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Biomedical subjects

G F Hoffmann

Publications and source records attributed to G F Hoffmann.

At least 109 records · Page 6Linked to original sources
PubMed1999

Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis.

The clinical use of molecular analyses in recessive disorders relies on the exact characterization of both mutant alleles in the affected patient. This can be problematic when only part of the gene is examined or when relevant DNA alterations are not recognized by standard methods. We present a child in whom phenylketonuria was apparently caused by homozygosity for the mutation E390G in exon 11 of the phenylalanine hydroxylase (PAH) gene. However, the clinical severity of the disease was not quite as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene. Presence of a large deletion involving exons 9, 10 and 11 of the phenylalanine hydroxylase gene was confirmed by long-range PCR. Diagnostic DNA analyses should include a comprehensive examination of the whole relevant gene in the patient and confirmation of carrier status in both parents.

DNA Mutational Analysis↗
PubMed1999

A review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delC).

An overview is given of the current knowledge on the human tyrosine hydroxylase gene and on the biochemical aspects of diagnosing defects in this gene. Diagnostic biochemical findings are described in four cases of genetically confirmed tyrosine hydroxylase deficiency. Decreased CSF levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), together with normal pterin and CSF tyrosine and 5-hydroxyindoleacetic acid (5-HIAA) concentrations are the diagnostic hallmarks of tyrosine hydroxylase deficiency. At the metabolite level the diagnosis can only be made reliably in CSF. Strict adherence to a standardized lumbar puncture protocol and adequate reference values are essential for diagnosis of this 'new' treatable neurometabolic disorder. Measurements of HVA, vanillylmandelic acid (VMA) or catecholamines in urine are not relevant for diagnosing tyrosine hydroxylase deficiency. The diagnosis should be considered in all children with unexplained hypokinesia and other extrapyramidal symptoms. Three of our patients are homozygous for a mutation in exon 6 (698G > A) of the tyrosine hydroxylase gene and one patient was compound heterozygous for the same mutation and a novel truncating mutation in exon 3 (291delC).

Amino Acid Metabolism, Inborn Errors↗
PubMed1999

Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy.

The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl-CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from gross organic aciduria to only slightly or intermittently elevated or even normal excretion of glutaric acid, making the diagnosis sometimes difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no correlation between genotype and clinical phenotype. GA I causes unique age- and location-specific neuropathological sequelae. Starting in the second half of gestation, maturation of the frontal and temporal cortex is hindered, leading to the characteristic appearance of frontotemporal atrophy. Between 6 and 18 months of age, relatively mild neurological symptoms may become exacerbated by fever or a catabolic state in the course of common infections or routine immunizations, by fasts required for surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently, the underlying pathophysiology could be delineated to an environmentally triggered age- and location-specific overstimulation of the NMDA 2B receptor subtype. Current therapy prevents brain degeneration in more than 90% of affected infants who are treated prospectively. Without treatment, more than 90% of affected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatment. GA I may be recognized in routine neonatal screening performed with tandem mass spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely diagnosis depends on the recognition of relatively nonspecific physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative urinary organic acid analysis by gas chromatography--mass spectrometry.

Animals↗
PubMed1999

D-2-hydroxyglutaric aciduria: further clinical delineation.

It has recently been recognized that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with a severe and a mild phenotype. Whereas the clinical and neuroimaging findings of the severe phenotype were homogeneous among the patients, the findings in the mild phenotype were much more variable, leaving the clinical picture poorly defined. We were able to collect the clinical, biochemical and neuroimaging data on an additional 8 patients with D-2-hydroxyglutaric aciduria, 4 with the severe and 4 with the mild phenotype. With the new information, it becomes clear that the mild phenotype shares the essential characteristics of the severe phenotype. The most frequent findings, regardless of the clinical phenotype, are epilepsy, hypotonia and psychomotor retardation. Additional findings, mainly occurring in the severe phenotype, are episodic vomiting, cardiomyopathy, inspiratory stridor and apnoeas. The most consistent MRI finding is enlargement of the lateral ventricles, occipital more than frontal. Regardless of the clinical phenotype, early MRI shows in addition subependymal cysts and signs of delayed cerebral maturation. Later MRI may reveal multifocal cerebral white-matter abnormalities. Two patients had vascular abnormalities, but it is as yet unclear whether these are related to D-2-hydroxyglutaric aciduria or are incidental findings.

Brain↗
PubMed1999

Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I.

Glutaric aciduria type I (GA I) is a recessive disorder caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). The biochemical hallmark of the disease is the accumulation of glutaric acid and, to a lesser degree, of 3-hydroxyglutaric acid and glutaconic acid in body fluids and tissues. A substantial number of patients show only slightly, intermittently elevated or even normal urinary excretion of glutaric acid, which makes early diagnosis and treatment to prevent the severe neurological sequelae difficult. Furthermore, elevated urinary excretion of glutaric acid can also be found in a number of other disease states, mostly related to mitochondrial dysfunction. Stable-isotope dilution assays were designed for both glutaric acid and 3-hydroxyglutaric acid and their diagnostic sensitivity and specificity were evaluated. Control ranges of glutaric acid in urine were 1.1-9.7 mmol/mol creatinine before and 4.1-32 after hydrolysis. The respective values of 3-hydroxyglutaric acid were 1.4-8.0 and 2.6-11.7 mmol/mol creatnine. For other body fluids, control ranges in mumol/l/L were: for glutaric acid 0.55-2.9 (plasma), 0.18-0.63 (cerebrospinal fluid) and 0.19-0.7 (amniotic fluid); and for 3-hydroxyglutaric acid, 0.2-1.36 (plasma), < 0.2 (cerebrospinal fluid) and 0.22-0.41 (amniotic fluid). Twenty-five patients with GCDH deficiency were studied. Low excretors (12 patients) were defined by a urinary glutaric acid below 100 mmol/mol creatinine down into the normal range, while high excretors (13 patients) had glutaric acid excretions well above this value. With and without hydrolysis there was an overlap of glutaric acid values between patients and controls. Diagnostic sensitivity and specificity of 100% could only be achieved by the quantitative determination of 3-hydroxyglutaric acid with the newly developed stable-isotope dilution assay, allowing an accurate diagnosis of all patients, regardless of the amount of glutaric acid excreted in urine.

Amino Acid Metabolism, Inborn Errors↗
PubMed1999

Adenylosuccinase deficiency: possibly underdiagnosed encephalopathy with variable clinical features.

Adenylosuccinase deficiency is an autosomal recessive inherited defect of purine synthesis. In enzyme deficient patients, two normally undetectable compounds, succinylaminoimidazole carboxamide riboside and succinyladenosine, accumulate in urine, cerebrospinal fluid and, to a minor extent, in plasma. Analysing 150 highly selected urine specimens from patients with unidentified neurogenerative disorders we discovered the first two German cases of adenylosuccinase deficiency. The deficiency causes moderate to severe mental retardation, often accompanied by epileptic seizures and/or autistic features, and is occasionally associated with growth retardation and muscular hypotonia. Of the two German cases we present here, one patient fits into the clinical picture outlined by previous reports. The other patient, however, shows a pattern of symptoms so far undescribed: severe early infantile epileptic encephalopathy with reduced myelination. On mutation analysis this patient is the first to reveal a 39 base pair deletion in the adenylosuccinase gene in contrast to the point mutations detected in previous cases. Adenylosuccinase deficiency may be an underdiagnosed metabolic disorder with variable expression. This should be taken into consideration in patients with unclassified neurological conditions.

Adenylosuccinate Lyase↗
PubMed1999

A severely affected infant with absence of cysteinyl leukotrienes in cerebrospinal fluid: further evidence that leukotriene C4-synthesis deficiency is a new neurometabolic disorder.

Leukotrienes are potent oxygenated metabolites derived from the 5-lipoxygenase pathway of arachidonic acid metabolism. They comprise the cysteinyl leukotrienes (LTC4, LTD4, LTE4) and LTB4. The rate limiting step in the formation of cysteinyl leukotrienes is the conversion of LTA4 to LTC4 catalyzed by the enzyme LTC4 synthase. Recently, the first inborn error of leukotriene synthesis, LTC4-synthesis deficiency, has been identified in a patient with a fatal developmental syndrome. We report on an additional infant presenting with severe muscular hypotonia, symmetrical extension in the lower extremities and psychomotor retardation who died at the age of 6 months. Despite intensive investigations no specific diagnosis could be made. Leukotrienes were subsequently analyzed in the cerebrospinal fluid. Concentrations of LTC4, LTD4 and LTE4 were below the detection limit (< 5 pg/ml) whereas LTB4 was found to be in the upper normal range. The absence of cysteinyl leukotrienes with normal LTB4 concentration in cerebrospinal fluid is unique and seems to be pathognomonic for LTC4-synthesis deficiency. Our patient most likely represents the second case described so far with this condition. This report provides further evidence that LTC4-synthesis deficiency represents a new neurometabolic disorder.

Fatal Outcome↗
PubMed1999

Identification of a mutation cluster in mevalonate kinase deficiency, including a new mutation in a patient of Mennonite ancestry.

Mevalonate kinase (MKase) deficiency (MKD) is a rare autosomal recessive disorder in the pathway of cholesterol and nonsterol isoprenoid biosynthesis. Thus far, two disease-causing missense alleles have been identified, N301T and A334T. We report four additional mutations associated with MKD: L264F, T243I, L265P, and I268T, the last found in a patient of Mennonite ancestry. Electrophoretic analysis of bacterially expressed wild-type and mutant MKase indicated that I268T and T243I mutants produced normal or somewhat reduced amounts of MKase protein; conversely, L264F and L265P mutations resulted in considerably decreased, or absent, MKase protein. Immunoblot analysis of MKase from all patients suggested that the MKase polypeptide was grossly intact and produced in amounts comparable to control levels. Three mutations resulted in significantly diminished MKase enzyme activity (<2%), whereas the I268T allele yielded approximately 20% residual enzyme activity. Our results should allow more-accurate identification of carriers and indicate a mutation "cluster" within amino acids 240-270 of the mature MKase polypeptide.

Alleles↗
PubMed1999

Biochemical and molecular genetic characteristics of the severe form of tyrosine hydroxylase deficiency.

BACKGROUND: Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Recently, mutations were identified in cases of autosomal recessive dopa-responsive dystonia and infantile parkinsonism. We describe a patient with severe symptoms and a new missense mutation in TH. METHODS: Relevant metabolites in urine and cerebrospinal fluid were measured by HPLC with fluorometric and electrochemical detection. All exons of the TH gene were amplified by PCR and subjected to single-strand conformation polymorphism analysis. Amplimers displaying aberrant migration patterns were analyzed by DNA sequence analysis. RESULTS: The patient presented with severe axial hypotonia, hypokinesia, reduced facial mimicry, ptosis, and oculogyric crises from infancy. The major metabolite of dopamine, homovanillic acid, was undetectable in the patient's cerebrospinal fluid. A low dose of L-dopa produced substantial biochemical but limited clinical improvement. DNA sequencing revealed a homozygous 1076G-->T missense mutation in exon 10 of the TH gene. The mutation was confirmed with restriction enzyme analysis. It was not present in 100 control alleles. Secondary structure prediction based on Chou-Fasman calculations showed an abnormal secondary structure of the mutant protein. CONCLUSIONS: We describe a new missense mutation (1076G-->T, C359F) in the TH gene. The transversion is present in all known splice variants of the enzyme. It produces more severe clinical and biochemical manifestations than previously described in TH-deficient cases. Our findings extend the clinical and the biochemical phenotype of genetically demonstrated TH deficiency.

Amino Acid Sequence↗
PubMed1998

Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency.

We describe two patients with mevalonate kinase deficiency and prominent hematologic abnormalities and cholestatic liver disease. Patient R.B. was not anemic at birth, but developed petechiae and cutaneous extramedullary hematopoiesis, hepatosplenomegaly, leukocytosis, and recurrent febrile events without positive bacterial or viral cultures. Patient N.M. manifested minor anomalies, hepatosplenomegaly, anemia, thrombocytopenia, recurrent febrile crises, and facial rashes. Mevalonic aciduria was found by urinary organic acid analysis, and mevalonate kinase deficiency was documented in both. The clinical spectrum of normocytic hypoplastic anemia, leukocytosis, thrombocytopenia, and abnormal blood cell forms led to diagnoses of congenital infection, myelodysplastic syndromes, or chronic leukemia in these patients before recognition of mevalonate kinase deficiency. Mevalonate kinase deficiency represents a single-gene abnormality that may be associated with significant hematologic findings. Recognition of the variability of this disorder with some patients manifesting only mild neurologic findings, yet significant hepatosplenomegaly, normocytic anemia, thrombocytopenia, and leukocytosis is important for all specialists who need to be aware of this organic aciduria.

Anemia↗
PubMed1998

Characterization of the mevalonate kinase 5'-untranslated region provides evidence for coordinate regulation of cholesterol biosynthesis.

Using a probe derived from the 5'-untranslated region of the human mevalonate kinase (MK) cDNA, we screened a lambda gt 11 genomic library and obtained a single clone containing the 5' untranslated region of the gene. Nucleotide sequencing identified several putative regulatory elements, including two Sp1 (GC box) elements and a CCAAT box. A canonical TATA box was not detected. Directly adjacent to one Sp1 element was a sterol regulatory element (SRE), 5'-CACCCCAG-3', which was a 7/8 base pair match to the consensus sequences identified in the genes encoding 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase and reductase, and the LDL receptor. There was no Sp1 element upstream of the SRE. Northern blot analysis in human CRL1508T cells revealed that quantities of MK poly A+ RNA increased for cells grown in the presence of lipid-deficient calf serum, and further increased upon addition of 1 microM lovastatin. Primer extension analysis with human poly A+ RNA suggested at least 4 transcription initiation sites downstream from the CCAAT box. To assess sterol responsiveness of transcription initiation, a 1.4 kb genomic fragment upstream of the translational start site was fused to the pSV2cat vector for transient expression in COS-7 cells, with chloramphenicol acetyltransferase (CAT) as the reporter gene. This construct demonstrated modest levels of CAT expression which was induced > 2-fold when cells were grown in lipoprotein-deficient calf serum. Our data provide further evidence for coordinate regulation of cholesterol biosynthesis in response to sterol.

Animals↗