Considerations for radiotherapy in Bloom Syndrome: A case series.

Bloom Syndrome (BS) is a genetic DNA repair disorder, caused by mutations in the BLM gene. The clinical phenotype includes growth retardation, immunodeficiency and a strong predisposition to different types of malignancies. Treatment of malignancies in BS patients with radiotherapy or chemotherapy is believed to be associated with increased toxicity, but clinical and laboratory data are lacking. We collected clinical data of two Dutch BS patients with solid tumors. Both were treated with radiotherapy before the diagnosis BS was made and tolerated this treatment well. In addition, we collected fibroblasts from BS patients to perform in vitro clonogenic survival assays to determine radiosensitivity. BS fibroblasts showed less radiosensitivity than the severely radiosensitive Artemis fibroblasts. Moreover, studies of double strand break kinetics by counting 53BP1 foci after irradiation showed similar patterns compared to healthy controls. In combination, the clinical cases and laboratory experiments are valuable information in the discussion whether radiotherapy is absolutely contraindicated in BS, which is the Case in other DNA repair syndromes like Ataxia Telangiectasia and Artemis.

Early diagnosis of ataxia telangiectasia in the neonatal phase: a parents' perspective.

Ataxia telangiectasia (A-T) is a severe neurodegenerative disorder with variable immunodeficiency. Together with the Dutch A-T community, we investigated the opinion of A-T parents on an early A-T diagnosis in the asymptomatic phase of the disease. During an annual national meeting for A-T patients and families, the topic of an early A-T diagnosis was discussed in relation to the recent introduction of neonatal screening for severe combined immunodeficiency (SCID) in the Netherlands. Based on the discussion, individual arguments were identified and processed into a questionnaire, which was sent out to 64 A-T parents (32 families). Arguments included were insecurity to diagnosis, possible medical advantages, appropriate genetic counseling and family planning, loss of "golden" year(s), and early cancer screening for parents. The response rate was 55% (n = 35 parents). Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.Conclusion: The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives. In addition, the knowledge of being carriers of an ATM gene mutation influenced decisions about family planning. Parents who opposed against an early diagnosis emphasized the joy of having a seemingly healthy child until diagnosis.What is Known:• Ataxia telangiectasia (A-T) is a devastating DNA repair disorder with a huge impact on quality of life of patients and their parents.• Patients with A-T may incidentally be identified at birth as the consequence of neonatal screening for severe combined immunodeficiency (SCID).What is New:• The majority of Dutch parents of A-T patients (74%) would have preferred an early diagnosis of their child in the asymptomatic phase of the disease.• Major arguments for an early A-T diagnosis were (1) the experienced insecurity in diagnostic trajectories and its impact on families and (2) the knowledge of being ATM mutation carriers when deciding about family planning. An argument against an early diagnosis is losing the joy of having a seemingly healthy child until diagnosis.

Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline.

Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes.

The diagnostic pathway in complex paediatric neurology: a cost analysis.

BACKGROUND: The diagnostic trajectory of complex paediatric neurology may be long, burdensome, and expensive while its diagnostic yield is frequently modest. Improvement in this trajectory is desirable and might be achieved by innovations such as whole exome sequencing. In order to explore the consequences of implementing them, it is important to map the current pathway. To that end, this study assessed the healthcare resource use and associated costs in this diagnostic trajectory in the Netherlands. METHODS: Fifty patients presenting with complex paediatric neurological disorders of a suspected genetic origin were included between September 2011 and March 2012. Data on their healthcare resource utilization were collected from the hospital medical charts. Unit prices were obtained from the Dutch Healthcare Authority, the Dutch Healthcare Insurance Board, and the financial administration of the hospital. Bootstrap simulations were performed to determine mean quantities and costs. RESULTS: The mean duration of the diagnostic trajectory was 40 months. A diagnosis was established in 6% of the patients. On average, patients made 16 physician visits, underwent four imaging and two neurophysiologic tests, and had eight genetic and 16 other tests. Mean bootstrapped costs per patient amounted to €12,475, of which 43% was for genetic tests (€5,321) and 25% for hospital visits (€3,112). CONCLUSION: Currently, the diagnostic trajectories of paediatric patients who have complex neurological disease with a strong suspected genetic component are lengthy, resource-intensive, and low-yield. The data from this study provide a backdrop against which the introduction of novel techniques such as whole exome sequencing should be evaluated.

Alpha-fetoprotein, a fascinating protein and biomarker in neurology.

Alpha-fetoprotein (AFP) is present in fetal serum in concentrations up to 5,000,000 µg/l. After birth, AFP gene expression is turned down with a subsequent fall of the serum concentrations of this albumin-like protein to 'adult values' of circa 0.5-15 µg/l from the age of 2 years onwards. Irrespective of its assumed important functions, individuals with AFP deficiency appear fully healthy. The other way around, the presence of AFP in the circulation after the first years of life doesn't seem to harm, since individuals with 'hereditary persistence of AFP' are also without clinical abnormalities. During pregnancy, AFP (in maternal serum) has long been recognized as a marker for congenital anomalies of the fetus. Equally well known is AFP as biomarker for hepatocellular carcinoma and some other malignancies. There are at least four neurodegenerative disorders, all inherited as autosomal recessive traits and characterized by the presence of cerebellar ataxia, abnormal ocular movements, and neuropathy, for which an elevated concentration of serum AFP is an important diagnostic biomarker. The availability of a reliable biomarker is not only important during screening or diagnostic processes, but is also relevant for objective follow-up during (future) therapeutic interventions.

Open reduction versus endoscopically controlled reconstruction of orbital floor fractures: a retrospective analysis.

The aim of this study was to compare the postoperative results of open reduction versus endoscopically controlled reconstructions of orbital floor fractures. The medical records of 83 patients, treated between January 2000 and December 2008, were reviewed for enophthalmos, diplopia and complications. Fifty-eight patients were operated on using open reduction and in 25 patients the open reduction was endoscopically controlled. A significantly better outcome, regarding enophthalmos and diplopia improvement, was found in the endoscopically controlled group. Endoscopically controlled reconstruction of orbital floor fractures seems to be a more accurate and successful treatment.

Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours.

BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T. METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity. RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype. CONCLUSION: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.

Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations.

BACKGROUND: In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form. OBJECTIVE: To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4). METHODS: SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed. RESULTS: 151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype. CONCLUSIONS: Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed.

In vivo proton MR spectroscopy findings specific for adenylosuccinate lyase deficiency.

Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29 ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3 ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder.

Elevated CSF N-acetylaspartylglutamate in patients with free sialic acid storage diseases.

OBJECTIVE: To investigate body fluids of patients with undiagnosed leukodystrophies using in vitro (1)H-NMR spectroscopy (H-NMRS). METHODS: We conducted a cross-sectional study using high-resolution in vitro H-NMRS on CSF and urine samples. RESULTS: We found a significant increase of free sialic acid in CSF or urine in 6 of 41 patients presenting with hypomyelination of unknown etiology. Molecular genetic testing revealed pathogenic mutations in the SLC17A5 gene in all 6 patients. H-NMRS revealed an increase of N-acetylaspartylglutamate in the CSF of all patients with SLC17A5 mutation (range 13-114 micromol/L, reference <12 micromol/L). CONCLUSION: In patients with undiagnosed leukodystrophies, increased free sialic acid in CSF or urine is a marker for free sialic acid storage disorder and facilitates the identification of the underlying genetic defect. Because increase of N-acetylaspartylglutamate in CSF has been observed in other hypomyelinating disorders, it can be viewed as a marker of a subgroup of hypomyelinating disorders.

Clinical spectrum of ataxia-telangiectasia in adulthood.

OBJECTIVE: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. METHODS: Retrospective analysis of the clinical characteristics and course of disease in 13 adult patients with variant A-T of 9 families and 6 unrelated adults with classic A-T and mutation analysis of the ATM gene and measurements of ATM protein expression and kinase activity. RESULTS: Patients with variant A-T were only correctly diagnosed in adulthood. They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later. Four patients with variant A-T developed a malignancy. Patients with classic and variant A-T had elevated serum alpha-fetoprotein levels and chromosome 7/14 rearrangements. The mildest variant A-T phenotype was associated with missense mutations in the ATM gene that resulted in expression of some residual ATM protein with kinase activity. Two splicing mutations, c.331 + 5G>A and c.496 + 5G>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5G>A resulted in less ATM protein and kinase activity than the missense mutations. CONCLUSIONS: Ataxia-telangiectasia (A-T) should be considered in patients with unexplained extrapyramidal symptoms. Early diagnosis is important given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment. Measurement of serum alpha-fetoprotein and chromosomal instability precipitates the correct diagnosis. There is a clear genotype-phenotype relation for A-T, since the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype.

High myopia and congenital myopathy with partial pachygyria in cutis laxa syndrome.

PURPOSE: Several types of inborn errors of the O-glycan biosynthesis are known, leading to clinically very distinct phenotypes. Children with O-mannosyl glycan biosynthesis defects commonly present as a severe form of congenital muscular dystrophy with decreased alpha-dystroglycan staining, congenital eye anomalies, and brain migration defects. Alpha-dystroglycan is an O-mannosylated glycoprotein with additional mucin type O-glycans. METHODS: Based on overlapping clinical features with O-mannosyl glycan defects, especially with muscle-eye-brain disease, the authors performed a muscle biopsy in a child with severe congenital hypotonia, high myopia, partial pachygyria, mental retardation, cutis laxa, and an inborn error affecting the biosynthesis of both mucin type O-glycans and N-linked glycans. RESULTS: The histology showed no signs of muscle dystrophy, but a mild myopathy with slight increase in the muscle fiber diameter variability and type I fiber predominance. No significant decrease in the alpha-dystroglycan staining was detected; therefore, in spite of the phenotypic similarities the authors could not confirm the role of abnormal dystroglycan in the etiology of the muscle weakness and the developmental anomalies. CONCLUSIONS: High myopia, muscle weakness, and cortical neuronal migration abnormalities are common in disorders of O-mannosylation and also observed in the authors' patient. However, compared to the severe generalized defect observed in mannosyl glycan defects, in this child the cerebral white matter and cerebellum were spared, and no muscle dystrophy could be confirmed. This is the first description of high myopia in cutis laxa syndrome in combination with congenital disorders of glycosylation.

[Diagnosis in cerebrospinal fluid: possible applications in neurological practice]. / Diagnostiek in hersenvocht: toepassingsmogelijkheden in de neurologische praktijk.

Examination of the cerebrospinal fluid (CSF) is part of the modern diagnostics of many neurological diseases. When an acute or chronic meningitis or encephalitis is suspected, the distinction between an acute viral and a bacterial intrathecal infection can generally be rapidly made via examination of the CSF. In case of a chronic infection this will determine the direction of further microbiological analysis. When there are clinical indications for subarachnoid haemorrhage but no abnormalities on the CT-scan, it can be either demonstrated or excluded by means of spectrophotometric analysis of blood pigments in the CSF. In case of possible multiple sclerosis (MS) and contraindications for MRI, or if the combination of the clinical symptoms and MRI does not yield a definitive diagnosis, then the demonstration of unique oligoclonal IgG-bands in the CSF is an important parameter in confirming a diagnosis of 'MS'. In practice, metastases to the leptomeninges are often detected by means of (repeated) cytopathological analysis of the CSF, which has a higher sensitivity and specificity than MRI. Examination of the CSF also plays an important role in the diagnosis of (hereditary) metabolic encephalopathies in childhood. In case of watery discharge from the nose or ear following trauma or neurosurgery, it can be determined whether or not this is leaking CSF. Analysis of certain brain-specific proteins in the CSF can contribute to the differential diagnosis of dementia syndromes. The added diagnostic value of examination of the CSF in hypokinetic rigidity syndromes is still unclear. The complications of a spinal puncture often remain limited to post-puncture headache. Contraindications include intracranial space-occupying abnormalities, compression of the spinal cord, haemorrhagic diathesis and abnormalities around the puncture site.

A spinal intradural enterogenous cyst with well-differentiated muscularis propria.

We report a case of a newborn presenting with severe compression of the spinal cord due to a large, solitary mass extending from C4 to T2. Neurosurgical exploration revealed a large intradural, extramedullary cystic lesion, compressing the spinal cord. Slowly progressive respiratory failure due to severe myelopathy led to the death of the child 19 days postpartum. At autopsy, a well-differentiated enterogenous cyst was found, the cyst wall containing gastric and esophageal type mucosa, and a bona fide muscularis propria. The gastrointestinal tract was completely normal. The possible developmental history of intradural enterogenous cysts is discussed.

Increased urinary leukotriene E(4) during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome.

BACKGROUND: The hyperimmunoglobulinaemia D and periodic fever syndrome is a hereditary periodic fever, caused by deficiency of the enzyme mevalonate kinase. It is unclear how this defect leads to recurrent fever episodes. AIM: To assess the involvement of cysteinyl leukotrienes in the pathogenesis of fever attacks as reflected by urinary leukotriene E(4) (LTE(4)) excretion. METHODS: Urinary LTE(4) was measured in seven patients while febrile and afebrile. RESULTS: LTE(4) was raised during fever in all subjects (46-199 nmol/mol creatinine, mean 92; normal <40). Urinary LTE(4) was normal between attacks, as well as in normal children with fever as a result of miscellaneous causes. CONCLUSION: Our results suggest that cysteinyl leukotrienes play a role in the pathophysiology of this disorder. As no effective treatment is yet available, leukotriene receptor antagonists might offer a new therapeutic approach for patients with the hyperimmunoglobulinaemia D and periodic fever syndrome.

Clinical and biochemical effects of zileuton in patients with the Sjögren-Larsson syndrome.

UNLABELLED: The Sjögren-Larsson syndrome (SLS) is an inborn error of lipid metabolism, characterised clinically by congenital ichthyosis, mental retardation and spasticity. Patients also suffer from severe pruritus. The degradation of leukotriene (LT) B4 is one of the defective metabolic routes in SLS. Zileuton inhibits the synthesis of LTB4 and the cysteinyl leukotrienes. Five SLS patients were treated with zileuton for 3 months. Favourable effects were found on pruritus score (P = 0.006), general well-being, and background activity of electroencephalographic studies. Neuropsychological test results did not change significantly. There was, however, a clinically important trend towards improvement in the speed of information processing. Results of cerebral MRI and proton magnetic resonance spectroscopy did not change during therapy. Urinary concentrations of LTB4 and omega-OH-LTB4 decreased significantly (P=0.02 and P=0.003 respectively), while their concentrations in CSF were normal at baseline and remained so after therapy. CONCLUSION: Patients with Sjögren-Larsson syndrome might benefit from treatment with zileuton, especially with respect to the agonising pruritus. The findings reported here, point to a crucial role for leukotriene B4 in the pathogenesis of pruritus.