Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype. Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired rotarod performance. Central nervous system (CNS) histology was grossly intact, but CNS myelination was delayed and overall myelin volume was decreased. Heme concentrations in liver and brain were similar to those of T1/T2 mice. Notably, ALA and PBG concentrations in the cerebral spinal fluid and CNS regions were markedly elevated in R167Q+/+ mice compared with T1/T2 mice. When the T1/T2 mice were administered phenobarbital, ALA and PBG markedly accumulated in their liver and plasma, but not in the CNS, indicating that ALA and PBG do not readily cross the blood-brain barrier. Taken together, these studies suggest that the severe HD-AIP neurological phenotype results from decreased myelination and the accumulation of locally produced neurotoxic porphyrin precursors within the CNS.

Urine sepiapterin excretion as a new diagnostic marker for sepiapterin reductase deficiency.

Sepiapterin reductase deficiency (SRD) causes depletion of biogenic amines in the brain, early onset motor disorder, and intellectual disability. The diagnostic marker for this rare disease is increased sepiapterin and biopterin in CSF. Through a new analytic methodology we demonstrated accumulation of sepiapterin in urine of four SRD patients several times greater than that found in healthy controls and carriers, regardless of age or treatment. Our findings suggest a new interpretation of current theories of peripheral pterin metabolism and provide a new noninvasive diagnostic tool for children with early onset cryptogenetic developmental delay and/or movement disorder.

Mild hypohydration increases the frequency of driver errors during a prolonged, monotonous driving task.

UNLABELLED: The aim of the present study was to examine the effect of mild hypohydration on performance during a prolonged, monotonous driving task. METHODS: Eleven healthy males (age 22±4y) were instructed to consume a volume of fluid in line with published guidelines (HYD trial) or 25% of this intake (FR trial) in a crossover manner. Participants came to the laboratory the following morning after an overnight fast. One hour following a standard breakfast, a 120min driving simulation task began. Driver errors, including instances of lane drifting or late breaking, EEG and heart rate were recorded throughout the driving task RESULTS: Pre-trial body mass (P=0.692), urine osmolality (P=0.838) and serum osmolality (P=0.574) were the same on both trials. FR resulted in a 1.1±0.7% reduction in body mass, compared to -0.1±0.6% in the HYD trial (P=0.002). Urine and serum osmolality were both increased following FR (P<0.05). There was a progressive increase in the total number of driver errors observed during both the HYD and FR trials, but significantly more incidents were recorded throughout the FR trial (HYD 47±44, FR 101±84; ES=0.81; P=0.006) CONCLUSIONS: The results of the present study suggest that mild hypohydration, produced a significant increase in minor driving errors during a prolonged, monotonous drive, compared to that observed while performing the same task in a hydrated condition. The magnitude of decrement reported, was similar to that observed following the ingestion of an alcoholic beverage resulting in a blood alcohol content of approximately 0.08% (the current UK legal driving limit), or while sleep deprived.

[Methylmalonic aciduria associated with myoclonic convulsions, psychomotor retardation and hypsarrhythmia]. / Aciduria metilmalónica asociada a convulsiones mioclónicas, retraso psicomotor e hipsarritmia.

INTRODUCTION: Organic acidurias have long been known to cause neurological problems, such as convulsions, stupor, coma, and psychomotor and mental retardation. The organic acidurias include propionic aciduria, methylmalonic aciduria (MMA), isovaleric acidemia, lactic acidemia and glutaric acidemia type I. However, the association of MMA with electrical activity of the brain characterised by a hypsarrhythmic pattern, refractory convulsions and psychomotor retardation is very rare. CASE REPORTS: Two patients, one male and one female, were seen to have psychomotor retardation, erratic attacks of myoclonic convulsions, hypsarrhythmic encephalographic pattern and an increase in the urinary excretion of methylmalonic acid, as shown by gas chromatography and mass spectrometry, all of which supported a diagnosis of MMA in both cases. In one patient, the brain MRI with gadolinium showed lesions compatible with brain atrophy. Protein restrictions, the administration of vitamin B12 and l carnitine re established the normal neurological state and reduced the urinary excretion of methylmalonic acid in one of them. CONCLUSIONS: To the best of our knowledge these are the first cases of MMA that have been seen accompanied by hypsarrhythmia. The rareness of this clinical presentation with the characteristics described above make us suspect that we are dealing with a new clinical syndrome.

Melatonin production in infants.

This study investigated the relationships of the excretion of the melatonin metabolite, 6-sulfatoxymelatonin, to prenatal, natal, and postnatal variables and its possible relation to psychomotor development. nocturnal urinary excretion of 6-sulfatoxymelatonin was studied over a 13-hour period in 355 term infants at 8 weeks of age (n = 320) and 16 weeks of age (n = 96). data on a variety of perinatal factors including pregnancy course, delivery, early postnatal course, birth weight, medical problems, growth (length, weight, and head circumference), and psychomotor development were collected at 1, 3, 6, 9, 12, and 18 months. the relationship between nocturnal 6-sulfatoxymelatonin excretion at 8 and 16 weeks of age and these factors was investigated and analyzed. 6-sulfatoxymelatonin levels at 16 weeks of age were significantly lower in infants with abnormal vs normal development at 3 months of age (7.27 + 1.44 vs 7.97 + 1.06, p = 0.05) as well as at 6 months of age (7.15 + 1.29 vs 7.95 + 1.10, p = 0.04). no other significant relation was evident among growth, perinatal complications, medical problems, and 6-sulfatoxymelatonin excretion at 8 weeks of age and at 16 weeks of age. low melatonin excretion in the first weeks of life correlates with delayed psychomotor achievements at 3 and 6 months of age. this association suggests a causal or predictive link between melatonin and neurodevelopment in infants.

Methylmalonic semialdehyde dehydrogenase deficiency: psychomotor delay and methylmalonic aciduria without metabolic decompensation.

A patient presenting with developmental delay but no episodes of metabolic acidosis was found to excrete significant amounts of methylmalonate (MMA) without any associated increased excretion of malonate, ethylmalonate, 3-hydroxypropionate, or beta-alanine. In contrast to patients with methylmalonic aciduria due to deficient mutase or impaired cobalamin metabolism, there was no increase of propionylcarnitine in blood or urine. The activity of methylmalonyl-CoA mutase and the pathway for cobalamin metabolism were also intact. The quantitative levels of the various labeled enantiomers of 3-hydroxyisobutyric (3-HIBA), 3-aminoisobutyric (3-AIBA), MMA, and propionylcarnitine were compared following separate intravenous infusions of equimolar doses of [2H8]-valine or [2H4]thymine in this patient and another with methylmalonyl-CoA mutase deficiency. Levels of labeled S- and R-3-HIBA and S- and R-3-AIBA indicated an isolated defect in methylmalonic semialdehyde dehydrogenase in this patient. This condition can be recognized by plasma MMA levels of approximately 8.5 microM (cf. 400 microM in mutase deficiency), urine MMA of 20-55 micromol/kg/24 h (cf. 1150 micromol/kg/24 h), no increase in propionylcarnitine following an oral carnitine load, and increased excretion of S-3-AIBA-nearly 10 times that observed in mutase deficiency. The ratio of R-AIBA to S-AIBA of <1 also reflects this disorder.

Melatonin treatment in an institutionalised child with psychomotor retardation and an irregular sleep-wake pattern.

An institutionalised 13 year old girl with psychomotor retardation suffered from an irregular sleep-wake pattern. Multiple measurements of urinary sulphatoxy-melatonin (aMT6) concentrations were abnormally low, without any significant day-night differences. Administration of exogenous melatonin (3 mg) at 18:00 resulted in increased nocturnal urinary aMT6 concentrations and improvements in her sleep-wake pattern. Melatonin may help disabled children suffering from sleep disorders.

Urinary MHPG and clinical symptoms in patients with unipolar depression.

The relationship between levels of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) and symptom scores on the Hamilton Rating Scale for Depression was examined in 31 patients with unipolar depression. Patients with either low MHPG or high MHPG showed significant sleep disturbance in the form of early morning awakening. Patients with mid-range or high MHPG showed decreased work and activities. Endogenomorphy factor scores represented a blend of these findings.

Urinary adenosine 3',5'-monophosphate in the switch process from depression to mania.

Marked elevations of urinary adenosine 3',5'-monophosphate occurred on the day of rapid switch from a depressed into a manic state in patients with manic-depressive illness. It is suggested that this increase might serve a trigger function for the process by which catecholamines are elevated during the manic phase of the illness.