Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations

Pontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1. We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotype-phenotype correlation.

Pontocerebellar hypoplasia type 2: variability in clinical and imaging findings

We report 24 children (14 girls) who presented with the typical neuroimaging findings of pontocerebellar hypoplasia (PCH) to describe the clinical spectrum of type 2. Twenty-one presented with the classical form described by Barth; characteristic features (15/21) were breathing and/or sucking problems during neonatal period and early onset hyperkinetic movement disorder. Eighteen were normocephalic at birth, but all developed microcephaly during infancy. Development was severely affected with none of the children being capable of sitting, walking, or talking. Social contact and visual fixation were persistently poor. Dyskinetic movement disorder was present in all, in some together with mild spasticity. Seizures occurred in 14 (in 7 as neonates). Eight children died (age 1 day-6 years). Neuroimaging showed an absent or severely flattened pons, different degrees of vermian hypoplasia, with cerebellar hemispheres (wing-like structures) being equally or more affected. Three (all girls) were less severely affected clinically and did not develop the dyskinetic movement disorder, motor and cognitive development were somewhat better. Microcephaly was also a prominent sign. Severity of pontocerebellar neuroimaging findings did not differentiate between the typical and atypical clinical group and did not correlate with clinical outcome.

Is right coronary artery hypoplasia and sudden death an underdiagnosed association?

Determining whether hypoplasia of a coronary artery has caused or contributed to death is often complicated by an absence of histologic evidence of myocardial ischemia in the area of the heart supplied by the affected artery and also by the lack of data for assessing coronary artery size at autopsy. A 45-year-old woman is reported who collapsed and died and who was found at autopsy to have a dominant, small-caliber, right coronary artery, with acute and chronic ischemic changes in the posterior interventricular septum supplied by the diminutive vessel. This case provides evidence that small-caliber coronary arteries may be associated with a lethal outcome. Given the difficulties that may occur in determining whether there is a causal link between small coronary artery caliber and death, it is possible that this may be an underdiagnosed cause of sudden cardiac death, rather than a coincidental finding of minimal significance.

A Deletion in the VLDLR Gene in Eurasier Dogs with Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation (DWLM).

Dandy-Walker-like malformation (DWLM) is the result of aberrant brain development and mainly characterized by cerebellar hypoplasia. DWLM affected dogs display a non-progressive cerebellar ataxia. Several DWLM cases were recently observed in the Eurasier dog breed, which strongly suggested a monogenic autosomal recessive inheritance in this breed. We performed a genome-wide association study (GWAS) with 9 cases and 11 controls and found the best association of DWLM with markers on chromosome 1. Subsequent homozygosity mapping confirmed that all 9 cases were homozygous for a shared haplotype in this region, which delineated a critical interval of 3.35 Mb. We sequenced the genome of an affected Eurasier and compared it with the Boxer reference genome and 47 control genomes of dogs from other breeds. This analysis revealed 4 private non-synonymous variants in the critical interval of the affected Eurasier. We genotyped these variants in additional dogs and found perfect association for only one of these variants, a single base deletion in the VLDLR gene encoding the very low density lipoprotein receptor. This variant, VLDLR:c.1713delC is predicted to cause a frameshift and premature stop codon (p.W572Gfs*10). Variants in the VLDLR gene have been shown to cause congenital cerebellar ataxia and mental retardation in human patients and Vldlr knockout mice also display an ataxia phenotype. Our combined genetic data together with the functional knowledge on the VLDLR gene from other species thus strongly suggest that VLDLR:c.1713delC is indeed causing DWLM in Eurasier dogs.

Natural course of pontocerebellar hypoplasia type 2A

INTRODUCTION Pontocerebellar hypoplasia Type 2 (PCH2) is a rare autosomal recessive condition, defined on MRI by a small cerebellum and ventral pons. Clinical features are severe developmental delay, microcephaly and dyskinesia.Ninety percent carry a p.A307S mutation in the TSEN54-gene. Our aim was to describe the natural course including neurological and developmental features and other aspects of care in a homogeneous group of PCH2 patients all carrying the p.A307S mutation. PATIENTS AND METHODS Patients were recruited via the German patients' organizations. Inclusion criteria were imaging findings of PCH2 and a p.A307S mutation. Data were collected using medical reports and patient questionnaires discussed in a standardized telephone interview. RESULTS Thirty-three patients were included. When considering survival until age 11 years, 53% of children had died Weight, length and head circumference, mostly in the normal range at birth, became abnormal, especially head circumference (-5.58 SD at age 5 yrs). Neurologic symptoms: Choreathetosis was present in 88% (62% with pyramidal signs), 12% had pure spasticity. Epileptic seizures were manifest in 82%, status epilepticus in 39%. Non-epileptic dystonic attacks occurred in 33%. General symptoms: feeding difficulties were recorded in 100%, sleep disorder in 96%, apneas in 67% and recurrent infections in 52%; gastroesophageal reflux disease was diagnosed in 73%, 67% got percutaneous endoscopic gastrostomy and 36% a Nissen-fundoplication. Neurodevelopmental data: All children made progress, but on a low level: such as fixing and following with the eyes was seen in 76%, attempting to grasp objects (76%), moderate head control (73%), social smile (70%), rolling from prone to supine (58%), and sitting without support (9%). Ten percent lost achieved abilities on follow-up. The presence of prenatal symptoms did not correlate with outcome. CONCLUSION Phenotype of this genetically homogeneous group of PCH2 children was severe with reduced survival, but compatible with some developmental progress. Our data support the hypothesis of an early onset degeneration which thereafter stabilizes.

Pulmonary hypoplasia and anasarca syndrome in Cika cattle

BACKGROUND: Hydrops foetalis is defined as excessive fluid accumulation within the foetal extravascular compartments and body cavities. It has been described in human and veterinary medicine, but despite several descriptive studies its aetiology is still not fully clarified. Pulmonary hypoplasia and anasarca (PHA) syndrome is a rare congenital abnormality in cattle that is characterised by hydrops foetalis including extreme subcutaneous oedema (anasarca) and undeveloped or poorly formed lungs (pulmonary hypoplasia). Until now, sporadic cases of PHA were reported in cattle breeds like Australian Dexter, Belted Galloway, Maine-Anjou, and Shorthorn. This report describes the first known cases of PHA syndrome in Slovenian Cika cattle. CASE PRESENTATION: A 13-year-old cow aborted a male calf in the seventh month of pregnancy, while a male calf was delivered by caesarean section on the due date from a 14-year-old cow. The pedigree analysis showed that the calves were sired by the same bull, the dams were paternal half-sisters and the second calf was the product of a dam-son mating. Gross lesions were similar in both cases and characterized by severe anasarca, hydrothorax, hydropericardium, ascites, hypoplastic lungs, absence of lymph nodes, and an enlarged heart. The first calf was also athymic. Histopathology of the second affected calf confirmed severe oedema of the subcutis and interstitium of the organs, and pulmonary hypoplasia. The lymph vessels in the subcutis and other organs were severely dilated. Histopathology of the second calf revealed also lack of bronchus associated lymphoid tissue and adrenal gland hypoplasia. CONCLUSIONS: The findings were consistent with known forms of the bovine PHA syndrome. This is the first report of the PHA syndrome occurring in the local endangered breed of Cika cattle. Observed inbreeding practice supports that this lethal defect most likely follows an autosomal recessive mode of inheritance. In the light of the disease phenotype it is assumed that a mutation causing an impaired development of lymph vessels is responsible for the hydrops foetalis associated malformations in bovine PHA.

Examination of FGFRL1 as a candidate gene for diaphragmatic defects at chromosome 4p16.3 shows that Fgfrl1 null mice have reduced expression of Tpm3, sarcomere genes and Lrtm1 in the diaphragm

Fgfrl1 (also known as Fgfr5; OMIM 605830) homozygous null mice have thin, amuscular diaphragms and die at birth because of diaphragm hypoplasia. FGFRL1 is located at 4p16.3, and this chromosome region can be deleted in patients with congenital diaphragmatic hernia (CDH). We examined FGFRL1 as a candidate gene for the diaphragmatic defects associated with 4p16.3 deletions and re-sequenced this gene in 54 patients with CDH. We confirmed six known coding single nucleotide polymorphisms (SNPs): c.209G > A (p.Pro20Pro), c.977G > A (p.Pro276Pro), c.1040T > C (p.Asp297Asp), c.1234C > A (p.Pro362Gln), c.1420G > T (p.Arg424Leu), and c.1540C > T (p.Pro464Leu), but we did not identify any gene mutations. We genotyped additional CDH patients for four of these six SNPs, including the three non-synonymous SNPs, to make a total of 200 chromosomes, and found that the allele frequency for the four SNPs, did not differ significantly between patients and normal controls (p > or = 0.05). We then used Affymetrix Genechip Mouse Gene 1.0 ST arrays and found eight genes with significantly reduced expression levels in the diaphragms of Fgfrl1 homozygous null mice when compared with wildtype mice-Tpm3, Fgfrl1 (p = 0.004), Myl2, Lrtm1, Myh4, Myl3, Myh7 and Hephl1. Lrtm1 is closely related to Slit3, a protein associated with herniation of the central tendon of the diaphragm in mice. The Slit proteins are known to regulate axon branching and cell migration, and inhibition of Slit3 reduces cell motility and decreases the expression of Rac and Cdc42, two genes that are essential for myoblast fusion. Further studies to determine if Lrtm1 has a similar function to Slit3 and if reduced Fgfrl1 expression can cause diaphragm hypoplasia through a mechanism involving decreased myoblast motility and/or myoblast fusion, seem indicated.

Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review

The objective was to analyze the outcome following prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor antagonists (ARBs). For this purpose, a systematic review of published case reports and case series dealing with intrauterine exposure to ACE-Is or to ARBs using Medline as the source of data was performed. The publications retained for analysis included patients who were described individually, revealing, at minimum, the gestational age, substance used, period of medication intake, and the outcome. In total, 72 reports were included; 37 articles (118 well-documented cases) described the prenatal exposure to ACE-Is; and 35 articles (68 cases) described the prenatal exposure to ARBs. Overall, 52% of the newborns exposed to ACE-Is and 13% of the newborns exposed to ARBs did not exhibit any complications (P<0.0001). Neonatal complications were more frequent following exposure to ARBs and included renal failure, oligohydramnios, death, arterial hypotension, intrauterine growth retardation, respiratory distress syndrome, pulmonary hypoplasia, hypocalvaria, limb defects, persistent patent ductus arteriosus, or cerebral complications. The long-term outcome is described as positive in only 50% of the exposed children. Fetopathy caused by exposure to ACE-Is or ARBs has relevant neonatal and long-term complications. The outcome is poorer following exposure to ARBs. We propose the term "fetal renin-angiotensin system blockade syndrome" to describe the related clinical findings. Thirty years after the first description of ACE-I fetopathy, relevant complications are, at present, regularly described, indicating that the awareness of the deleterious effect of prenatal exposure to drugs inhibiting the renin-angiotensin system should be improved.

Important excess morbidity due to upper airway anomalies in the perioperative course in infant cardiac surgery

BACKGROUND: The study aimed at defining the excess morbidity or mortality caused by an additional airway malformation in children with congenital heart disease requiring surgery. METHODS: All patients requiring surgery for heart disease during an 8-year period ending in 2003 who had an associated upper airway malformation were retrospectively studied. All patients were seen in 2004 for a prospective follow-up examination. RESULTS: Eleven patients with upper airway anomalies were identified (tracheobronchial malacia in 6 patients, long-segment tracheal stenosis in 3, and bilateral vocal cord paralysis and tracheal hemangioma in 1 patient each). They accounted for 1.5% of the entire cardiac surgical load of 764 patients. In 5 infants, the airway anomaly was diagnosed before cardiac repair, in 6 patients thereafter. Diagnosis was made by bronchoscopy in all patients, by additional bronchography in 2. Failure of rapid postoperative extubation was the most common finding. Airway management was surgical in 2 and conservative in 8 patients, 1 newborn having been denied therapy because of the severity of airway hypoplasia. Compared with patients with isolated cardiac disease, those with additional airway anomalies had significantly longer duration of postoperative mechanical ventilation (median, 24 days versus 3), perioperative hospitalization (median, 72 days versus 11) and total number of days of hospitalization during the first year of life (median, 104 days versus 14). After a maximum follow-up of 8 years (median, 37 months) only 3 of 10 surviving patients remained symptomatic owing to the airway malformation. CONCLUSIONS: Upper airway anomalies accompanying heart disease in infancy resulted in a significant prolongation of perioperative intensive care and hospital stay, as well as duration of mechanical ventilation. Failure of early postoperative extubation was the leading symptom.

Natale und neonatale Zähne

Natal teeth have been defined as teeth which are present at birth, while neonatal teeth erupt during the first 30 days. Their occurrence is rare, the prevalence ranges from 1:2000 to 1:3000 with a higher frequency in the lip and palate clefts and syndroms. In about 85% natal or neonatal teeth are lower central incisors (60% in pairs), rare are upper teeth, molars and multiple teeth. In almost 90% they are part of the deciduous dentition. A lot of possible causes of early eruption are discussed, but only the relation to hereditary factors seems to be evident. An autosomal dominant trait is often described. The appearance of these teeth is dependent on the degree of maturity, but most of the time it is loose, small, discoloured and hypoplastic. Histologically, enamel hypoplasia with normal prism structure is apparent. No significant disturbances of the dentin structures are observed, only cervically dentin becomes atubular with spaces and enclosed cells. A large vascular pulp and failure of root formation are further investigations. Our microhardness measurements showed values from 24.3-32.4 KHN for enamel and 48.3-62.2 KHN for dentin, while normal deciduous teeth have an enamel hardness of 322.0 +/- 17.5 KHN. The thickness of enamel was never more than 280 microm compared to up to 1200 microm in normal teeth. This shows the retarded development of natal and neonatal teeth, because mineralization has not finished at the time of birth. In accordance with developmental age tooth structure and appearence are normal. In consideration of complications as Riga-Fede-disease, feeding problems, possibility of infection and hypermobility most of the time extraction is the treatment of choice, but in the interest of protecting the child this decision should be made carefully.

Hepatic encephalomyelopathy in a calf with congenital portosystemic shunt (CPSS)

A 4-month-old female Holstein Friesian calf was referred to the Veterinary Teaching Hospital, University of Berne, Switzerland for evaluation of ataxia, weakness, apathy and stunted growth. Clinical examination revealed generalized ataxia, propioceptive deficits, decreased menace response and sensibility. Postmortem examination did not reveal macroscopic changes of major organs. Histologically, the brain and the spinal cord lesions were characterized by polymicrocavitation, preferentially affecting the white matter fibers at the junction of grey and white matter and by the presence of Alzheimer type II cells. The liver revealed lesions consistent with a congenital portosystemic shunt, characterized by increased numbers of arteriolar profiles and hypoplasia to absence of portal veins. The pathological investigations along with the animal history and clinical signs indicated a hepatic encephalomyelopathy due to a congenital portosystemic shunt.

Cerebellar cortical degeneration with selective granule cell loss in Bavarian mountain dogs

Three Bavarian mountain dogs aged between 18 and 20 months, not related to each other, were presented with chronic signs of cerebellar dysfunction. On sagittal T2-weighted magnetic resonance imaging brain images, the tentative diagnosis of cerebellar hypoplasia was established based on an enlarged cerebrospinal fluid space around the cerebellum and an increased cerebrospinal fluid signal between the folia. Post-mortem examination was performed in one dog and did show an overall reduction of cerebellar size. On histopathologic examination, a selective loss of cerebellar granule cells with sparing of Purkinje cells was evident. Therefore, the Bavarian mountain dog is a breed where cerebellar cortical degeneration caused by the rather exceptional selective granule cell loss can be seen as cause of chronic, slowly progressive cerebellar dysfunction starting at an age of several months.

Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior-Løken syndrome

BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1-6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/hypoplasia, retinal degeneration and mental retardation. In Senior-Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS. METHODS: Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis. RESULTS: Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in-frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP.

Adrenal gland development and defects

The network regulating human adrenal development is complex. Studies of patients with adrenal insufficiency due to gene mutations established a central role for transcription factors GLI3, SF1 and DAX1 in the initial steps of adrenal formation. Adrenal differentiation seems to depend on adrenocorticotropic hormone (ACTH) stimulation and signalling, including biosynthesis and action of POMC, PC1, TPIT, MC2R, MRAP and ALADIN, all of which cause adrenocortical hypoplasia when mutated in humans. Studies of knockout mice revealed many more factors involved in adrenal development; however, in contrast to rodents, in humans several of those factors had no adrenal phenotype when mutated (e.g. WT1, WNT4) or, alternatively, human mutations have not (yet) been identified. Tissue profiling of fetal and adult adrenals suggested 69 genes involved in adrenal development. Among them were genes coding for steroidogenic enzymes, transcription and growth factors, signalling molecules, regulators of cell cycle and angiogenesis, and extracellular matrix proteins; however, the exact role of most of them remains to be elucidated.

Cerebellar disorders in childhood: cognitive problems

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.