First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.

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ABSTRACT. Accurate diagnosis and management of in-group of conditions and not all are associated with characteristic born errors of monoamine neurotransmitter and tetrahy-findings. Indeed, some affected subjects are symptomless. In drobiopterin metabolism depend on reliable reference addition, there are a variety of conditions that may mimic the ranges of key metabolites. Cerebrospinal fluid (CSF) was clinical and/or biochemical picture but that are not due to a collected in a standardized way from 73 children and young primary defect in biopterin metabolism. adults with neurologic disease, with strict exclusions. InIn clinical practice, differential diagnosis, decisions on maneach specimen, concentrations of homovanillic acid (HVA), agement, and monitoring of therapy for the patients with the 5-hydroxyindoleacetic acid (HIAA), total neopterin, 7,8-inborn errors of BH4 metabolism are dependent on the correct dihydrobiopterin, and tetrahydrobiopterin (BH4) were choice and interpretation of biochemical investigations and remeasured using HPLC. There was a continuous decrement quire that reliable reference ranges are available for key metabin CSF HVA, HIAA, and BH4 during the first few years olites. The present article documents such ranges for the followof life; this was independent of height (or length). Age-ing metabolites in CSF: HVA, HIAA, BH4, BH2 (a metabolite related reference ranges for each metabolite are given. of BH4), and NEO (neopterin plus 7,8-dihydroneopterin, derivExtensive correlations between HVA, HIAA, 7,8-dihydro-atives of the BH4 precursor dihydroneopterin triphosphate). biopterin, and BH4 were further analyzed by multiple Although pediatric reference ranges have been established for regression. Age and CSF BH4 were significant explanatory CSF amine metabolites (3-7) and for total biopterins and neopvariables for CSF HIAA, but CSF I-IVA had only HIAA terins (8-12), these have never been generated using the same as a significant explanatory variable. (Pediatr Res 34: 10-CSF samples; therefore, close study of the relationship between 14,1993) these variables has not been possible. These relationships are carefully examined in the present article. Abbreviations MATERIALS AND METHODS

The neurologic complications of cystathionine beta-synthase deficiency are thought to be secondary to accumulation of homocyst(e)ine in the CNS. Treatment of this disorder with betaine has been shown to improve the behavior of individuals, to reduce plasma total homocysteine, and to correct secondary abnormalities of serine. To test the hypothesis that homocyst(e)ine accumulates within the CNS and that this can be reduced by treatment with betaine, we measured total homocysteine and related metabolites in the plasma of 10 children with cystathionine beta-synthase deficiency and cerebrospinal fluid of five children before and during betaine therapy. In plasma, betaine significantly lowered total homocysteine (but not to the normal range) and had a variable effect on methionine. In the cerebrospinal fluid, total homocysteine was raised before treatment (mean 1.2 microM) and was significantly reduced by betaine (mean 0.32 microM) but not to the normal range (<0.10 microM). Cerebrospinal fluid methionine was raised before and during treatment, but betaine did not cause a significant further increase. Cerebrospinal fluid serine was significantly reduced before treatment and rose to the normal range with betaine. Cerebrospinal fluid S-adenosylmethionine was normal before treatment and rose significantly with treatment; there were no significant changes in cerebrospinal fluid 5-methyltetrahydrofolate. The demonstration of accumulation of homocysteine within the CNS lends support to the hypothesis that this may be one cause of the neurologic complications of cystathionine beta-synthase deficiency. Betaine is effective in reducing cerebrospinal fluid homocysteine, but concentrations are still significantly raised during treatment.