Spinal manifestations of CLN1 disease start during the early postnatal period.

AIM: To understand the progression of CLN1 disease and develop effective therapies we need to characterize early sites of pathology. Therefore, we performed a comprehensive evaluation of the nature and timing of early CLN1 disease pathology in the spinal cord, which appears especially vulnerable, and how this may affect behaviour. METHODS: We measured the spinal volume and neuronal number, and quantified glial activation, lymphocyte infiltration and oligodendrocyte maturation, as well as cytokine profile analysis during the early stages of pathology in Ppt1-deficient (Ppt1-/- ) mouse spinal cords. We then performed quantitative gait analysis and open-field behaviour tests to investigate the behavioural correlates during this period. RESULTS: We detected significant microglial activation in Ppt1-/- spinal cords at 1 month. This was followed by astrocytosis, selective interneuron loss, altered spinal volumes and oligodendrocyte maturation at 2 months, before significant storage material accumulation and lymphocyte infiltration at 3 months. The same time course was apparent for inflammatory cytokine expression that was altered as early as one month. There was a transient early period at 2 months when Ppt1-/- mice had a significantly altered gait that resembles the presentation in children with CLN1 disease. This occurred before an anticipated decline in overall locomotor performance across all ages. CONCLUSION: These data reveal disease onset 2 months (25% of life-span) earlier than expected, while spinal maturation is still ongoing. Our multi-disciplinary data provide new insights into the spatio-temporal staging of CLN1 pathogenesis during ongoing postnatal maturation, and highlight the need to deliver therapies during the presymptomatic period.

Neuropsychology and brain morphology in Klinefelter syndrome - the impact of genetics.

Klinefelter syndrome (KS, 47,XXY) is associated with increased psychiatric morbidity and cognitive disabilities, although the neuropsychological phenotype shows great variability. Androgen receptor polymorphism (CAG repeat length), skewed X-chromosome inactivation and parent-of-origin of the extra X-chromosome have been suggested to influence cognitive function and psychological traits. These issues have not been clarified for KS patients. We studied X-chromosome inactivation pattern, CAG repeat length and parent-of-origin in relation to educational and cohabitation status, personality and autism traits, psychological distress, cognitive function and brain volumes in 73 KS patients and 73 controls. Grey matter (GM) volume of left insula was significantly decreased in KS patients with skewed X-inactivation (z = 5.78) and we observed a borderline significant difference in global brain matter volume where KS patients with skewed X-chromosome inactivation tended to have smaller brains. Skewed X-inactivation, CAG repeat length and parent-of-origin were not correlated with educational and marital status, personality traits, autism traits, and psychological distress, prevalence of depression and anxiety or cognitive function. Interestingly our results regarding brain volumes indicate that X-inactivation has an influence on GM volume in left insula and might also be related to global GM volume, indicating a possible effect of X-linked genes on the development of GM volume in KS patient. Skewed X-inactivation, CAG repeat length and parent-of-origin have no impact on the neuropsychological phenotype in KS (http://www.clinicaltrials.gov (Clinical trial NCT00999310)).

The efficacy and safety of long-term Norditropin® treatment in children with Prader-Willi syndrome.

Prader-Willi syndrome is a genetic disorder that is associated with short stature, partial growth hormone deficiency, small hands and feet, learning and behavioural problems, and hyperphagia leading to severe, often morbid, obesity. Growth hormone therapy is associated with an improvement in height and body composition. We evaluated the efficacy and safety of long-term growth hormone treatment in a retrospective observational multinational study of 41 prepubertal children (mean age 3.8±3.0 years) with genetically diagnosed Prader-Willi syndrome treated with growth hormone (0.03-0.06 mg/kg/day) for >12 months [mean duration 4.1 (range 0.9-9.5) years]. Height, weight, and body composition measurements were recorded at baseline and at 6 month intervals until last observation. Mean (SD) gain in height at 12 months was 0.9 (0.2) SD score (p<0.0001). At last observation (after approximately 6 years) mean gain in height was 1.3 (0.3) (p=0.0001) with 85% of children achieving height>- 2 SD score. Body composition improved during treatment with an estimated 9.1% increase in lean body mass and 9.1% decrease in fat mass at last observation (p=0.019). Scoliosis was reported in 3 patients at baseline and 8 patients at last observation. Sleep apnoea was recorded in 3 (7.3%) patients. There were no other severe adverse events reported. Long-term growth hormone treatment of prepubertal children with Prader-Willi syndrome was associated with significant improvements in height and body composition. Treatment was well tolerated. The development of scoliosis warrants monitoring by an orthopaedic specialist.

Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease).

OBJECTIVE: To explore the onset and progression of cardiac involvement in juvenile neuronal ceroid lipofuscinosis (JNCL). METHODS: The study population comprised an unselected group of 29 children and adolescents with genetically verified JNCL. We focused on T-wave abnormalities on an EKG, cardiac hypertrophy, and left ventricular systolic function on echocardiography, and heart rates and heart rate variability (HRV) on 24-hour EKG recordings. The surviving patients were observed for 7½ years. The 24-hour EKG recording was repeated after 3 years. RESULTS: Abnormally deeply inverted T waves were present in one-third of the initial EKG recordings and were reported as early as 14 years of age. We found coherence between the presence of repolarization disturbances of the ventricular myocardium at the initial recordings and risk of death during the observation period. At increasing age, heart rate and HRV, expressed as the vagal index (number of adjacent RR intervals deviating more than 6%), were significantly reduced, suggesting an age-dependent bidirectional effect of JNCL on heart rate: one through decreasing parasympathetic activity on the heart and the other through a direct negative influence on sinus node automaticity. Coherence between bradycardia and arrhythmia and occurrence of sinus arrests and atrial flutter with increasing age indicated an age-dependent decrease in sinus node activity also. In the early 20s, a high frequency of ventricular hypertrophy occurred. CONCLUSIONS: Progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus node dysfunction occur in JNCL. We recommend that the attention on heart involvement in JNCL and other neuronal ceroid lipofuscinosis subtypes should be intensified.

Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.

BACKGROUND: Episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are autosomal dominant disorders characterised by paroxysmal ataxia and migraine, respectively. Point mutations in CACNA1A, which encodes the neuronal P/Q-type calcium channel, have been detected in many cases of EA2 and FHM1. The genetic basis of typical cases without CACNA1A point mutations is not fully known. Standard DNA sequencing methods may miss large scale genetic rearrangements such as deletions and duplications. The authors investigated whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1. METHODS: The authors used multiplex ligation dependent probe amplification (MLPA) to screen for intragenic CACNA1A rearrangements. RESULTS: The authors identified five previously unreported large scale deletions in CACNA1A in seven families with episodic ataxia and in one case with hemiplegic migraine. One of the deletions (exon 6 of CACNA1A) segregated with episodic ataxia in a four generation family with eight affected individuals previously mapped to 19p13. In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia. CONCLUSIONS: Large scale deletions and duplications can cause CACNA1A associated channelopathies. Direct DNA sequencing alone is not sufficient as a diagnostic screening test.

[The molecular genetic background of hereditary craniosynostoses and chondrodysplasias]. / Den molekylaergenetiske baggrund for en raekke arvelige kraniosynostoser og kondrodysplasier.

Fibroblast growth factors are structurally related proteins associated with cell growth, differentiation, migration, wound healing, angiogenesis, and oncogenesis. At the cellular level, their function is mediated by transmembrane tyrosinekinase receptors, fibroblast growth factor receptors. Four genes encoding fibroblast growth factor receptors have been identified, and mutations in three of these, FGFR1, FGFR2, and FGFR3, can cause different congenital, autosomal dominant disorders affecting the craniofacial and skeletal development: craniosynostosis and chondrodysplasias. The craniosynostosis syndromes: Apert syndrome, Beare-Stevenson syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Muenke syndrome, Pfeiffer syndrome and Saethre-Chotzen syndrome can be caused by mutation in either FGFR1, FGFR2, or FGFR3. Saethre-Chotzen syndrome can also be caused by mutation in a functionally related gene, ACS. The same mutation can cause different syndromes, and the same syndrome can be caused by mutations in different genes. The chondrodysplasias: achondroplasia, hypochondroplasia, and thanatophoric dysplasia are all caused by mutations in FGFR3.

Fertility in Prader-Willi syndrome: a case report with Angelman syndrome in the offspring.

UNLABELLED: We report on a 32-y-old woman with Prader-Willi syndrome (PWS) and her daughter with Angelman syndrome (AS). PWS in the mother was confirmed as due to a deletion of 15q11-q13, and molecular analysis in the neonate indicated an inherited maternal deletion of the same region. Features of AS in early infancy, such as jerky movements, feeding problems and poor sleep, were observed. At 5 mo of age, a triphasic high voltage EEG pattern was reported. CONCLUSIONS: This case confirms the non-Mendelian inheritance of PWS and AS and, in addition to previous reports, provides evidence of fertility in PWS women. We recommend the provision of information regarding fertility in females with PWS to parents, guardians and individuals with PWS, and frequent EEG monitoring for early AS diagnosis. Given the different genetic aetiologies for PWS and AS, cytogenetic and molecular genetic analysis is strongly indicated for counselling and risk estimation.

Epilepsy and pregnancy: effect of antiepileptic drugs and lifestyle on birthweight.

OBJECTIVE: To investigate the impact of epilepsy and antiepileptic drugs on length of gestation and anthropometric measures of the newborn. DESIGN: Cohort study based on questionnaires mailed to all pregnant women who attended for prenatal care at our department from August 1989 to January 1997. SETTING: Department of Obstetrics and Gynaecology at Aarhus University Hospital, Denmark. PARTICIPANTS: One hundred and ninety-three singleton pregnancies in women with epilepsy were compared with 24,094 singleton pregnancies in women without epilepsy. MAIN OUTCOME MEASURES: Preterm delivery, small for gestational age, mean gestational age, gestational age-adjusted birthweight, head circumference, and body length. RESULTS: Children of women with epilepsy who smoked had lower gestational age and were at increased risk of preterm delivery (OR 3.4; 95% CI 1.8-6.5), compared with children born by nonepileptic women who smoked. Birthweight adjusted for gestational age was reduced by 102 g (95% CI 40-164) in women with epilepsy, and the risk of delivering a child who was small for gestational age was increased (adjusted OR 1.9, 95% CI 1.3-2.7), compared with women without epilepsy. Newborn babies of women with epilepsy treated by drugs had a reduced adjusted birthweight (208 g, 95% CI 116-300), head circumference (0.4 cm, 95% CI 0.0-0.7), and body length (0.5 cm, 95% CI 0.1-1.0), compared with the newborn infants of women without epilepsy. CONCLUSIONS: Women with epilepsy who smoked were at increased risk of preterm delivery compared with healthy smokers. Children of women with drug treated epilepsy had lower birthweight, length, and head circumference than children of women without epilepsy.

[The objective structured clinical examination in postgraduate pediatric training. The first Danish experiences]. / Den objektive strukturerede kliniske eksamen som led i speciallaegeuddannelsen i paediatri. De første danske erfaringer.

To evaluate the usefulness of an objective structured clinical examination (OSCE) for identifying weaknesses of the educational program and for providing feedback to trainees in paediatrics an 8-station OSCE was given. Ten residents on different levels of training participated. Stations covered a wide spectrum of clinical situations and included three video-recordings of patients. Skills in history-taking, examination, listing of differential diagnoses, planning of work-up as well as in communication and counselling were assessed. Verbal as well as written feedback was provided to all the trainees. In five trainees skills in examination were relatively weak, and subsequently it was possible to implement improvements in the educational program. Strengths and weaknesses of the educational program can be identified, but the benefits of the OSCE should be balanced with the extra workload and logistical difficulties.

Smoking during pregnancy and hospitalization of the child.

OBJECTIVES: To study the association between smoking during pregnancy and hospitalization of the child before 8 months of age. DESIGN: A follow-up study of 1974 children born in 1991 and 1992. RESULTS: Overall, 158 (8%) of the children were hospitalized during the first 8 months of life. Compared with children whose mothers did not smoke during pregnancy, children with mothers who smoked 1 to 14 cigarettes per day had no increased risk of being hospitalized (relative risk: 1.1; 95% confidence interval: 0.8-1.5), whereas children whose mothers smoked 15 or more cigarettes per day had twice as high a risk of being hospitalized (relative risk: 2.0; 95% confidence interval: 1.2-3.3). When only hospitalizations before 2 months of age were analyzed, smoking during pregnancy was associated an increased risk similar to that described above. Hospitalization of the child was independent of the smoking habits of the father, and an increased risk of hospitalization associated with smoking was found not only among children with symptoms from the respiratory system but also among children with symptoms from the gastrointestinal system and the skin. The association between smoking during pregancy and hospitalization of the child persisted after adjustment for postpartum smoking habits and a number of socio-demographic and lifestyle factors. CONCLUSIONS: Smoking 15 or more cigarettes per day during pregnancy influenced the health of the children, and several points indicated that the effect of in utero exposure was independent of postpartum smoking habits. If all pregnant women smoking 15 or more cigarettes per day stopped smoking, approximately 5% of all admissions to hospitals before 8 months of age could be avoided. smoking during pregnancy, hospitalization of children.

A distinct difference in clinical expression of two siblings with Aicardi-Goutières syndrome.

Two sibs with an encephalopathy, including intracerebral calcification and a white matter disease, are reported. In the younger sister, the cerebrospinal fluid showed chronic pleocytosis and clinically she strictly fits to the diagnosis of Aicardi-Goutières syndrome. Both sisters were affected by a spastic tetraplegia, truncal hypotonia and dystonic posturing, but the clinical course and the neuroradiological findings were milder in the older sister and she showed no cerebrospinal fluid pleocytosis. The present cases and recent reports of intrafamilial variability of Aicardi-Goutières syndrome may raise interesting aspects as to the limits and criteria of this syndrome.

[Benign paroxysmal torticollis. Recurrent involuntary twisting of the head in infants and young children]. / Benign paroksystisk torticollis. Recidiverende tvangsholdning af hovedet hos spoed- og småbørn.

Benign paroxysmal torticollis occurs in infancy and early childhood. The etiology is unknown, although a vasomotor labyrinthine pathophysiology is possible. We report four cases with onset at ages of two to six months of recurrent episodes of torticollis and discomfort persisting between three hours and seven days. In three cases the torticollis was alternating. Photography or videorecording made by the parents during the attacks were helpful for the diagnosis in three cases. MRI may in some cases be necessary to rule out a space occupying lesion in the posterior fossa.

[Juvenile neuronal ceroid lipofuscinosis]. / Juvenil neuronal ceroid lipofuscinosis.

Neuronal ceroid-lipofuscinosis is a group of neurodegenerative diseases which are characterized by an abnormal accumulation of lipopigment in neuronal and extraneuronal cells. The diseases can be differentiated into several subgroups according to age of onset, the clinical picture, neurophysiological and neuropathological abnormalities and ultrastructural studies documenting different profiles of the lipopigment. Several eponyms have been used in the designation of the diseases. Latest, an international designation abbreviated CLN has been recommended, with the addition of figures according to the subtypes. The most common type in Denmark is CLN3, also called Spielmeyer-Vogt's disease. The incidence is 1.6 per 100,000. It is characterized by slowly progressing behavioral and visual symptoms that start when the child is about four to nine years old. During the second decade of life, the disease is accompanied by seizures and severe psychomotor deterioration. Most patients die before the age of 30 years. Recently, it has been shown that this type of CLN disease is due to a mutation in a gene located on chromosome 16 (16p 12.1). A brief description of the other subtypes of CLN is given.

[EEG and early diagnosis of Angelman syndrome]. / Eeg og tidlig diagnostik af Angelmans syndrom.

The diagnosis of Angelman syndrome has seldom been made in infancy because the typical craniofacial dysmorphism and the typical outbursts of unprovoked laughter are not fully developed before the second and third year of life. Other features such as mental retardation or absence of language, though invariably present, are less obvious in the first year of life. We describe three children in whom consecutive electroencephalographic (EEG) studies show very large amplitude slow activity at 2-3/s, often rhythmic, usually occurring in prolonged runs and often more prominent posteriorly, sometimes with spikes or sharp-wave activity, and invariably associated with a diffuse rhythmic activity at 4-6/ s of 200 microvolts. The changes were present as early as six months of life. They preceded development of seizure and occurred much earlier than the craniofacial dysmorphology. It is concluded that methodical use of EEG in the elucidation of children with developmental disorder and knowledge of the characteristic EEG picture may help to identify patients with Angelman syndrome at an early age and before the clinical features become obvious.

Sudden death due to rupture of a saccular intracranial aneurysm in a 13-year-old boy.

This case report describes sudden death in a young boy resulting from an undiagnosed saccular intracranial aneurysm located at the right posterior cerebral artery. It is suggested that the rupture might have been provoked by xylometazolin aerosol, which can increase blood pressure.

The central nervous system in Tay syndrome.

Trichothiodystrophy (brittle sulfur-deficient hair) is a marker for several autosomal recessive neurocutaneous syndromes with neurological manifestations and mental retardation. In Tay syndrome, the trichothiodystrophy is accompanied by congenital ichthyosis, short stature, delayed physical and mental development and pyramidal tract signs with increase in muscular tone and brisk tendon reflexes. The pathogenesis of these neurological manifestations is not fully elucidated. We present a case of Tay syndrome in which a cranial MRI revealed an almost total lack of myelin within the cerebral hemispheres and a patchy hypomyelination of the cerebellum. In accordance, a strongly prolonged visual evoked response pointed to a dysfunction of the white matter in Tay syndrome.