Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross-sectional study.

BACKGROUND: Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. Detailed long-term neurological outcome is unknown. Here we present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. METHODS: Neurological outcome was assessed in 24 patients (age 1-26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Intelligence quotient (IQ) was derived from standardized IQ tests with five severity levels of intellectual disability (ID). MRI's and treatments were assessed. RESULTS: Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Minor coordination problems were identified in 17 (71%), fine motor disability in 11 (46%), posture/muscle tone deviancies in 11 (46%) and abnormal reflexes in 8 (33%). Six patients (25%) had an IQ > 85, 7 (29%) borderline, 7 (29%) mild, 3 (13%) moderate, and 1 severe ID. Cerebral ventriculomegaly on MRI was progressive in 11. Three patients showed normal neurologic exam, IQ, and MRI. Eleven patients were treated with pyridoxine only and 13 by additional lysine reduction therapy (LRT). LRT started at age <3 years demonstrated beneficial effect on IQ results in 3 patients. DISCUSSION: Complex MND and CP occurred more frequently in PDE-ALDH7A1 (46% and 12%) than in general population (7% and 0.2%, Peters et al., 2011, Schaefer et al., 2008). Twenty-five percent had a normal IQ. Although LRT shows potential to improve outcomes, data are heterogeneous in small patient numbers. More research with longer follow-up via the International PDE Registry (www.pdeonline.org) is needed.

MR spectroscopy and diffusion tensor imaging of the brain in Sjögren-Larsson syndrome.

Diffusion tensor imaging (DTI) is reported for the first time in a patient with Sjögren-Larsson syndrome, an autosomal recessive neurocutaneous disorder. Magnetic resonance spectroscopy (MRS) revealed normal levels of choline, creatine and N-acetyl aspartate (NAA) and the characteristic lipid signals in the white matter brain tissue. Conventional MRI showed increased signal intensity around the lateral ventricles indicating abnormal myelination. DTI revealed normal apparent diffusion coefficient (ADC) values, but reduced fractional anisotropy (FA) in the white matter. After co-registration of the parameters obtained with DTI with the results of MRS (36 voxels), significant correlations were obtained of lipid content with FA (r=0.81), ADC (r=-0.62), choline (r=0.51), and NAA (r=0.44) (P<0.01, all). These results suggest that in Sjögren-Larsson syndrome, the white matter lipid signals originate from the neurons, with NAA and choline reflecting neuron density and myelination. The comparatively high FA/low ADC values in these lipid-rich locations, indicate a loss of diffusion in directions perpendicular to the fibers. The overall loss of FA in the white matter may reflect a loss of brain tissue water content in SLS patients compared with controls and precede the formation of atrophy.

MR spectroscopy of the brain in Leigh syndrome.

Brain magnetic resonance spectroscopy in two patients with Leigh syndrome revealed the presence of lactate in gray and white matter brain tissue and relatively high choline levels in the white matter. The latter observation, most probably related to an ongoing demyelination process, underlines specific involvement of white matter metabolism in Leigh syndrome even in cases without involvement of the white matter as visualized on MRI. Magnetic resonance spectroscopy might thus be of help in differentiating Leigh syndrome from a range of other mitochondrial diseases, such as ophthalmoplegia and Kearns-Sayre syndrome, showing lack of lactate in brain tissues appearing normal on MRI.

Instrumented finger-to-nose test classification in children with ataxia or developmental coordination disorder and controls.

BACKGROUND: During childhood, many conditions may impact coordination. Examples are physiological age-related development and pathological conditions, such as early onset ataxia and developmental coordination disorder. These conditions are generally diagnosed by clinical specialists. However, in absence of a gold phenotypic standard, objective reproducibility among specialists appears limited. METHODS: We investigated whether quantitative analysis of an upper limb coordination task (the finger-to-nose test) could discriminate between physiological and pathological conditions impacting coordination. We used inertial measurement units to estimate movement trajectories of the participants while they executed the finger-to-nose test. We employed random forests to classify each participant in one category. FINDINGS: On average, 87.4% of controls, 74.4% of early onset ataxia and 24.8% of developmental coordination disorder patients were correctly classified. The relatively good classification of early onset ataxia patients and controls contrasts with the poor classification of developmental coordination disorder patients. INTERPRETATION: In absence of a gold phenotypic standard for developmental coordination disorder recognition, it remains elusive whether the finger-to-nose test in these patients represents a sufficiently accurate entity to reflect symptoms distinctive of this disorder. Based on the relatively good results in early onset ataxia patients and controls, we conclude that quantitative analysis of the finger-to-nose test can provide a reliable support tool during the assessment of phenotypic early onset ataxia.

Pyridoxine dependent epilepsy: Is late onset a predictor for favorable outcome?

AIM: In pyridoxine dependent epilepsy (PDE), patients usually present with neonatal seizures. A small subgroup is characterized by late-onset beyond 2 months of age. We aim to analyze the observation of relatively good cognitive outcome in this subgroup of late-onset PDE patients. METHODS: We retrospectively analyzed data from four metabolically and genetically confirmed late-onset patients with PDE due to antiquitin (ALDH7A1) deficiency. Data were analyzed regarding ALDH7A1 mutations, alpha-Aminoadipic semialdehyde (α-AASA) and pipecolic acid (PA) levels, medication during pregnancy, delivery, treatment delay, amount of seizures, pyridoxine dose, adjuvant therapy and findings on brain MRI. RESULTS: Results showed that three patients had relatively good outcome (IQ 80-97), while one patient did not undergo formal testing and was considered mildly delayed. We were unable to find a clear association between the above-mentioned variables and cognitive outcome, although a less severe genotype may be present in three patients, and maternal medication could be accountable for better outcome in two patients. INTERPRETATION: We suggest that favorable outcome in late onset PDE might be explained by a combination of factors. A yet unknown protective factor, different genetic variations, functional variation and secondarily variation in treatment regimens and absence of neonatal seizure induced brain damage.

Neurobehavioral relationships and puberty: another transformation?

In a follow-up study of the Groningen Perinatal Project (GPP) on minor neurological dysfunction (MND) at 12 and 14 years the onset of puberty appeared to play a role. The children were selected on the presence (n = 185) and absence (n = 185) of MND at 9 years. Puberty was defined by the presence of three or more physical puberty signs. With the onset of puberty the incidence of MND decreased. The neurobehavioral relationships became more explicit after the onset of puberty. All types of MND were related to behavioural and cognitive problems at this developmental stage. In normal children, boys showed an increase of strength during puberty whereas the movements of girls became more fluent. The apparent changes in neurological function during puberty were interpreted as a transformation of the central nervous system. The possible causes are discussed. The conclusion is that gonadal hormones and especially oestrogens, play a role. The fact that two-thirds of the children with MND and behavioural problems outgrow the problems during puberty, can be of great help. Finally, any longitudinal study of brain function, which includes the age of puberty, should pay attention to the pubescent stage.

Minor neurological dysfunction after the onset of puberty: association with perinatal events.

In order to study the hypotheses that puberty is related to a decrease of minor neurological dysfunction (MND) and that persisting MND is associated with perinatal factors, two groups (174 normal, 172 MND) of the Groningen Perinatal Project were followed from 12 to 14 years. At 14 years almost all the children had entered puberty (n = 329) defined as the presence of three or more puberty signs. In the MND group 55% of the children were normal at 14 years and in 45% MND signs were still present, though in a less extensive form. The latter phenomenon was most clear in children who had just begun puberty. The effect of puberty was similar in both sexes. MND which persisted into puberty was related to neonatal neurological deviancy, lower social class, lower obstetrical optimality score and male sex. After differentiation with specific MND clusters, it appeared that fine manipulative disability was associated with neonatal neurological deviancy, with minor physical anomalies and with lower social class; choreiform dyskinesia with asphyxia; hypotonia with constitutionally related factors; and coordination problems with pre-maturity (< 32 weeks).

Cerebral 1H MR spectroscopy showing elevation of brain guanidinoacetate in argininosuccinate lyase deficiency.

MR spectroscopy in a patient with argininosuccinate lyase deficiency revealed elevated cerebral guanidinoacetate signals, indicating that the phenomenon of increased levels of this compound in brain tissue is not limited to creatine deficiencies.

High cerebral guanidinoacetate and variable creatine concentrations in argininosuccinate synthetase and lyase deficiency: implications for treatment?

Cerebral creatine and guanidinoacetate and blood and urine metabolites were studied in four patients with argininosuccinate synthetase (ASS) or argininosuccinate lyase (ASL) deficiency receiving large doses of arginine. Urine and blood metabolites varied largely. Cerebral guanidinoacetate was increased in all patients, while cerebral creatine was low in ASS and high in ASL deficiency. Because high cerebral guanidinoacetate might be toxic, lowering the arginine supplementation with additional creatine supplementation might be important.

1H chemical shift imaging of the brain in guanidino methyltransferase deficiency, a creatine deficiency syndrome; guanidinoacetate accumulation in the gray matter.

MR spectroscopy results in a mild case of guanidinoacetate methyltransferase (GAMT) deficiency are presented. The approach differs from previous MRS studies in the acquisition of a chemical shift imaging spectral map showing gray and white matter with the corresponding spectra in one overview. MR spectroscopy revealed guanidinoacetate (GAA) in the absence of creatine. New is that GAA signals are more prominent in gray matter than in white. In the prevailing view, that enzyme deficiency is localized in liver and pancreas and that all GAA is transported into the brain from the blood and the cerebrospinal fluid, this would be compatible with a more limited uptake and/or better clearance of GAA from the white matter compared to the grey matter.

Normal very-long-chain fatty acids in peroxisomal D-bifunctional protein deficiency: a diagnostic pitfall.

We present a relatively mild case of peroxisomal D-bifunctional protein deficiency with inconsistent screening results in plasma for peroxisomal disorders.

Nocturnal enuresis and minor neurological dysfunction at 12 years: a follow-up study.

On follow-up at 12 years to assess the relationship between minor neurological dysfunction (MND) and primary nocturnal enuresis (NE), the frequency of NE was found to be significantly higher in children with MND (N = 167) than in those who were neurologically normal (N = 174). There was no relationship between NE and sex in the MND group, nor with the neonatal neurological condition. Among MND children, those with NE more often had language comprehension and arithmetic problems and they required special help for behavioural problems more than did those without such problems. The relationship between NE and MND was affected by socio-economic class and family history. It is concluded that children with MND are more vulnerable to NE, particularly in the presence of lower social class and a positive family history.

Minor neurological dysfunction from birth to 12 years. I: Increase during late school-age.

To study the hypothesis that the frequency of minor neurological dysfunction (MND) stabilizes around the age of nine years, two groups of the Groningen Perinatal Project (GPP) were re-examined at 12 years. The study group (N = 174) was selected on the basis of the presence of MND at nine years; the control group comprised 172 neurologically normal children. The hypothesis was rejected: extrapolation of the findings to the total GPP population showed that the over-all rate of MND increased. Control children who developed MND were mainly boys who had been neurologically abnormal at birth or were born preterm and/or had experienced an adversity in combination with asphyxia. Interval complications between nine and 12 years were related to the emergence of MND.

Minor neurological dysfunction from birth to 12 years. II: Puberty is related to decreased dysfunction.

To determine whether puberty is related to decreased minor neurological dysfunction (MND), 174 children from the Groningen Perinatal Project who had had MND at nine years were re-examined at 12 years. No signs of MND could be demonstrated in 39 of the children, 33 of whom showed at least three signs of puberty. The presence of minor physical anomalies was associated with persisting MND. The authors hypothesise that puberty is related to a decrease in MND, and discuss the role of hormonal changes in relation to the decrease in minor signs. Re-examination at 14 years will be necessary to confirm this hypothesis, since 68 per cent of the children had not yet reached puberty. Children with MND reached puberty no later than those without.

Neuroglycopenia in normoglycaemic patients, and the potential benefit of ketosis.

We report a patient with recurrent symptoms of neuroglycopenia due to a defective glucose transport into brain. The potential benefit of ketosis in neuroglycopenia is discussed from the therapeutic concept of a ketogenic diet in GLUT1-deficiency syndrome.

Neurobehavioural relationships after the onset of puberty.

The behavioural and cognitive development were studied of 68 children with and 259 without minor neurological function (MND) at 14 years, when the majority of children showed three or more physical signs of puberty. MND was differentiated into fine manipulative disability, co-ordination problems, choreiform dyskinesia and hypotonia. The normal group was subdivided into those who had been normal at 12 years and those who had had MND. All types of MND were related to cognitive and behavioural problems. Fine manipulative disability was related to behavioural and cognitive difficulties; co-ordination problems to learning difficulties; and choreiform dyskinesia and hypotonia were related to attention difficulties and school failure, notwithstanding normal IQ. Besides MND, socio-economic class, family adversities and female gender contributed to the development of behavioural and cognitive problems. The behaviour of children with MND at 12 years who were normal at 14 years did not differ from that of normal children.

Is minor neurological dysfunction at 12 years related to behaviour and cognition?

Behavioural and cognitive development at 12 years were studied in 172 children with and 174 children without minor neurological dysfunction (MND). MND could be differentiated into fine manipulative disability, co-ordination problems, hypotonia and choreiform dyskinesia. Fine manipulative disability related significantly to problems of cognition and behaviour; co-ordination problems to cognitive problems; and hypotonia and choreiform dyskinesia to behavioural problems, the former more than the latter. Socio-economic status and family adversity contributed to the risk for development of both cognitive and behavioural problems; gender did not. The onset of puberty seemed to change these relationships: follow-up is needed for definite conclusions.