C. Jakobs

The biochemistry, metabolism and inherited defects of the pentose phosphate pathway : A review

SummaryThe recent discovery of two defects (ribose-5-phosphate isomerase deficiency and transaldolase deficiency) in the reversible part of the pentose phosphate pathway (PPP) has stimulated interest in this pathway. In this review we describe the functions of the PPP, its relation to other pathways of carbohydrate metabolism and an overview of the metabolic defects in the reversible part of the PPP.

GAMT deficiency : Features, treatment, and outcome in an inborn error of creatine synthesis

Background: Guanidinoactetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine synthesis. The authors analyzed clinical, biochemical, and molecular findings in 27 patients. Methods: The authors collected data from questionnaires and literature reports. A score including degree of intellectual disability, epileptic seizures, and movement disorder was developed and used to classify clinical phenotype as severe, moderate, or mild. Score and biochemical data were assessed before and during treatment with oral creatine substitution alone or with additional dietary arginine restriction and ornithine supplementation. Results: Intellectual disability, epileptic seizures, guanidinoacetate accumulation in body fluids, and deficiency of brain creatine were common in all 27 patients. Twelve patients had severe, 12 patients had moderate, and three patients had mild clinical phenotype. Twenty-one of 27 (78%) patients had severe intellectual disability (estimated IQ 20 to 34). There was no obvious correlation between severity of the clinical phenotype, guanidinoacetate accumulation in body fluids, and GAMT mutations. Treatment resulted in almost normalized cerebral creatine levels, reduced guanidinoacetate accumulation, and in improvement of epilepsy and movement disorder, whereas the degree of intellectual disability remained unchanged. Conclusion: Guanidinoactetate methyltransferase deficiency should be considered in patients with unexplained intellectual disability, and urinary guanidinoacetate should be determined as an initial diagnostic approach.

The metabolism of phytanic acid and pristanic acid in man : A review

The branched-chain fatty acid phytanic acid is a constituent of the diet, present in diary products, meat and fish. Degradation of this fatty acid in the human body is preceded by activation to phytanoyl-CoA and starts withone cycle of α-oxidation. Intermediates in this pathway are 2-hydroxy-phytanoyl-CoA and pristanal; the product is pristanic acid. After activation, pristanic acid is degraded by peroxisomal β-oxidation. Several disorders havebeen described in which phytanic acid accumulates, in some cases in combination with pristanic acid. In classical Refsum disease, the enzyme that converts phytanoyl-CoA into 2-hydroxyphytanoyl-CoA – phytanoyl-CoA hydroxylase – is deficient, resulting in highly elevated levels of phytanic acid in blood and tissues. Also in rhizomelic chondrodysplasia punctata, phytanic acid accumulates, owing to a deficiency in the peroxisomal import of proteins with a peroxisomal targeting sequence type 2. In patients affected with generalized peroxisomal disorders, degradation of both phytanic acid and pristanic acid is impaired owing to absence of functional peroxisomes. In bifunctional protein deficiency, the disturbed oxidation of pristanic acid results in elevated levels of this fatty acid and a secondary elevation of phytanic acid. In addition, several variant peroxisomal disorders with unknown aetiology have been described in which phytanic acid and/or pristanic acid accumulate. This review describes the discovery of phytanic acid and pristanic acid and the initial attempts to elucidate the origins and fates of these fatty acids. The current knowledge on the α-oxidation and β-oxidation of these branched-chain fatty acids is summarized. The disorders in which phytanic acid and/or pristanic acid accumulate are described and some remarks are made on the pathogenic mechanisms of elevated levels of phytanic acid and pristanic acid.

Alexander disease Ventricular garlands and abnormalities of the medulla and spinal cord

Background: Alexander disease is most commonly associated with macrocephaly and, on MRI, a leukoencephalopathy with frontal preponderance. The disease is caused by mutation of the GFAP gene. Clinical and MRI phenotypic variation have been increasingly recognized. Methods: The authors studied seven patients with Alexander disease, diagnosed based on mutations in the GFAP gene, who presented unusual MRI findings. The authors reviewed clinical history, MRI abnormalities, and GFAP mutations. Results: All patients had juvenile disease onset with signs of brainstem or spinal cord dysfunction. None of the patients had a macrocephaly. The MRI abnormalities were dominated by medulla and spinal cord abnormalities, either signal abnormalities or atrophy. One patient had only minor cerebral white matter abnormalities. A peculiar finding was the presence of a kind of garland along the ventricular wall in four patients. Three patients had an unusual GFAP mutation, one of which was a duplication mutation of two amino acids, and one an insertion deletion. Conclusion: Signal abnormalities or atrophy of the medulla or spinal cord on MRI are sufficient to warrant DNA analysis for Alexander disease. Ventricular garlands constitute a new sign of the disease. Unusual phenotypes of Alexander disease are found among patients with late onset and protracted disease course.

Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect.

Recently, 3 patients with a creatine synthesis defect have been described. They presented with developmental regression, extrapyramidal movement abnormalities, and intractable epilepsy, and they improved with treatment of creatine monohydrate. We report 2 unrelated boys with a creatine synthesis defect and nonspecific presenting signs of psychomotor retardation, behavioral problems, and, in 1, mild epilepsy. Metabolic urine screening revealed elevations in all metabolites, expressed as millimoles per mole of creatinine, which suggests decreased creatinine excretion. This finding led to the correct diagnosis. We propose to include the assessment of the overall concentrations of amino acids and organic acids relative to creatinine in routine metabolic urine screening. Ann Neurol 2000;47:540–543.

An accurate stable isotope dilution gas chromatographic–mass spectrometric approach to the diagnosis of guanidinoacetate methyltransferase deficiency

A gas chromatography-mass spectrometry (GC-MS) method is described for the quantification of guanidinoacetate in different body fluids, using a two step derivatisation procedure which involves a reaction with hexafluoroacetylacetone to form a bis(trifluoromethyl)pyrimidine ring structure followed by a reaction with pentafluorobenzyl bromide. 13C2-labelled guanidinoacetate is used as an internal standard. Bis(trifluoromethyl)pyrimidine pentafluorobenzyl derivatives were separated on a polar capillary GC-column and were quantified using negative chemical ionisation mass fragmentography. The detection limit of the method is 1 pmol guanidinoacetate in a 100 microl sample. Control values were obtained for urine (53.9 +/- 25.9 mmol mol(-1) creatinine), plasma (1.08 +/- 0.31 micromol l(-1)), cerebrospinal fluid (CSF) (0.114 +/- 0.068 micromol l(-1)) and amniotic fluid (3.44 +/- 0.64 micromol l(-1)). The applicability of the method is illustrated by the determination of guanidinoacetate in urine, plasma and CSF of a patient affected with guanidinoacetate methyltransferase deficiency. In all body fluids of this patient, guanidinoacetate was highly elevated.

High frequency of creatine deficiency syndromes in patients with unexplained mental retardation

Cerebral creatine deficiency syndromes (CCDSs) are inborn errors of metabolism that include two autosomal recessive creatine biosynthesis defects (arginine–glycine amidinotransferase [AGAT; OMIM 602360] and guanidinoacetate methyl transferase [GAMT; OMIM 601240] deficiency) and an X-linked creatine transporter defect (OMIM 300036).1 The clinical phenotype is variable, associating nonspecific mental retardation, epilepsy, extrapyramidal movement disorders, and autistic behavior. The frequency of CCDS is unknown and probably underestimated. We report a high frequency of CCDS in mentally retarded children, mostly boys with an X-linked creatine transporter deficiency. Over a period of18 months, children referred to the Department of Pediatric Neurology with unexplained mild to severe mental retardation, normal karyotype, and absence of fragile X syndrome were prospectively screened for CCDS. Children were from diverse ethnic backgrounds. Children with polymalformative syndromes were excluded. Creatinine metabolism was evaluated using creatine/creatinine and guanidinoacetate (GAA)/creatinine ratios on a spot urine.2 Diagnosis was further confirmed using brain proton MR spectroscopy (H-MRS) and …

Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men

SummarySuccinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS–742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS–742, form the framework for human trials.

D-2-Hydroxyglutaric aciduria: Biochemical marker or clinical disease entity?

D‐2‐Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D‐2‐hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early‐infantile‐onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D‐2‐hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid γ‐aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D‐2‐hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes. Ann Neurol 1999;45:111–119

Stable isotope dilution analysis of N-acetylaspartic acid in CSF, blood, urine and amniotic fluid: Accurate postnatal diagnosis and the potential for prenatal diagnosis of canavan disease

SummaryA sensitive and selective analytical technique is described for the determination ofN-acetylaspartic acid in body fluids using stable isotope dilution in combination with positive chemical ionization mass spectrometry with selected ion monitoring.Control mean and ranges have been established: in urine 19.5 and 6.6–35.4 µmol/mmol creat.; in plasma 0.44 and 0.17–0.81 µmol/L; in cerebrospinal fluid 1.51 and 0.25–2.83 µmol/L; and in amniotic fluid 1.27 and 0.30–2.55 µmol/L.In a patient with Canavan disease,N-acetylaspartic acid concentration was elevated 80-fold in urine and 20-fold in plasma compared to the control means. A subsequent pregnancy of the mother was monitored and theN-acetylaspartic acid concentration in the amniotic fluid was within the control range and a healthy child was born.