfan, VP-16, and cyclophosphamide (BU/VP/CY) (n = 8) were compared with those receiving total body irradiation in addition to VP-16 and cyclophosphamide (TBI/VP/CY) (n = 8). TRAP values were within the normal range before therapy and decreased after BU/VP/CY by 37% (p <. 02) and after TBI/VP/CY by 39% (p <.02). During TBI and after VP-16, a temporary increase in TRAP values occurred, which was not related to changes in individual antioxidants. In vitro experiments confirmed that VP-16 had an antioxidative effect. The concentration of uric acid declined in both groups and correlated with TRAP (BU/VP/CY: r =.80, p <.001; TBI/VP/CY: r =.84, p <.001). Levels of NTBI, which is normally not found in plasma, increased rapidly during conditioning therapy (p <.02 in both groups) and correlated inversely with TRAP (weighted intraindividual Spearman rank correlation coefficient for both groups: NTBI and TRAP: r = -.59, p <.001) and PUFA (in the radiochemotherapy group: r = -.67, p <.001). Whereas PUFA declined (p <.02 in both groups), TBARS increased (p <. 05 in both groups). Furthermore, an increase of allantoin and ubiquinone-10/total coenzyme-Q10 ratio in the BU/VP/CY group was found (allantoin: p <.02; ubiquinone-10/total coenzyme-Q10 ratio: p <.05). Antioxidants only partially recovered to baseline values until day 14 after BMT. Our findings indicate oxidative stress after high-dose radiochemotherapy and suggest a contribution of NTBI therein.

Allantoin↗
PubMed2000

Urinary alpha-tocopherol metabolites in alpha-tocopherol transfer protein-deficient patients.

Patients with alpha-tocopherol transfer protein (alpha-TTP) defects experience neurological symptoms characteristic of vitamin E deficiency and depend on continuous high alpha-tocopherol supplements. We investigated the excretion of 2,5,7, 8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC), a urinary metabolite of alpha-tocopherol, as a putative marker for the alpha-tocopherol status of alpha-TTP-deficient patients and control subjects. In three patients vitamin E supplementation was stopped for short periods of time, during which plasma alpha-tocopherol concentrations and urinary alpha-CEHC excretion were measured. In the patients, plasma alpha-tocopherol decreased below normal (<5 micromol/l) but alpha-CEHC excretion remained above the range of unsupplemented control subjects (0.118-0.306 mg/day, n = 6). In healthy subjects, however, alpha-CEHC excretion was increased only after surpassing a plasma alpha-tocopherol threshold of 30-40 micromol/l. Such a threshold did not exist in patients. The general mechanism of alpha-tocopherol degradation did not appear to differ between patients and control subjects. The presumed mechanism of omega- and subsequent beta-oxidation was supported by the detection of alpha- CPHC, an alpha -CEHC homolog with a side chain longer by 3 carbon atoms, both in supplemented patients and in control subjects.

Adolescent↗
PubMed1999

Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes.

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.

Adolescent↗
PubMed1999

Progress in neuropathology of the neuronal ceroid lipofuscinoses.

Since the last, 6th, International Congress on Neuronal Ceroid-Lipofuscinoses, neuropathological advances in neuronal ceroid lipofuscinoses (NCL) have been made in several areas: (1) In adult NCL (ANCL) lipopigments have now been repeatedly confirmed to contain subunit c of mitochondrial ATP synthase and even sphingolipid activators (saposins). ANCL lipopigments have also been confirmed in extracerebral tissues including skin, skeletal muscle, and spleen, but not yet lymphocytes (2). Among circulating blood cells not only B cells and subclasses of T lymphocytes, i.e., CD4(+), CD8(+), and CD56 cells, but also monocytes have been found to contain NCL lipopigments, indicating that this precursor cell in the digesting macrophage system also has an impaired metabolic catabolism for lipopigments (3). Immunohistochemical studies indicate that microglial reaction in NCL brain is limited to resident microglia without contribution by circulating monocytes (4). The granular osmiophilic deposit (GROD) type of NCL has now been established not only in infantile, but also in late-infantile, juvenile, and protracted-juvenile NCL (5). A European Tissue Registry established within the framework of a European Concerted Action on Neuronal Ceroid-Lipofuscinosis may form the basis for additional collaborative studies on NCL, including both biopsy and autopsy tissues.

Brain↗