Long term follow-up of the dietary intake in propionic acidemia.

Long-term dietary management of Propionic acidemia (PA) includes natural protein restriction, and supplementation with medical formula enriched with leucine (Leu) and free of valine (Val), isoleucine (Ileu), methionine (Met), and threonine (Thr). As PA medical formulas have high leucine content, concerns started to arise regarding potential long-term health risks of unbalanced leucine intake. PA patients have chronically low plasma levels of Ile and Val, which led to the paradoxical need to supplement with propiogenic single amino acids (AAs). Our report takes a retrospective look at the long-term dietary management of four patients and its reflection on their plasma amino acids. The patients' total protein intake was above the recommended dietary allowance (RDA) and had a high Leu/Val and Leu/Ile intake ratios in diet. Despite adequate total protein intake, patients had chronically low plasma Ile and Val and a high plasma Leu/Val and Leu/Ile ratios, which could be attributed to high Leu intake. We conclude that the best approach to PA dietary management is to only use medical formula with patients not meeting their RDA through natural protein, and to monitor plasma amino acids levels closely.

Treatable inborn errors of metabolism causing neurological symptoms in adults.

BACKGROUND: The identification of inborn errors of metabolism (IEM) in adults presenting with a wide range of neurological symptoms is a relatively new field in medicine. We sought to identify which treatable IEM have been diagnosed for the first time in adults and generate a protocol for metabolic screening targeting those treatable disorders. METHODS: Medline/Pubmed searches of English language literature limited to the adult age group were performed. Diseases identified through this search were then compared to previously published lists of treatable IEM in both adults and children. RESULTS: 85% of the treatable conditions known to cause global developmental delay or intellectual disability in children had reports where the diagnosis of that IEM was made in one or more adult patients with neurological symptoms. Screening tests in blood, urine, CSF and MRI can detect most of these treatable conditions but the diagnostic accuracy of these screening tests in adults is not clear. CONCLUSION: Treatable IEM need to be considered in the differential diagnosis of neurological symptoms in patients of any age.

Intracranial calcification after cord blood neonatal transplantation for krabbe disease.

Infantile-onset Krabbe disease results from a deficiency of the lysosomal enzyme galactocerebrosidase and leads to death from profound central and peripheral demyelination. Neonatal hematopoietic cell transplantation may result in near-normal cognitive development and partial rescue of gross motor development. The long-term course of the disorder for treated patients seems to involve slowly progressive neurological impairment. We describe the detailed 3-year outcomes of this experimental procedure using umbilical cord blood in a prenatally-diagnosed newborn with Krabbe disease. Substantial perivascular calcifications and atrophy of the white matter developed in the first year post-transplantation. Despite persistent neuroradiological and electrophysiological evidence of leukodystrophy, at age 3 years she has had only mildly impaired non-motor development and moderately impaired motor skills. The cause of these severe white matter changes may have been due to ongoing Krabbe disease or to effects of the chemotherapy regimen or to an interaction of these factors. Extended long-term follow-up of children neonatally transplanted for Krabbe disease is needed before the full utility and limitations of neonatal transplantation can be determined.

Guanidino compounds in guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis.

The first inborn error of creatine metabolism (guanidinoacetate methyltransferase [GAMT] deficiency) has recently been recognized in an infant with progressive extrapyramidal movement disorder. The diagnosis was established by creatine deficiency in the brain as detected by in vivo magnetic resonance spectroscopy and by defective GAMT activity and two mutant GAMT alleles in a liver biopsy. Here, we describe characteristic guanidino-compound patterns in body fluids of this index patient with GAMT deficiency. Concentrations of guanidino compounds (creatine and guanidinoacetate) and creatinine were determined by cation-exchange chromatography and by color reaction with picric acid, respectively, in urine, plasma, and cerebrospinal fluid (CSF). Creatine concentrations were low in plasma, CSF, and urine while guanidinoacetate concentrations were markedly elevated. Daily urinary creatinine excretion was low, whereas creatinine concentrations in random urine samples were not always discriminative. Guanidino compound to creatinine ratios were not informative, as low creatinine concentrations resulted in high values for all determined compounds. During a 22-month period of oral treatment with creatine-monohydrate, plasma and urinary creatine concentrations increased to levels high above the normal range, and daily urinary creatinine excretion-proportional to total body creatine-became normalized. Guanidinoacetate concentrations remained elevated even during additional substitution of ornithine, which inhibits guanidinoacetate synthesis in vitro. The results indicate that GAMT deficiency can be recognized noninvasively by determination of guanidino compounds (creatine and guanidinoacetate) in body fluids. A deficiency of creatine, but not an accumulation of guanidinoacetate, can be corrected by treatment with oral creatine substitution.

Decreased platelet membrane anisotropy in patients with adrenoleukodystrophy treated with erucic acid (22:1)-rich triglycerides.

Low platelet count and bleeding diathesis have been observed in patients with adrenoleukodystrophy (ALD) treated with erucic acid (22:1)-rich triglycerides ("Lorenzo's oil'). To investigate possible alterations of biophysical membrane properties, we measured platelet membrane anisotropy, which is inversely related to membrane fluidity, in 16 patients with and in 3 patients without treatment. In patients on treatment, platelet membrane anisotropy was significantly decreased. Additionally, we found increased platelet concentrations of 22:1 and compromised in vitro platelet aggregation response. The decrease of platelet membrane anisotropy is probably a main cause of bleeding diathesis. Long-term haematological side-effects must be considered in ALD patients treated with Lorenzo's oil.

Guanidinoacetate methyltransferase deficiency: a newly recognized inborn error of creatine biosynthesis.

In an infant with progressive, severe extrapyramidal movement disorder and extremely. low urinary creatinine excretion, in vivo proton magnetic resonance spectroscopy of the brain showed a depletion of creatine and an accumulation of guanidinoacetate, the immediate precursor of creatine. The suggested defect in creatine biosynthesis at the level of guanidinoacetate methyltransferase was confirmed by the demonstration of defective activity of this enzyme in liver tissue and by identification of the underlying genetic defect. Creatine substitution by means of oral creatine monohydrate at high dosage (4-8 g per day) resulted in a striking improvement of the extrapyramidal movement disorder, normalisation of abnormal slow background activity in the EEG, and disappearance of bilateral abnormal signal intensities in the globus pallidus. The low urinary creatine excretion normalized and brain creatine and creatine phosphate, as measured by in vivo magnetic resonance spectroscopy, increased significantly. Guanidinoacetate methyltransferase deficiency is a new, treatable inborn error of metabolism. Screening methods and non-invasive diagnosis of the enzyme defect are needed for the early detection and treatment of patients with this effect.

Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism.

BACKGROUND: The creatine/creatine-phosphate system is essential for the storage and transmission of phosphate-bound energy in muscle and brain. In infants, inefficiency or failure of this metabolic pathway can impair the development of motor control and mentation. METHODS: We studied and treated an infant with extrapyramidal signs who was shown--by assay for urinary creatinine and by analysis of brain metabolites with use of nuclear magnetic resonance spectra--to have depletion of body and brain creatine, due to inborn deficiency of guanidinoacetate methyltransferase (GAMT). FINDINGS: Long-term oral administration of creatine-monohydrate (4-8 g per day) to this index patient resulted in substantial clinical improvement, disappearance of magnetic resonance (MRI) signal abnormalities in the globus pallidus, and normalisation of slow background activity on the electroencephalogram (EEG). During the 25-month treatment period, both brain and total body creatine concentrations became normal. INTERPRETATION: Oral creatine replacement has proved to be effective in one child with an inborn error of GAMT. It may well be effective in the treatment of other disorders of creatine synthesis.

Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.

In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver. Two mutant GAMT alleles were identified that carried a single base substitution within a 5' splice site or a 13-nt insertion and gave rise to four mutant transcripts. Three of the transcripts encode truncated polypeptides that lack a residue known to be critical for catalytic activity of GAMT. Deficiency of GAMT is the first inborn error of creatine metabolism. It causes a severe developmental delay and extrapyramidal symptoms in early infancy and is treatable by oral substitution with creatine.

Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes.

Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expression of X-ALD and in their female relatives; these clinical expressions were cerebral childhood ALD, adrenomyeloneuropathy (AMN), and "Addison disease only" (ADO) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5' portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis.

Glyceroltrioleate/glyceroltrierucate therapy in 16 patients with X-chromosomal adrenoleukodystrophy/adrenomyeloneuropathy: effect on clinical, biochemical and neurophysiological parameters.

UNLABELLED: We have investigated the effect of glyceroltrioleate/glyceroltrierucate (GTO/GTE) therapy on X-chromosomal adrenoleukodystrophy in 16 patients with adrenoleukodystrophy (n = 6), adrenomyeloneuropathy (n = 3), Addison disease without neurological involvement (n = 2), and neurologically and endocrinologically asymptomatic patients (n = 5). Therapy was carried out for 19.4 +/- 10 months. All patients showed a normalization of C 26:0 plasma fatty acid concentrations. None of the seven neurologically asymptomatic patients developed neurological symptoms. Somatosensory evoked potentials of the tibialis nerve was the most sensitive electrophysiological parameter, showing a slight improvement in neurologically asymptomatic patients during therapy. In none of the patients with normal cranial MRI at start of therapy (n = 6) has MRI deterioration been observed whilst on therapy. Follow up of the neurologically asymptomatic children supports the hypothesis that GTO/GTE therapy might prevent the development of neurological symptoms. Six of the nine neurologically symptomatic patients deteriorated to varying degrees whilst on therapy. MRI alterations have worsened in all patients with clinical deterioration. CONCLUSION: GTO/GTE treatment should be initiated in all neurological asymptomatic boys before first neurological symptoms develop. To discover these patients very long-chain fatty acid determination should be performed in all family members at risk when adrenoleukodystrophy or adrenomyeloneuropathy is diagnosed.

Creatine deficiency in the brain: a new, treatable inborn error of metabolism.

In a patient with extrapyramidal movement disorder and extremely low creatinine concentrations in serum and urine, in vivo proton magnetic resonance spectroscopy disclosed a generalized depletion of creatinine in the brain. Oral substitution of arginine, a substrate for creatine synthesis, resulted in an increase of brain guanidinoacetate as the immediate precursor of creatine but did not elevate cerebral creatine levels. In contrast, oral substitution of creatine-monohydrate led to a significant increase of brain creatine, a decrease of brain guanidinoacetate, and a normalization of creatinine in serum and urine. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine-phosphate before oral substitution of creatine and a significant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patient's neurologic symptoms. This is the first report of a patient with complete creatine deficiency in the brain. Magnetic resonance spectroscopy during arginine and creatine treatment point to an inborn error of creatine biosynthesis at the level of guanidinoacetete-methyltransferase.

Symmetric hypoplasia of the temporal cerebral lobes in an infant with glutaric aciduria type II (multiple acyl-coenzyme A dehydrogenase deficiency).

Symmetric hypoplasia of the temporal cerebral lobes was demonstrated by magnetic resonance imaging of the brain in a macrocephalic male patient with glutaric aciduria type II within the first week of life. Psychomotor development was normal until the age of 11 months, when the patient died of sudden cardiac arrest. Autopsy revealed symmetric hypoplasia of the temporal cerebral lobes with loss of axons and hypomyelination in the temporal medullary layers.

Liposomal amphotericin-B (AmBisome) for treatment of cutaneous widespread candidosis in an infant with methylmalonic acidaemia.

In a 10-week-old infant with vitamin B12-unresponsive methylmalonic acidaemia, cutaneous candidosis (Candida albicans) progressed rapidly despite topical antifungal treatment. After 1 week of intravenous therapy with liposomal amphotericin-B (AmBisome) the dermatitis disappeared completely and blood cultures were sterile. No side-effects were observed. This is one of the first experiences in the treatment of infants with this new antifungal agent.

Mucopolysaccharidosis I and intracranial tumor in a patient with high-pressure hydrocephalus.

In a 19-month-old patient with mucopolysaccharidosis I (Pfaundler-Hurler, MPS I/H) high-pressure hydrocephalus required the implantation of a ventriculo-peritoneal shunt. Despite a reduction in both ventricular volume and intracranial pressure, clinical symptoms suggesting compression of the brain stem persisted. Brain MRI revealed a tumor within the posterior cranial fossa. Cytologic examination of the cerebrospinal fluid was suggestive of a poorly differentiated ependymoma. High-pressure hydrocephalus is a common complication in MPS I/H. As changes in mucopolysaccharide metabolism may be associated with an increased risk of developing neoplasms, the possibility of an intracranial tumor should be considered in patients with MPS I/H and high-pressure hydrocephalus.

Multiple sclerosis-like syndrome in a woman heterozygous for adrenoleukodystrophy.

A 28-year-old asymptomatic woman was diagnosed to be heterozygous for adrenoleukodystrophy (ALD) by elevated very long-chain fatty acids in serum and fibroblasts after ADL had been diagnosed in her son. A year later she had transient unilateral blurred vision. Evoked potentials and brain magnetic resonance imaging showed further separate cerebral white matter lesions suggesting multiple sclerosis (MS). MS-like syndromes in women heterozygous for ALD may be more frequent than previously recognized.

[Zellweger syndrome, neonatal adrenoleukodystrophy or infantile Refsum's disease in a case with generalized peroxisome defect?]. / Zellweger-Syndrom, neonatale Adrenoleukodystrophie oder infantile Refsumsche Erkrankung bei einem Fall mit generalisiertem Peroxisomendefekt?

An eleven month-old boy presented clinically with craniofacial dysmorphia, severe psychomotor retardation, neurological deterioration, no response to visual and acoustic stimuli, failure to thrive, hepatomegaly and adrenal insufficiency. Specific biochemical markers for a peroxisomal deficiency disorder (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease) revealed pathological results for very long chain fatty acids, phytanic acid, pristanic acid, plasmalogen biosynthesis and catalase, thus confirming the clinical diagnosis. Comparison of clinical and biochemical findings in the patient with the characteristics of the three peroxisomal deficiency disorders showed overlapping with each of these disorders, which corresponds to the current view that these three peroxisomal disorders differ only with respect to onset and severity of the clinical manifestations, but not with regard to the biochemical defects.